Journal articles on the topic 'Duc de Vicence'

25 years ago, we started in Antioquia the campaign “No more blind from diabetes”. This campaign was possible due to the collaboration of the Hospital San Vicente Fundación, Antioquia University, the Ophthalmology programs of Pontificia Bolivariana University and CES University. This campaign is held annually around November 14. In 2022 we commemorated version No. 25. Results: We have evaluated approximately 15,000 patients to the present time, an average of 600 per year. Among all these patients 50% attend for the first time each year, 70% are females and 80% are type 2 diabetics. We found a prevalence of diabetic retinopathy (DR) of 15.5% and 64% of these patients are females. These patients have been diagnosed with diabetes for about 12 years and they have shown poor metabolic control of their diabetes with an average glycosylated Hemoglobin A1C (HbA1C) of 11.2% (normal range below 5.7%). The stage of the retinopathy showed that 70% of the patients had the non-proliferative form. We found that 1 out of 3 patients presented with severe visual loss due to severe non-proliferative retinopathy and macular edema. The main etiology of chronic vision loss in diabetic patients is diabetic macular edema found in 22% of the patients and the majority were females with type 2 diabetes over 60 years of age with an average HbA1C of 10%. Conclusions: This is the largest screening and ongoing test for DR done in Colombia, South America. This study focuses on the most vulnerable population and the results provide relevant information about the epidemiology of this disease. The results generate awareness about early diagnosis, medical care of its complications, education of the population, and the proper guidance for their treatment and rehabilitation.

A doença renal crônica (DRC) se caracteriza pela perda da capacidade de filtração do sangue e de manter a homeostase devido à perda progressiva da função dos néfrons. A atividade física é importante para minimizaras consequências associadas a patologia e ao tratamento. Desta forma, o presente estudo teve como objetivo verificar os fatores associados a permanecer ativo fisicamente no período de 2018 a 2020 de pacientes em hemodiálise (HD). Tratou-se de um estudo longitudinal retrospectivo com 91pacientes em hemodiálise na Clínica Renal do Hospital São Vicente de Paulo do município de Cruz Alta/RS. Foram analisados: o nível de atividade física (utilizando pedômetro), características sociodemográficas e de saúde (através de um questionário fechado), aptidão cardiorrespiratória, força de preensão manual, resistência muscular localizada de membros inferiores, independência funcional, depressão e o nível de atividade física (NAF). Para verificar os fatores associados ao nível de atividade física foi utilizado Teste Exato de Fisher com p≤0,05. Como resultado desse estudo, verificou-se que indivíduos com maior grau de escolaridade, sem depressão, independentes nas atividades de vida diária (AVDs) e que não apresentam fragilidade possuíram maior NAF. Concluiu-se que o NAF se relaciona diretamente com os fatores citados; além disso, ressaltou a importância da atividade física e de um programa de treinamento físico para doentes renais visando a promoção da saúde e a disposição da equipe profissional de divulgá-lo para que os pacientes se sintam motivados.

En esta propuesta se analizará la reflexión del profesor Vicent Martínez Guzmán en su etapa inicial en la investigación filosófica. Es muy conocido todo su trabajo y reflexión en la filosofía para la paz, un fértil campo de estudio que inauguró en España en los noventa y que se ha ido consolidando como una materia en sí misma. Sin embargo, el trabajo filosófico inicial del profesor Martínez Guzmán, el que precisamente le llevó a ser pionero en la creación de una “filosofía para hacer las paces”, como finalmente le denominaba, no es tan conocido. Se trata de la reflexión desde la fenomenología lingüística, especialmente centrada en el filósofo John Austin, objeto de estudio de Martínez Guzmán en su tesis doctoral. El lenguaje ordinario, como ya preocupó a Austin, será el nicho oportuno para estudiar, lejos de una visión logicista del lenguaje, lo que hacemos cuando hablamos. Y en ese hacer que es el hablar hacemos también las paces.The aim of this paper is to analyze the reflection of Professor Vicent Martínez Guzmán in his initial stage in philosophical research. He is well known for all his work and reflection on the philosophy for peace, a fertile field of study that he inaugurated in Spain in the nineties and that has been consolidated as a subject in itself. However, the initial philosophical work of Professor Martínez Guzmán, which precisely led him to be a pioneer in the creation of a “philosophy to make peace”, as he finally called it, is not so well known. In the paper we will observe his reflection from the linguistic phenomenology, especially centered on the philosopher John Austin, object of study of Martínez Guzmán in his doc-toral thesis. Ordinary language, as Austin has already established, will be the appropriate niche to study, far from a logicist vision of language, what we do when we speak. And it is by talking that we also make peace.

Настоящая работа является первым общим описанием на русском языке двух некрополей Кампокиаро (Кампобассо, Италия) – Виченне и Морионе, датируемых последней третью VII в. – началом VIII в. Культурное содержание некрополей показывает прочные связи с населением центральноазиатского происхождения. Важнейшим признаком некрополей являются захоронения с конем, соответствующие евразийскому кочевому погребальному обряду. Автор поддержал выводы европейских исследователей о том, что с большой долей вероятности некрополи оставлены булгарами дукса–гаштальда Алзеко, зафиксированными Павлом Диаконом в VIII в. на территориях Бояно, Сепино и Изернии. Аналогии некрополей Кампокиаро с погребениями Аварского каганата показывают присутствие в аварском обществе булгар со схожим погребальным обрядом. Из тысяч погребений с конем, оставленных аварским населением, булгарам могла принадлежать большая часть. Авары и булгары составляли основу и правящую верхушку каганата. Народ Алзеко являлся той частью булгар, которая в 631 г. боролась за каганский престол, что указывает на высокое положение булгар и их большое количество. После поражения эта группа булгар мигрировала последовательно в Баварию, Карантанию и Италию. Несколько десятков лет проживания в венедской, а затем в лангобардской и романской среде привели к гетерогенности погребального инвентаря, но не изменили сам обряд. Булгары лангобардского королевства составляли новый военный слой, который представлял из себя профессиональную кавалерию, получивший землю. Эта конная дружина является ранним примером европейского феодального воинского и социального сословия, которое станет называться рыцарством. Библиографические ссылки Акимова М.С. Материалы к антропологии ранних болгар // Генинг В.Ф., Халиков А.Х. Ранние болгары на Волге (Больше–Тарханский могильник). М.: Наука, 1964. С. 177–191. Амброз А.К. Кинжалы VI – VIII вв, с двумя выступами на ножнах // СА. 1986. № 4. С. 53–73. 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Abstract Background: TNBC constitutes an aggressive and heterogeneous group of tumors with variable response to neoadjuvant therapy (NAT) that currently lacks clinically available profiling strategies for prediction. We aimed to develop an integrated model based on imaging, pathological and clinical data capable to predict NAT response in TNBC early during therapy. METHOD AND MATERIALS:125 Stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433) who had DCE-MRI at baseline (BL) and post 2 cycles (C2) of NAT, and had surgery were included in this analysis. Tumor volume was calculated using 3D measurements at BL and C2 time points DCE-MRI. Percent tumor volume reduction (TVR) between BL and C2 was calculated. Demographic, clinical, and pathological data (age, T and N stage, histology, androgen receptor expression, Ki-67, stromal tumor infiltrating lymphocytes level (sTIL), and PD-L1 expression), and treatment response at surgery (pCR vs non-pCR) were documented. Recursive partitioning was used to identify TVR cutoff value. Multivariate logistic regression and ROC analysis were used to assess associations and build and evaluate predictive models. RESULTS: 61 (49%) TNBC pts showed pCR at surgery, and 64 (51%) non-pCR. Recursive partitioning analysis identified ≥ 55% TVR as the optimal cutoff values for pCR prediction at C2. TVR, N stage and sTIL were significantly associated with pCR in the multivariate analyses (p<0.002, p<0.01, p<0.001, respectively). Integrated model containing TVR (≥55% vs <55%), N stage (N0 vs N+) and sTIL (≥20% vs <20%) was predictive of pCR with AUC 0.84 (95% CI:0.77-0.91). Integrated model performance was significantly better than TVR only or clinical only (sTIL, and N stage) models (p<0.001). CONCLUSION: Integrated model that included imaging (DCE-MRI TVR), clinical (N stage) and pathological (sTIL) data showed high accuracy for prediction of NAT response in TNBC patients early during treatment. Validation of these results in a large prospective study is ongoing. Citation Format: Gaiane Margishvili Rauch, Rosalind P. Candelaria, Mary Saber Guirguis, Medine Boge, Rania M. M. Mohamed, Nabil Elshafeey, Jia Sun, Gary J Whitman, Jessica Leung, Huong C Le-Petross, Lumarie Santiago, Deanna Lane, Marion Scoggins, David Spak, Miral M Patel, Frances Perez, Jason B. White, Elizabeth Ravenberg, Wei Peng, Debu Tripathy, Vicente Valero, Jennifer Litton, Lei Huo, Clinton Yam, Alastair Thompson, Jingfei Ma, Stacy L. Moulder, Wei Yang, Beatriz E. Adrada. Integrated model for early prediction of neoadjuvant systemic therapy response in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-07.

Abstract The potential of cell-free tumor DNA (ctDNA) for early tumor detection in asymptomatic patients is yet to be established. In the case of pregnancy associated breast cancer (BC), early detection is of special interest, since it is an entity of special aggressiveness due to a delay in diagnosis, along with the negative effect of mammary gland involution when BC is diagnosed during the postpartum period (PPBC). Indeed, PPBC has double metastatic risk and worst prognosis. With a potential applicability for cancer screening during breastfeeding, here we explored the presence of ctDNA in breast milk (BM) from women with BC associated to pregnancy. Matched samples from breast tumor, plasma and BM from a cohort of 14 women diagnosed during pregnancy or breastfeeding were analysed by droplet digital PCR and a targeted next generation sequencing panel (NGS). Thirteen patients had early-stage disease (11% Stage I, 61% Stage II and 28% Stage III) whilst one was diagnosed at advanced stage. BM harboured ctDNA, since mutations present in the tumor tissue were detected in 86% of the cases by ddPCR and in 71,4% by NGS (difference owing to technique sensitivity). Matched plasma samples had detectable ctDNA levels in only 8% of the cases. In one of the patients, a BM sample collected 18 months prior to BC diagnosis revealed the presence of a pathogenic PIK3CA mutation later detected in the surgically removed tumor. With the ultimate goal of applying the NGS in BM as a technique for early detection of BC in the postpartum period, we have collected samples from healthy volunteers and patients at high risk of developing BC (defined as women becoming pregnant at >40 years or carriers of germ-line pathogenic variants associated with BC -ie: BRCA1, BRCA2, PALB2, RAD51C/D). The application of NGS in BM as a technique for early detection of BC in the postpartum period, identified in a high-risk woman (criteria of enrolment was the age, 46yo) an AKT1 pathogenic mutation in the right-sided BM anticipating by 6 months the radiological diagnosis of a Luminal A tumor, stage pT1bN0M0. In summary, our data provides evidence that ctDNA in BM is highly prevalent even at initial tumor stages, and could be exploited for early breast cancer screening during breastfeeding. Citation Format: Cristina Saura, Carolina Ortiz, Enrique Javier Arenas, Judit Matito, Anna Suñol-Camas, Octavi Cordoba, Alex Martinez-Sabadell, Itziar Garcia-Ruiz, Ignacio Miranda, Clara Morales-Comas, Estela Carrasco Lopez, Cristina Viaplana, Vicente Peg, Paolo Nuciforo, Neus Bayo, Josep Maria Miquel, Marina Gomez-Rey, Guillermo Villacampa, Silvia Arevalo, Javier Carmona, Martín Espinosa-Bravo, Judith Balmaña, Rodrigo Dienstmann, Joaquin Arribas, Josep Tabernero, miriam sanso, Ana Vivancos. ctDNA IN BREAST MILK FOR EARLY DETECTION OF PREGNANCY ASSOCIATED BREAST CANCER [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-14.

Abstract Background: The addition of trastuzumab+/-pertuzumab to chemotherapy has changed the natural history of earlyHER2+ breast cancer. However, trials with targeted therapy alone are needed to avoid acute and chronic toxicities of chemotherapy. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular and dimerization domains (ECD2, ECD4) of HER2. The biparatopic nature of zanidatamab results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab has demonstrated antitumor activity in heavily pre-treated HER2 overexpressing metastatic breast cancer with an acceptable safety profile. We hypothesized that zanidatamab would be a safe and effective regimen for women with node negative stage I HER2+ BC. Methods: Patients with 1-3 cm, clinically node negative HER2+ BC were enrolled in a single-institution investigator-initiated clinical trial. Patients had HER2+ breast cancer: HER2 3+ by IHC or IHC 2+ and ISH +. Patients received six to ten doses of zanidatamab, 20 mg/kg IV every 2 weeks prior to surgery. Patients with ER+ tumors also received neoadjuvant endocrine therapy. Post-menopausal patients received letrozole 2.5 mg daily, and pre-menopausal patients received tamoxifen 20 mg daily or GNRH and letrozole 2.5 mg. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab. Results: Twenty patients with HER2+ breast cancer were enrolled. Median age was 62 years old (range 30-73). Fifteen patients had HER2 3+, and 5 HER2 2+/ISH+ tumors with a median size of 1.95 cm (range 1-3 cm) and 10 patients had tumors >2 cm. Seven patients were pre-menopausal. Six received tamoxifen and 8 letrozole. Eleven patients completed 6 cycles and 9 patients will receive 10 cycles of zanidatamab. Eleven patients already had surgery the remainder patients will have surgery by Oct 30, 2023. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). Treatment was tolerated well. There were no grade 3 or 4 toxicities. One patient had minor infusion related reaction and grade 2 acne, and 2 grade 2 diarrhea. Conclusions: Neoadjuvant zanidatamab demonstrates significant preliminary efficacy, (pCR/RCB-1 64%) with a good safety profile in patients with stage I node negative HER2+ BC. An update of efficacy and safety of all patients will be presented at the time of meeting Citation Format: Vicente Valero, Jason Mouabbi, Heather Alonzo, Paula Pohlmann, Adaeze Lheme, Amy Hassan, Rashmi Murthy, Xuelin Huang, Wei Qiao, Miral Patel, Gaiane Rauch, Cristina Checka, W. Fraser Symmans, Kelly Hunt, Debu Tripathy, Funda Meric-Bernstam. Neoadjuvant zanidatamab for stage I node negative HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-03.

Abstract Purpose: Neoadjuvant immunotherapy (NIT) in combination with neoadjuvant chemotherapy (NCT) was recently approved for treatment of TNBC patients with increased rates of pathologic complete response (pCR) compared to NCT alone. The aim of this study was to evaluate if dynamic contrast-enhanced (DCE)-MRI performed after 2 and/or 4 cycles of NIT + NCT, can predict which patients will achieve pCR, potentially triaging them to continuation of NIT+NCT or, when appropriate, to de-escalation trials. Alternatively, identified chemoresistant tumors who are unlikely to achieve pCR may be directed to other treatment strategies, including novel targeted trials, and avoid the unnecessary toxicity of NIT. Methods and Materials: Preliminary analysis included 64 patients from prospective IRB-approved study (NCT02276443) with stage I-III TNBC who underwent DCE-MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of NIT combined with standard of care NCT (Paclitaxel +/- carboplatin). Tumor volumes were calculated using 3 axis measurements of the index lesion at the DCE MRI and percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. pCR was assessed at surgery after completion of neoadjuvant treatment. Correlation between pCR and TVR was evaluated using ROC analysis. Results: 59% (38/64) of TNBC patients achieved pCR after NIT+NCT. DCE-MRI after 2 cycles of NIT+NCT was able to predict pCR with an AUC of 0.71 (95% CI: 0.57-0.84). TVR >90% at C2 predicted pCR with PPV 86%, and TVR < 35% predicted chemoresistance with NPV 100%. Following 4 cycles of treatment DCE-MRI was able to predict pCR with an AUC of 0.81 (95% CI: 0.69-0.92). TVR >95% at C4 was predictive of chemosensitivity with PPV 82%, while TVR < 75% was predictive of chemoresistance with NPV 100%. Conclusions: DCE-MRI volumetric changes early during NIT + NCT were able to predict pCR status of TNBC patients as either excellent responders or nonresponders, triaging them to SOC neoadjuvant therapy with option for de-escalation trials, or targeted therapies, respectively. These preliminary results will be validated in the larger cohort after completion of the ongoing prospective clinical trial. Citation Format: Gaiane Rauch, Mary Guirguis, Miral Patel, Rosalind Candelaria, Rania Mohamed, Tanya Moseley, H. T. Carisa Le-Petross, Jessica Leung, Gary Whitman, Deanna Lane, Marion Scoggins, Frances Perez, Jia Sun, Sanaz Pashapoor, Zhan Xu, Jason White, Peng Wei, Brandy Reed, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Anil Korkut, Lei Huo, Kelly Hunt, Alyson Clayborn, Jennifer Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Wei Yang, Jingfei Ma, Beatriz Adrada. Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-07.

Abstract Background: Inflammatory breast cancer (IBC) is a rare but aggressive tumor type accounting for up to 10% of breast cancer deaths. One-third of IBCs express high PD-L1 that can be targeted by atezolizumab (Az). MEK inhibitor cobimetinib (Co) not only inhibits the RAS-MAPK pathway but can further enhance immune-mediated killing. Thus, we hypothesize that Az+Co may enhance the efficacy of chemotherapy in metastatic IBC (mIBC). We opened a trial to test this hypothesis with a comprehensive multi-omics biomarker assessment. Patients and Methods: In a single-center, open-label phase II study, cohort 1 received one cycle of Az+ Co, followed by four cycles of Az+Co+eribulin (E) to induce a maximum clinical response, followed by Az+Co maintenance. Pre and Post one cycle of Az+Co tumors were collected for immunohistochemistry (IHC), multiplex immunofluorescence (mIF), whole-exome sequencing (WES), and RNA sequencing (RNAseq). Blood was collected for circulating tumor DNA (ctDNA). Results: Seventeen patients were enrolled in cohort 1. Seven had PR, and three had SD as the best responses. Fourteen had pre, and six had pre/post tumors. The levels of PD-L1 expression at pre/post were not associated with responses. WES revealed the median tumor mutation burden at pre- was 9mt/Mb. More than 50% had TP53 and PI3K pathway mutations at pre. RTK-RAS and Notch pathways were altered in 4/9 cases. PRDM9 and DPY19L2 single-gene mutations were commonly noted in pre. No cancer-associated gene aberration, including potential biomarkers of anti-PDL1 agent response was associated with clinical outcomes. Transcriptomic gene set enrichment analysis demonstrated a greater degree of TNFa and TGFb signaling, Oxphos, angiogenesis, and epithelial-to-mesenchymal transition (EMT) processes in tumors from patients with poor response. Immune profiling by RNAseq revealed two responders to have elevated effector memory T cells, NK T cells, myeloid dendritic cells, and M1 macrophage signatures in pre-samples, but post-samples were not available. mIF confirmed a higher frequency of NK-T cells. The ctDNA analysis from serially collected blood samples is ongoing. Discussion: In this comprehensive multi-omics analysis of pre-and-post-Az+Co, we observed several novel findings, while conventional biomarkers for Az and Co did not correlate with clinical responses. EMT, Oxphos, Notch, and chronic inflammation pathways, which are not previously well reported, were observed in this IBC cohort. These markers warrant further validation to see if they carry significance as therapeutic targets in IBC. Citation Format: Bora Lim, Angela Alexander, Jie S. Willey, Huiming Sun, Suyu Liu, Anisha B. Patel, Edwin Roger Parra, Cara Haymaker, Luisa Solis Soto, Alejandra Serrano, Baohua Sun, Cibelle Freitas Pinto Lima, Auriole Tamegnon, Renganayaki K. Pandurengan, Dzifa Douse, Jessica Lan, Luthra Raja, Randy Chu, Mark Knafl, Scott E. Woodman, Haifeng Zhu, Katja Shulze, Katherine Fedenko, Walter Darbonne, Naoto T. Ueno, Vicente Valero. Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-19.

Abstract Background: Non-small cell lung cancer (NSCLC) is often diagnosed late with many patients (pts) not responding to first line therapy or only responding for a limited time. BNT116 is an intravenously administered uridine RNA-based lipoplex cancer vaccine comprising six mRNAs (MAGE A3, CLDN6, KK-LC-1, PRAME, MAGE A4, MAGE C1), each encoding a tumor-associated antigen (TAA) frequently expressed in NSCLC. Here, we present preliminary results from pts with advanced unresectable or metastatic NSCLC (ECOG 0-1) receiving BNT116 + docetaxel (DTX). Methods: LuCa-MERIT-1 (NCT: 05142189, EudraCT: 2021-004739-94) is a first-in-human, open label, Phase I trial to determine safety (dose limiting toxicities [DLTs]; treatment-emergent adverse events [TEAEs]) and clinical activity (RECIST v1.1) of BNT116 alone or in combinations. The cohort reported here will inform the dose of BNT116 in combination with DTX. Pts must have progressed on PD-1/PD-L1 inhibitor and a platinum-based chemotherapy. Biomarker analysis includes e.g., immunogenicity (ELISpot, n=3), cytokines (MSD, n=20), ctDNA (Avenio ctDNA Surveillance, n=~20), and PD-L1 (IHC, n=20). Results: As of 01 DEC 2023, 20 pts (median age 66 years) have received BNT116 in addition to DTX at 75 mg/m2 Q3W. The combination demonstrated a manageable safety profile. All pts experienced at least one TEAE. TEAEs ≥Grade 3/4, (incidence rate ≥10%) include neutropenia (n=10 [50%]), pneumonia (n=3 [15%]), hypertension (n=3 [15%]), lymphocyte count decreased, diarrhea, and fatigue (each n=2 [10%]). Serious TEAEs were observed in ten pts (50%), of which three were considered as related to BNT116 (Grade 3 cytokine release syndrome, Grade 3 bronchospasm, and Grade 3 pyrexia) and three were considered as related to DTX (Grade 3 diarrhea, Grade 3 rash, and Grade 4 febrile neutropenia). No DLTs within the dose confirmation period or deaths under treatment were observed. Seven of 20 pts (35%) had a partial response, 10 of 20 pts (50%) had stable disease. The objective response rate was 35% (95% CI: 15.4-59.2) and the disease control rate was 85% (95% CI: 62.1-96.8). Robust antigen-specific T-cell responses and cytokine induction were observed even with the addition of DTX and the use of prophylactic dexamethasone on Day 2 of each cycle. Conclusions: BNT116 + DTX shows encouraging antitumor activity, consistent induction of immune responses, a manageable safety profile, and no signs of additive toxicity. Updated safety and clinical activity data will be presented along with additional biomarker data. (Funded by BioNTech) Citation Format: Bala Başak Öven, David Vicente Baz, Jürgen Wolf, Ozturk Ates, Erdem Göker, Patrick Brück, Michael Wenger, Neru Munshi, Iryna Tsyhankova, Iryna Tsyhankova, Malgorzata Kaczorowska, Thomas Schell, Janet L. Markman, Huyuan Yang, Özlem Türeci, Uğur Şahin, Patrick Forde, Akin Atmaca. Preliminary results from LuCa-MERIT-1, a first-in-human Phase I trial evaluating the fixed antigen mRNA vaccine BNT116 + docetaxel in patients with advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT051.

Abstract BACKGROUND: Patients with stage III inflammatory breast cancer (IBC) are treated with tri-modality therapy consisting of neoadjuvant systemic therapy followed by modified radical mastectomy and post-mastectomy radiation therapy. Triple negative IBC (TN-IBC) is the subtype of IBC associated with the worst survival outcomes. Pathological complete response (pCR) rates after neoadjuvant chemotherapy have been historically low, with reports ranging between 13% and 42%. It is unknown if the addition of immune checkpoint inhibition to chemotherapy leads to improved pCR rate in TN-IBC as these patients were underrepresented in the seminal studies that led to the approval of chemoimmunotherapy for high-risk early-stage triple negative breast cancer (TNBC). METHODS: We conducted a retrospective analysis of patients with stage III TN-IBC who underwent breast surgery after receiving neoadjuvant chemoimmunotherapy. Patients were seen at Dana-Farber Cancer Institute (DFCI) or MD Anderson Cancer Center (MDACC). The analysis population consisted of all patients that were seen at either institution no more than 30 days after starting immunotherapy. The primary objective was the estimation of the pCR rate. An additional cohort of patients with TN-IBC treated with neoadjuvant chemotherapy and pembrolizumab while participating in the multi-institutional PELICAN trial (NCT03515798) will be added to the analysis at the time of the meeting. RESULTS: Thirty-seven patients (16 DFCI, 21 MDACC) were identified as having stage III TN-IBC and having received neoadjuvant chemoimmunotherapy. Twenty-five patients met criteria for inclusion in the analysis population. Patients in the DFCI cohort initiated treatment with chemoimmunotherapy between May 2021 and June 2022, and in the MDACC cohort between June 2021 and October 2022. Most patients were White (N=20, 80%), premenopausal (N=15, 60%) and overweight/obese (N=19, 76%). All patients received pembrolizumab-based therapy (Table 1). Among the 25 patients in the analysis population, 10 (40%) (95% CI: 21% to 61%) achieved a pCR, 6 patients experienced RCB-II and 9 RCB-III. At the time of last follow up, 84% of patients were alive. The results will be updated at the time of the meeting to include an additional cohort of 17 patients from the PELICAN trial. CONCLUSIONS: The addition of immune checkpoint inhibition to neoadjuvant chemotherapy led to a higher pCR rate in TN-IBC than most historical estimates. However this is still lower than what has been reported in TNBC in general. The investigation of novel systemic therapies is warranted in TN-IBC. Table 1. Patient characteristics and treatment received (analysis population) Citation Format: Filipa Lynce, Samuel Niman, Anthony Gonçalves, Megumi Kai, Sean Ryan, Elizabeth Troll, Rachel Layman, Antonio Giordano, Azadeh Nasrazadani, Faina Nakhlis, Jennifer Bellon, Laura Warren, Caroline Block, Susan Schumer, Anthony Lucci, Savitri Krishnamurthy, Florence Lerebours, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Trédan, Sylvain Ladoire, Leonor Lopez Almeida, Christophe Zemmour, Sara Tolaney, Vicente Valero, François BERTUCCI, Meredith Regan, Wendy Woodward. Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-06.

Abstract Background: Cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy frequently lead to a complete cell-cycle arrest (CCCA) in luminal EBC. However, the rates of pathological complete response (pCR) or Residual Cancer Burden (RCB) 0-I are modest. The effect of this treatment in terms of molecular downstaging as assessed by a genomic signature more refined than Ki67 remains undetermined. We aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in HR-positive/HER2-negative EBC pts with an Oncotype DX RS ≥18. Methods: DxCARTES was a multicenter, open-label, non-comparative, phase 2 trial across 16 hospitals in Spain. Participants were pre- and post-menopausal women aged ≥18 years with centrally confirmed HR-positive/HER2-negative, Ki67≥20%, stage II-IIIB EBC with a RS ≥18. Eligible pts with baseline RS 18-25 (cohort A) and RS 26-100 (cohort B) received six 28-days cycles of letrozole (2.5 mg QD), ± goserelin if premenopausal, plus palbociclib (125 mg QD, 3/1 schedule) before surgery. Tumor samples were prospectively collected at baseline and surgery for Ki67 and RS assessments. The coprimary endpoint was the proportion of pts in either cohort who achieved RS ≤25 or a pCR (ypT0/is ypN0) at surgery. Secondary endpoints included analysis of RCB, preoperative endocrine prognostic index (PEPI), CCCA (Ki67<2.7%), overall response rate (ORR) as per RECIST v.1.1, and safety as per CTCAE v.5.0. A Simon’s 2-stage design was planned to recruit 33 pts in each cohort. Interim futility analyses were planned with 12 and 18 pts included in cohort A and B, respectively. The analyses were designed to attain an 80% power, with a 10% drop out rate assumption, at a nominal 1-sided α level of 2.5%. The response probabilities for null (H0) and alternative hypotheses (H1) in cohort A were H0: ≤ 72% and H1: ≥ 93%, and in cohort B were H0: ≤ 13% and H1: ≥ 35%, respectively. Results: Between May 5, 2019 to Dec 30, 2019, 67 pts were enrolled and received the study treatment (33 pts allocated to cohort A and 34 pts to cohort B). Pts’ characteristics at diagnosis were well balanced between the two cohorts and of the 67 pts included, 32.8% were premenopausal, 49.3% had axillary node involvement, and median Ki67 was 27% (24-37.5%). A total of 32 pts from cohort A and 33 pts from cohort B were evaluable for the coprimary endpoint. Median duration of treatment was 5.6 months (IQR 5.5-5.8) and median time from the last dose of palbociclib and surgery was 10.5 days (IQR 5.5-14). At surgery, 22 of 32 (68.8%) pts in cohort A and 19 of 33 (57.6%) pts in cohort B had RS ≤25. No pts in cohort A and 2 of 33 (6.1%) pts in cohort B achieved a pCR, meeting the coprimary endpoint in cohort B, but not in cohort A. In cohort A, the proportion of pts with RCB 0-1 was 5.3%, PEPI 0 was 11.1%, and CCCA was 58.1%. In cohort B, the proportion of pts with RCB 0-1 was 23.1%, PEPI 0 was 33.3%, and CCCA was 59.4%. The ORR by breast MRI was 78.1% (25 of 32 pts) in cohort A and 63.6% (21 of 33 pts) in cohort B. The most common grade 3-4 adverse event in both cohorts was neutropenia (23 of 33 [69.7%] pts in cohort A vs 20 of 34 [58.8%] pts in cohort B). No deaths were observed during the study in either cohort. Conclusions: Our results suggest that the neoadjuvant palbociclib plus letrozole activity is independent of the molecular aggressiveness of the disease. Although the prognostic value of molecular downstaging is unknown, a significant proportion of HR-positive/HER2-negative EBC pts with high RS at baseline achieve a pathological or molecular downstaging with this regimen. Further investigation is needed to determine if this strategy could avoid the use of chemotherapy in this population. Citation Format: Antonio Llombart-Cussac, Ángel Guerrero-Zotano, Manuel Ruiz, Begoña Bermejo, Miguel Gil-Gil, Juan de la Haba, Emilio Alba, Vanesa Quiroga, Vicente Carañana, Ander Urruticoechea, Serafín Morales, Meritxell Bellet, Antonio Antón, José Manuel Pérez-García, María Fernández-Abad, Sonia Servitja, Pedro Sánchez-Rovira, Sofia Braga, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes. Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-12.

Abstract PURPOSE Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer. Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) predicts better survival. Early prediction of the treatment response can potentially triage non-responding patients to alternative protocol treatments, spare them of the unneeded toxicity, and improve pCR. We evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on the dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI) MRI images obtained early during NAST to predict pCR. MATERIALS AND METHODS This IRB-approved prospective study (NCT02276443) included 182 patients with biopsy proven stage I-III TNBC who had multiparametric MRIs at baseline (BL), post 2 cycles (C2), and post 4 cycles (C4) of NAST before surgery. Tumors and peritumoral regions of 5 mm and 10 mm in thickness were segmented on the 2.5 minutes DCE subtraction images and on the b=800 DWI images. Ten histogram-based first order texture features including mean, minimum, maximum, standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentile, and 300 radiomic Grey Level Co-occurrence matrix (GLCM) features along with their absolute and relative differences between the 3 imaging time points were extracted from the tumors and from the peritumoral regions with an in-house Matlab toolbox. Treatment response at surgery (pCR vs non-pCR) was documented. The samples were divided into training and testing datasets by a 2:1 ratio. Area under the receiver operating characteristics curve (AUC ROC) was calculated for univariate analysis in predicting pCR. Logistic regression with elastic net regularization was performed for texture feature selection. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. RESULTS Of 182 TNBC patients, 88 (48%) had pCR and 94 (52%) did not achieve pCR. Eight multivariate models combining radiomic features from both DCE and DWI tumoral and peritumoral regions had AUC > 0.8 (0.807-0.831) with p-value < 0.001 in both training and testing sets. The highest AUC=0.831 was obtained from a model consisting of 15 radiomic features: tumor DWI (5 GLCM features) at C2, peritumoral region on DCE (skewness) at C2, tumor DCE (1st, 5th percentile) at C4, tumor DWI (3 GLCM features) at C4, peritumoral region DWI (1 GLCM feature) at C4, and the relative difference between C4/C2 on DCE (5th, 95th percentile and mean). CONCLUSION Multi-parametric MRI-based radiomics models from the tumor and the peritumoral regions showed high accuracy as potential early predictors of NAST response in TNBC patients. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-06.

Abstract Background: Recent data suggest that HER2-low breast cancer (BC) may represent a distinct entity. Approximately 55-60% of BC are considered as Her2-low, of which 80% are Luminal-like tumors. Recent studies support potential clinic-pathological and molecular features differences between Estrogen Receptor (ER) positive HER2-low and ER positive Her2-0 disease. Among patients (pts) with high genomic risk (Oncotype DX RS) HER2-low expression was associated with a significant improvement in overall survival compared to Her2-0. The objective of our study is to compare disease characteristics and outcomes between HER2-low and Her2-0 in estrogen receptor (ER) positive, early (e) BC. (Murtai R et al. The Breast. 60(2021)62-69. Methods: A single center retrospective study of all pts. with ER positive, Her2 negative eBC, for whom Oncotype DX test was performed between 1/Nov/2012 and 14/Febr/2019. The pts were separated into HER2-low (immunohistochemistry (IHC) +1 or + 2 and in situ hybridization not amplified) or HER2-0. Clinic-pathological features included were: demographics, tumour size, nodal status, histologic grade, Her2 expression, ER and progesterone receptor (PR), Ki-67, presence of lymph-vascular (LV1) tumor cell invasion and Oncotype recurrence score (RS) result. Results: A total of 344 pts were screened, of whom 297 pts were included (Exclusion for: Her2 “negative” expression (45 pts); HER2 positive disease by IHC (1 pts); metastatic disease (1 pts)). The distribution of HER2-0 and HER2-low subgroups was 121 pts (41%) and 176 pts (59%). The pathological characteristics according to Her2 expression status are summarized in Table 1. Median age was 57 year (38-79), similar between both groups: Her2-0 58 yr (41-78) and 56 yr (38-79) in Her2 low. The postmenopausal status was 76 pts (62,8%) Her2-0 Vs 113 pts (64,2%) in Her2 low. 1 pts was male. Proliferation Index: Ki67% < 20 was: 65 pts (53,7%) Her2-0 Vs 86 pts (48,5%) in Her2 low; 65 pts (13,5%) had Lympho-vascular invasion in Her2 low; 115 pts (95%) were ER positive in Her2-0 Vs 157 pts (89,2%) in Her2 low; PR positive > 20 was 106 pts (87,6%) in Her2-0 Vs 137 (78,7%) in Her2 Low. The median follow-up was 72 month (SD+- 22,52). 5 pts had a recurrence: 4 pts were Her2 low (1 local and 3 distant metastasis) and 1 Her2-0 with distant metastasis. Most of the pts received adjuvant hormone therapy. There were no statistically significant differences between both groups owing to neither the clinic-pathologic features nor the recurrence score. It was not reached the mínimum number of events for a survival analysis. Conclusions: Our results show that HER2-low eBC pts have similar characteristics and survival rates compared to HER2-0 BC pts without significant differences. Table 1. Baseline pathological characteristics. Citation Format: Elena Galve, Fernando Pikabea-Diaz, Borja Lopez-de-San-Vicente-Hernandez, Covadonga Figaredo-Berjano, Jairo Legaspi-Folgueira, Maria Angeles Sala-Gonzalez, Juan Fernando Arango-Arteaga, Sara Fernandez-Ferrer, Pablo Leonardo Loaiza-Jaramillo, Pablo Casado-Cuesta, Marina Temino-Frances, Anne Bilbao-Penas, Purificacion Martinez-del-Prado. Clinical and pathologic characteristics in early breast cancer Her2-low and high risk Oncotype DX RS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-09.

Abstract Background and Purpose Triple negative breast cancer (TNBC) is a biologically aggressive tumor and a refractory subtype of breast cancer due to the lack of therapeutic targets, such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. In this study, we investigated the accuracy of radiomic models based on the dynamic contrast enhanced (DCE) MRI images obtained after the completion of NAST as discriminators of treatment response in TNBC patients. Materials and Methods This IRB-approved prospective study (ARTEMIS trial, NCT02276443) included 181 patients with biopsy proven stage I-III TNBC who Had MRIs after completion of NAST and before surgery. Patients were classified as pathologic complete response (pCR) and non-pCR at the surgery. Tumors were segmented on the 2.5 minutes DCE subtraction images. Regions with necrosis or clip artifacts were excluded from the contour. If tumors were not visible, the tumor bed was contoured. Whole-tumor histogram-based first order texture features (p=10) including mean, minimum, maximum, Standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentiles, and radiomic (p=300) Grey Level Co-occurrence matrix (GLCM) features were extracted with an in-house Matlab toolbox. The samples were split into training and testing data sets by a 2:1 ratio. For univariate analysis area under the receiver operating characteristics curve (AUC ROC) was performed for pCR status prediction. For texture feature selection logistic regression with elastic net regularization was performed. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. A P-value less than 0.05 was considered statistically significant. Results Of the total 181 patients, 88 (49%) had pCR and 93 (51%) had non-pCR. Univariate analysis identified 7 statistically significant first order imaging features (Minimum, Maximum, Mean, 1st Percentile, 5th Percentile, 95th Percentile, and 99th Percentile) with AUC >= 0.7 (p< 0.001), in both training and testing data sets. Percentile 5 showed highest AUC = 0.78 (p< 0.001). Two multivariate models were statistically significant at cross-validation with AUC>=0.7. The first model combined 2 first order data (Percentile 1 and Percentile 5) with AUC = 0.73 (p< 0.001). The second model combined 8 first order features (Percentile 1, 5, 95, 99, Mean, Minimum, Maximum, and Skewness) and 24 GLCM features with AUC = 0.7 (p=0.003). Conclusion DCE-MRI radiomic features from tumor and tumor bed regions in TNBC may be helpful imaging biomarkers for predicting treatment response after NAST. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Huiqin Chen, Jia Sun, Peng Wei, Jennifer K. Litton, Vicente Valero, Clinton Yam, Mark Pagel, Jingfei Ma, Gaiane Rauch. A Pre-operative Dynamic Contrast Enhanced MRI-Based Radiomics Models as Predictors of Treatment Response after Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-35.

Abstract Background and Purpose Early prediction of neoadjuvant systemic therapy (NAST) response in triple negative breast cancer (TNBC) patients could potentially aid in the selection of alternative therapies and avoid unnecessary toxicity in patients unlikely to achieve pathologic complete response (pCR) with NAST. In this study, we investigated the radiomic features of the peritumoral and the tumoral regions from dynamic contrast enhanced (DCE) MRI acquired at different time points of NAST for early treatment response prediction in TNBC. Methods and Materials This study included 182 biopsy-confirmed stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433). All patients underwent DCE-MRI on a GE 3T MRI scanner at baseline (BL), after two (C2) and four (C4) cycles of doxorubicin/cyclophosphamide based chemotherapy and before surgery. The peritumoral and the tumoral regions were segmented manually by two fellowship-trained radiologists using early phase (2.5 min) DCE-MRI subtraction images. Ten first order radiomic features, 300 grey-level-co-occurrence matrix (GLCM) features along with their absolute and relative differences (C4/BL, C2/BL, C4/C2) between the 3 imaging time points were extracted from the peritumoral and the tumoral regions. Patients were randomly divided into training and testing sets in a 2:1 ratio. For univariate analysis, area under the receiver operating characteristics curve (AUC ROC) was measured to determine the features most predictive of pCR/non-pCR. Wilcoxon Rank Sum test was used to test the statistical significance of predictive performance. In multivariate analysis, radiomic models were established using logistic regression with elastic net regularization followed by 5-fold cross validation for performance assessment. Results Eighty-eight (48%) patients had pCR (59 training, 29 testing) and 94 (52%) patients had non-pCR (63 training, 31 testing). Twenty-five radiomic features (4 from peritumoral C4, 5 from tumoral C4, 4 from peritumoral C4/BL, 6 from tumoral C4/BL, 2 from peritumoral C4/C2 and 4 from tumoral C4/C2) were statistically significant with AUC ≥ 0.75 in both the training and the testing sets at the univariate analysis. The significant features at C4 had AUCs of 0.75-0.79 for the training set and 0.76-0.81 for the testing set. Changes measured between C4 and BL or C2 showed AUC of 0.76-0.84 in the training and 0.75-0.81 in the testing datasets. Eleven multivariate regression models comprised of radiomic features at BL, C2, C4 and their changes (C4/BL, C4/C2 and C2/BL) showed an AUC of 0.80-0.84 for cross validation and an AUC of 0.80-0.82 for independent testing. Conclusions Radiomic models using longitudinal DCE MRI parameters of peritumoral and tumoral regions during NAST have the potential to predict pCR in TNBC patients undergoing NAST. Citation Format: Bikash Panthi, Rania M. Mohamed, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-34.

Abstract Background Previous randomized clinical trials have shown no significant benefit with the addition of anthracyclines to neoadjuvant treatment for HER2-positive breast cancer. However, these studies did not focus on inflammatory breast cancer (IBC), or a small minority of patients on these trials. The study aims to compare pathologic complete response rates with and without anthracyclines in HER2-positive IBC. Methods We reviewed patients diagnosed with Stage III HER2-positive IBC who underwent neoadjuvant therapy and modified radical mastectomy at MD Anderson Cancer Center and Dana-Farber Cancer Institute between 2014 and 2021. Patients received either docetaxel/trastuzumab/pertuzumab-doxorubicin/cyclophosphamide (THP-AC) or docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). The primary outcome was pathologic complete response (pCR) rate, defined as ypTisT0/N0. Secondary outcomes included 2-year event-free survival (EFS) and overall survival (OS). Univariate and multivariable analyses were performed with adjustments for clinically relevant covariates. Results Ninety-nine patients were included in the analysis. Thirty-nine patients received TCHP and 60 received THP-AC. The median follow-up time was 3.02 years. Three patients had disease progression during neoadjuvant therapy. pCR rates did not differ between the two regimens (48.7% TCHP vs. 51.7% THP-AC; p = 0.774). Patient’s baseline characteristics did not significantly affect the pCR rate, except for age. A multivariable logistic regression model adjusted for age and estrogen receptor (ER) status did not show a significant association between pCR and regimen (odds ratio 1.232, 95% CI 0.537–2.829 for THP-AC vs. TCHP, p = 0.623). The 2-year EFS rates for TCHP and THP-AC were 57% and 74%, respectively. In univariate analysis, patients who received THP-AC had better EFS than patients who received TCHP (hazard ratio [HR] 0.423, 95% CI 0.214–0.835, p = 0.013). The EFS benefit of THP-AC remained statistically significant after adjusting for age and type of adjuvant therapy in the final reduced multivariable Cox model (HR 0.441, 95% CI 0.220–0.882, p = 0.021). Univariate analysis did not show a significant association between EFS and other baseline covariates (body mass index, race, N and M category, nuclear grade, ER status, and HER2-targeted therapy). OS did not differ between the THP-AC and TCHP groups (HR 0.419, 95% CI 0.122–1.440, p = 0.167). Conclusions The present analysis revealed that a non–anthracycline-containing regimen in HER2-positive IBC patients had no significant difference in pCR rates but was associated with lower 2-year EFS when compared to an anthracycline-containing regimen. However, OS was similar. Limitations of the study include a small sample size, lack of temporal analysis, and retrospective design with its possible selection bias. Further investigation of the optimal neoadjuvant regimen for patients with HER2-positive IBC is warranted. Citation Format: Toshiaki Iwase, Sridhar Nithya, Megumi Kai, Jie Willey, Wenli Dong, Yu Shen, Savitri Krishnamurthy, Anthony Lucci, H. T. Carisa Le-Petross, Azadeh Nasrazadani, Sadia Saleem, Rachel Layman, Vicente Valero, Debu Tripathy, Wendy Woodward, Yee Chung Cheng, Faina Nakhlis, Jennifer Bellon, Filipa Lynce, Naoto Ueno. Neoadjuvant HER2-targeted regimens with or without anthracyclines for HER2-positive inflammatory breast cancer (IBC): a multicenter retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-03.

Abstract Background: Axillary management in clinically node-positive patients who converted to ycN0 after neoadjuvant chemotherapy (NAC) for breast cancer (BC) remains under research with the aim of de-escalation of axillary lymph node dissection (ALND). A magnetic seed is one of the several positive lymph nodes marking techniques used in targeted axillary dissection (TAD) for patients with cN1 breast cancer undergoing neoadjuvant systemic therapy. It has been criticized for its potential masking effect due to the artefact it produces in the MRI sequences used to assess a proper breast response. This study evaluates if the magnetic seeds placed before NAC for guided TAD have influenced in the breast MRI response assessments. Methods: From October 2021 to June 2023, patients with cT0-4 cN1 breast cancer who were candidates for primary systemic treatment were prospectively recruited. Once a breast lesion and axillary node positivity were confirmed, a based hydrogel marker and a magnetic seed, respectively, were placed prior NAC. Once systemic treatment was completed, imaging techniques were used to assess the response, with MRI being the imaging technique of choice to assess breast response and axillary ultrasound the imaging technique of choice to assess axillary response. Surgical pathological confirmation of response in the axilla was by TAD, including sentinel lymph node and magnetic clipped node resection. Results: A total of 43 patients were included and their characteristics are shown in Table 1. In 16 patients (37%) the tumour was located in the upper outer quadrant (UOQ). In this group, the susceptibility artefact produced by the magnetic seed in the MRI created a black hole obscuring the axilla with a mean diameter of 69 mm (range: 57-76 mm). In no case did the halo interfere with the correct MRI visualisation of the breast marker. By MRI, the mean distance of the artifact halo from the breast marker or residual breast lesion was 40 mm (range: 13-79 mm). Overall, complete radiological response (ycCR) was reported in 20 patients (46%), breast only in 21 (49%) and axilla only in 38 (88%) patients. In 5 patients, preoperative axillary ultrasound revealed residual axillary disease, confirmed by FNA, lead to direct ALND. In the remaining 38 patients the axillary TAD assessment was completed. In all cases, the magnetic clipped node was successfully surgically removed. Pathological complete response (pCR) was confirmed in 9 (21%), breast only in 11 (26%) and axilla only in 13 (30%) patients. MRI diagnostic performance in detecting residual breast disease after NAC was not altered by the magnetic clipped node artifact when comparing the tumour location in the UOQ to the other quadrants (AUC 0.764 vs. 0.702; p=0.698). Conclusions: Surgical axillary staging remains the most reliable method for assessing the axillary response after NAC. Target axillary dissection guided by magnetic seed placed before NAC is an effective and accurate technique. The artifact generated in the MRI does not interfere with the pre-surgical breast response assessment after neoadjuvant systemic treatment. Table 1: Patients and tumor characteristics Citation Format: Martin Espinosa-Bravo, Joaquin Rivero Deniz, Clara Morales Comas, Javier de la Torre Fernandez de Vega, Irene Vives Rosello, Enrica Esposito, Vicente Peg Camara, María De Les Neus Rus Calafell, Ignacio Miranda Gomez, Christian Siso Raber. Magnetic Seeds, used to Locate the Metastatic Axillary Lymph Node placed before Neoadjuvant Chemotherapy for Breast Cancer Treatment, do not interfere the pre-surgical MRI Breast response assessment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-04.

Abstract OBJECTIVE To evaluate the efficacy of combined treatment with ultrasound-guided cryoablation and endocrine therapy (ET) in hormone receptor-positive (ER+), HER2-negative (HER-) invasive breast cancer (BC) patients with clinical stage I/II who are not candidates for axillary surgery. PATIENTS AND METHODS Patients with ER+, HER- invasive BC in clinical stage I/II who did not undergo sentinel lymph node biopsy (SLNB) or target axillary dissection (TAD) were included. They received treatment consisting of ultrasound-guided cryoablation combined with daily letrozole 2.5 mg orally. Cryoablation was performed as the initial treatment for BC < 15mm, followed by adjuvant ET, while neoadjuvant ET was administered for 6-12 months before cryoablation for BC ≥ 15mm. Cryoablation was performed using the ICEfx Galil argon gas system (Boston Scientific, USA) and the ProSense liquid nitrogen system (IceCure Medical Ltd, Caesarea, Israel). Follow-up breast ultrasound examinations were conducted every six months. Patients with a minimum follow-up of 12 months after cryoablation were included in the study. Core needle biopsies were performed if recurrence was suspected, and rescue cryoablation was considered for confirmed relapse. The tolerance and safety of the procedures were recorded. RESULTS From March 2019 to July 2023, a total of 96 patients with 105 ER+, HER2- invasive BC in clinical stage I/II who did not undergo SLNB or TAD were treated with ultrasound-guided cryoablation and ET. Among them, 58 patients (aged 58-96 years, mean 83, SD ±7.64) with 64 BC lesions (ranging from 5 to 60mm, mean 17, SD ±13.75) were followed up for a minimum of 12 months, with a mean follow-up period of 24 months (ranging from 12 to 50 months). The invasive carcinomas included 40 ductal, 16 lobular, 5 colloid, and 3 papillary cases. The ipsilateral breast tumor recurrence rate was 1,72% (1/58 patients). One patient with lobular carcinoma experienced a relapse at 17 months. Rescue cryoablation was performed, and after 25 months, she remains free of recurrence. Therefore, local control was achieved in all patients. Six patients died from causes unrelated to BC during the follow-up period. All procedures were well-tolerated with local anesthesia, and no serious complications were reported. CONCLUSION Ultrasound-guided cryoablation with ET constitutes an effective combined treatment for the local control of ER+, HER2- BC in patients with clinical stage I/II and omission for surgical axillary staging. Cryoablation is a very well tolerated procedure without morbidity. Citation Format: José María Oliver Goldaracena, Pilar Zamora, Covadonga Marti, Vicenta Córdoba Chicote, Maria José Roca Navarro, Diego Garrido Alonso, Ylenia Navarro Monforte, Teresa Diaz de Bustamante Durban, Fernando García Martínez, Jose Ignacio Sanchez-Mendez, Elisa York Pineda, Laura Yebenes Gregorio, Adolfo Loayza, Laura Frías Aldeguer, Elisa Moreno Palacios, Marcos Melendez Gisper, Joaquin Gomez Ramirez, Luis Asensio Gómez, Virginia Martínez Marín, David Hardisson Hernáez, Alberto Berjón García. Cryoablation and endocrine therapy for clinical stage I/II, ER+ breast cancer in patients with omission of surgical axillary staging. A retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-07.

Abstract Background: Treatment options for patients (pts) with leptomeningeal metastasis (LM) are limited, and the prognosis is poor (median overall survival (OS) ~ 4-5 months). Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine in pts with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen in the metastatic setting, including pts with brain metastases. TBCRC049 (NCT03501979) is an investigator-initiated, phase 2, single-arm study evaluating the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM. We have previously demonstrated therapeutic levels of tucatinib in CSF in pts with HER2+ LM (Stringer-Reasor et al, ASCO 2021). We now report efficacy outcomes of the study. Methods: Eligible pts were adults with HER2+ metastatic breast cancer, Karnofsky performance status (KPS) > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Pts with treated or concurrent/new brain metastases were allowed. Pts received tucatinib 300 mg orally twice daily starting with cycle 1, day 1 (C1D1); capecitabine 1000 mg/m2 orally twice daily on days 1-14 of a 21-day cycle, starting on C1D1; and trastuzumab loading dose of 8 mg/kg IV on C1D1, and then 6 mg/kg IV once every 21 days, starting with C2D1. The primary endpoint was OS. Planned enrollment was 30 pts; however, due to lack of accrual since the FDA approval of tucatinib (4/2020), the study was closed after 17 patients were enrolled. Results: Baseline disease characteristics at LM diagnosis are shown in Table 1. Eight pts (47%) had abnormal CSF cytology (positive or equivocal). All pts had MRI evidence of LM in the brain, and 14/17 (82%) had brain metastases, of which 11 (65%) had received prior treatment for brain metastases. Median age at study treatment initiation was 53 years. Median number of treatment cycles received was 5 (range: 2-27). Median OS time was 11.9 months (95% CI: 4.1, NR). At data cutoff (6/22/21), 7/17 pts (41%) remained alive and median followup was 17 months(8-26). Median time to CNS progression was 6.9 months (95% CI: 2.8, 13.8). Conclusions: In pts with LMD from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median OS time was nearly 1 year. This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM. Further studies evaluating brain-penetrant oral drugs in this rare pt population are needed. Baseline Disease Characteristics (N=17)Number%Baseline CSF cytologyPositive529%Negative847%Equivocal318%None obtained1*6%Symptoms attributable to LMDYes1588%No212%MRI evidence of LMDBrain only1165%Brain and Spine635%History of brain metastasisYes1482%Prior treatment1165%New/concurrent diagnosis – no prior treatment318%No318%Extra-CNS DiseaseYes1165%No635%*One patient had VP shunt and difficulty sampling fluid; all CSF sent for research PK and non-PK studies Citation Format: Rashmi K Murthy, Barbara O'Brien, Donald A Berry, Akshara Singareeka-Raghavendra, Maria Gule Monroe, Jason Johnson, Jason White, Jennifer Childress, Justin Sanford, Jill Schwartz-Gomez, Michelle Melisko, Aki Morikawa, Sherise Ferguson, John F de Groot, Ian Krop, Vicente Valero, Mothaffar Rimawi, Antonio Wolff, Debu Tripathy, Nancy U Lin, Erica Stringer-Reasor. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-02.

Abstract Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) represents an independent prognostic factor in HER2-positive early-stage breast cancer (EBC) treated with trastuzumab/pertuzumab-containing regimens. Among distinct subsets of TILs, conventional CD8+ αβ T cells require TCR signaling as a part of adaptive immunity, while γδ T cells display also innate-like activity via the NKG2D receptor contributing to a very rapid tumor immunosurveillance. Specific γδ T cell subsets were associated with remission and improved overall survival of patients with triple-negative breast cancer. However, very little is known about circulating αβ and γδ T cells and their immunological status in HER2-positive breast cancer. In this substudy, we aimed to characterize the αβ and γδ T cell subsets and the association with clinical outcome in peripheral blood of patients with HER2-positive EBC enrolled in the PHERGain trial, which assessed the possibility of chemotherapy de-escalation with neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab using an 18F-fluorodeoxyglucose-PET and pathological response-adapted strategy. Methods: Peripheral blood was obtained from 24 consecutive patients who were assigned to the trastuzumab and pertuzumab group (+/- endocrine therapy as per hormone receptor status) before randomization (baseline) and after 2 treatment cycles (6 weeks). Blood samples were also collected from 48 age-matched healthy donors who represented the control group. Absolute numbers of CD3+, CD3+/CD4+, CD3+/CD8+, and CD3+/CD56+ according to the TCR expression, and annexin V apoptotic rate on αβ and γδ T cells were evaluated by flow cytometry. Subset distribution of T cell differentiation within naïve, central memory, effector memory, and terminally differentiated effector memory cells was also determined. The changes in the frequency of peripheral T cells and rate of apoptotic subsets between timepoints, patients, and healthy donors were compared with Wilcoxon test. The analyses were set at two-sided 0.05 level of significance. Results: Among 24 patients with evaluable blood samples at both timepoints, median age was 50.5 years (IQR 45.8-61), 45.8% had node-positive disease, 79.2% had hormone receptor-positive status, 79.2% had tumors with HER2 IHC 3+ status, and 54.2% achieved a pathological complete response (ypT0/is ypN0) after treatment. At baseline, levels of αβ and γδ T cells in EBC patients were significantly lower than levels in healthy subjects (P ≤0.05). After 6 weeks of study treatment, these levels in EBC patients did not significantly differ from those at baseline. Baseline rates of apoptotic subsets were higher in EBC patients than rates in healthy subjects (P <0.01), but after 6 weeks of study treatment all apoptotic subsets were significantly reduced in EBC patients compared with those at baseline (P ≤0.05). No evidence of association was found between peripheral T cells and pathological complete response in EBC patients. Conclusions: These data suggest a potential involvement of T cell apoptosis on the mechanism of action mediated by dual HER2 blockade with trastuzumab and pertuzumab in patients with HER2-positive EBC. However, further validation is required. Additional data on the subset distribution of T cell differentiation status will be presented at the meeting. Citation Format: Juan Carlos Andreu-Ballester, José Manuel Pérez-García, Begoña Bermejo, Vicente Carañana, Vega Iranzo, Joaquín Gavilà, Ana Santaballa, María Carmen Gómez-Soler, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Antonio Llombart-Cussac. Analysis of αβ and γδ circulating T cells in the PHERGain randomized phase 2 trial for patients with HER2-positive early breast cancer receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy: LINGain [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-30.

Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-06.

Abstract Background: The CLEOPATRA trial established trastuzumab, pertuzumab and a taxane (THP) as a standard of care for first line metastatic, HER2-positve breast cancer with median progression-free survival (PFS) of 18.7 months and median OS of 57 months. NRG BR004 was a phase III, placebo-controlled trial designed to determine whether the addition of the PD-L1 inhibitor, atezolizumab, to THP would improve progression-free survival (PFS), relative to THP/placebo in patients with newly documented HER2-positive measurable metastatic breast cancer. Methods: BR004 was designed to detect an improvement in the primary endpoint of PFS in patients with measurable disease from 16.5 to 22.5 months with addition of atezolizumab (HR 0.733). A sample size of 600 would provide 80% power with a type I error rate of 0.05 to detect such an improvement when 326 PFS events had been reported. Monthly accrual was projected at 30 patients per month with completion of accrual in 24 months. In addition to routine monitoring of safety data by the IDMC every 6 months, a formal analysis of the toxicity data was to be performed 16 weeks after the 100th patient had been randomized with review by the IDMC. Results: First patient was randomized on May 1, 2019, and after 37 months 190 patients had been randomized. Several amendments were not successful in addressing the low accrual rate. The IDMC began regular monitoring of safety and accrual data in July 2020 and reviewed the formal safety analysis in February 2022. As of the February 2022 IDMC meeting, four Grade 5 adverse events (AEs) had been reported (2 occurring in 2020 and 2 in 2021), one of which occurred in a patient with evolving liver failure due to rapid disease progression at the start of therapy. The recommendation was to continue without modification, but notice was given the Grade 5 AEs had occurred on the same treatment arm without unblinding. When additional Grade 5 AEs occurred on 3/4/2022 and 4/27/2022 both on the same study arm with none reported on the other arm, accrual was held until the IDMC could review updated safety data, narratives of the Grade 5 AEs and the overall context of the trial. There was no evidence of clinically important imbalances between Grade 3 and Grade 4 AEs between the arms., Based on an uncertain but material safety signal, the ongoing accrual challenges, and determination that the clinical question being addressed was no longer sufficiently compelling, the IDMC recommended that the trial should be permanently closed to further enrollment. Summary safety data from 187 treated patients are provided in the Table. A decision was made to discontinue atezolizumab/placebo in patients receiving the investigational component of the trial therapy and unblind investigators and patients. The study will continue to collect information on PFS events, deaths and late immune AEs through April of 2024 when PFS and OS will be analyzed. Conclusions: The imbalance in Grade 5 AEs which occurred on BR004 coupled with continued poor accrual and the changing landscape in HER2+ MBC resulted in early closure of enrollment and unblinding of patients. Follow-up continues to assess PFS, OS and monitor for delayed immune AEs. Support: U10CA180868, -189867, -180822; U24CA196067; and Genentech. Citation Format: Charles E. Geyer, Jr, Gong Tang, Priya Rastogi, Vicente Valero, Stephen K. Chia, Erin F. Cobain, Elias Obeid, David B. Page, Andrew S. Poklepovic, William J. Irvin, Jr., Adam M. Brufsky, Irene L. Wapnir, Jennifer M. Suga, Eleftherios (Terry) Mamounas, Norman Wolmark. Safety Analyses of NRG BR004: A Randomized, Double-blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab with Atezolizumab or Placebo in First-line HER2-Positive Metastatic Breast Cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-05.

Abstract Accumulating physical and hematologic toxicities make the indefinite use of chemotherapy unfeasible for many patients with metastatic/recurrent HER2– IBC or TNBC. Whether maintenance immunotherapy has a role in the treatment of these patients is unclear. We conducted a single-arm phase II trial of pembrolizumab monotherapy in patients with metastatic/recurrent HER2– IBC or TNBC (regardless of their PD-L1 expression status) and report here the clinical data from this trial. Methods: Eligible patients were enrolled between 2015 and 2022 and had had a CR, a PR, or SD after a minimum of 3 cycles of chemotherapy for metastatic/recurrent disease. PD-L1 expression status was not used to determine eligibility. Patients received 200 mg of pembrolizumab every 3 weeks (q3w) until disease progression, intolerable toxicity, or 2 years. In late 2021, the study was amended to allow patients who had received ≥8 cycles of q3w therapy to transition to q6w dosing (400 mg), based on the FDA’s approval of both dosing regimens across all indications. The primary endpoint was the 4-month disease control rate (DCR); exploratory endpoints included safety and correlative biomarkers from tissue and blood to ascertain associations between clinical response and PD-L1 expression, T-cell clonality, and immune profiling. Results: Of 43 patients (median age, 54 years; range, 34-77 years), 11 had IBC (10 with triple-negative IBC and 1 with ER+ HER2– IBC), and 32 had TNBC. The 4-month DCR was 58.1% (95% CI: 43.4%-72.9%). During a median follow-up of 11.4 months, 25 patients died. The entire cohort’s median OS and PFS times were 26.0 months (95% CI: 11.0-33.5 months) and 4.8 months (95% CI: 3.0-7.1 months), respectively. The median OS times of the IBC and TNBC groups did not differ significantly, nor did those of the CR, PR, and SD groups. The median PFS times of the IBC group (2.2 months) and TNBC group (4.8 months) did not differ significantly (p = .12), but those of the CR, PR, and SD groups did (not reached, 10.3 months, and 3.4 months, respectively; p = .01). Among the 37 patients who are off study treatment, most patients (84%; n=31/37) discontinued treatment owing to disease progression rather than toxicities (n=2), and the toxicities overall were consistent with the known profile of single-agent anti-PD1. Five patients had grade 3 events; there were no grade 4 or 5 events. Three patients had irreversible endocrinopathies (thyroiditis and adrenal insufficiency) requiring hormone replacement, but only 1 patient discontinued pembrolizumab because of these events. One patient discontinued treatment because of optic neuritis requiring steroids. Four patients completed 2 years of treatment without disease progression. Conclusions: Pembrolizumab maintenance therapy achieves acceptable disease control after induction chemotherapy. The PFS in this trial compares favorably to the expected durations of response to later lines of therapy. The toxicity profile of pembrolizumab compares favorably with those of chemotherapy and ADCs, which may provide a rationale for the use of ICIs in this setting. However, whether pembrolizumab maintenance therapy is helpful in TNBC patients who have received concurrent pembrolizumab with neoadjuvant chemotherapy is unknown, as these patients were excluded from the trial. Acknowledgements: This trial was supported by Merck. Citation Format: Toshiaki Iwase, Angela Alexander, Vivian Chiv, Megumi Kai, Kumiko Kida, Charla Parker, Angela N. Marx, Evan Cohen, Hui Gao, James Reuben, Xiaoping Wang, Savitri Krishnamurthy, Diane Liu, Yu Shen, David Ramirez, Debu Tripathy, Daniel Booser, Clinton Yam, Vicente Valero, Bora Lim, Naoto T. Ueno, Jie S. Willey. Phase II study of Pembrolizumab Maintenance treatment in patients with HER2-negative inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) after response to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-04.

Abstract PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant therapy (NAT). Pathologic complete response (pCR) has become a prognostic marker for overall and disease-free survival. The aim of this study was to determine if dynamic contrast-enhanced (DCE)-MRI after 2 and/or 4 cycles of NAT can identify patients with a high likelihood of achieving pCR, triaging them to standard of care (SOC), or, when appropriate, to de-escalation trials. Conversely, we aimed to identify chemoresistant tumors that are unlikely to achieve pCR and may benefit from escalated targeted trials. METHOD AND MATERIALS 309 patients with stage I-III TNBC underwent DCE-MRI (temporal resolution: 9-12 sec) at baseline (BL), 2 cycles (C2), and 4 cycles (C4) of SOC doxorubicin/cyclophosphamide (AC) NAT as part of a prospective IRB-approved study (NCT02276443). Tumor volumes of the index lesion were calculated using 3 axis measurements during the early phase of the DCE-MRI (60s). Percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. Patients were randomly assigned to a training or a validation cohort in a 1:1 ratio. pCR was assessed at surgery after completion of SOC NAT. Correlation between pCR and TVR was evaluated using ROC analysis. RESULTS Of 309 TNBC patients, 136 (44%) achieved pCR. Following 2 cycles of NAT, TVR >80% was predictive of pCR (chemosensitivity), while TVR ≤ 55% was predictive of non-pCR (chemoresistance) with PPV 80%, NPV 89%, AUC 0.811 (0.73~0.893, p< 0.0001) in the training cohort, and PPV 82%, NPV 85%, AUC 0.815 (CI:0.736~0.894, p< 0.0001) in the validation cohort. Following 4 cycles of NAT, TVR >90% was predictive of pCR, while TVR ≤80% was predictive of non-pCR with PPV 80%, NPV 84%, AUC 0.827 (0.756~0.898, p< 0.0001) in the training cohort and with PPV 73%, NPV 82%, AUC 0.785 (CI:0.709~0.862, p< 0.001) in the validation cohort. Using this model, the pCR status was correctly classified in 50% of TNBC patients using C2 DCE-MRI in the training cohort, and 54% in the validation cohort. Only 8% were misclassified in the training cohort, and 10% in the validation cohort. Using C4 DCE-MRI, the pCR status of 61% and 57% of TNBC was correctly classified in the validation and the testing cohorts, respectively. 12% were misclassified in the validation cohort, and 21% in the testing cohort. CONCLUSION DCE-MRI after 2 and 4 cycles of AC-based NAT correctly predicted the pCR status of 54% and 57% of TNBC patients, respectively, as either excellent responders or nonresponders with high AUC 0.811 and 0.827. This may allow patients to be triaged to SOC NAT with option of de-escalation or early targeted therapies for non-responders. Citation Format: Mary S. Guirguis, Beatriz Adrada, Miral Patel, Frances Perez, Rosalind Candelaria, Wei Yang, Jia Sun, Rania M. Mohamed, Medine Boge, H. T. Carisa Le-Petross, Jessica Leung, Gary J. Whitman, Deanna L. Lane, Marion E. Scoggins, Tanya Moseley, Benjamin Musall, Jason White, Sanaz Pashapoor, Peng Wei, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Mark Pagel, Lei Huo, Kelly K. Hunt, Elizabeth Ravenberg, Alastair M. Thompson, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Stacy Moulder, Clinton Yam, Jingfei Ma, Gaiane Rauch. DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-15.

Abstract Background: Metastatic TNBC is an aggressive breast cancer subtype with poor prognosis and limited systemic therapy options. While pembrolizumab in combination with chemotherapy is approved for PD-L1 positive TNBC, limited immunotherapy options exist for patients with progressive and/or PD-L1 negative disease. TGFβ released by cancer cells and stromal fibroblasts attenuates the intrinsic antitumor potential of immune cells within the tumor microenvironment mediating resistance to immunotherapy. Consequently, inhibition of TGFβ signaling could potentially enhance antitumor responses to anti-PD-L1/PD-1 therapies. Bintrafusp alfa is a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. Preclinical studies have shown that eribulin downregulates TGFβ by phosphorylation of Smad proteins. Therefore, combining eribulin with bintrafusp alfa may have a synergistic effect. This study evaluated the combination of bintrafusp alfa with eribulin in patients with metastatic TNBC. Methods: This is a phase 1b, open label, single center study evaluating bintrafusp alfa in combination with eribulin in patients with metastatic TNBC who had relapsed/progressed on prior therapies. Patients with ER/PR ≤10% with measurable disease were enrolled. Patients who received prior anti-PD-1/PD-L1 therapies in the metastatic setting were excluded. Patients received bintrafusp alfa 1200 mg intravenously every 2 weeks in combination with eribulin (1.4 mg/m2 (dose level 1), 1.1 mg/m2, or 0.7 mg/m2) on days 1, 8, 22, 29 on every 6-week cycle. Primary objectives were to determine the recommended phase II dose (RP2D) as well as to evaluate the safety and tolerability of eribulin in combination with the fixed dose of bintrafusp alfa. Secondary objective was to determine the overall response rate (ORR) according to RECIST 1.1. Bayesian optimal interval (BOIN) design was employed to identify the RP2D. Toxicities assessed using CTCAE v4.03. Tumor assessments were performed every 6 weeks. Results: A total of 25 patients were enrolled on the study. Twenty-one patients were evaluable (3 screen failures, 1 received only one dose of study treatment). Median age 59 (range 27-85). Median number of prior therapies 2 (range 0-8). The most common reason for protocol discontinuation was disease progression (n = 15, 71%). Four patients experienced dose limiting toxicities (DLTs); 3 with decreased neutrophil count and 1 with increased aspartate aminotransferase. Five patients (24%) experienced grade 4 toxicities (increased aspartate aminotransferase, hypokalemia, hypophosphatemia, neutropenia). Nine patients (43%) experienced grade 3 toxicities. Three patients (14%) discontinued study due to toxicity. Total of 2 deaths were observed, none related to treatment. Most common toxicities (any grade) include anemia (n = 13 patients), elevated aspartate aminotransferase (11), neutropenia (n = 10), elevated aminotransferase (9), headache (n = 9), hypokalemia (n = 8), hyperglycemia (n = 8), leukopenia (n = 8), and fatigue (n = 8). RP2D was eribulin 1.1 mg/m2 with bintrafusp alfa 1200 mg. Six patients had PR (28.6%), 2 had SD (9.5%) and 12 had PD (57.1%) as the best response. One patient withdrew before response evaluation. Median PFS was 1.7 months (95% CI: (1.2, 5.9) and median OS was 11.1 months (95%CI: (5.2, 15.7). Conclusions: The combination of bintrafusp alfa with eribulin has manageable safety profile with meaningful clinical activity in patients with TNBC. Further studies evaluating TGF inhibitors in breast cancer are warranted. Citation Format: Senthil Damodaran, Diane Liu, Jill Schwartz, Vicente Valero, David Ramirez, Sadia Saleem, Naoto T. Ueno, Nuhad K. Ibrahim, Meghan S. Karuturi, Rashmi K. Murthy, Stacy Moulder, Jennifer K. Litton. A phase Ib trial of bintrafusp alfa and eribulin in patients with metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-03.

Abstract Background: In the metastatic setting, low HER2 expression is associated with clinical benefit from trastuzumab deruxtecan, a HER2-targeting antibody drug conjugates. However, little is known about the biological significance of low HER2 expression in patients with early stage triple-negative breast cancer (TNBC) receiving neoadjuvant therapy (NAT). Methods: Out of 595 patients with stage I-III TNBC enrolled on the prospective ARTEMIS trial (NCT02276443) from 2015-2021, we identified 367 patients with available HER2 immunohistochemistry (IHC) results on pre-NAT tumor tissue (HER2-zero: n=218; HER2-low [IHC 1+, 2+]: n=149). All patients were treated with anthracycline-based NAT. In cases where sufficient pre-NAT tumor tissue were available, additional IHC and/or RNAseq were performed. Differential gene expression (DGE) and pathway analysis were performed using DEseq2. Gene set enrichment analysis (GSEA) was performed using the Hallmark gene sets. Deconvolution analyses were performed using CIBERSORT. We controlled for multiple hypothesis using a false discovery rate (FDR) threshold with the Benjamini-Hochberg method, accepting as significant genes with at least a 2-fold change and < 5% FDR. Results: Table 1 summarizes baseline clinicopathological features of the 367 patients. Compared to HER2-zero tumors, HER2-low tumors were less likely of metaplastic histology (p=0.001), associated with lower Ki67 (p=0.017) and were more likely to be androgen receptor (AR)-positive (p=0.01). There were no significant differences in tumor-infiltrating lymphocytes (TILs) infiltration and PD-L1 expression between HER2-zero and HER2-low tumors. Among the 226 patients with sufficient pre-NAT tissue for RNAseq, DGE analyses demonstrated upregulation of genes involved in fatty acid metabolism (ACSM1) and steroid hormone metabolism (DHRS2, UGT2B28) in HER2-low tumors compared with HER2-zero tumors. Deconvolution analyses revealed no significant differences between predicted proportions of immune cell subpopulations between HER2-low and HER2-zero tumors. Although rates of pCR were not significantly different between patients with HER2-zero (46%) and HER2-low tumors (40%) (p=0.34), non-pCR in patients with HER2-low tumors was associated with increased expression of EREG, which encodes an EGFR ligand, while non-pCR in patients with HER2-zero tumors was associated with downregulation in genes involved in immune response pathways. GSEA further identified the Hallmark allograft rejection (FDR q=0.001), interferon gamma response (FDR q=0.002), and interferon alpha response pathways (FDR q=0.007) as the 3 most significantly downregulated pathways in HER2-zero tumors from patients experiencing a non-pCR relative to HER2-zero tumors from patients experiencing a pCR. Conclusion: In early stage TNBC, low HER2 expression is associated with increased AR expression and upregulation of genes associated with fatty acid and steroid hormone metabolism. Gene expression analyses suggest that drivers of resistance to NAT differ between HER2-low and HER2-zero tumors. Biological differences between HER2-zero and HER2-low tumors exist and may influence future personalized treatment for patients with early stage TNBC. Citation Format: Clinton Yam, Ziyi Li, Anil Korkut, Wencai Ma, Elisabeth Kong, Holly A. Hill, Hussein Abbas, Sausan Abouharb, Beatriz Adrada, Banu K. Arun, Carlos H. Barcenas, Ajit Bisen, Daniel Booser, Aman Buzdar, Rosalind Candelaria, Junjie Chen, Alyson Clayborn, Senthil Damodaran, Qingqing Ding, Haven Garber, Gabriel N. Hortobagyi, Kelly K. Hunt, Nuhad K. Ibrahim, Adaeze Iheme, Meghan S. Karuturi, Kimberly Koenig, Rachel M. Layman, Jangsoon Lee, Jennifer K. Litton, Melissa Mitchell, Giancarlo Moscol, Jason Mouabbi, Rashmi K. Murthy, Oluchi Oke, Paula Pohlmann, David Ramirez, Elizabeth Ravenberg, Sadia Saleem, Mediget Teshome, Vicente Valero, Jason White, Madison Williams, Wendy Woodward, Chasity Yajima, Naoto T. Ueno, Ken Chen, Gaiane Rauch, Lei Huo, Debu Tripathy. HER2-01 Clinical and Molecular Characteristics of HER2-low/zero Early Stage Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-01.

Abstract Background: Clinical outcomes according to HER2 immunohistochemistry (IHC) in patients with early-stage HER2-negative breast cancer have differed across studies. For early-stage TNBC (eTNBC), less representation of this subtype in cohorts studied to date has limited interpretation of results. We sought to evaluate outcomes according to HER2 IHC in a multi-institutional cohort of patients (pts) with eTNBC who received neoadjuvant therapy (NAT). Methods: Pts diagnosed with stage I-III TNBC (including HR-low; ER and PR < 10%) who received NAT and underwent surgery between 1/1/16-6/30/19 were identified across three institutional prospective databases. HER2 was defined as low (1+ or 2+/ISH non-amplified) or HER2-0 according to local testing at diagnosis. Pathological complete response (pCR) was defined as no residual invasive disease in breast and axilla. Multivariable logistic regression was used to compare pCR rates (HER2-low vs HER2-0) adjusting for age at diagnosis, race, anatomic clinical stage, germline BRCA1/2 (gBRCA), histology, HR status and receipt of anthracycline and taxane NAT. Recurrence-free (RFS), distant recurrence-free (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios. Results: A total of 978 pts were identified of which 388 (39.7%) had HER2-low and 590 (60.3%) had HER2-0 tumors at diagnosis. Median age was 50.3 (range: 21.0-83.4) yrs. 174 (17.8%) pts had HR-low tumors. 142 (14.5%) pts had a known gBRCA mutation. 790 pts (80.8%) received anthracycline- and taxane NAT. No significant differences were observed in age, race, gBRCA, histology, HR status (low vs negative), clinical tumor size, or type of NAT between HER2-low and HER2-0 groups. Clinical nodal positivity was higher in HER2-low (55.2%) vs HER2-0 (46.6%), p=0.011. No significant difference in pCR was observed between HER2-low (32.0%) and HER2-0 (32.7%) groups, adjusted p=0.928. Among pts with residual disease (RD) post-NAT with HER2 IHC also available in the RD sample, 244/363 (67.2%) had concordant HER2 status. 70/225 (31.1%) of HER2-0 tumors at diagnosis had IHC expression post-NAT (66 HER2-low, 4 HER2-positive); 48/138 (34.8%) of HER2-low tumors at diagnosis were HER2-0 post-NAT. At a median follow-up of 3.1 yrs, RFS did not significantly differ between HER2-low vs HER2-0 pts with pCR (p=0.368) or in those with RD post-NAT (p=0.573). Similarly, DRFS did not differ according to HER2 category for pts with pCR (p=0.509) or RD (p=0.812), nor did OS for pts with pCR (p=0.514) or RD (p=0.285) (Table 1). Conclusion: In a large cohort of pts with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. High rate of discordance in HER2 IHC between diagnostic and RD post-NAT was observed, highlighting the importance of repeat IHC testing in serial samples given the development of antibody drug conjugates for HER2-low breast cancer. Table 1. RFS, DRFS and OS by HER2 expression Citation Format: Ana Garrido-Castro, Danielle Brandes Zakon, Qingchun Jin, Michael Grimm, Akshara Singareeka Raghavendra, Melissa Hughes, Mathew Cherian, Julie Vincuilla, Tonia Parker, Paolo Tarantino, Elizabeth Mittendorf, Tari King, Vicente Valero, Debu Tripathy, Bhuvaneswari Ramaswamy, Sara Tolaney, Nabihah Tayob, Nancy Lin, Daniel Stover, Carlos Barcenas. Clinical outcomes in early-stage TNBC according to HER2-low status [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-05.

Abstract Background: Despite being a rare presentation of breast cancer, inflammatory breast cancer (IBC) is responsible for up to 10% of all breast cancer-related deaths. Most IBCs express HER2, with up to 40% of all IBCs being HER2-positive and 40% being HER2-low. Additionally, IBC more often exhibits PD-L1 expression compared to non-IBC, suggesting a preeminent role for immune evasion in the development and progression of IBC. No systemic treatment approaches have been yet developed specifically for IBC, and standard treatments commonly lead to poor outcomes. Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate currently approved for patients with pretreated HER2-positive and HER2-low metastatic breast cancer. Early-phase data highlighted the safety and potential synergy of combining T-DXd with the immune checkpoint inhibitor durvalumab. The aim of TRUDI is to evaluate the clinical activity and safety of neoadjuvant T-DXd with durvalumab among patients with HER2-expressing IBC. Trial Design: TRUDI is an ongoing, open label, multicenter, two cohort investigator-initiated phase II neoadjuvant trial for patients with stage III HER2-expressing IBC. The trial was activated in May 2023, with enrollment ongoing. Eligible participants are women and men with previously untreated, stage III (T4d, any N) breast cancer, clinically determined to be IBC. Patients will be included in two cohorts, depending on the locally determined HER2 status (with any hormone receptor [HR] status): Cohort 1 (n=36) for patients with HER2-positive disease (HER2 IHC 3+ or 2+/ISH amplified); Cohort 2 (n=27) for patients with HER2-low disease (HER2 IHC 1+ or 2+/ISH not amplified). Patients will receive eight cycles of T-DXd (5.4 mg/kg IV every 21 days) combined with durvalumab (1125 mg IV every 21 days), followed by modified radical mastectomy and post-mastectomy radiation. Post-surgical systemic treatment will follow local standards. Tumor tissue will be collected at baseline, cycle 1 day 8, and at surgery; blood will be collected at baseline, cycle 4 day 1, cycle 7 day 1 and at surgery; stool will be collected at baseline, after 3-6 weeks of treatment and surgery. The primary endpoint is pathologic complete response (pCR; ypT0/Tis ypN0). Patients in each cohort will be enrolled based upon Simon two-stage designs: in Cohort 1, if ≥8/20 patients with HER2-positive IBC experience pCR then a total of 36 patients will be enrolled. In Cohort 2, if ≥1/18 patients with HER2-low IBC experience pCR then a total of 27 patients will be enrolled. Secondary endpoints include the residual cancer burden at surgery, event free survival, distant progression or distant disease-free survival, as well as safety of the regimen. Exploratory objectives will investigate biomarker analyses on tissue, blood, and microbiome to explore the association of HER2 expression, immune variables, and stool composition on the efficacy of T-DXd with durvalumab among patient with HER2-expressing IBC. To our knowledge, this is the first and only ongoing study testing the combination of an anti-HER2 antibody-drug conjugate with immunotherapy for the neoadjuvant treatment of patients with IBC. Clinical trial information: NCT05795101. Citation Format: Paolo Tarantino, Samuel Niman, Antonio Giordano, Faina Nakhlis, Jennifer Bellon, Wendy Woodward, Azadeh Nasrazadani, Sadia Saleem, Anthony Lucci, Michelle DeMeo, Naoto Ueno, Sara Tolaney, Vicente Valero, Meredith Regan, Rachel Layman, Filipa Lynce. TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-06.

BackgroundInterstitial lung disease (ILD) is a severe extra-articular manifestation of rheumatoid arthritis (RA). Usual interstitial pneumonia (UIP) is the most frequent, and severe ILD pattern in RA. Abatacept (ABA) has demonstrated effectiveness in RA-ILD during a 12-month period of treatment[1-2].ObjectivesTo assess the effectiveness and safety of ABA in RA-ILD patients with radiological pattern of UIP during a long-term follow-up.MethodsFrom a large observational multicenter study of 392 RA-ILD patients treated with ABA, we selected those with UIP. We analyzed from baseline the following outcomes:a) forced vital capacity (FVC),b) diffusing capacity of the lungs for carbon monoxide (DLCO),c) chest high resolution computed tomography (HRCT),d) dyspnea (modified Medical Research Council scale) ande) arthritis activity (DAS28-ESR).ResultsWe included a total of 172 patients with UIP (91 women/81 men; mean age 66.9±10.1 years). Baseline demographic and clinical characteristics are shown inTable 1. The median ILD duration up to ABA initiation was relatively short, with a median of 11 [3-39] months. Mean baseline values of FVC and DLCO were >80% and >60%, respectively. During the follow-up, median of 24 [10-44] months, 70.2% and 66.9% of patients showed an improvement/ stabilization of FVC and DLCO, respectively. Evolution of these parameters along 48 months is displayed inFigure 1. Available chest HRCT images improved/ stabilized in 64.5% of patients. Stabilization or improvement of dyspnea was found in 78.6% of patients. The majority of patients showed articular remission or low activity (mean DAS28-ESR of 4.3±1.5 at baseline and 2.5±1.5 at 48 months). ABA was withdrawn in 39 (22.6%) patients due to ILD worsening (17), articular inefficacy (9), serious infections (7) and other causes (n=6, development of malignancy in 3, diagnosis of giant cell arteritis and change to tocilizumab in 1, and 2 deceases).ConclusionABA shows a lasting effectiveness and safety in RA-ILD patients with UIP, the most aggressive pattern.References[1]Rheumatology (Oxford).2020 Dec 1;59(12):3906-3916. doi: 10.1093/rheumatology/keaa621[2]Rheumatology (Oxford).2021 Dec 24;61(1):299-308. doi: 10.1093/rheumatology/keab317Table 1.Main general features at baseline.RA-ILD patients with UIP (n=172)Age, years mean±SD67±10Women, n (%)91 (53)Smoker ever, n (%)87 (51)ILD duration up to ABA, months, median [IQR]11 [3-39]RF// ACPA, n (%)160 (93)// 153 (89)DAS28-ESR, mean±SD4.3±1.5FVC (% of the predicted), mean±SD85±22DLCO (% of the predicted), mean±SD65±19ABA monotherapy, n (%)78 (45)ABA combined + MTX/other cDMARD, n (%)94 (55)Prednisone at baseline, mg/day, median [IQR]5 [5-10]Previous immunosuppressive therapy, n (%)MTX122 (71)Leflunomide76 (44)Sulfasalazine24 (14)Hydroxychloroquine49 (29)Anti-TNF71 (41)Rituximab20 (12)Tocilizumab19 (11)Figure 1.Evolution of pulmonary function tests (mean % of the predicted FVC and DLCO) in RA-ILD patients with UIP pattern at baseline and 48 months.Acknowledgements: Members of the Spanish Collaborative Group of Abatacept in RA-ILD:Luis Arboleya, Javier Narváez, Juan Carlos Fernández, Belén Miguel, Iván Cabezas, Andrea García Valle, Clara Aguilera, Susana Romero, Ignacio Villa, Sabela Fernández Aguado, Raquel Almodóvar, Clara Ojeda, Blanca García-Magallón, Antonio Juan Mas, Manuel J. Moreno, Ana Ruibal, Rosa Expósito, José Antonio Bernal, Evelin C. Cervantes, Sebastián Rodríguez-García, Raúl Castellanos-Moreira, Iván, Manuel Rodríguez Gómez, Eva Salgado, Enrique Raya, Pilar Morales, Lorena Expósito, Mª Noelia Álvarez Rivas, José Luis Andreu, Esther F. Vicente, Ana M. López-Robles, Mireia López-Corbeto, Cristina Hidalgo, Jesús C. Fernández-López, Alejandro Olivé, Samantha Rodríguez, Iñigo Hernández, Neus Quillis, Angel García-Aparicio, Sonia Castro-Oreiro, Julia Fernández-Melón, Paloma Vela, María C. Fito, Manuel Rodríguez-Gómez, Deseada Palma-Sánchez, Lorena Expósito, José María Andreu Ubero.Acknowledgements:NIL.Disclosure of InterestsBelén Atienza-Mateo: None declared, Ana Serrano-Combarro: None declared, N. Del-Val: None declared, Libe Ibarrola Paino: None declared, Ivette Casafont-Solé: None declared, Rafael Melero: None declared, Alba Pérez-Linaza: None declared, Isabel Serrano-García: None declared, Santos Castañeda: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Nuria Vegas-Revenga: None declared, Lucia C. Domínguez-Casas: None declared, Maria Camila Osorio: None declared, Elena Cañadillas: None declared, C. Peralta-Ginés: None declared, C. Delgado-Beltran: None declared, Carolina Díez: None declared, Trinidad Pérez Sandoval: None declared, M. Retuerto-Guerrero: None declared, Lorena Pérez Albaladejo: None declared, R. López-Sánchez: None declared, Mª Guadalupe Mazano: None declared, Anahy Brandy-Garcia: None declared, Patricia López Viejo: None declared, Gemma Bonilla: None declared, Olga Maiz-Alonso: None declared, Maria del Carmen Carrasco Cubero: None declared, Marta Garijo Bufort: None declared, Mireia Moreno: None declared, ANA URRUTICOECHEA-ARANA: None declared, Sergi Ordoñez: None declared, C. González-Montagut Gómez: None declared, Juan Ramón De Dios Jiménez de Aberásturi: None declared, Fernando Lozano Morillo: None declared, Tomas Vazquez Rodriguez: None declared, Patricia Carreira: None declared, J M Blanco: None declared, Carlos Fernández-Díaz: None declared, J. Loricera: None declared, Iván Ferraz-Amaro: None declared, Diego Ferrer: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Lilly, Bristol-Myers, Janssen, Galapagos and MSD, Consultant of: Abbvie, Pfizer, Roche, Lilly, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD, Novartis and Roche.

BackgroundInterstitial lung disease (ILD) is a severe extra-articular manifestation of rheumatoid arthritis (RA). Abatacept (ABA) has demonstrated efficacy in RA-ILD[1-2].Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations[3].However, it has not been studied in RA-ILD.Objectivesto compare the effectiveness of ABA in RA-ILD patients according to the route of administration (IV-ABA vs SC-ABA).MethodsNational multicenter study of RA-ILD patients on treatment with ABA. They were divided into 2 groups according to the route of administration: a) IV, and b) SC. We analyzed from baseline the following outcomes in both groups:a) forced vital capacity (FVC),b) diffusing capacity of the lungs for carbon monoxide (DLCO),c) chest high resolution computed tomography (HRCT),d) dyspnea (assessed with the modified Medical Research Council scale),e) arthritis activity (assessed with DAS28-ESR or described in clinical records), andf) sparing corticosteroids effect.ResultsWe studied a total of 392 [SC-ABA/IV-AB; 288/91(available data)] patients. Baseline demographic and clinical characteristics are shown inTable 1. Patients were followed-up for a median [IQR] of 24 [10-48] months. FVC and DLCO remain stable during the first 24 months in both SC-ABA and IV-ABA[Figure 1].Dyspnea stabilized or improved in 85% of patients (89% of IV-ABA; 83% of SC-ABA). ABA was withdrawn in 80 patients: 60 (39%) in SC-ABA group and 20 (22%) in IV-ABA group. ILD worsening and articular inefficacy were the most common reasons of ABA discontinuation.ConclusionIn RA-ILD, ABA seems equally effective and safe regardless of the route of administration IV or SC.References[1] Rheumatology (Oxford). 2020 Dec 1;59(12):3906-3916.[2] Rheumatology (Oxford). 2021 Dec 24;61(1):299-308.[3] Arthritis Rheum. 2011 Oct;63(10):2854-64.Table 1.Main general features at baseline of RA-ILD patients with subcutaneous vs intravenous ABA.All ABA (n=392)ABA IV (n=91)ABA SC (n=288)pAge, years mean±SD65 ± 1066 ± 1066 ± 100.85Women n (%)226 (58)54 (59)166 (58)0.77Smoker ever n (%)210 (54)49 (54)154 (53)0.95ILD duration up to ABA, months, median [IQR]11 (3-38)11 (2-48)10 (3-36)0.65RF n (%)347 (89)78 (86)256 (89)0.41ACPA n (%)344 (89)76 (85)256 (90)0.25DAS28-ESR4.35±1.584.19±1.524.38±1.530.35ILD pattern n (%) NIU172 (44)47 (52)122 (42) NINE117 (30)20 (22)94 (33)0.14 Other98 (25)23 (26)72 (25)FVC (% of the predicted) mean±SD87 ± 2182 ± 2288 ± 210.26DLCO (% of the predicted) mean±SD67 ± 2067 ± 2067 ± 190.97Prednisone at baseline, mg/day, median [IQR]5 (5-10)7.5 (5-10)5 (5-10)0.34ACPA, anti-citrullinated protein antibodies; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; RF, rheumatoid factor; UIP, usual interstitial pneumonia.Figure 1.Evolution of pulmonary function tests (mean % of the predicted FVC and DLCO) in RA-ILD patients with SC-ABA vs IV-ABA therapy at baseline and 24 months.Members of the Spanish Collaborative Group of Abatacept in RA-ILD patients:Luis Arboleya-Rodríguez, Javier Narváez, Juan Carlos Fernández, Belén Miguel, Iván Cabezas, Andrea García Valle, Clara Aguilera Cros, S. Romero-Yuste, Ignacio Villa Blanco, Sabela Fernández Aguado, Raquel Almodóvar, C. Ojeda-García, C. Aguilera-Cros, B. García-Magallón, Antonio Juan Mas, M. J. Moreno-Ramos, A. Ruibal-Escribano, Rosa Expósito, José Antonio Bernal, Evelin C. Cervantes, S. Rodríguez-García, R. Castellanos-Moreira, Iván Castellví, Manuel Rodríguez, Eva Salgado, Enrique Raya, Pilar Morales, Lorena Expósito, Mª Noelia Álvarez, José Luis Andreu, E. F. Vicente-Rabaneda, A. M. López-Robles, M. López-Corbeto, C. Hidalgo-Calleja, J.C. Fernández-López, Alejandro Olivé, S. Rodríguez-Muguruza, Iñigo Hernández, N. Quillis-Marti, J.A. Bernal-Vidal, A. García-Aparicio, S. Castro-Oreiro, J. Fernández-Melón, P. Vela Casasempere, María C. Fito, M. Rodríguez-Gómez, D. Palma-Sánchez, L. Expósito-Pérez, José María Andreu.Acknowledgements:NIL.Disclosure of InterestsAna Serrano-Combarro: None declared, Belén Atienza-Mateo: None declared, N. Del-Val: None declared, Libe Ibarrola Paino: None declared, Ivette Casafont-Solé: None declared, Rafael Melero: None declared, Alba Pérez Linaza: None declared, Isabel Serrano-García: None declared, Santos Castañeda: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Nuria Vegas-Revenga: None declared, Lucía Domínguez Casas: None declared, C. Delgado-Beltran: None declared, Carolina Díez: None declared, Trinidad Pérez Sandoval: None declared, M. Retuerto-Guerrero: None declared, Lorena Pérez Albaladejo: None declared, R. López-Sánchez: None declared, Mª Guadalupe Mazano: None declared, Anahy Brandy-Garcia: None declared, Patricia López Viejo: None declared, Gemma Bonilla: None declared, Olga Maiz: None declared, Maria del Carmen Carrasco Cubero: None declared, Marta Garijo Bufort: None declared, Mireia Moreno: None declared, ANA URRUTICOECHEA-ARANA: None declared, Sergi Ordoñez: None declared, C. González-Montagut Gómez: None declared, C. Peralta-Ginés: None declared, Juan Ramón De Dios Jiménez de Aberásturi: None declared, Maria Camila Osorio: None declared, Elena Cañadillas: None declared, Fernando Lozano Morillo: None declared, Tomas Vazquez Rodriguez: None declared, Patricia Carreira: None declared, J M Blanco: None declared, Carlos Fernández-Díaz: None declared, J. Loricera: None declared, Iván Ferraz-Amaro: None declared, Diego Ferrer: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen, Galapagos and MSD, Consultant of: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD, novartis and Roche.

Abstract Objective: 1st: Assess the presence of residual infiltrating component in the surgical specimen of patients with Luminal Her2- tumors ≤ 2cm and ultrasound-negative axilla, following ultrasound-guided cryoablation. 2nd: Demonstrate that preoperative seed placement prior to cryoablation does not interfere with tumor cell elimination by freezing. Methods: Between April 2021 and April 2023, we performed preoperative cryoablation on 52 patients aged 53 to 79 years (mean 64) with 52 unifocal invasive ductal carcinomas (IDC) measuring 4 to 20 mm (mean 10), low grade (24 G1, 28 G2), 31 Luminal A and 21 B, Ki67 between 3 and 30% (mean 13). On ultrasound, all IDCs were visible and axilla-negative. 26 of them (50%) were referred from the screening program of the Community of Madrid. The tumor-to-skin surface distance ranged from 2 to 18 mm (mean 9 mm). All patients underwent mammography-tomosynthesis, staging, and biopsy under ultrasound guidance. The minimum time elapsed until surgery was 6 days, and the maximum was 78 days (mean 22). All patients underwent mammography-tomosynthesis, staging, and biopsy under ultrasound guidance. MRI was performed to rule out extensive intraductal component in 17 out of 20 patients with associated intraductal carcinoma (IDC) in the diagnostic biopsy. Preoperative marking with ferromagnetic seed placement was performed in all cases prior to cryoablation, using a single dose of anesthesia and through the same skin access. We used the ICEfx Galil Boston Scientific cryoablation system with 17G or 14G needles, applying the standard triple-phase protocol: freezing-passive thawing-freezing for approximately 40 minutes. The correct placement of the seed was subsequently confirmed by mammography. Results: There were no significant complications in any case. Out of 52 low-risk unifocal IDCs: -32 were pure IDCs (without associated intraductal component in diagnostic biopsy): no residual IDC was identified in the tumor specimen. -20 were mixed IDCs (with associated IDC in the diagnostic biopsy): *In 4 cases, residual IDC was found in the surgical specimen, with some foci of IDC remaining at the periphery of the post-cryoablation necrosis. *In 8 patients, foci of IDC were detected distant from the cryoablation zone. The pathologist determined that all samples had tumor-free margins. Conclusions: Cryoablation is effective in 100% of cases for pure infiltrating tumors ≤ 2cm. The presence of scattered IDC nests away from the cryoablation zone or at the margin of fat necrosis does not indicate technique failure, as all surgical specimens were determined to have tumor-free margins by the pathologist. For mixed infiltrating tumors, the ice ball should broadly cover the tumor size estimated by ultrasound and MRI. Standard adjuvant treatment will equalize the risk of recurrence with conventional lumpectomy. Table 1: 52 cases IDC unifocal ≤2cm Table 2: IDC Pure ≤2cm. Table 3: IDC mixed: IDC+DCIs ≤2cm Analysis of surgical specimen Citation Format: Maria José Roca Navarro, Pilar Zamora, Ylenia Navarro Monforte, Diego Garrido Alonso, Vicenta Córdoba Chicote, Teresa Diaz de Bustamante Durban, José María Oliver Goldaracena, Laura Yebenes Gregorio, Covadonga Marti, Jose Ignacio Sanchez-Mendez, Elisa Moreno, Laura Frías Aldeguer, Adolfo Loayza Galindo, Alberto Berjón García, Marcos Melendez Gisper, Carmen Martín Hervás, Lara Miralles, Cristina Escabias del Pozo, Younes Abadi, Elisa York Pineda, Gonzalo Garzón Moll, David Hardisson Hernáez, Alicia Hernández Gutiérrez, César Casado Sánchez, Virginia Martínez Marín, Shirin Zarbakhsh, Joaquin Gomez Ramirez. Preoperative cryoablation in 52 Her2- Luminal invasive ductal carcinomas ≤ 2cm. Analysis of the tumor specimen [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-12.

Abstract Background: Adherence to BCCPG improves clinical outcomes for patients with breast cancer. However, implementation of international BCCPG may not be feasible in low- and middle-income countries (LMICs) due to limitations in resources and personnel. A potential solution for this issue is developing national/regional guidelines considering local healthcare contexts. In Mexico, the National Consensus on Diagnosis and Treatment of Breast Cancer (known as the Colima Consensus, http://consensocancermamario.com) is considered the national BCCPG, and it is updated bi-yearly since 1994. The aim of this study was to evaluate physicians’ uptake of the Colima Consensus recommendations, and to identify barriers and attitudes that may impact adherence. Methods: A cross-sectional, 30-item survey exploring attitudes towards the Colima Consensus, as well as barriers limiting adherence to its recommendations, was e-mailed to Consensus attendees, members of the Mexican Society of Oncology, and of the Mexican Mastology Association, with answers collected over 3 weeks. Descriptive statistics, including means, medians, and standard deviations were used to analyze the participants’ sociodemographic characteristics, attitudes, and perceived barriers. X2 tests were used to evaluate associations between physicians’ characteristics/attitudes and adherence. Results: Among 1553 physicians invited to participate, 320 (21%) answered the survey, of which 25 (8%) were unaware of the Colima Consensus. Two hundred ninety-five participants completed the entire survey and were included in this analysis. Fifty-six percent were male, 65% were age 30-49, 44% practiced in Mexico City, and 8% were foreign. Regarding specialty, 26% were surgical oncologists, 14% medical oncologists, and 10% radiation oncologists. Over half of respondents (57%) worked in both public and private practice, while 19 and 23% worked only in public or private practice, respectively. Sixty-two percent had access to a multidisciplinary breast cancer team. Eighty-five percent reported using the Colima Consensus to guide clinical decision making and 77% adhered to its recommendations in most/all cases. Forty-two percent used the Colima Consensus as their only guideline reference. Surgical oncologists were more likely than medical oncologists to use the Colima Consensus as their only guideline reference (29 vs. 12%, p<0.01). The most commonly reported barriers to adherence were lack of resources (51%) and logistical issues (31%). Physicians working without a dedicated multidisciplinary breast cancer team were significantly more likely to report a lack of resources as a barrier than those with a multidisciplinary team (63 vs. 43%, p<0.01). No differences were found in other barriers according to participants’ characteristics. Regarding attitudes towards the Colima Consensus, 88% agreed/strongly agreed that it was a valuable teaching tool, 88% considered it a trustworthy source of information, and 89% believed it led to improved quality of care. Seventy-six percent of the participants agreed/strongly agreed that the Consensus’ recommendations were free of bias and 58% considered that its use led to reduced costs of care. Conclusions: Initial results of our study show high levels of adherence and positive attitudes towards the Colima Consensus, with a significant proportion of physicians using it as their main guideline reference. Lack of resources and logistical issues were the main barriers hampering implementation of recommendations, particularly for physicians working without a multidisciplinary breast cancer team. Our results highlight the relevance of local BCCPG and of multidisciplinary collaborations, and suggest a need for the creation of stratified recommendations for various healthcare settings and resources. Citation Format: Bertha Alejandra Martinez-Cannon, Enrique Soto-Perez-de-Celis, Aura A. Erazo Valle-Solis, Claudia Arce Salinas, Enrique Bargallo Rocha, Veronica Bautista Piña, Ma. Guadalupe Cervantes Sanchez, Christian Haydee Flores Balcazar, Maria del Carmen Lara Tamburrino, Ana Lluch Hernandez, Antonio Maffuz Aziz, Victor Manuel Perez Sanchez, Adela Poitevin Chacon, Efrain Salas Gonzalez, Laura Torrecillas Torres, Vicente Valero, Yolanda Villaseñor Navarro, Jesus Cardenas Sanchez. Physicians’ attitudes and perceived barriers to adherence to national breast cancer clinical practice guidelines (BCCPG) in Mexico [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-17-05.

Abstract Introduction: Neoadjuvant chemotherapy (NACT) is becoming standard of care for presurgical treatment of triple negative breast cancer (TNBC) patients. Achievement of pathological complete response (pCR) after NACT is associated with improved outcomes. There is currently an unmet need in development of imaging and clinical tools for prediction of pCR to NACT in TNBC. We investigated use of deep learning convolution neural networks (CNNs) for early prediction of pCR in a TNBC cohort on the basis of MRI acquired before the initiation and at the midpoint, after completion of four cycles of NACT (C4). Materials and Methods: Baseline and C4 MRIs of 112 TNBC patients were collected from an ongoing prospective clinical trial (NCT02276443). Four patients were excluded because they underwent different treatment for the second regimen. Among the 108 patients, 52 patients (48%) had pCR confirmed at surgery. Positive enhancement integral (PEI) derived from the early phases of DCE MRI, and apparent diffusion coefficients (ADC) derived from DWI MRI (b = 100 and 800 s/mm2), were used for our investigation. The images were aligned and the tumor regions were cropped from all images. All tumor patches were normalized between [0, 1], and were padded to form matrices of the same size of 192×192×64 for PEI, or the size of 192×192×16 for ADC. The CNN was constructed using stacked 3D convolution and MaxPooling layers. It consisted of up to four channels for the inputs (baseline and C4 PEI and ADC). Features extracted from each channel were concatenated and regressed for pCR prediction via three densely connected layers. Binary cross-entropy was used as the loss function for CNN training, and the loss was optimized using an Adam optimizer with the initial learning rate of 0.0001. Because of the currently limited sample size, four-fold cross-validation was used for CNN training and evaluation. The patients were divided into four groups, each group had 27 patients and the pCR:non-pCR ratio was controlled as 13:14. For each fold, one group was reserved as the independent testing group, and the other three groups were combined for network training and internal validation. Receiver operating characteristic (ROC) curve was plotted for each fold of testing, and area under the curve (AUC) was calculated. Final performance of the CNN was determined by averaging the AUCs of the four testing folds. Additionally, to test the prediction efficacy of each input, we trained the CNN under the same settings but used PEI or ADC only as input, and the results were compared. Results: The CNN trained with PEI only achieved an average AUC of 0.65 ± 0.09. The second CNN trained with ADC only achieved an average AUC of 0.72 ± 0.07. The third CNN trained with both PEI and ADC achieved an average AUC of 0.73 ± 0.06. Conclusion and Discussion: Using baseline and mid-treatment MRIs, deep learning CNN showed promising performance to predict pCR in the early course of NACT. The prediction AUC for the independent testing groups was largely improved by using ADC to train the network, indicating that ADC can have more critical information than PEI in assisting pCR prediction during the early course of NACT. Future work includes curation of a larger patient data for network training and evaluation to improve the prediction performance and further validate generalization of the network. We will also explore more advanced network structures, through which the prediction performance can be improved. Four-fold cross-validation AUCs of the network using different data as inputs.PEIADCPEI+ADCFold 10.570.640.66Fold 20.760.800.77Fold 30.660.700.68Fold 40.590.740.79Average0.65 ± 0.090.72 ± 0.070.73 ± 0.06 Citation Format: Zijian Zhou, Nabil A Elshafeey, David E Rauch, Beatriz E Adrada, Rosalind P Candelaria, Mary S Guirguis, Wei Yang, Medine Boge, Rania M Mohamed, Gary J Whitman, Deanna L Lane, Huong C Le-Petross, Jessica WT Leung, Lumarie Santiago, Marion E Scoggins, David A Spak, Miral M Patel, Frances Perez, Debu Tripathy, Vicente Valero, Clinton Yam, Stacy Moulder, Jason B White, Jong Bum Son, Mark D Pagel, Jingfei Ma. Deep learning for early prediction of neoadjuvant chemotherapy response in triple negative breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-03.

Abstract Background: The erythropoietin (EPO) receptor activation can stimulate tumor proliferation and may be implicated in resistance to anti-HER2 therapies. EPO administration can be used for the management of chemotherapy-induced anemia. We aim to assess if EPO intake during the adjuvant anti-HER2 treatment impacts the outcomes of HER2-positive early breast cancer (EBC) patients. Methods: For this post hoc analysis of the ALTTO trial (NCT00490139), we categorized two cohorts according to the use of EPO during adjuvant anti-HER2 treatment: i) at least one EPO dose (EPO-cohort) vs ii) no EPO (non-EPO-cohort). We compared their baseline characteristics to identify potential confounders. The primary endpoint disease-free-survival (DFS), and the secondary endpoint overall survival (OS) were compared between these two cohorts, with subgroup analysis according to menopausal status, tumor characteristics, and anti-HER2 treatment. Kaplan Meier method, log-rank test, and Cox regression model adjusted for confounders were performed for DFS and OS (removal criterion p<0.10). The frequency of cardiovascular and thromboembolic adverse events (AEs) of EPO interest was compared between both cohorts. Results: Out of the 8,381 patients recruited in the ALTTO trial, 123 (1.5%) received EPO concomitantly with adjuvant treatment, 59 in the single HER2 blockade (Lapatinib (L)-alone or Trastuzumab (T)-alone) and 64 in dual blockade (T→L or T+L) arms. The median age of EPO-cohort patients was 54 (range: 27-74) years, and 39% were premenopausal, while most had pathologic tumor size >2 cm (56.9%), positive nodal status (58.5%), positive hormone receptor (HR) status (61.8%), and poorly differentiated or undifferentiated histologic grade (64.2%). Baseline characteristics were similar in both cohorts, except for the timing of chemotherapy, for which 93.5% of patients from the EPO-cohort were enrolled in the concurrent designs (2/2B) vs 44.2% in the non-EPO-cohort (p<0.001). Median FU was 6.9 years, with 6,409 (76.5%) patients still on follow-up. For the entire ALTTO cohort, the estimated 3- and 7-year DFS were 88.3% (95% CI: 87.6% - 89.0%) and 80.1% (95% CI: 79.1% - 81.0%), respectively. No difference in DFS by EPO administration (Yes/No) was observed (log-rank p=0.70). The effect of EPO remained non-significant when controlled for the four stratification factors and all other characteristics (p=0.91). The effect of EPO administration on DFS was significant for the subgroup of premenopausal women (p=0.041), favoring the EPO-cohort, noting that this result is based on small event numbers. The interaction was found significant in Cox analysis (p=0.024), remaining significant after adjustment for important prognostic variables (p=0.032). For the entire ALTTO cohort, 758 (9.0%) deaths occurred, with 3-year OS estimate 95.7% (95% CI: 95.2% - 96.1%) and 7-year OS estimate 89.9% (89.2% - 90.6%). The OS results are consistent with those for DFS regarding the lack of a significant association with EPO and the significance (p<0.10) of menopausal status and EPO interaction. In the EPO-cohort (n=123), eight (6.5%) AEs of EPO interest were recorded, while from the non-EPO-cohort (n=8,147), 417 (5.1%) reported similar AEs. Three fatal and 25 life-threatening AEs of EPO interest were recorded in the non-EPO-cohort, and none in the EPO-cohort. Conclusion: EPO administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a harmful impact on survival outcomes, however the sample size of patients who received EPO is rather small. These findings contrast with data suggesting poorer outcomes with EPO, therefore further investigation of tumour microenvironment is needed to better understand these results, particularly in the premenopausal subgroup. Citation Format: Diogo Martins-Branco, Marie Kassapian, Véronique Debien, Rafael Caparica, Daniel Eiger, Urania Dafni, Charitini Andriakopoulou, Sarra El-Abed, Miguel Izquierdo, Malou Vicente, Saranya Chumsri, Martine Piccart-Gebhart, Alvaro Moreno-Aspitia, Ann Søegaard Knop, Janine Lombard, Evandro de Azambuja. The impact of erythropoietin administration concomitantly with adjuvant anti-HER2 treatment on the patients’ outcome: Sub-analysis of the ALTTO study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-14-05.

Abstract Background: Metastatic IBC is an unmet clinical need due to the aggressiveness of this breast cancer subtype. Gene expression analysis of IBC samples post-neoadjuvant chemotherapy has revealed that dysregulation of immune pathways is common in tumors that do not have a complete pathologic response (pCR) to chemotherapy. The immune checkpoint PD-L1 is expressed in a third of IBC cases, and the MEK inhibitor, cobimetinib, has been shown to enhance the expression of PD-L1, the target of atezolizumab. Taken together, dual targeted therapy with atezolizumab and cobimetinib is hypothesized to be synergistic. Eribulin is a standard of care chemotherapy used in patients who have progressed on anthracycline-taxane based regimens. Materials and Methods: Patients received triple or double combination therapy depending on the timing of their enrollment. Patients with metastatic IBC who had measurable disease after at least 1 standard regimen were eligible. Any receptor subtype was allowed, and PD-L1 positivity was not required. The study began with a single cohort (n=17 patients) receiving all 3 agents with a lead-in phase to determine the MTD of cobimetinib in this setting. The study was later amended to include only atezolizumab and eribulin (cohort 2). Ten patients were treated in cohort 2. The study closed early due to lack of efficacy in cohort 2 and the changing landscape of metastatic breast cancer therapies. In cohort 1, atezolizumab was given every 2 weeks (840 mg), cobimetinib was given at 60/40/20 mg once daily, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. In cohort 2, atezolizumab was given every 3 weeks (1200 mg) during the PD window and cycles 1-4, and then every 4 weeks (1680 mg) during maintenance, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. Results: The MTD of cobimetinib was 40mg. In cohort 1, 17 patients were treated, 14 had at least 1 restaging evaluation. Seven patients had a partial response (50%) and 3 stable disease. The cohort was predominantly triple receptor-negative (n=13/17), with a median age of 51 yrs. The median PFS for patients in cohort 1 was 6.2 months (0-54.1). There were 2 exceptional responders, both with triple negative subtype, one of whom remains on therapy for >4.5 years without evidence of disease. The median overall survival was 29.6 months (2.9-133). The AE profile was largely expected, with 3 irAEs (1 grade 5 colitis, and 2 grade 2 pneumonitis), and one other patient with cardiac dysfunction requiring discontinuation of cobimetinib and atezolizumab. The MTD of cobimetinib was 40 mg. Cobimetinib-related toxicities were mild and largely gastrointestinal tract related. In cohort 2, only 1 patient experienced PR, and the median PFS was 3 months (1.2-6.2) and overall survival 8.3 months (1.8-19.9). One patient experienced autoimmune related hepatitis requiring discontinuation of protocol therapy. Due to excesive myelosuppression, dose of erublin was reduced to 1.1 mg per meter squared on day 1 and 8 and pegfilgastrim was added on day 9< Conclusions: The response profile of the triple combination demonstrated promise, and suggests that MEK inhibition may warrant further investigation as a strategy in metastatic IBC in a larger sample size. However, there does not appear to be synergy between atezolizumab and eribulin without the addition of targeted therapy. Citation Format: Angela Alexander, Hope Murphy, James Reuben, H. T. Carisa Le-Petross, Deanna Lane, Monica Huang, Savitri Krishnamurthy, Yun Gong, Dan Gombos, Nimisha Patel, Richard Allen, Suyu Liu, Anisha Patel, Andrew Futreal, Ignacio Wistuba, Rachel Layman, Naoto Ueno, Debu Tripathy, Bora Lim, Vicente Valero. Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-02.

BackgroundInterstitial lung disease (ILD) is a severe complication of rheumatoid arthritis (RA). Abatacept (ABA) has demonstrated efficacy in the treatment of RA-ILD, especially if it is initiated early during the ILD[1-2].ObjectivesTo compare the efficacy of ABA in RA-ILD patients according to ILD duration.MethodsNational multicenter study of 392 RA-ILD patients treated with ABA. Patients with ABA initiation early in the disease (during the first 6 months since ILD diagnosis) were compared to those in whom ABA was started after 2 years of ILD diagnosis (“early” vs “late” group, respectively). We analyzed in the 2 groups the following outcomes: a) forced vital capacity (FVC), b) diffusing capacity of the lungs for carbon monoxide (DLCO), c) chest high resolution computed tomography (HRCT), d) dyspnea and e) arthritis activity.ResultsA total of 157 patients were included in the “early” group and 135 patients in the “late” group. Baseline demographic and clinical characteristics are shown in Table 1. Mean baseline values of FVC were significantly higher in the “early” group. The evolution of FVC and DLCO for 48 months is shown in Figure 1. Both parameters remained stable during 12 months of ABA therapy, with no statistically significant differences found (although lower stable values of FVC in the “late” group). Available chest HRCT images improved/stabilized in 75% and 51% of patients in the “early” and “late” group, respectively. Stabilization or improvement of dyspnea was found in most patients of both groups.ConclusionOur results suggest that an early administration of ABA in RA-ILD may be preferable to preserve lung function. However, treatment with ABA at any time of the course in the ILD seems to prevent interstitial lung progression.References[1]Rheumatology. 2020 Dec 1;59(12):3906-3916[2]Rheumatology. 2021 Dec 24;61(1):299-308Table 1.Main general features at baseline of RA-ILD patients with EARLY vs LATE initiation of ABA in ILD course.All RA-ILD (n=392)EARLY RA-ILD (n=157)LATE RA-ILD (n=135)EARLY vs LATE pAge years mean±SD65 ± 1066 ± 1066 ± 100.97Women n (%)226 (58)88 (56)80 (59)0.58Smoker ever n (%)210 (54)86 (55)68 (50)0.45ILD duration up to ABA months median [IQR]11 [3-38]2 [1-4]51 [36-89]<0.001RF n (%); ACPA n (%)347 (89); 344 (89)138 (88); 136 (87)123 (91); 118 (89)0.37; 0.56DAS28-ESR4.35 ± 1.584.16 ± 1.614.40 ± 1.590.26ILD pattern n (%) NIU172 (44)68 (44)56 (42)0.95 NINE117 (30)48 (31)43 (33)FVC (% pred) mean±SD87 ± 2189 ± 2882 ± 190.015DLCO (% pred) mean±SD67 ± 2066 ± 2065 ± 210.76ABA monotherapy n (%)179 (46)72 (46)62 (46)0.99ABA combined n (%)211 (54)85 (54)72 (53)Prednisone at baseline, mg/day median [IQR]5 (5-10)7.5 (5-10)5 (5-10)0.57Previous IS therapy n (%) MTX293 (75)126 (81)97 (72)0.073 LFN175 (45)68 (43)61 (45)0.75 SSZ57 (15)24 (15)18 (13)0.64 HCQ107 (27)54 (34)42 (31)0.55 Anti-TNF; RTX; TCZ107 (15); 51 (13); 43 (11)51 (34); 17 (11); 20 (13)34 (25); 19 (14); 15 (11)0.17; 0.40; 0.67Figure 1.Evolution of pulmonary function in RA-ILD patients with EARLY and LATE initiation of ABA in ILD course.Members of the Spanish Collaborative Group of ABA in RA-ILD:L. Arboleya, J. Narváez, J. Carlos Fernández, Belén Miguel, Iván Cabezas, A. García Valle, C. Aguilera Cros, S. Romero-Yuste, I. Villa Blanco, S. Fernández Aguado, Raquel Almodóvar, C. Ojeda-García, C. Aguilera-Cros, B. García-Magallón, Antonio Juan Mas, M. J. Moreno-Ramos, A. Ruibal-Escribano, Rosa Expósito, José Antonio Bernal, Evelin C. Cervantes, S. Rodríguez-García, R. Castellanos-Moreira, Iván Castellví, Manuel Rodríguez, Eva Salgado, Enrique Raya, Pilar Morales, Lorena Expósito, Noelia Álvarez, José Luis Andreu, E. F. Vicente-Rabaneda, A. M. López-Robles, M. López-Corbeto, C. Hidalgo-Calleja, J.C. Fernández-López, Alejandro Olivé, S. Rodríguez-Muguruza, Iñigo Hernández, N. Quillis-Marti, J.A. Bernal-Vidal, A. García-Aparicio, S. Castro-Oreiro, J. Fernández-Melón, P. Vela Casasempere, María C. Fito, M. Rodríguez-Gómez, D. Palma-Sánchez, L. Expósito-Pérez, J. M. Andreu.Acknowledgements:NIL.Disclosure of InterestsAna Serrano-Combarro: None declared, Belén Atienza-Mateo: None declared, N. Del-Val: None declared, Libe Ibarrola Paino: None declared, Ivette Casafont-Solé: None declared, Rafael Melero: None declared, Alba Pérez Linaza: None declared, Isabel Serrano-García: None declared, Santos Castañeda: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Nuria Vegas-Revenga: None declared, Lucía Domínguez Casas: None declared, C. Delgado-Beltran: None declared, Carolina Díez: None declared, Trinidad Pérez Sandoval: None declared, M. Retuerto-Guerrero: None declared, Lorena Pérez Albaladejo: None declared, R. López-Sánchez: None declared, Mª Guadalupe Mazano: None declared, Anahy Brandy-Garcia: None declared, Patricia López Viejo: None declared, Gemma Bonilla: None declared, Olga Maiz: None declared, Maria del Carmen Carrasco Cubero: None declared, Marta Garijo Bufort: None declared, Mireia Moreno: None declared, ANA URRUTICOECHEA-ARANA: None declared, Sergi Ordoñez: None declared, C. González-Montagut Gómez: None declared, C. Peralta-Ginés: None declared, Maria Camila Osorio: None declared, Elena Cañadillas: None declared, Juan Ramón De Dios Jiménez de Aberásturi: None declared, Fernando Lozano Morillo: None declared, Tomas Vazquez Rodriguez: None declared, Patricia Carreira: None declared, J M Blanco: None declared, Carlos Fernández-Díaz: None declared, J. Loricera: None declared, Iván Ferraz-Amaro: None declared, Diego Ferrer: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen, Galapagos and MSD, Consultant of: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD, novartis and Roche.

Abstract Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P&lt; 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P&lt; 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Abstract Background: The pathologic complete response (pCR) rate in inflammatory breast cancer (IBC) patients is worse than in non-IBC patients; new drug combinations are warranted to improve pCR rates across all IBC molecular subtypes. Based on our preclinical data, we added neratinib to standard neoadjuvant chemotherapy in both HER2+ (synergy) and HER2-/hormone receptor (HR)+ (high frequency of ERBB2 mut) untreated IBC, as a single-center, non-randomized phase I/II trial. Patients and Method: This study enrolled three cohorts: Cohort I phase Ib (C1P1B), Cohort I Phase II (C1P2) and Cohort II (C2). In C1P1B to determine the recommended phase 2 dose (RP2D), we enrolled patients with HER2+ metastatic or locally advanced breast cancer. Patients received paclitaxel/trastuzumab/pertuzumab (THP) + neratinib x 4 cycles (up to 8 cycles per physician’s discretion). For C1P2 and C2, we enrolled Stage III – IV primary IBC patients. In C1P2, patients with HER2+ IBC received neratinib (RP2D) combined with THP x 4 cycles followed by doxorubicin/cyclophosphamide (AC) x 4 cycles. Per stage I design, 11 patients were enrolled with plan to enroll 20 more patients in Stage II if at least 6 had a pCR. In C2, patients with HER2-/HR+ IBC received neratinib 200 mg/day combined with paclitaxel x 4 cycles followed by AC x 4 cycles. Stage I design planned for enrollment of 16 patients with enrollment of 15 more patients on stage II, if at least 2 Stage I patients had pCR. In all three cohorts, patients initiated prophylactic anti-diarrheal medication (loperamide & budesonide) with the first dose of neratinib. Results: From 2018 to 2022, thirty-four patients were enrolled and treated (n=4 C1P1B, n=14 C1P2, n=16 C2). In C1P1B, observed DLTs (dose limiting toxicities) were Grade (Gr) 2 Diarrhea, n=2 (50%); Gr3 diarrhea, n=2 (50%); 2 patients had a serious adverse event (SAE); 3 patients (55%) had Gr2 nausea. The RP2D was established at 80 mg/day (dose level 0). For patients in C1P2, the most frequently occurring adverse events (AEs) included Gr2 Alopecia, n=14 (100%); Gr2&3 Diarrhea, n=14 (100%); Gr2/3 Nausea, n=12 (86%); Gr2/3 Anemia, n=7 (50%); Gr2/3 Fatigue, n=8 (57%); Gr2/3 Hypokalemia, n=6 (57%); and Gr2/3 Neutrophil count decreased, n= 7 (50%). 6 patients had an SAE. Of the first 11 patients, 5 (46%) had pCR, 1 (9%) RCB-1, 1 (9%) RCB-II and 1 (9%) RCB-III. Three patients stopped study treatment for toxicity (27%), were non-evaluable and replaced. Of these, one had RCB-III (33.3%), one progression of disease (PD) (33.3%), and one came off study for toxicity (33.3%). Rather than replacing additional non-evaluable patients, the study was closed to new patient accrual. In C2, the most frequently occurring AEs were Gr2 diarrhea, n=7(44%); Gr3 diarrhea, n=8 (50%); Gr2 alopecia, n=14 (88%); Gr2/3 Anemia, n=10 (63%); Gr2/3 Nausea, n=7 (44%); Gr2/3 Neutropenia, n= 7 (44%). 3 patients had an SAE. Of 16 patients in this cohort, 1 had pCR (6%), 5 RCB-II (31%), 4 RCB-III (25%), 3 came off study for toxicity (19%) and 3 had PD (19%). C2 also closed to new patient accrual given the high toxicity profile. Conclusion: The addition of neratinib did not improve the pCR rate in HER2+ or HER2-/HR+ subtypes of IBC, and increased toxicities were observed. The trial closed to new patient entry March 2022. However, some patients achieved significant response. Biomarker analysis is ongoing. Evaluable participants will continue long-term follow-up per protocol. Acknowledgments: This study is supported by PUMA Biotechnology. Citation Format: Angela N. Marx, Megumi Kai, Min Fu, Hope E. Murphy, Jie S. Willey, Huiming Sun, Angela Alexander, Roland L. Bassett, Gary J. Whitman, H. T. Carisa Le-Petross, Miral Patel, Banu K. Arun, Sausan Abouharb, Parijatham S. Thomas, Carlos H. Barcenas, Nuhad K. Ibrahim, Vicente Valero, Naoto T. Ueno, Rachel M. Layman, Bora Lim, Wendy Woodward, Anthony Lucci. A phase 1b study of neratinib with THP in metastatic and locally advanced breast cancer, and phase II study of THP followed by AC in HER2 + primary inflammatory breast cancer (IBC), and neratinib with taxol followed by AC in HR+/HER2- IBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-09.

Abstract Introduction:. Patients with locally advanced triple-negative breast cancer (TNBC) typically receive neoadjuvant therapy (NAT) to downstage the tumor and to improve the outcome of the subsequent breast conservation surgery. A critical unmet need is the lack of a method to accurately predict how a patient with TNBC will respond to NAT before surgery. In this work, we applied a clinical-computational framework to predict response of TNBC early in the course of NAT, by integrating quantitative MRI with mechanism-based mathematical modeling. Methods:. Patients and Data. Multiparametric quantitative MRI was acquired in patients (n = 46) before, and after 2 and 4 cycles of Adriamycin/Cyclophosphamide (A/C) regimen as part of the MD Anderson Cancer Center TNBC Moonshot Program. Within each imaging session, dynamic contrast-enhanced (DCE-), diffusion-weighted imaging (DWI), and a pre-contrast T1-map were acquired. Image processing. The processing pipeline consisted of three components. First, the images within each visit were registered to account for patient motion, and the parametric maps from the DCE and DWI images were computed. Second, inter-visit image registration was achieved by a non-rigid registration applied on breast, with a rigid penalty applied on the tumor region to preserve its size and shape. Third, post-processing was performed for preparation of modeling, including segmentation of the breast contour and tissues, and calculation of voxel-wise cellularity within tumors. Mathematical modeling. A predictive model was developed based on a reaction-diffusion equation (Eq. 1). The mobility of tumor cells is represented by diffusion coupled to mechanical properties of the tissue (Eq. 2), and the proliferation of the tumor is described with logistic growth. The injection and decay of administered therapies, inducing tumor cell death, is also represented in the model (Eq. 3). The variables and parameters used are listed in Table 1. Eq. 1: ∂N(x,t)/∂t = ∇⋅(D(x,t) ∇N(x,t)) + k(x) (1 - N(x,t)/θ)N(x,t) - (λ1(x,t) + λ2(x,t))N(x,t). Eq. 2: D(x,t) = D0 e-γσ(x,t). Eq. 3: λn(x,t) = αne-βn t C(x,t), n = 1, 2. For each patient, the domain and initial condition were generated from the pre-treatment images, and the images acquired during NAT were used for patient-specific calibration of parameters. The calibrated model was then used to predict the response to be observed at the end of NAT. We evaluated the model by comparing its predictions of tumor volume, longest axis, voxel-wise cellularity, and total tumor cellularity to the imaging measurements at the end of A/C. Results:. Our model predicted the tumor volume, total cellularity, and longest axis with a Pearson correlation coefficient (PCC) of 0.85, 0.80, and 0.60, respectively. The accuracy of voxel-wise cellularity achieved a PCC with the median (range) of 0.89 (0.77 - 0.93) between the prediction and the actual measurement. Moreover, we set criteria of 70% shrinkage of tumor volume to define response versus non-response cases, with which our model achieved a differentiation sensitivity/specificity of 0.90/0.73. Discussion:. Preliminary results of our study demonstrate the potential of the clinical-computational framework as a powerful tool for predicting response to NAT. Once validated, the method could also assist in optimizing treatment plans on a patient specific basis, or guiding patient selection in trials for novel NAT regimens. Table 1. Summary of the variables and parameters in the modelQuantitiesDefinition AssignmentDomainsΩbreast tissue domainGenerated from pre-treatment MRITEnd time point of NAT procedureDetermined from NAT schedulexCoordinate in breast tissueAssociated with spatial domain, ΩttimeAssociated with temporal domain, [0, T]VariablesN(x,t)Tumor cell numberInitialized from pre-treatment ADC, computed via Eq. 1D(x,t)Diffusive mobility of tumor cellsComputed via Eq. 2λn(x,t)Death rate induced by nth type of drugComputed via Eq. 3, n = 1 and 2 for A/Cσ(x,t)Von Mises stressComputed from gradient of N(x,t), based on Hormuth et al., 2018C(x,t)Spatiotemporal distribution of drugsAssigned based on NAT schedule and DCE imagesParametersk(x)Proliferation rate of tumor cellsLocally calibratedθTumor cells carry capacityGlobally calibratedαnEfficacy rate of nth type of drugGlobally calibratedβnDecay rate of of nth type of drugGlobally calibratedD0Diffusion coefficient of tumor cells in the absence of mechanical restrictionsGlobally calibratedγStress-tumor cell diffusion coupling constantAssigned based on Hormuth et al., 2018 Citation Format: Chengyue Wu, Angela M. Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E. Adrada, Rosalind P. Candelaria, Rania M. Mohamed, Medine Boge, Lei Huo, Jason White, Debu Tripathy, Vicente Valero, Jennifer Litton, Stacy Moulder, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M. Rauch, Thomas E. Yankeelov. Forecasting treatment response to neoadjuvant systemic therapy in triple negative breast cancer viamathematical modeling and quantitative MRI [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-08.

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in &gt;5% but &lt; 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p&lt; 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-01.

Abstract Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is &gt;4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P&lt; 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

Методом ионно-лучевого распыления двух мишеней (одна из сплава CoFeB, вторая из TiO2) на вращающуюся ситалловую подложку получена серия образцов с градиентом состава и толщины композита (CoFeB)x(TiO2)1–x. На дифрактограммах aморфных композитов обнаружено гало, соответствующее среднему межатомному расстоянию, близкому по величине к значениям межплоскостных расстояний самых интенсивных дифракционных линий в сплавах CoFe. Методом ИК-спектроскопии проведена идентификация мод, соответствующих межатомным связям в аморфных композитах (CoFeB)x(TiO2)1–x различного состава. Установлено наличие связей с кислородом всех элементов композита Fe–O, Co–O, Ti–O, B-O, а также образование промежуточных химических связей Ti–O–B, Ti–O–Co между атомами диэлектрической и металлической компонент композита. На основе полученных данных предложена модель аморфных композитов (Co45Fe45B10)x(TiO2)1–x, в которой металлические частицы представляются в виде ядра из металлических кластеров CoFe с оболочкой из оксидов и боридов/оксиборидов d-металлов, распределенных в диэлектрической матрице диоксида титана TiO2–х. ИСТОЧНИК ФИНАНСИРОВАНИЯРабота выполнена при поддержке Минобрнауки России в рамках государственного заданияВУЗам в сфере научной деятельности на 2017–2019 годы. Проект № 3.6263.2017/ВУ. REFERENCES Zolotukhin I. V., Kalinin Yu. E., Stognay O. V. New directions of physical materials science. Voronezh, Voronezh State University Publ., 2000, 456 p. (in Russ.) Gridnev S. A., Kalinin Yu. E., Sitnikov A. V., Stognay O.V. Nonlinear phenomena in nano- and microheterogeneous systems. Moscow, BINOM. Lab knowledge Publ., 2012, 352 p. (in Russ.) Stognay O. V. Electric transport and magnetic properties of amorphous nano-granulated metal-dielectric composites. Doc. Sci. diss, Voronezh, 2004, 280 p. 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The article presents studies that discuss the relationship between the teaching work of preschool teachers and their health. Research was carried out in three different places: from 2010 to 2017 in the databases of the Scientific Electronic Library Online (SciELO Brazil), from 2000 to 2017 in the Portal da Associação Nacional de Pós-graduação e Pesquisa em Educação - ANPEd (Portal of the National Association of Postgraduate and Research in Education) and from 2000 to 2017 at the Banco de Teses da Capes/MEC- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/Ministério da Educação (Capes Bank of Theses/MEC - Coordination of Improvement of Higher Personnel Education / Ministry of Education). In the "article search" field, we used the descriptors (isolated and associated): "illness", "teacher" and "early childhood education", and later added "sickness". Search was carried out in "general" and "summary" fields. Among these papers, theses and dissertations were found 17 papers that analysed the relationship between the sickness of the preschool teachers and their work, it was shown that this relatively new group of teachers who are still constructing their professional identity, is still poorly studied although it presents itself as a risk group for illness, so more studies are needed to identify problems and seek solutions.ResumoO artigo apresenta estudos que abordam a relação do trabalho docente das professoras de educação infantil com a sua saúde. Pesquisou-se nas bases – Scientific Electronic Library Online (SciELO Brasil) o período de 2010 até 2017, no Portal da Associação Nacional de Pós-graduação e Pesquisa em Educação (ANPEd) o período de 2000 a 2017 e no Banco de Teses da Capes/MEC – Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/Ministério da Educação (de 2000 a 2017). No campo “pesquisa de artigos”, utilizamos os descritores (isolados e associados): “doença”, “professora” e “educação infantil”, posteriormente acrescentou-se “adoecimento”. Pesquisou-se nos campos em “geral” e “resumo”. Entre artigos, teses e dissertações encontrou-se 17 trabalhos que analisavam a relação do adoecimento das professoras de educação infantil com seu trabalho. Constatou-se que esse grupo de professoras, por ser relativamente novo e por estar em construção a sua identidade profissional, ainda é pouco estudado, embora apresente-se como grupo de risco para adoecimento, portanto mais estudos são necessários para identificar problemas e buscar soluções. ResumenEl artículo presenta estudios que abordan la relación del trabajo docente de las profesoras de educación infantil con su salud. La investigación se realizó en el portal de la Asociación Nacional de Postgrado e Investigación en Educación (ANPEd), en el período de 2000 a 2017 y en el Banco de Tesis de la Capes/MEC – Coordinación de Perfeccionamiento de Personal de Nivel Superior/Ministerio de Educación (de 2000 a 2017). En el campo "investigación de artículos", utilizamos los descriptores (aislados y asociados): "enfermedad", "profesora" y "educación infantil", posteriormente se añadió “enfermarse”. Se ha investigado en los campos en "general" y "resumen". Entre los artículos, tesis y disertaciones se encontraron 17 trabajos que analizaban la relación de la enfermedad de las profesoras de educación infantil con su trabajo, se constató que ese grupo de profesoras por ser un grupo relativamente nuevo, por estar en construcción de su identidad profesional, todavía es poco estudiado, aunque se presenta como grupo de riesgo para enfermarse, por lo que más estudios son necesarios para identificar problemas y buscar soluciones.Keywords: Early childhood education, Teachers, Health, Job.Palavras chave: Educação infantil, Professores, Saúde, Trabalho.Palabras clave: Educación infantil, Profesores, Salud, Trabajo.ReferencesARANDA, S. M. Um olhar implicado sobre o mal-estar docente. 2007. 149f. Tese (Doutorado em Educação) ? Programa de Pós-Graduação em Educação, Universidade Federal do Rio Grande do Sul, Porto Alegre. 2007.ARAÚJO, T. M. et al. Saúde e trabalho docente: dando visibilidade aos processos de desgaste e adoecimento docente a partir da construção de uma rede de produção coletiva. Educação em Revista, Belo Horizonte, n. 37, p. 183-212, jul. 2003.ARAÚJO, T.; CARVALHO, F. M. Condições de trabalho docente e saúde na Bahia: estudos epidemiológicos. Educação & Sociedade, Campinas, vol. 30, n. 107, p. 427-449, maio/ago. 2009. Disponível em http://www.cedes.unicamp.br. Acesso em 10 de abr. 2017.ASSIS, M. S. Ama, guardiã, crecheira, pajem, auxiliar... em busca da profissionalização do educador da educação infantil. In: ANGOTTI, M. (Org.). Educação Infantil: da condição de direito a condição de qualidade no atendimento. Editora Alínea: São Paulo, Campinas, 2009, p. 37-50.BERALDO, K. E. A. Educadoras de creche: percepção de motivos de satisfação, de insatisfação e de estresse vinculados ao desempenho profissional. 2006. 200f. Tese. (Doutorado em Psicologia) ? Programa de Pós-Graduação em Psicologia, Universidade de São Paulo, São Paulo, 2006.BRANQUINHO, N. das G. S. Qualidade de vida no trabalho e vivências de bem-estar e mal-estar em professores da rede pública municipal de Unaí/MG. 2010. 117 f. Dissertação (Mestrado em Psicologia) – Programa de Pós-Graduação em Psicologia, Universidade de Brasília, Brasília, 2010.BRASIL. Decreto-Lei 9.694 de 20 de dezembro de 1996. Estabelece as diretrizes e bases da educação nacional. Disponível em: <http://portal.mec.gov.br/arquivos/pdf/ldb.pdf>. Acesso em: 27 jun. 2017.BRASIL. Resolução CNE/CP nº 1, de 15 de maio de 2006. Institui Diretrizes Curriculares Nacionais para o Curso de Graduação em Pedagogia, licenciatura. Disponível em: <http://portal.mec.gov.br/arqui­vos/pdf/ldb.pdf>. Acesso em: 27 jun. 2017.CARNEIRO, N. Estresse ocupacional do gestor escolar na educação infantil. 2017. 102 páginas. Dissertação (mestrado em Programa de Pós-graduação em Saúde, Ambiente e Trabalho) Universidade Federal da Bahia, Salvador, 2017.CORTEZ, P.; SOUZA, M. V.; AMARAL, L. O.; SILVA, L. A saúde docente no trabalho: apontamentos a partir da literatura recente. Cadernos de Saúde Coletiva, Rio de Janeiro, v.25, n. 1, p.113-122, jan./mar., 2017.DEFINA-IQUEDA, A. P. Auto percepção da voz e interferências de problemas vocais: um estudo com professores da rede municipal de Ribeirão Preto/SP. 2006. 165f. Dissertação (Mestrado em Saúde) ? Programa de Pós-Graduação em Saúde, Universidade de São Paulo, Ribeirão Preto, 2006.ESTEVE, J. S. O mal-estar docente. Bauru, São Paulo: EDUSC, 1999.LEHMANN, B. A. et al. Trabalho e Saúde das Professoras da educação infantil das escolas públicas municipais da região sul do Rio Grande do Sul – Caderno online Issuu.com/trabalhodocenteesaude. Acesso em 10 de abril de 2017.MARTINS, L. Maria. Educação Infantil: assumindo desafios. In: SILVA, A.; SANTOS, B. R.; SEQUEIRA, C. H. (orgs). Infância e adolescência em perspectiva. São Vicente, SP, Prefeitura Municipal de São Vicente, 2006, v. I, p. 66-76.MARTINS, M. de F.; VIEIRA, J.; FEIJÓ J.; GONÇALVES, V. B. O trabalho das docentes da Educação Infantil e o mal-estar docente: o impacto dos aspectos psicossociais no adoecimento. Cadernos de Psicologia Social do Trabalho, São Paulo, v.17, n.2, p. 281-289, 2014.PINTO, M. de F. N.; DUARTE, A. M. C.; VIEIRA, L. M. F.. O trabalho docente na educação infantil pública em Belo Horizonte. Rev. Bras. Educ. [online]. 2012, vol.17, n.51, pp.611-626. ISSN 1413-2478. http://dx.doi.org/10.1590/S1413-24782012000300007PURIN, P. C. O trabalho na rede municipal de Cidreira/RS: limites e possibilidades de uma práxis emancipadora. 2011. 69f. Dissertação (Mestrado em Educação) ? Programa de Pós-Graduação em Educação, Universidade Federal do Rio Grande do Sul, Porto Alegre, 2011.ROMANOWSKI, J. P.; ENS, R. T. As pesquisas denominadas de tipo “estado da arte” em educação. Diálogo Educacional, Curitiba, v.6, n.9, p.37-50, set./dez. 2006. Disponível em: http://www.redalyc.org/articulo.oa?id=189116275004. Acesso em: 20 jun. 2017.SANTOS, M. N.; MARQUES, A. Condições de saúde, estilo de vida e características de trabalho de professores de uma cidade do sul do Brasil. Ciência e Saúde Coletiva, Rio de Janeiro, v.18, n3, p.837-846, mar., 2013.SILVA, L. G.; SILVA M. C. Condições de trabalho e saúde de professores pré-escolares da rede pública de ensino de Pelotas, RS, Brasil. Ciência e Saúde Coletiva, Rio de Janeiro, v.18, n.11, 3137-3146, nov. 2013.SILVEIRA, L.; MEIRELES, J.; ESLABÃO, L.; VIEIRA, J.; MARTINS M. de F. Mal-Estar docente e absenteísmo: uma relação de trabalho e saúde das professoras de Educação Infantil. Revista Latino-Americana de Estudos em Cultura e Sociedade, v.1, p. 01-07, 2015.SOLIMÕES, A. C. Impacto na precarização do trabalho sobre a saúde das docentes. 2015. 157p. Dissertação (Mestrado em Instituto de Ciências da Educação Programa de Pós-graduação em Educação). Universidade Federal do Pará, Belém, 2015.SOUZA, A.; LEITE, M. P. Condições de trabalho e suas repercussões na saúde dos professores da educação básica no Brasil. Educação & Sociedade, Campinas, v.32, n.117, p. 1105-1121, out./dec. 2011.VIEIRA, J.; GONÇALVES, V. B.; MARTINS, M. de F. D. Trabalho docente e saúde das professoras de Educação Infantil de Pelotas, Rio Grande do Sul. Trabalho, Educação e Saúde, Rio de Janeiro, v. 14 n. 2, p. 559-574, maio/ago. 2016.VIEIRA, J.; MARTINS, M.de F. D. Educação básica e saúde do professorado: efeitos dos descuidos das políticas educacionais. Diálogo crítico-educativo, Pelotas, Vlll, p. 157-170, 2017.VIEIRA, L. F.; OLIVEIRA, T. G. As condições do trabalho docente na educação infantil no Brasil: alguns resultados de pesquisa (2002-2012) Revista Educação em Questão, Natal, v. 46, n. 32, p. 131-154 maio/ago., 2013.ZENARI, M. S.; BITAR, M.; NEMR Nair. Efeito do ruído na voz de educadoras de instituições de educação infantil. Revista de Saúde Pública, São Paulo, v.46, n.4, p. 657-664, ago. 2012.

This 21st century is known as a period in which access to information and communi- cation technology (ICT) are widely open. This brings good in various fields, one of which is educa- tion. In relation to the use of technology in education sector, Kurniawan developed a learning model based on ICT that is a combination of the components of animation technology with aspects of Eng- lish learning specifically reading comprehension. The model is called Creative Reading Learning Model aiming to increase vocabulary understanding, concept and the use of previously owned knowledge. The model emphasizes the role of educators in preparing learning and students in under- standing learning through the help of animation technology that can arise prior knowledge to under- stand learning materials. This study aims to complete the Research and Development phase until the product is complete and analyze the pedagogical implications of the application of Creative Reading as a form of triggering metalinguistic awareness in the test group. Data obtained through observation. The results of this study indicate that children understand most of the vocabulary presented. Related to metalinguistic awareness, there are children who have used English intentionally with an under- standing of form and meaning as the basis. Keywords: Creative Reading, English, Learning Models, Reading Comprehension, Vocabulary Reference Abdon, M. M., Maghanoy, J. M., Alieto, E. O., Buslon, J. B., Rillo, R. M., & Bacang, B. G. (2019). Phonological Awareness Skills of English As Second Language (Esl) Learners: the Case of First-Grade Filipino Bilinguals. Sci.Int.(Lahore), 31(5), 647–652. Altman, C., Goldstein, T., & Armon-Lotem, S. (2018). Vocabulary, metalinguistic awareness and language dominance among bilingual preschool children. Frontiers in Psychology, 9(OCT), 1–16. https://doi.org/10.3389/fpsyg.2018.01953 Cadena, C. M. Z. (2006). Effectiveness of Reading and Improving Reading Comprehension in Young ESL Readers (Universidad Del Norte Maestria). Retrieved from http://manglar.uninorte.edu.co/bitstream/handle/10584/718/45686016.pdf;jsessionid=E69 B0580514D369C34D96E4B48A8C9AC?sequence=1 Ceballos, M. R. S., Grenna, M., Joy, M., & Chall, J. S. (2012). Stages of Reading Development. Reading Difficulties and Dyslexia: An Interpretation for Teachers, 20–28. https://doi.org/10.4135/9788132108375.n3 Copland, F., Garton, S., & Burns, A. (2014). Challenges in Teaching English to Young Learners: Global Perspectives and Local Realities. TESOL Quarterly, 48(4), 738–762. https://doi.org/10.1002/tesq.148 de Souza, G. N., Brito, Y. P. dos S., Tsutsumi, M. M. A., Marques, L. B., Goulart, P. R. K., Monteiro, D. C., & de Santana, Á. L. (2018). The Adventures of Amaru: Integrating learning tasks into a digital game for teaching children in early phases of literacy. Frontiers in Psychology, 9(DEC), 1–8. https://doi.org/10.3389/fpsyg.2018.02531 Flemban, F. Y. (2018). Animated Pedagogical Agent’s Roles and English Learners’ Prior Knowledge: The Influence on Cognitive Load, Motivation, and Vocabulary Acquisition. University of South Florida. Georgescu, C.-A. (2010). Using Blogs in Foreign Language Teaching. Educational Sciences Series, 62(1A), 186–191. Guilford, J. P. (1977). Way Beyond the IQ. New York: Bearly Limited. Karavas, E. (2014). Applied Linguistics to Foreign Language Teaching and Learning. An introduction to Applied Linguistics. In National and Kapodistrian University of Athens. Retrieved from http://opencourses.uoa.gr/courses/ENL6/ Kurniawan, M. (2012). Students’ Perspectives Toward the Use of Teacher’S Edublog in Efl Learning (Satya Wacana Christian University Salatiga). 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RESUMENLa investigación arqueológica sobre el mundo funerario hispanorromano ha conocido en los últimos años un empuje realmente extraordinario, tanto desde el punto de vista conceptual, como instrumental y aplicado. La literatura científica viene alumbrando desde hace algo más de dos décadas multitud de trabajos sobre los aspectos legales y jurídicos –públicos y privados– asociados a la muerte, la topografía sepulcral, los rituales empleados y su carácter celebrativo, las tipologías de enterramientos y las formas arquitectónicas empleadas, la ornamentación y la iconografía funerarias, la composición y el simbolismo de urnas y ajuares, y su papel en el funus y la conmemoración del fallecido, la bioantropología, y también la escatología, por cuanto entre otras cuestiones se han empezado a identificar sepulturas no convencionales o anómalas. Todo ello es analizado con afán de síntesis, planteando propuestas de futuro, entre las cuales destacan la necesidad de extremar el rigor y la interdisciplinariedad de las intervenciones, de reducir la excavación en beneficio de la exégesis, y de entender y abordar los conjuntos urbanos como yacimientos únicos, en el espacio y en el tiempo. Palabras clave: Hispania, Alto Imperio, funus, ritual, formas arquitectónicas, escatología Topónimos: HispaniaPeriodo: Antigua Roma ABSTRACTArchaeological research on the Hispano-Roman funerary world has achieved in recent years a remarkable thrust, both from the conceptual point of view as well as instrumental and applied. For more than two decades, scientific literature has illuminated several works about legal and juridical aspects on public and private issues associated with death, the burial topography, the rituals carried out, and their celebratory character. They have focused as well on the types of burials, the most used architectonical forms, the ornamentation, and funerary iconography, the composition, and symbolism of urns and grave goods and their role in the funus and the commemoration of the deceased, bio anthropology, and, also, eschatology, among other issues, to start identifying unconventional or anomalous graves. From all this, it is analyzed with the aim of synthesis, planning forward proposals for the future, among which are the need to be rigorous and interdisciplinary in the interventions, to reduce excavation for the benefit of exegesis, and to understand and address urban complexes as unique archaeological sites, in space and time.Keywords: Hispania, High Empire, funus, ritual, architectonical forms, eschatologyPlace names: HispaniaPeriod: Ancient Rome REFERENCIAS Alfayé, S. (2009): “Sit tibi terra gravis: magical-religious practices against Restless dead in the ancient world”, en Marco, F.; Pina, F. y Remesal, J. 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De la Prehistoria al ocaso de la ciudad romana, Córdoba—(2020c): “Las necrópolis de Corduba-Colonia Patricia: topografía, vías funerarias y monumentos”, en Ruiz Osuna, A. (Coord.), La muerte en Córdoba. Creencias, ritos y cementerios (1). De la Prehistoria al ocaso de la ciudad romana, Córdoba, 127-153. —(Ed.) (2021a): Morir en Hispania. Topografía, rituales y prácticas mágicas en ámbito funerario, Spal Monografías Arqueología XXXVII, Sevilla.—(2021b): “Busta y ustrina en la Córdoba romana: el ritual de cremación en la capital de la Bética”, en Ruiz Osuna, A. (Ed.): Morir en Hispania. Topografía, rituales y prácticas mágicas en ámbito funerario, Sevilla, 47-76.Ruiz Osuna, A.; Rubio, M. (2021): “Urnas de tradición indígena en Corduba-Colonia Patricia. Una propuesta actualizada para el ámbito funerario”, Sagvntvm 53, Valencia, pp. 131-150.Sánchez Hernando, L. J. (2020): “El paisaje vegetal del entorno de la necrópolis romana de Llanos del Pretorio (Córdoba), y el uso funerario de la madera como materia prima energética”, en Vaquerizo, D.; Ruiz, A. y Rubio, M. (Eds.), El sepulcretum romano de Llanos del Pretorio (Córdoba, España), Bari, 141-148.—(2021): “El uso de las materias primas de origen vegetal en el mundo funerario de la Hispania romana”, en Ruiz Osuna, A. (Ed.), Morir en Hispania. Topografía, rituales y prácticas mágicas en ámbito funerario, Sevilla, 447-459.Sánchez Hidalgo, F. (2020): “La arquitectura funeraria extramuros al noreste de Augusta Emerita: recintos funerarios, mausoleos y su organización entre el Alto y el Bajo Imperio. Excavación arqueológica realizada en el antiguo cuartel militar de Artillería Hernán Cortés de Mérida”, Anas 31-32 (2018-2019), Mérida, 29-52. Saquete, J.C. (2002): “Notas sobre una tumba con jardín, una multa sepulcral y el paisaje suburbano de Augusta Emerita”, Madrider Mitteilungen 43, Mainz am Rhein, 207-219.Schattner, Th. G. (2002): Munigua. Cuarenta años de Investigaciones, Sevilla.Seco, I. (2010): Piedras con alma: El betilismo en el Mundo Antiguo y sus manifestaciones en la Península Ibérica, Universidad de Sevilla. Sevilla, A. (2014): Funus Hispaniense. Espacios, usos y costumbres funerarias en la Hispania romana, BAR International Series 2610, Oxford.—(2015): “Un tipo especial de funus acerbum y de ajuar funerario como reflejo de la condición social del difunto. Los casos documentados en Hispania”, Cuadernos de Arqueología Universidad de Navarra 23, Pamplona, 97-121. Struck, M. (2007): “Körpergrabtraditionen im römischen Britannien”, en Faber, A. et alii (Eds.), Körpergräber des 1. – 3. Jahrhunderts in der Römischen welt, Frankfurt, 431-444.Stylow, A.U. (2002a): “La epigrafía funeraria de la Bética”, en Vaquerizo, D. (Ed.), Espacio y usos funerarios en el Occidente Romano, Córdoba, vol. I, 353-367.—(2002b): “Von der Schrift der Sieger zum Sieg der Schrift. Imitation, Eigenständigkeit und Differenzierung in der epigraphischen Kultur Hispaniens”, en Urso, G. (Ed.), Hispania terris omnibus felicior. Atti del convegno internazionale, Pisa, 163-181.Stylow, A. U. y López Melero, R. (1995): “Epigraphische Miszellen aus der Provinz Jaén, 1. Eine Grabbuße zugunsten der Res publica Aiungitanorum”, Chiron 25, München, 357-386.Tirelli, M. (2001): “ …ut … largius rosae et esc[a]e … poneretur. I rituali funerari ad Altinum tra offerte durevoli e deperibili”, en Heinzelmann, M. et alii (Eds.), Culto dei morti e costumi funerari romani..., Wiesbaden, 243-253.Vaquerizo, D. (Ed.) (2002): Espacio y usos funerarios en el Occidente romano, Córdoba, 2 vols. —(2004): Immaturi et innupti. Terracotas figuradas en ambiente funerario de Corduba, Colonia Patricia, Instrumenta 15, Barcelona.—(2005): “Arqueología de la Corduba republicana”, en Melchor, E.; Mellado, J. y Rodríguez Neila, J.F. (Eds.), Julio César y Corduba: Tiempo y espacio en la Campaña de Munda (49-45 a.C.), Córdoba, 165-205.—(2010a): Necrópolis urbanas en Baetica, Tarragona-Sevilla.—(Ed.) (2010b): Las áreas suburbanas en la ciudad histórica. Topografía, usos, función, Córdoba. —(2014): “Mortes singulares y miedo a los muertos en el mundo romano: reflexiones, indicios, escatología”, en Neira Jiménez, M. L. (Coord.), Religiosidad, rituales, y prácticas mágicas en los mosaicos romanos, Madrid, 211-246.—(2020a): “Parcelaciones funerarias en necrópolis cordubenses. Reflexiones a partir de dos hallazgos recientes”, Archivo Español de Arqueología 93, Madrid, 147-172. —(2020b): “La gestión del espacio funerario en la Córdoba romana: viae sepulcrales, recintos y mensurae sepulcrorum”, en Vaquerizo, D.; Ruiz, A. y Rubio, M. (Eds.), El sepulcretum de Llanos del Pretorio (Córdoba), Bari, 173-196. —(2020c): “La muerte en época romana: ritual, escatología y miedo a los muertos”, en Ruiz Osuna, A. (Coord.), La muerte en Córdoba. Creencias, ritos y cementerios (1). De la Prehistoria al ocaso de la ciudad romana, Córdoba, 95-126. Vaquerizo, D. y Ruiz, A. (2020): “El mundo funerario cordubense de época altoimperial. Topografía, ritual y formas arquitectónicas”, en Vaquerizo, D.; Ruiz, A. y Rubio, M. (2020), El sepulcretum romano de Llanos del Pretorio (Córdoba, España), Bari, 7-26.Vaquerizo, D., Ruiz, A. y Rubio, M. (Eds.) (2020): El sepulcretum romano de Llanos del Pretorio (Córdoba, España), Bari. Vargas, S. (2020): “La vida eterna: el ajuar-tipo de las necrópolis romanas cordubenses”, en Ruiz Osuna, A. (Coord.), La muerte en Córdoba. Creencias, ritos y cementerios (1). De la Prehistoria al ocaso de la ciudad romana, Córdoba, 249-267.

1 Modo de enfoque do problemaTodo e qualquer estudo de direito há de partir não de análises pré-jurídicas ou sociológicas, mas é imperioso que seja ele perquirido à luz do Direito positivo. Despiciendo, daí, todo envolvimento com posições e estudos realizados em outros países, salvo para aprimoramento cultural. Evidente que a análise do Direito comparado passa a interessar se o direito alienígena possuir norma igual ou assemelhada à existente no Direito brasileiro. A menção retrospectiva do direito comparado resultaria inútil, da perspectiva de utilidade prática deste trabalho. Mesmo porque, como assinala Marcelo Caetano “há países onde o expropriado pode requerer a reversão ou retrocessão dos bens, restituindo a indenização recebida, ou o expropriante tem o dever de oferecer os bens ao expropriado mediante a devolução do valor pago" (Princípios fundamentais do Direito Administrativo, 1977, p. 468) enquanto que "noutros países entende-se que, em qualquer caso, a conversão dos bens desapropriados no montante da indenização paga é definitiva. Portanto, nunca haverá lugar a reversão ou retrocessão dos bens” (idem, ibidem). Afigura-se-nos dispensável e sem qualquer utilidade prática a apresentação de uma resenha da doutrina estrangeira a propósito do tema. Apenas será feita menção a alguns autores, na medida em que suas afirmações interessarem à análise. Observe-se, tão-somente que o direito de retrocessão em espécie é reconhecido em diversas legislações. Na Itália há previsão legal (art. 60 da Lei 2.359, de 25.6.1865) o mesmo ocorrendo na França (art. 54 do Dec. 58.997, de 23. 10. 58, que fixa o prazo de 10 anos a contar do decreto de desapropriação para que se requeira a retrocessão). Em Portugal há dispositivo semelhante (art. 8 º da Lei 2 .030, de 22.6.48); o que acontece também na Espanha (art. 54 da Lei de 15. 12. 54) e na Alemanha (Lei de 23. 2.57, em seu § 102) Demais de tal inicial observação, perigoso é o estudo de qualquer instituto jurídico atrelado à lei. Impõe-se a análise de determinado instituto a partir da Constituição. Daí inicia-se o estudo da retrocessão. 2 Desapropriação. Desvio de poderDispõe o § 22 do art. 153 da Lei Maior "que é assegurado o direito de propriedade, salvo o caso de desapropriação por necessidade ou utilidade pública ou por interesse social, mediante previa e justa indenização em dinheiro...”. Assegura-se o direito de propriedade que cede apenas, ante o interesse coletivo, representado pelo Estado. Ao mesmo tempo em que garante a propriedade, a Constituição assegura ao Estado o poder de retirá-la mediante desapropriação. Esta pode ser entendida como "o procedimento administrativo através do qual o Poder Público compulsoriamente despoja alguém de uma propriedade e a adquire para si, mediante indenização, fundada em um interesse público" (Elementos de Direito Administrativo, Celso Antônio Bandeira de Mello, 1980, p. 188). Caracteriza-se a desapropriação pela retirada compulsória do bem do domínio particular, com sua transferência ao domínio público, sob fundamento de interesse público mediante indenização. O fulcro da permissão legal para a transferência do domínio é o interesse público, ou seja, finalidade prevista no próprio ordenamento jurídico a ser perseguido pelo Estado. Sob a rubrica interesse público albergam-se todos os conteúdos possíveis de utilidade coletiva desde que alcançados pelo sistema de normas (sob o rótulo interesse público acolhe-se a necessidade ou utilidade pública e o interesse social). O poder de desapropriação deflui do domínio eminente que possui o Poder Público sobre todas as coisas materiais e imateriais sujeitas ao âmbito espacial de validade do sistema jurídico. O poder de desapropriação pode ser decomposto em três aspectos: a) transferência compulsória de alguma coisa; b) mediante indenização e c) sob o fundamento de interesse público. A desapropriação, como forma originária de aquisição de domínio, implica na compulsoriedade da transferência do bem do domínio particular para o público. Sempre haverá indenização, devidamente apurada através do processo próprio ou mediante acordo de vontades. E, o que mais nos interessa, há que vir fundamentada em interesse público, sob pena de invalidade. A competência, no Direito, não é dada a qualquer título. Sempre é outorgada a determinado agente para que persiga interesses coletivos ou mais propriamente denominados públicos, sendo estes apurados pela análise de todo o sistema de normas. A visão completa da competência apenas pode ser entrevista, pois, em contraste com a finalidade descrita na norma legal. Desviando-se o agente administrativo dos fins que lhe foram traçados pelo sistema de normas, incide no desvio de poder (ou de finalidade, como dizem alguns). 3 Conceito de retrocessãoA retrocessão implica no direito do expropriado de retomar a propriedade do imóvel que lhe fora retirada compulsoriamente pelo Poder Público. Os léxicos consignam que "retrocessão é o ato pelo qual o adquirente de um bem transfere de volta a propriedade desse bem àquele de quem o adquiriu" (Novo Dicionário Aurélio, lª ed., p. 1.231). Assinala Oliveira Cruz que "a retrocessão é um instituto de Direito Público, destinado a fazer voltar ao domínio do desapropriado os bens que saíram do seu patrimônio, por efeito de uma desapropriação por utilidade pública" (Da desapropriação, p. 119). E, acrescenta que "a retrocessão tem, indiscutivelmente, uma feição real porque significa um direito que só se desliga do imóvel quando preenchidos os fins determinantes da desapropriação" (ob. cit., p. 121). Assim entendida a retrocessão, como defluente do próprio preceito constitucional que assegura a propriedade e resguarda sua retirada apenas e exclusivamente pela desapropriação por necessidade, utilidade pública ou interesse social, não há como confundi-la com a preempção ou prelação, ou assimilá-la a qualquer tipo de direito pessoal. A fixação de tal premissa é fundamental para todo o desenvolvimento do trabalho e para alicerçar as conclusões que serão apontadas ao final. Daí porque não se pode concordar com a assertiva feita por alguns autores de que se cuida de simples obrigação imposta ao Poder Público de oferecer ao ex-proprietário o bem que lhe desapropriou, se este não tiver o destino para o qual fora expropriado (Múcio de Campos Maia, "Ensaio sobre a retrocessão", in RDA, 34/1-11). Pela própria dúvida no conteúdo do conceito, já os autores manifestaram-se surpresos e a jurisprudência claudicou sobre a análise do tema. Muitos julgados, inclusive, chegaram a admitir a inexistência da retrocessão no Direito brasileiro. Mas, pela análise que será feita e pelas conclusões a que se chegará, ver-se-á não só da existência do instituto no Direito brasileiro, sendo despicienda a indagação do Direito Civil a respeito, defluindo o instituto da só análise do texto constitucional brasileiro. A retrocessão é mero corolário do direito de propriedade, constitucionalmente consagrado e decorre do direito emergente da não utilização do bem desapropriado para o fim de interesse público. Sob tal conteúdo é que o conceito será analisado. 4 Desenvolvimento histórico, no BrasilEm estudo sobre o aspecto histórico do desenvolvimento da retrocessão no Direito brasileiro Ebert Chamoun escreveu que o inc. XXII do art. 179 da Constituição do Império, de 25. 3. 1824 dispôs sobre a possibilidade da desapropriação. E a Lei provincial 57, de 18.3.1836 pela vez primeira cuidou da retrocessão, assegurando que, na hipótese de desapropriação caberia "recurso à Assembleia Legislativa provincial para a restituição da propriedade ... " A admissibilidade da retrocessão foi aceita pelo STF que assim deixou decidido: “que abrindo a mesma Constituição à plenitude o direito de propriedade no art. 72, § 17, a exceção singular da desapropriação por utilidade pública presumida, desde a certeza de não existir tal necessidade, o ato de desapropriação se equipara a violência (V) e deve se rescindir mediante ação do espoliado" (O Direito, vol. 67, 1895, p. 47). A referência é à Constituição republicana de 24.2.1891. Em sua Nova Consolidação das Leis Civis vigentes em 11 de agosto de 1899, Carlos de Carvalho escrevia o art. 855 "se verificada a desapropriação, cessar a causa que a determinou ou a propriedade não for aplicada ao fim para o qual foi desapropriada, considera-se resolvida a desapropriação, e o proprietário desapropriado poderá reivindicá-la". Diversas leis cuidaram do assunto, culminando com a edição do art. 1.150 do CC (LGL\2002\400) que dispôs: ''A União, o Estado, ou o Município, oferecerá ao ex-proprietário o imóvel desapropriado, pelo preço por que o foi, caso não tenha o destino para que se desapropriou". Criou-se, assim, o direito de preempção ou preferência, como cláusula especial à compra e venda. As Constituições que se seguiram igualmente asseguraram o direito de propriedade (a de 1934, no art. 113, 17; a de 1937, no art. 122, 14; a de 1946, no § 16 do art. 141). A Constituição de 1967 igualmente protegeu, juridicamente, a propriedade, permanecendo a garantia com a EC 1/69. 5 Hipóteses de retrocessãoO instituto da retrocessão foi bem analisado por Landi e Potenza quando escrevem que "fatta l'espropriazione, se l'opera non siasi eseguita, e siano trascorsi i termini a tal uopo concessi o prorogati, gli espropriati potranno domandare che sia dall'autorità giudiziaria competente pronunciata la decadenza dell'ottenuta dichiarazione di pubblica utilità, e siano loro restituiti i beni espropriati. In altri termini, la mancata esecuzione dall'opera dimostra l'insussistenza dell’interesse pubblico, che aveva determinato l'affievolimento del diritto di proprietà" (Manuale di Diritto Amministrativo, 1960, p. 501). Mas não é só a falta de destinação do bem a interesse público ou a não construção da obra para que teria sido o imóvel desapropriado que implica na possibilidade de retrocessão, afirmam os autores citados. Também no caso em que ''l'opera pubblica sia stata eseguita: ma qualche fondo, a tal fine espropriato, non abbia ricevuto in tutto o in parte la prevista destinazione" (ob. cit., p. 501). A retrocessão, pois, deflui, do que se lê da lição dos autores transcritos, na faculdade de o expropriado reaver o próprio bem declarado de utilidade pública, - quando lhe tenha sido dado destinação diversa da declarada no ato expropriatório ou não lhe tenha sido dada destinação alguma. De outro lado, esclarece André de Laubadere que "si l'immeuble exproprié ne reçoit pas la destination prévue dans la déclaration d'utilité publique, il est juste que le propriétaire exproprié puisse le récupérer. C'est l'institution de la rétrocession" (Traité deDroit Administratif, 6." ed., 2. 0 vol., p. 250). No direito brasileiro, os conceitos são praticamente uniformes. Eurico Sodré entende que "retrocessão é o direito do ex-proprietário de reaver o imóvel desapropriado, quando este não tenha tido utilização a que era destinado" (A desapropriação por necessidade ou utilidade pública, 1928, pp. 85-86). Firmino Whitaker afirma que "é direito que tem o ex-proprietário de readquirir o imóvel desapropriado mediante a restituição do valor recebido, quando não tenha sido o mesmo imóvel aplicado em serviço de ordem pública" (Desapropriação, 3ª ed., p. 23, 1946). Cretella Junior leciona que "é o direito do proprietário do imóvel desapropriado de reavê-lo ou de receber perdas e danos, pelos prejuízos sofridos, sempre que ocorrer inaproveitamento, cogitação de venda ou desvio de poder do bem expropriado" (Comentários às leis de desapropriação, 2.ª ed., 2.ª tiragem, 1976, p. 409). Fazendo a distinção prevista por Landi e Potenza, escreve Marienhoff que "la retrocesión, en cambio, sólo puede tener lugar en las dos siguientes hipótesis: a) cuando, después de la cesión amistosa o avenimiento, o después de terminado el juicio de expropiación, el expropiante afecta el bien o cosa a un destino diferente del tenido en cuenta por el legislador ai disponer la expropiación y hacer la respectiva calificación de utilidad publica; b) cuando efectuada la cesión amistosa o avenimiento, o terminado el juicio de expropiación, y transcurrido cierto plazo el expropiante no le dá al bien o cosa destino alguno" (Tratado de Derecho Administrativo, T. IV, 2ª ed., p. 369). Embora os autores costumem distinguir as hipóteses de cabimento da retrocessão, parece-nos que no caso de o Poder Público alterar a finalidade para que houvera decretado a desapropriação não existe o direito à retrocessão. Isto porque a Constituição Federal como já se viu, alberga no conceito "interesse público" a mais polimorfa gama de interesses. Assim, se desapropriado imóvel para a construção de uma escola, mas constrói-se um hospital, não nos parece ter havido "desvio de poder" ou de "finalidade". Simplesmente houve desvio do fim imediato, mas perdura o fim remoto. O interesse público maior, presente no ordenamento jurídico ficou atendido. Simplesmente, por interesses imediatos do Poder Público, mas sempre dentro da competência outorgada pela legislação, o agente entendeu de dar outra destinação à coisa expropriada. Em tal hipótese, não parece ter havido desvio de poder, hábil a legitimar a retrocessão. De tal sentir é Celso Antônio Bandeira de Mello quando afirma "convém ressaltar enfaticamente, contudo, que a jurisprudência brasileira pacificou-se no entendimento de que se o bem desapropriado para uma específica finalidade for utilizado em outra finalidade pública, não há vício algum que enseje ao particular ação de retrocessão (tal como é concebida hoje), considerando que, no caso, inexistiu violação do direito de preferência" (ob. cit., p. 210). Cita o autor a jurisprudência mencionada (RDP, 2/213, 3/242 e em RDA, 88/158 e 102/188). A doutrina é remançosa em afirmar a possibilidade de ser o bem empregado em outra finalidade diversa da alegada no decreto expropriatório ou na lei, desde que também de utilidade pública (Adroaldo Mesquita da Costa, in RDA, 93 /377; Alcino Falcão, Constituição Anotada, vol. II, pp. 149/SO; Carlos Maximiliano, Comentários à Constituição Brasileira, 1954, vol. III, p. 115; Diogo Figueiredo Moreira Neto, Curso de Direito Administrativo, vol. 2, p. 116; Ebert Chamoun, Da retrocessão nas desapropriações, pp. 74 e ss.; Hely Lopes Meirelles, Direito Administrativo Brasileiro, 2.ª ed., p. 505; Pontes de Miranda, Comentários à Constituição de 1967, com a Emenda Constituição n.º 1, de 1969, T. V, pp. 445/6; Cretella Junior, Tratado de Direito Administrativo, vol. IX, pp. 165/6). A jurisprudência a respeito é farta (RTJ, 39/495, 42/195 e 57 /46). Mais recentemente decidiu-se que "não cabe retrocessão quando o imóvel expropriado tem destino diverso, vias de utilidade pública" (RDA, 127 /440). Poucos autores manifestam-se em sentido contrário, ou seja, pela inadmissibilidade de aplicação do destino do bem em outra finalidade que não a invocada no decreto ou lei que estipula a desapropriação (Hélio Moraes de Siqueira, A retrocessão nas desapropriações, p. 61 e Miguel Seabra Fagundes, Da desapropriação no Direito brasileiro, 1949, p. 400). Tais indicações foram colhidas na excelente Desapropriação – Indicações de Doutrina e Jurisprudência de Sérgio Ferraz, pp. 122/124. Já diversa é a consequência quando o imóvel não é utilizado para qualquer fim, ficando ele sem destinação específica, implicando, praticamente, no abandono do imóvel. Daí surge, realmente, o problema da retrocessão. Mas, emergem questões prévias a serem resolvidas. Como se conta o prazo, se é que há, para que se legitime o expropriado, ativamente? Em consequência da solução a ser dada à questão anterior, cuida-se a retrocessão de direito real ou pessoal, isto é, a não utilização do bem expropriado enseja reivindicação ou indenização por perdas e danos? Estas questões são cruciais e têm atormentado os juristas. Passemos a tentar equacioná-las. 6 Momento do surgimento do direito de retrocessãoEntende Cretella Júnior que há dois momentos para que se considere o nascimento do direito de ingressar com a ação de retrocessão. Mediante ato expresso ou por ato tácito. "Mediante ato expresso, que mencione a desistência do uso da coisa expropriada e notifique o ex-proprietário de que pode, por ação própria, exercer o direito de retrocessão" (Comentários às leis de desapropriação, p. 415) ou através de ato tácito, ou seja, pela conduta da Administração que permita prever a desistência de utilização do bem expropriado, possibilitando ao antigo proprietário o exercício do direito de preferência...” (ob. cit., p. 416). De igual teor a lição de Eurico Sodré, A desapropriação por necessidade ou utilidade pública, 2.ª ed., p. 289. A jurisprudência já se manifestou em tal sentido (RTJ, 57 /46). Ebert Chamoun (ob. cit., pp. 80 e ss.) entende que apenas por ato inequívoco da administração tem cabimento a ação de retrocessão. Jamais se poderia julgar pela procedência da ação que visasse a retrocessão, desde que o Poder Público alegue que ainda vá utilizar o bem. Afirma o citado autor que "é assim, necessário frisar que o emprego, pelo expropriante do bem desapropriado para fim de interesse público não precisa ser imediato. Desde que ele consiga demonstrar que o interesse público ainda é presente e que a destinação para esse escopo foi simplesmente adiada, porque não é oportuna, exequível ou aconselhável, deve ser julgado improcedente o pedido de indenização do expropriado, com fundamento no art. 1.150 do CC (LGL\2002\400)" (ob. cit., p. 84). De igual teor a lição de Pontes de Miranda (Comentários. T. V, p. 445). Celso Antonio Bandeira de Mello tem posição intermediária. Afirma que "a obrigação do expropriante de oferecer o bem em preferência nasce no momento em que este desiste de aplicá-lo à finalidade pública. A determinação exata deste momento há que ser verificada em cada caso. Servirá como demonstração da desistência, a venda, cessão ou qualquer ato dispositivo do bem praticado pelo expropriante em favor de terceiro. Poderá indicá-la, também, a anulação do plano de obras em que se calcou o Poder Público para realizar a desapropriação ou outros fatos congêneres" (ob. cit., p. 209). A propósito, já se manifestou o STF que "o fato da não utilização da coisa expropriada não caracteriza, só por si, independentemente das circunstâncias. desvio do fim da desapropriação" (RTJ. 57/46). Do mesmo teor o acórdão constante da RDA, 128/395. 7 Prazo a respeito. AnalogiaOutros autores entendem que há um prazo de cinco anos para que o Poder Público destine o imóvel à finalidade Pública para que efetuou a desapropriação. Assim se manifestam Noé Azevedo (parecer in RT 193/34) e Seabra Fagundes (ob. cit., pp. 397 /8). O prazo de cinco anos é já previsto na doutrina francesa. Afirma Laubadere que "si les immeubles expropriés n'ont pas reçu dans le délai de cinq ans la destination prévue ou ont cessé de recevoir cette destination, les anciens propriétaires ou leurs ayants droit à titre universel peuvent en demander la rétrocession dans un délai de trente ans à compter également de l'ordonance d'expropriation, à moins que l'expropriant ne requère une nouvelle déclaration d'utilité publique" (ob. cit., p. 251). Tal orientação encontra por base o art. 10 do Dec.-lei 3.365/41 (LGL\1941\6) que estabelece: "a desapropriação deverá efetivar-se mediante acordo ou intentar-se judicialmente dentro de cinco anos, contados da data da expedição do respectivo decreto e findos os quais este caducará". Claro está que não tendo a lei previsto o direito à retrocessão, o intérprete há de buscar a solução para o problema (interpretação prudencial) dentro do próprio sistema normativo, para suprir ou colmatar a lacuna (a propósito deste tema, especificamente, veja se nosso "Lacuna e sistema normativo", in RJTJSP, 53/13-30). Esta surge no momento da decisão. Como todo problema jurídico gira em torno da decidibilidade, admite-se a interpretação analógica ao se entender que o prazo para que o Poder Público dê ao imóvel destinação específica ou outra permitida pelo direito (finalidade prevista no ordenamento) igualmente será o prazo de cinco anos. Neste, caduca o interesse público. Daí legitimar-se o expropriado a ingressar com a ação de retrocessão. Caso se entenda da inadmissibilidade de fixação de prazo, deixar-se-á à sorte o nascimento do direito ou, então, como pretende Cretella Junior, à manifestação volitiva do Poder Público decidir sobre a oferta do imóvel a alguém, com o que caracterizaria expressamente a vontade de alienar ou dispor do imóvel. Nunca haveria um prazo determinado, com o que padeceria a relação jurídica de segurança e estabilidade. Permaneceria o expropriado eternamente à disposição do Poder Público e perduraria, constantemente, e em suspense, até que a Administração decida como e quando destinará ou desafetará o imóvel. A solução que se nos afigura mais compatível com a realidade brasileira é a de se fixar o prazo de cinco anos, por aplicação analógica com o art. 10, retro citado. Está evidente que a só inércia não caracteriza a presunção do desvio. Se a Administração desapropria sem finalidade pública, o ato pode ser anulado, mesmo sem o decurso do prazo de cinco anos. Mas, aqui, o fundamento da anulação do ato seria outro e não se cuidaria do problema específico da retrocessão. 8 Natureza do direito à retrocessãoDiscute-se, largamente, sobre a natureza do direito à retrocessão. Para uns seria direito pessoal e eventual direito resolver-se-ia em indenização por perdas e danos. Para outros, cuida-se de direito real e, pois, há possibilidade de reivindicação. Magnífica resenha de opiniões é feita por Sérgio Ferraz em seu trabalho Desapropriação, pp. 117/121. Dentre alguns nomes que se manifestam pelo reconhecimento de que se cuida de direito pessoal e, pois, enseja indenização por perdas e danos encontram-se Ebert Chamoun (ob. cit., p. 31), Cretella Junior (Tratado . . ., vol. IX, pp. 159, 333/4), Múcio de Campos Maia ("ensaio sobre a retrocessão ", in RT 258/49). A jurisprudência já se tem manifestado neste sentido (RDA, 98/ 178 e 106/157). A propósito da pesquisa jurisprudencial, veja-se, também, o repertório de Sergio Ferraz. A solução apontada pelos autores encontra fundamento no art. 35 do Dec.-lei 3.365/41 (LGL\1941\6) ao estabelecer que "os bens expropriados, uma vez incorporados à Fazenda Pública, não podem ser objeto de reivindicação, ainda que fundada em nulidade do processo de desapropriação. Qualquer ação julgada procedente, resolver-se-á em perdas e danos". Com base em tal artigo afirma Ebert Chamoun que "o direito do expropriado não é, evidentemente, um direito real, porque o direito real não se contrapõe, jamais, um mero dever de oferecer. E, por outro lado, se o expropriante não perde a propriedade, nem o expropriado a adquire, com o simples fato da inadequada destinação, é óbvio que a reivindicação que protege o direito de domínio, e que incumbe apenas ao proprietário, o expropriado não pode ter" (ob. cit., pp. 38/39). Mais adiante afirma que "o direito do ex-proprietário perante o poder desapropriante que não deu à coisa desapropriada o destino de utilidade pública, permanece, portanto, no direito positivo brasileiro, como direito nítido e irretorquivelmente pessoal, direito que não se manifesta em face de terceiros , eventuais adquirentes da coisa, nem ela adere, senão exclusivamente à pessoa do expropriante. Destarte, o poder desapropriante, apesar de desrespeitar as finalidades da desapropriação, desprezando os motivos constantes do decreto desapropriatório, não perde a propriedade da coisa expropriada, que ele conserva em sua Fazenda com as mesmas características que possuía quando da sua. aquisição" (ob. cit., pp. 44/45). Em abono de sua orientação invoca o dispositivo mencionado e afirma "quaisquer dúvidas que ainda houvesse acerca da natureza do direito do expropriado seriam espancadas por esse preceito, límpido e exato, consectário perfeito dos princípios gerais do nosso direito positivo, dispositivo que se ajusta, como luva, ao sistema jurídico brasileiro relativo à aquisição de propriedade, à preempção e à desapropriação" (ob. cit., p. 47). De outro lado, autores há que entendem cuidar-se de direito real. Dentre eles Hely Lopes Meirelles (Direito Administrativo Brasileiro, 2.ª ed., p. 505), Seabra Fagundes (ob. cit., p. 397), Noé Azevedo (parecer citado, in RT, 193/34), Pontes de Miranda (Comentários . . . ", T. V, pp. 443/6 e Vicente Ráo (O direito e a vida dos direitos, 2.ª ed., p. 390, nota 113). Apontam-se, também, diversos julgados (RDA, 48/231 e 130/229). 9 Crítica às posiçõesRealmente não se confundem as disposições do art. 1.149 com o art. 1.150 do CC (LGL\2002\400). O primeiro refere-se a pacto de compra e venda e tem por pressuposto a venda ou a dação em pagamento. Implica manifestação volitiva, através de contrato específico, em que se tem por base a vontade livre dos negócios jurídicos, assim exigida para validade do contrato. Já o art. 1.150 constitui norma de Direito Público, pouco importando sua inserção no Código Civil (LGL\2002\400) (Pontes de Miranda, Tratado de Direito Privado, T. XIV, 2.ª ed., § 1.612, p. 172). Em sendo assim, a norma do art. 1.150 do CC (LGL\2002\400) que determina o oferecimento do imóvel desapropriado ao ex-proprietário para o exercício do direito de preferência não está revogada. Mas, daí não se conclui que há apenas o direito de prelação. Diverso é nosso entendimento. Pelo artigo referido, obriga-se a Administração a oferecer o imóvel (é obrigação imposta à Administração), mas daí não pode advir a consequência de que caso não oferecido o imóvel, não há direito de exigi-lo. A norma não é unilateral em prol do Poder Público. De outro lado, surge a possibilidade de exigência por parte do expropriado. E a tal exigência dá-se o nome de retrocessão. Superiormente ensina Hélio Moraes de Siqueira que "entretanto, não é na lei civil que se encontra o fundamento da retrocessão. Aliás, poder-se-ia, quando muito, vislumbrar os lineamentos do instituto. É na Constituição Federal que a retrocessão deita raízes e recebe a essência jurídica que a sustém. Mesmo se ausente o preceito no Código Civil (LGL\2002\400), a figura da retrocessão teria existência no direito brasileiro, pois é consequência jurídica do mandamento constitucional garantidor da inviolabilidade da propriedade, ressalvada a desapropriação por utilidade e necessidade pública e de interesse social, mediante prévia e justa indenização em dinheiro" (ob. cit., pp. 76/77). Idêntico entendimento deve ser perfilhado. Realmente, despiciendo é que o art. 35 do Dec.-lei 3.365/41 (LGL\1941\6) tenha estabelecido que "os bens expropriados, uma vez incorporados à Fazenda Pública, não podem ser objeto de reivindicação, ainda que fundada em nulidade do processo de desapropriação. Qualquer ação, julgada procedente, resolver-se-á em perdas e danos". A lei não pode mudar a norma constitucional que prevê a possibilidade da desapropriação sob fundamento de interesse público. O interesse público previsto na Constituição Federal é concretizado através das manifestações da Administração, em atos administrativos, possuindo, como condição de sua validade e de sua higidez o elemento finalidade ("finalidade-elemento teleológico contido no sistema. Conjunto de atribuições assumidas pelo Estado e encampadas pelo ordenamento jurídico", cf. nosso Ato Administrativo, ed. 1978, p. 48). Destina-se a finalidade a atender aos interesses públicos previstos no sistema normativo. Há por parte do agente administrativo emanador do ato, a aferição valorativa do interesse manifestado no decreto. É pressuposto lógico da emanação de qualquer ato administrativo que a competência do agente seja exercitada em direção a alcançar os objetivos ou os valores traçados no sistema de normas. Tal aferição valorativa é realizada no momento da expedição do ato. No decurso de certo tempo, pode desaparecer o interesse então manifestado. Mas, tal reconhecimento do desinteresse não pertence apenas à Administração Pública, mas também ao expropriado que pode provocá-lo, mediante ação direta. A Administração Pública, pela circunstância de ter adquirido o domínio da coisa expropriada, não fica isenta de demonstrar a utilidade da coisa ou a continuidade elo interesse público em mantê-la. Desaparecendo o interesse público, o que pode acontecer por vontade expressa da Administração, ou tacitamente, pelo decurso do prazo de cinco anos, contados dos cinco anos seguintes à transferência de domínio, que se opera pelo registro do título aquisitivo, que é a carta de adjudicação mediante prévio pagamento do preço fixado, nasce ao expropriado o direito de reaver a própria coisa. Trata-se de direito real, porque a perquirição da natureza do direito não deflui do momento atual do reconhecimento da desnecessidade da coisa, mas remonta ao momento do ato decretatório da utilidade pública. Já disse alhures (Ato Administrativo, pp. 122 e ss.) que a nulidade ou o ato inválido não prescreve. No caso a prescrição alcança o expropriado no prazo de cinco anos, contados do término dos cinco anos anteriores ao termo final do prazo de presunção da desnecessidade do imóvel. Explicando melhor: o Poder Público tem cinco anos, contados da data da aquisição da propriedade, que opera pelo registro da carta de adjudicação no Cartório do Registro de Imóveis competente, ou mediante registro da escritura pública lavrada por acordo das partes, no mesmo Cartório, para dar destinação específica, tal como declarada no decreto expropriatório ou outra destinação, havida como de interesse público. Passado tal prazo, abre-se ao expropriado o direito de haver a própria coisa, também pelo prazo de Cinco anos, nos termos do Dec. 20.910/32 (LGL\1932\1). A propósito já se decidiu que "a prescrição da ação de retrocessão, visando às perdas e danos, começa a correr desde o momento em que o expropriante abandona, inequivocamente, o propósito de dar, ao imóvel, a destinação expressa na declaração de utilidade pública" (PDA, 69/ 200). Ausente a utilidade pública, seja no momento da declaração, seja posteriormente. o ato deixa de ter base legal. Como afirma José Canasi, "la retrocesión tiene raiz constitucional implicita y surge del concepto mismo de utilidade publica. No se concibe una utilidad publica que puede desaparecer o deformarse a posteriori de la expropriación. Seria un engano o una falsidad" (La retrocesión en la Expropiación Publica, p. 47). Rejeita-se o raciocínio de que o expropriado, não sendo mais proprietário, falece-lhe o direito de pleitear reivindicação. Tal argumento serviria, também, para &e rejeitar a existência de direito pessoal. Isto porque, se o ex-proprietário já recebeu, de acordo com a própria Constituição Federal a justa indenização pela tomada compulsória de seu imóvel, nenhum direito teria mais. Não teria sentido dar-se nova indenização ao ex-proprietário, de vez que o Poder Público já lhe pagara toda quantia justa e constitucionalmente exigida para a composição do patrimônio desfalcado pela perda do imóvel. Aí cessaria toda relação criada imperativamente, pelo Poder Público. Inobstante, a pretensão remonta à edição do ato. O fundamento do desfazimento do decreto expropriatório reside exatamente na inexistência do elemento finalidade que deve sempre estar presente nas manifestações volitivas da Administração Pública. Demais, cessado o interesse público subsistente no ato expropriatório, a própria Constituição Federal determina a persistência da propriedade. A nosso ver, a discussão sobre tratar-se de direito real ou pessoal é falsa. Emana a ação da própria Constituição, independentemente da qualificação do direito. Ausente o interesse público, deixa de existir o fundamento jurídico da desapropriação. Logo, não podem subsistir efeitos jurídicos de ato desqualificado pelo ordenamento normativo. Trata-se de direito real, no sentido adotado por Marienhoff quando afirma que "desde luego, trátase de una acción real de "derecho público", pues pertenece al complejo jurídico de la expropiación, institución exclusivamente de derecho público, segun quedó dicho en un parágrafo precedente (n. 1.293). No se trata, pues, de una acción de derecho comun, ni regulada por este. El derecho privado nada tiene que hacer al respecto. Finalmente, la acción de retrocesión, no obstante su carácter real, no trasunta técnicamente el ejercicio de una acción reivindicatoria, sino la impugnación a una expropiación donde la afectación del bien o cosa no se hizo al destino correspondiente, por lo que dicha expropiación resulta en contravención con la garantia de inviolabilidad de propiedad asegurada en la Constitución. La acción es "real" por la finalidad que persigue: reintegro de un bien o cosa" (Tratado de Derecho Administrativo, vol. IV, p. 382, n. 1.430). De igual sentido a orientação traçada no Novíssimo Digesto Italiano, onde se afirma que "per tale disciplina deve escludersi che il diritto alla retrocessione passa considerarsi un diritto alla risoluzione del precedente trasferimento coattivo, esso e stato definito un diritto legale di ricompera, ad rem (non in rem) (ob. cit., voce - espropriazione per pubblica utilità", vol. VI, p. 950). Recentemente o Supremo Tribunal Federal decidiu que "o expropriado pode pedir retrocessão, ou readquirir o domínio do bem expropriado, no caso de não lhe ter sido dado o destino que motivou a desapropriação" (RDA 130/229). No mesmo sentido o acórdão constante da "Rev. Trim. de Jur.", vol. 104/468-496, rel. Min. Soares Muñoz. 10 Transmissibilidade do direito. Não se cuida de direito personalíssimoAdmitida a existência da retrocessão no Direito brasileiro in specie, ou seja, havendo a possibilidade de reaquisição do imóvel, e rejeitando-se frontalmente, a solução dada pela jurisprudência de se admitir a indenização por perdas e danos, de vez que, a nosso ver, há errada interpretação do art. 35 do Dec.-lei 3.365/41 (LGL\1941\6), surge a questão também discutida se o direito à retrocessão é personalíssimo, ou é transmissível, causa mortis. Pela negativa manifestam-se Ebert Chamoun (ob. cit., p. 68), Eurico Sodré (ob. cit., p. 76), Hely Lopes Meirelles (ob. cit., p. 505) e Pontes de Miranda (ob. cit., p. 446). Em sentido oposto Hélio Moraes de Siqueira (ob. cit., p. 64) e Celso Antônio Bandeira de Mello (oh. cit., p. 210). A jurisprudência tem se manifestado favoravelmente à transmissão do direito de retrocessão (RTJ 23/169, 57 / 46 e 73/155). Inaplicável no Direito Público o art. 1.157 do CC (LGL\2002\400). Disciplina ele relações de particulares, devidamente ajustado ao art. 1.149 que, como se viu anteriormente, cuida, também, de manifestações volitivas. Já, a desapropriação implica na tomada compulsória do domínio dos particulares, em decorrência de ato imperativo (tal como por nós conceituado a fls. 29 do Ato Administrativo). A imperatividade implica em manifestação de poder, ou seja, na possibilidade que goza o Poder Público de interferir na esfera jurídica alheia, por força jurídica própria. Já nas relações particulares, estão estes no mesmo nível; quando intervém o Estado o relacionamento é vertical e não horizontal. Daí porque o referido dispositivo legal não tem aplicação ao tema em estudo. O TJSP já deixou decidido que "os sucessores do proprietário têm direito de ser indenizados, no caso de o expropriante do imóvel expropriado não se utilizar deste, e procurar aliená-lo a terceiros, sem mesmo oferecê-lo àqueles (RT 322/193). Rejeitando, apenas o direito de preferência, de vez que entendendo a retrocessão como espécie de direito real, aceita-se a argumentação da transmissibilidade da ação. No mesmo sentido a orientação do Supremo Tribunal Federal (RTJ 59/631). As ações personalíssimas são de interpretação estrita. Apenas quando a lei dispuser que não se transmite o direito causa mortis é que haverá impossibilidade jurídica da ação dos herdeiros ou sucessores a qualquer título. No caso ora analisado, verificando-se da inaplicabilidade do art. 1.157 do CC (LGL\2002\400), percebe-se que defluindo o direito à retrocessão da própria Constituição Federal, inarredável a conclusão que se cuida de direito transmissível. 11 Montante a ser pago pelo expropriado, pela reaquisição do imóvelResta indagar qual o critério para fixação do montante a ser pago pelo ex-proprietário quando do acolhimento da ação de retrocessão. Inicialmente, pode-se dizer que o expropriado deve devolver o montante apurado quando do recebimento do preço fixado pelo juiz ou havido mediante acordo lavrado em escritura pública. Inobstante, se o bem recebeu melhoras que tenham aumentado seu valor, parece-nos que devam elas ser levadas em conta, para efeito de apuração do montante do preço a ser devolvido ao expropriante. O valor a ser pago, pois, será o recebido à época, por parte do expropriado acrescido de melhoramentos eventualmente introduzidos no imóvel, caso deste se cuide. 12 Correção monetáriaHá autores que afirmam que a correção monetária não fará parte do valor a ser devolvido, "in principio", pois, embora haja previsão legal de seu pagamento quando da desapropriação, há razoável fundamento de que se o Poder Público não destinou o imóvel ou deu margem a que ele não fosse utilizado, por culpa sua, de seu próprio comportamento, deve suportar as consequências de sua atitude. A Corte Suprema de Justiça da Nação Argentina prontificou-se pelo descabimento da atualização monetária, deixando julgado que ''en efecto, obvio parece decir que el fundamento jurídico del instituto de la retrocesión es distinto ai de la expropiación, como que se origina por el hecho de no destinarse el bien expropiado al fin de utilidad publica previsto por la ley. Si esta finalidad no se cumple, el expropiante no puede pretender benefíciarse con el mayor valor adquirido por el inmueble y su derecho, como principio, se limita a recibir lo que pagó por él" (Fallos, t. 271, pp. 42 e ss.). Outro argumento parece-nos ponderável. É que, a se admitir a devolução com correção monetária poderia facilitar a intervenção do Estado no domínio econômico, de vez que poderia pretender investir na aquisição de imóveis, para restituí-los, posteriormente, com acréscimo de correção monetária, com o que desvirtuar-se-ia de suas finalidades precípuas. Parece-nos, entretanto, razoável que se apure o valor real do imóvel devidamente atualizado e se corrija, monetariamente, o valor da indenização paga, para que se mantenha a equivalência econômica e patrimonial das partes. Há decisão admitindo a correção monetária da quantia a ser paga pelo expropriado (RDP 11/274) proferida pelo Min. Jarbas Nobre, do TFR. O valor do imóvel serviria de teto para o índice da correção. 13 Rito processualO tipo de procedimento a ser adotado nas hipóteses de ação de retrocessão previsto na legislação processual. É o procedimento ordinário ou sumaríssimo, dependendo do valor da causa. Não há qualquer especialidade de rito, de vez que independe de depósito prévio. Não se aplica, aqui, o procedimento desapropriação, às avessas. Isto porque, no procedimento de desapropriação há um rito especial e pode o Poder Público imitir-se previamente na posse da coisa, desde que alegue urgência na tomada e efetue o depósito do valor arbitrado. Tal característica do processo de desapropriação não está presente no rito processual da ação de retrocessão. Demais disso, a ação depende de prévio acolhimento, com produção de prova do abandono do imóvel, ou sua não destinação ao fim anunciado no decreto. 14 Retrocessão de bens móveisA desapropriação alcança qualquer tipo de coisa. Não apenas os imóveis podem ser desapropriados. Isto porque o art. 2.0 do Dec.-lei 3.365/41 (LGL\1941\6) dispõe "mediante declaração de utilidade pública, todos os bens poderão ser desapropriados pela União, pelos Estados, Municípios, Distrito Federal e Territórios”. Como assinala Celso Antônio Bandeira de Mello "pode ser objeto de desapropriação, tudo aquilo que seja objeto de propriedade. Isto é, todo bem, imóvel ou móvel, corpóreo ou incorpóreo, pode ser desapropriado. Portanto, também se desapropriam direitos em geral. Contudo, não são desapropriáveis direitos personalíssimos, tais os de liberdade, o direito à honra, etc. Efetivamente, estes não se definem por um conteúdo patrimonial, antes se apresentam como verdadeiras projeções da personalidade do indivíduo ou consistem em expressões de um seu status jurídico, como o pátrio poder e a cidadania, por exemplo (ob. cit., p. 194). De igual teor a lição de Ebert Chamoun (ob. cit., 94). A lição do autor merece integral subscrição, por ser da mais absoluta juridicidade. A Constituição Federal assegura o direito de propriedade. A única limitação é a possibilidade de desapropriação, por parte do Poder Público. Mas, como a Constituição não limita a incidência da expropriação apenas sobre imóveis e a lei específica fala em "bens", entende-se que todo e qualquer direito pode ser desapropriado. Por consequência, qualquer bem pode ser passível de retrocessão (verbi gratia, os direitos autorais). 15 Retrocessão parcialCaso tenha havido desapropriação de um imóvel e parte dele não tenha aproveitada para a finalidade precípua declarada no decreto, surge a questão de se saber se o remanescente não utilizado pode ser objeto da retrocessão. Pelas mesmas razões expostas pelas quais se admitiu a existência da retrocessão no Direito brasileiro e cuidar-se de direito real, pelo qual o expropriado pode reaver posse e propriedade do próprio imóvel, admite-se a retrocessão parcial. 16 RenúnciaCaso o expropriado renuncie ao direito de retrocessão, nada terá a reclamar. Tratando-se, como se cuida, de direito patrimonial, é ele renunciável. Nada obriga a manter seu direito. Como salienta Ebert Chamoun, "a renúncia é plenamente eficaz. Uma vez que consta do instrumento de acordo dispositivo que exprima o desinteresse do ex-proprietário pelo destino que venha ulteriormente a ser dado ao bem e no qual se revele, claro e indiscutível, o seu propósito de renunciar ao direito de preferência à aquisição e ao direito de cobrar perdas e danos em face da infração do dever de oferecimento, o não atendimento das finalidades previstas no decreto desapropriatório, não terá quaisquer consequências patrimoniais, tornando-se absolutamente irrelevante sob o ponto de vista do direito privado" (ob. cit., p. 93). Embora não se adote a consequência apontada pelo autor. aceita-se o fundamento da possibilidade da renúncia. 17 Retrocessão na desapropriação por zonaNeste passo, acompanha-se o magistério de Celso Antônio Bandeira de Mello, segundo quem "é impossível cogitar de ação de retrocessão relativa a bens revendidos pelo Poder Público no caso de desapropriação por zona, quanto à área expropriada exatamente para esse fim, uma vez que, em tal caso não há transgressão alguma à finalidade pública em vista da qual foi realizada (ob. cit., p. 210). De igual teor a orientação de Ebert Chamoun (ob. cit., p. 96). E a posição é de fácil compreensão. O "interesse público", na hipótese, foi ditada exatamente para que se reserve a área para ulterior desenvolvimento da obra ou para revenda. Destina-se a absorver a extraordinária valorização que alcançará o local. De qualquer forma, estará o interesse público satisfeito. lnadmite-se, em consequência, a ação de retrocessão, quando a desapropriação se fundar em melhoria de determinada zona (art. 4.0 do Dec.-lei 3.365/41 (LGL\1941\6)). A propósito os pareceres de Vicente Ráo (RDP 7 /79), Castro Nunes (RDP 7 /94) e Brandão Cavalcanti (RDP 7 /102). 18 Referência jurisprudencialAlém da jurisprudência já referida no curso da expos1çao da matéria, convém transcrever alguns acórdãos do STF que cuidam do assunto. Negativa de vigência ao art. 1.150 do CC (LGL\2002\400). "Não vejo na decisão recorrida negativa de vigência do art. 1.150 do CC (LGL\2002\400). De conformidade com a melhor interpretação desse dispositivo, o expropriante não está obrigado a oferecer o imóvel ao expropriado, quando resolve devolvê-lo ao domínio privado, mediante venda ou abandono" (RTJ 83/97. Também o mesmo repertório 56/785 e 66/250. Possibilidade do exercício da ação. "Se se verifica a impossibilidade da utilização do bem, ou da execução da obra, então passa a ser possível o exercício do direito de retrocessão. Não é preciso esperar que o desapropriante aliene o bem desapropriado" (RTJ 80/150). Destinação diversa do bem. "Incabível a retrocessão ou ressarcimento se o bem expropriado tem destino diverso, mas de utilidade pública" (RTJ 74/95; No mesmo sentido o mesmo repertório 48/749 e RDA 127 /440). Pressupostos da retrocessão. "Retrocessão. Seus pressupostos; devolução do imóvel ao domínio privado, · quer pela alienação, quer pelo abandono por longo tempo, sem destinação de utilidade pública. Ausência desses pressupostos. Ação julgada improcedente" (RTJ 83/96). Fundamento do direito à retrocessão. "Constituição, art. 153, § 22CC (LGL\2002\400), art. 1 .150. Desapropriamento por utilidade pública. Reversão do bem desapropriado. O direito à requisição da coisa desapropriada tem o seu fundamento na referida norma constitucional e na citada regra civil, pois uma e outra exprimem um só princípio que se sobrepõe ao do art. 35 do Dec.-Lei 3.365/41 (LGL\1941\6), visto que o direito previsto neste último (reivindicação) não faz desaparecer aqueloutro" (RTJ 80/139). Estes alguns excertos jurisprudenciais de maior repercussão, já que enfrentaram matéria realmente controvertida dando-lhe solução fundamentada. Há inúmeros julgados sobre o tema que, no entanto, dispensam transcrição ou menção expressa, pois outra coisa não fazem que repetir os argumentos já manifestados. Como se cuida de matéria controvertida e a nível de repertório enciclopédico, o importante é a notícia sobre o tema, sem prejuízo de termos feito algumas colocações pessoais a respeito. Nem tivemos o intuito de esgotar o assunto, de vez que incabível num trabalho deste gênero.

RESUMENNuestro conocimiento sobre las religiones protohistóricas se encuentra prejuiciado por categorías de pensamiento presentistas y el recurso a fuentes posteriores. Para lograr una caracterización mínima de la fenomenología de tales manifestaciones se propone una aproximación a partir de los materiales de la Edad del Hierro, con atención a los problemas y metodologías de la arqueología, que privilegie el estudio de casos particulares frente a la generalización céltica. A través del ejemplo de la cultura castreña, se examinará qué elementos constituyeron objeto de atención ritual y sobredimensión simbólica para una sociedad de la Edad del Hierro.PALABRAS CLAVE: Cultura Castreña, Edad del Hierro, protohistoria, ritual, arqueologíaABSTRACTOur knowledge of protohistoric religions is prejudiced by presentist ways of thinking and recourse to later sources. To achieve a minimum characterization of the phenomenology of such manifestations, I propose an approach based on Iron Age materials, being careful of the archaeological problems and methodologies, and favouring particular case studies rather than Celtic generalizations. Through the example of Castreño culture, I will examine which elements might have been the object of ritual attention and symbolic oversizing in an Iron Age society.KEY WORDS: Castro culture, Iron Age, Protohistory, ritual, archaeologyBIBLIOGRAFÍAAlmeida, C. A. F. (1980) “Dois Capacetes e tres copos, em Bronze, de Castelo de Neiva”, Gallaecia, 6, 245-257.Alonso Burgos, F. (2014): Estructura social y paisaje simbólico: las comunidades astures y el imperio romano. Tesis doctoral inédita, Universidad Complutense de Madrid.Angelbeck, B. y Grier, C. 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RESUMENUna de las manifestaciones más significativas de cada sociedad es el diseño de su ritual funerario, puesto que refleja las bases religiosas e ideológicas en las que se sustenta su organización. Aunque muchos de los procesos implicados en los funerales son efímeros, los cementerios y las sepulturas contienen información material que es estudiada por la arqueología con métodos cada vez más sofisticados, entre los que destacan los análisis isotópicos y genéticos. No menos importantes son los nuevos planteamientos teóricos. Si en la arqueología de la muerte tradicional los enterramientos eran ordenados por riqueza, sexo y cronología, en la actualidad se añaden otras perspectivas de estudio, como el papel asignado al género o la manipulación ideológica del ceremonial fúnebre. Finalmente, las nuevas ideologías del presente plantean retos y cortapisas que estimulan, pero también dificultan, el trabajo arqueológico. Palabras clave: arqueología funeraria, muerte, ideología, ritual, género, excavación de cementerios ABSTRACTOne of the most significant manifestations of every society is the design of its funeral ritual since it reflects the religious and ideological frames on which its organization is based. Although many of the processes involved in funerals are ephemeral, cemeteries and graves contain material information that is studied by archeology with increasingly sophisticated methods, including isotopic and genetic analyses. No less important are the new theoretical approaches. Within the traditional “Archeology of Death”, burials were ordered by wealth, sex, and chronology. Nowadays, other study perspectives are added, such as the role assigned to gender or the ideological manipulation of the funerals. Finally, the new ideologies of the present pose challenges and obstacles that stimulate, but also hinder, archaeological work. 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