Littérature scientifique sur le sujet « Epidermal Growth Factor Breast Neoplasms Breast Neoplasms »

Background The incidence of human epidermal growth factor receptor 2 (HER 2) positive breast cancers is rapidly rising worldwide. Although there have been many studies on HER 2 breast cancer treatment and management in recent years, there is a lack of comprehensive reports on the treatment outcomes and disparities within the available literature. Hence, this review aimed to determine the treatment outcomes and their associated factors among patients with HER2-positive breast cancer. Methods A computer-based systematic literature search was conducted using PubMed, EMBASE, and Google scholar databases of articles published from 2000 to 2020. The following key terms (HER 2 positive breast cancer, predictor, determinant, associated factor) and Medical Subject Headings (MeSH) terms (breast neoplasms, treatment outcome, and risk factors) were used to search the English language published articles. Results In most studies, trastuzumab was the most commonly used treatment regimen used in combination with chemotherapeutic agents. Generally, most of the studies (15 studies) showed that the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. Nonetheless, two studies showed that the absence of significant change in the overall survival despite adequate treatment was given to the study participants. In addition, three studies demonstrated a partial response after treating HER2-positive breast cancer patients. Conclusion Generally, the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. The addition of trastuzumab in most of the studies has shown improvement in the overall survival and the disease-free survival rate of the study patients.

Breast cancer accounts for a high burden among all the neoplasms in Latin America, with more-advanced stages at presentation, which could result in high mortality rates. The 4th International Consensus Conference for Advanced Breast Cancer (ABC4) is focused on standardizing therapy for advanced breast cancer (ABC) and has held 5 meetings so far. ABC4 took place in Lisbon, Portugal, from November 2 to 4, 2017; however, the first Latin American ABC conference was held in Lima, Peru, from 18 to 19 May, 2018, chaired by Fatima Cardoso, MD, PhD. During these 2 days, the ABC4 consensus recommendations for advanced and locally advanced breast cancer were presented. Local treatment and systemic therapy were discussed with local experts, mainly focusing on anti–human epidermal growth factor receptor 2 therapy and newly approved drugs for hormone receptor–positive breast cancer, such as as CDK4/6, mammalian target of rapamycin, and poly (ADP-ribose) polymerase inhibitors for triple-negative breast cancer. The discussion focused additionally on access to drugs and ABC4 consensus recommendations as regards Latin American patients.

BACKGROUND: Cancer stem cells (CSCs) eradication might serve as a robust approach for cancer eradication. MCF-7 as breast cancer continuous cell line is known to contain breast CSCs (BCSCs) for its capability to maintain its original tumor population. CSCs enriched culture is a fundamental tool for CSCs targeted therapy development. Effective and unsophisticated CSCs dedifferentiation protocol for producing CSCs enriched culture is needed.METHODS: MCF-7 cells were cultured initially in Dulbecco's Modified Eagle Medium (DMEM) low glucose medium then changed to DMEM:F12. Serum starvation was performed during each medium refreshment gradually with fetal bovine serum (FBS) concentration of 10%, 5%, 2.5% until reaching 1% FBS concentration. Stable MCF-7 culture was then adapted to serum free culture system, containing DMEM:F12, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and B27 supplement as dedifferentiation protocol for 18 days. Cluster of differentiation (CD)44 and CD24 double staining immunocytochemistry was performed to evaluate cell stemness.RESULTS: The population of cells expressing BCSCs markers (CD44+/CD24low) in non-adherent single cells subpopulation was significantly increased after the dedifferentiation procedure (70.39%) compared to control groups (0.71%) (p<0.05). In contrast, the expression of BCSCs marker in adherent single cells subpopulation and for both adherent and non-adherent mammosphere the BCSCs markers showed a stable expression.CONCLUSION: BCSCs enrichment of breast cancer cell cultures from MCF-7 breast cancer cell line can be performed. Breast cancer cell plasticity is observed during the dedifferentiation protocol. Development of dedifferentiation inducing protocols can serve as an important foundation for breast cancer therapy development through BCSCs elimination.KEYWORDS: breast neoplasms, cell line, dedifferentiation, immunohistochemistry, neoplastic stem cells

e12595 Background: Breast cancer is one of the most frequent neoplasms worldwide, contributing to women's morbimortality. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of cancer marked by negative estrogen receptors, progesterone receptors, and lack of the human epidermal growth factor 2 (C-erbB2, HER2/neu) gene overexpression. The high mobility group box-1 (HMGB1) is a factor that regulates malignant tumorigenesis, proliferation, and metastasis. Aim: Here, the HMGB1 expression was investigated as a prognostic factor for TNBC. Methods: Clinico-pathological data and surgical paraffin histopathology blocks were assessed from 85 patients treated at Haroldo Juaçaba Hospital (Ethics committee approval number 407.395). Samples were analyzed by immunofluorescence using the Tissue Microarray technique to determine the percentage of fluorescent cells with cytoplasmic HMGB1 (cHMGB1) expression. Results: The clinico-pathological data analysis indicated that patients were older than 50 years (68.2%) and diagnosed with grade 2–3 ductal carcinomas (91.8%). Tumor metastasis was observed in 9.9% of cases. TNBC patients that tumor cells presented high cHMGB1 fluorescence demonstrated increased local tumor recurrence compared with low expressing tumors (P=0.019). Five-year overall survival was simmilar between the patients with low (63%) versus high (66%) cHMGB1 expression (P=0.7441). Additionally, the risk of death was 0.8 (95% CI = 0.21–2.96). Conclusions: The cHMGB1 expression is associated with an increased tumor relapse in TNBC, not affecting patients' survival.

21034 Background: The AKT kinase, when phosphorylated to its activated form (pAKT), mediates many proliferative and survival effects of growth factor receptors such as members of the epidermal growth factor receptor (EGFR) family. Overexpression of AKT in breast neoplasms suggests that AKT activation is involved in breast cancer development and/or progression, and contributes to poor outcome. pAKT is frequently upregulated in Her-2/neu positive breast cancers. Activated AKT is able to phosphorylate in vitro serine 167 (pS167) of estrogen receptor alpha (ERa), resulting in ER-mediated transcriptional activity in the absence of estrogen and possibly contributing to tamoxifen resistance in ERa positive breast cancers. In addition, ERa is phosphorylated at S118 (pS118) by MAPK. Thus, it is possible that pAKT- mediated ERa phosphorylation is implicated in tumorigenesis and resistance to treatment with hormonal therapy in patients with breast cancer. Methods: Utilizing commercially available antibodies, IHC analysis of 125 paraffin-embedded, ERa positive, early breast cancer cases, stratified for stage, were tested for pAKT, PTEN, pS167, and pS118. Staining intensity and number of positive cells were assessed by 4 independent graders. Fisher's exact test was used to determine the significance of associations with a two-sided type I error of 5%. Results: Phosphorylation of AKT occurred in approximately one-half of cases. pS167 was phosphorylated in 66% of pAKT positive cases compared to 35% of pAKT negative cases (p<0.0001). When we analyzed nuclear pAKT staining, this association was more pronounced: 76% of pAKT(+) vs. 37% of pAKT(-) (p<0.0001). 69% of pS118(+) cases were pS167(+) compared to only 15% pS167(+) when pS118 was negative (p<0.0001). In approx. 32% of cases pAKT was present in both the cytoplasm and nucleus. 20% of samples had only cytoplasmic pAKT, while in 4% of cases pAKT was nuclear only, supporting the hypothesis that cytoplasmic phosphorylation of AKT may precede nuclear accumulation. Conclusions: Phosphorylation of pS167ERa is significantly associated with AKT activation (especially in the nucleus) in early breast cancer, supporting the hypothesis that these two events may be causally linked and contribute to breast cancer pathogenesis. No significant financial relationships to disclose.

Aim: To evaluate the presence of contrast enhancement at the site of calcifications on contrast-enhanced mammography (CEM) and histopathologic results at vacuum-assisted biopsy (VAB), and to examine the association with lesion size and immunohistochemical characteristics, in order to assess disease aggressiveness in malignant lesions. Methods: A total of 34 patients with 36 clusters of suspicious calcifications (BI-RADS 4) were investigated with CEM before the scheduled VAB. We evaluated the presence or absence of enhancement, histologic diagnosis, and, in case of malignant lesions, their size and the expression of Ki-67. Results: In our case series, 15/36 (41.7%) lesions were malignant. In 7 cases, contrast enhancement was found at the site of calcifications. Data about size of lesions and immunohistochemical characterization were not available for all malignant cases. In 5 cases with CEM enhancement, all lesions were >5 mm and overexpressing Ki-67 (>20%); in 6 cases with no contrast enhancement, the lesions were <5 mm and with low Ki-67 values (<20%). Conclusion: Our preliminary study provides indications on the ability of CEM to recognize neoplasms larger than 5 mm, with high proliferative index (Ki-67 >20%), and frequently human epidermal growth factor receptor 2–positive. Our preliminary results suggest that CEM could detect aggressive malignancies. This could be the starting point for planning further studies with larger numbers of cases, in an attempt to reduce overdiagnosis and consequent overtreatment.

Abstract Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure, congenital malformations and a propensity for developing malignancies at an early age. The underlying genetic defect in FA creates a state of cellular hypersensitivity to many traditional chemotherapy agents, making the treatment of malignancies in this population particularly challenging. We describe a 42-year-old female who presented with a solitary mass in her left breast. Core biopsy revealed an invasive ductal carcinoma that did not express estrogen (ER) or progesterone receptors (PR), but did express human epidermal growth factor receptor 2 (HER2). Staging work-up revealed diffuse skeletal metastatic disease. At her initial consultation with medical oncology, she was discovered to be pancytopenic. Further history revealed a sibling with aplastic anemia and that she had undergone chromosomal breakage testing for FA in the past, which was subsequently confirmed to be positive. She underwent a bone marrow aspirate and biopsy that showed metastatic marrow infiltration by non-hematopoietic cells. In addition there was morphological evidence of dyserythropoiesis and cytogenetic abnormalities on karyotyping, features suggestive of FA. She was initially started on trastuzumab monotherapy. Low dose radiation therapy was added due to local tumor progression. Combined HER2 directed therapy was to be implemented, but was held due to a functional decline in the patient. To date, she has not received definitive genetic testing to determine which FA subgroup she belongs to. This case highlights two important aspects of FA. The first is the inherent increase in susceptibility to neoplasms in this group, including solid tumors such as breast cancer. The genes associated with FA are involved in deoxyribonucleic acid (DNA) repair pathways, including mutations in the breast cancer susceptibility gene, BRCA2. The second is the heightened sensitivity to the toxic effects of many standard chemotherapy and radiation treatments. This creates unique challenges in the treatment of malignancies in this population and stresses the importance of targeted therapies. Disclosures No relevant conflicts of interest to declare.

e23120 Background: 15%-25% of breast cancer neoplasms exhibit Human epidermal growth factor receptor-2(HER2) amplification, as the driver mutation.Techniques to identify HER2 amplification include Immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH). Digital PCR (dPCR) has been increasingly explored in determining HER2 status in cases of indeterminate results on IHC, mainly in archived samples. In this study, we aim to demonstrate the clinical utility of the Quantstudio 3D Digital PCR system to evaluate HER2 levels from Formalin Fixed Paraffin Embedded (FFPE) tissue with RNaseP as a control target. Methods: 61 tissue samples were analyzed by IHC and dPCR in parallel in a double blinded manner. IHC equivocal samples were reflexed to FISH and compared to the results obtained from dPCR. Samples suboptimal for IHC or FISH were satisfactorily processed by dPCR. dPCR results were analyzed on the Thermofisher Cloud platform. The general turnaround time(TAT) was about 2 and 3 days for IHC and FISH respectively with that of dPCR being 24 hours. Results: All 9 IHC positive and 35 negative samples had similar results on dPCR using an amplification ratio threshold for a positive result of 1.8. Of 17 IHC-equivocal samples, 5 resulted as positive, 10 negative and 2 as equivocal by dPCR. There was 100% concordance between the dPCR and FISH results. Two IHC equivocal samples that were unanalyzable by FISH were negative on dPCR Conclusions: Our results demonstrate that the chip based dPCR was non-inferior for HER2 detection in FFPE samples in a clinical setting. Superior TAT's and objective results were obtained compared to more subjective techniques like FISH and IHC even with low sample input. dPCR requires controls but no standards for calibration as it gives absolute copy numbers. Further study is needed to understand dPCR interpretation in cases of chromosomal aneuploidy. [Table: see text]

Mammary Paget’s disease accounts for 1% to 3% of all breast tumors and manifests as a chronic eczematous lesion of the areolar skin. It can occur without any underlying neoplasia or can be present in association with an underlying invasive and/or in situ carcinoma of the breast. The present report describes a challenging nipple punch biopsy showing an infiltration of the lower third to two-thirds of the epidermis by large, ovoid, neoplastic cells. The morphology was consistent with mammary Paget's disease, although immunohistochemistry for cytokeratin-7 (CK7) was repeatedly negative. This resulted in an initial misdiagnosis and, subsequently, a delay in the patient's follow-up. Additional immunohistochemistry for GATA binding protein 3 (GATA3) and human epidermal growth factor receptor 2 (HER2), as well as a second opinion of a breast pathologist, resulted in the diagnosis of mammary Paget's disease. The aim of this article is to raise awareness among pathologists and prevent them from misdiagnosing CK7-negative Paget disease of the breast.

Background: The human epidermal growth factor type 2 (HER2) receptor is a membrane glycoprotein tyrosine kinase. In woman, HER2 expression is diagnosed in 30% of breast carcinomas and it is associated with a worse prognosis, higher rate of recurrence and mortality. In the bitch, the HER2 overexpression in canine mammary tumors is still controversial and the prognostic value remains uncertain. Thus, we aimed to verify the HER2 expression in canine mammary carcinomas and relate it to the type and histological grade, lymph node metastasis and clinical staging.Materials, Methods & Results: Ninety bitches diagnosed with mammary carcinoma were included in this study. The inclusion criteria were bitches with complete clinical examination, thoracic radiographic examination and submitted unilateral or bilateral mastectomy. Ninety-nine samples of mammary carcinoma were used and the fragments of tumor and regional lymph nodes were fixed in 10% neutral formalin for histopathological and immunohistochemistry analysis. The lesions were evaluated by two pathologists and classified according to the type and histological grade. HER2 expression was performed by semi-quantitative analysis of the slides according to the HerceptTestTM (Dako) recommended score. Simple carcinomas were the most frequent (51.51%) followed by complex carcinomas (46.47%) and in situ carcinoma (2.02%). The histological grade of 97 carcinoma samples was attributed, except in situ carcinoma, 37 (38.14%) of the neoplasms were grade I, 50 (51.55%) grade II and only 10 (10.31%) tumors were classified as grade III. Forty bitches were submitted to clinical staging (TNM) and 42.50% of the bitches received staging in grade I and, 25% of the bitches staged in grade IV and V, with metastases. The HER2 expression, 13/99 samples (13.13%) received score +2, 19/99 (19.19%) score +1 and absence of marking (score 0) was identified in 67 samples (67.80 %). Immunostaining in hyperplastic or normal epithelial cells was evidenced, often in association with weak or moderate cytoplasmic labeling. Of the samples expressing +2 score for HER2 (n = 13), eight samples (17.39%) were complex carcinoma and five (9.80%) simple carcinomas. There was no relationship between HER2 immunostaining with age, tumor size, TNM, histological type, histological gradation, lymph node metastasis and distance. Animals with lymph node metastasis, as well as those diagnosed with distant metastasis, did not present HER2 expression in the tumors.Discussion: The simple carcinoma seems to be the most frequent type histological diagnosed in canine mammary carcinomas, followed by carcinoma in mixed tumor and complex carcinoma. Tubulopapillary carcinomas are more invasive in the female dogs as well as in the woman. Carcinomas grade I and II are more frequent and present a better prognosis for the dog. However, bitches with grade III carcinoma survived for a shorter time when compared to dogs with grade I or II tumors. A factor that may have contributed to the lower number of bitches at worst prognostic stage (EC IV and V) is the current owners’ awareness that they have sought veterinary help earlier, as soon as they detect small nodules in mammary gland. Overexpression of HER2 in women breast cancer is diagnosed in 20-30% of cases, whereas in bitches, this expression is variable. Also the different percentages of canine HER2 immunostaining are due to the lack of standardization for the analysis of the immunostaining, the immunohistochemical techniques employed and the non-specificity of the HER2 antibody. In canine mammary carcinomas the HER2 expression in low and this immunostaining is not related to other established prognostic factors. This study reinforces the hypothesis put forward by other authors that in the bitch the expression of HER2 may not be related to malignancy and tumor progression.

Thesis (Ph. D.)--West Virginia University, 2004.
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Uvod: Karcinom dojke je heterogena bolest koju karakterišu različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodološko određivanje i analiza još uvek nisu standardizovani. Cilj: Utvrditi graničnu (“cut-off”) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao što su životna dob bolesnica, veličina tumora, histološki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodišnjeg perioda praćenja pacijentkinja. Metode: Retrospektivno je analizirano 120 patohistoloških izveštaja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. Rezultati: Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42±10,17 godina; prosečna veličina tumora 17,98±6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49±20,23 meseci. Vrednost “cut off” indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92±8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histološki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p > 0,05). Zaključak: Zbog heterogene prirode oboljenja, korišćenjem standardnih histopatoloških faktora i biomarkera teško je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima loše prognoze.
Introduction: Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. Objective: Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient's age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. Methods: Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. Results: The average patient’s age was 57.42±10.17 years; average tumor size 17.98±6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49±20.23 months. "Cut off" Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn’t show significant relationship between Ki-67 and patient’s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor’s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92±8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p> 0.05). Conclusion: Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis.

INTRODUÇÃO: Os carcinomas HER-2 positivos representam cerca de 20- 30% de todos os tumores da mama e se caracterizam por curso clínico mais agressivo, com alta proliferação celular e resistência a apoptose, determinados por cascatas de sinalizações intracelulares, tais como a via PI3K/AKT. O trastuzumabe, um anticorpo monoclonal humanizado que se liga à molécula de HER-2, é o tratamento padrão destas pacientes. A resposta a monoterapia com trastuzumabe varia de 12-30% e a persistência da ativação da via PI3K/AKT é um dos mecanismos de resistência. A ativação do AKT começa com a fosforilação do PIP2 a PIP3 pela PI3K. A desfosforilação do PIP3 é mediada pela PTEN e sua deficiência é um dos fatores possivelmente implicados na resistência ao trastuzumabe. Além da resistência à terapêutica, os tumores HER-2 positivos são heterogêneos quanto ao seu comportamento biológico. A busca de diferentes padrões morfológicos e moleculares neste grupo de carcinomas pretende identificar subgrupos prognósticos e preditivos, permitindo a individualização terapêutica. OBJETIVOS: Estudar a expressão imunoistoquímica de duas moléculas da via de sinalização PI3K/AKT (PTEN e AKT fosforilada) e explorar a via de sinalização androgênica através da expressão do receptor de androgênio e dos perfis morfológico e molecular apócrinos. METODOLOGIA: O estudo foi retrospectivo com revisão dos preparados histológicos e construção de blocos de microarranjos com amostras dos tumores para estudo imunoistoquímico. Na revisão foram avaliados: tipo histológico, características morfológicas apócrinas, presença de componente in situ, graus histológico e nuclear, receptores de estrogênio e progesterona, e atividade proliferativa através da expressão imunoistoquímica do Ki-67. Os preparados histológicos foram submetidos à pesquisa de PTEN, AKT fosforilada e receptor de androgênio. Pacientes, familiares e médicos foram contatados para recuperação do seguimento e evolução. RESULTADOS: Foram estudadas 104 pacientes portadoras de carcinoma primário da mama. A expressão de PTEN esteve reduzida em 20/104 (19,2%) dos casos e foi mais freqüente nos tumores com AKT positivo (p= 0,06). O grupo de tumores sem perda de expressão de PTEN apresentou maior atividade proliferativa. A AKT foi positiva em 71/104 (68,3%) casos e se associou a maior grau de diferenciação e à expressão de receptor de androgênio. O receptor de androgênio foi positivo em 89/104 (85,6%) dos casos e esteve associado ao menor grau histológico (p=0,018), receptor de estrogênio (p=0,008) e menor atividade proliferativa (p=0,001). A ausência da expressão do receptor de estrogênio (perfil molecular apócrino) foi identificada em 41/104 casos (39,4%) e se associou a tumores com grau histológico mais alto. O perfil morfológico apócrino foi identificado em 71 (68,3%) dos casos e se associou a alto grau histológico e nuclear. O seguimento foi possível em 55 casos e observamos tendência a menor sobrevida livre de doença nos tumores AKTpositivos e RA-negativos. CONCLUSÕES: Nossos resultados comprovam a heterogeneidade dos carcinomas mamários HER-2 positivos e indicam diferenças em pelos menos duas vias de sinalização celulares como possíveis explicações para as mesmas: a via PI3K/AKT e a androgênica
BACKGROUND: HER-2 positive carcinomas represent about 20-30% of all breast tumors and are characterized by a more aggressive clinical course with high cell proliferation and apoptosis resistance, determined by cascades of intracellular signals, such as the PI3K/AKT pathway. Trastuzumab, a humanized monoclonal antibody that binds to HER-2 molecule, is the standard treatment for these patients. The response to monotherapy with trastuzumab ranges from 12-30% and the persistence of activation of the PI3K/AKT pathway is one of mechanisms of resistance. Activation of AKT begins with the phosphorylation of PIP2 to PIP3 by PI3K. The dephosphorylation of PIP3 is mediated by PTEN and its deficiency is one of the factors possibly involved in resistance to trastuzumab. In addition to resistance to therapy, HER-2 positive tumors are heterogeneous in their biologic behavior. The search for different morphological and molecular patterns of carcinomas in this group aims to identify prognostic and predictive subgroups, allowing for customized therapy. OBJECTIVES: To study the immunohistochemical expression of two molecules of the signaling pathway PI3K/AKT (phosphorylated AKT and PTEN) and to explore the androgen signaling pathway through the expression of androgen receptor and apocrine morphological and molecular profiles. METHODS: This study retrospectively reviewed the histological preparations and built tissue microarray with tumor samples for immunohistochemical study. We assessed histologic type, apocrine morphology, presence of in situ component, histologic and nuclear grade, estrogen and progesterone receptors and proliferative activity through the immunohistochemical expression of Ki-67. The tissue preparations were examined for PTEN, phosphorylated AKT and androgen receptor. Patients, relatives and physicians were contacted for retrieval of follow-up data. RESULTS: We studied 104 primary breast cancer patients. The expression of PTEN was reduced in 20/104 (19.2%) cases and was more frequent in tumors with positive AKT (p = 0.06). The group of tumors without loss of PTEN expression showed higher proliferative activity. AKT was positive in 71/104 (68.3%) cases and was associated with a higher degree of differentiation and with expression of androgen receptor. The androgen receptor was positive in 89/104 (85.6%) cases and was associated with lower histological grade (p = 0.018), estrogen receptor (p = 0.008) and lower proliferative activity (p = 0.001). The absence of expression of estrogen receptor (apocrine molecular profile) was identified in 41/104 cases (39.4%) and was associated with tumors of higher histologic grade. The apocrine morphological profile was identified in 71 (68.3%) cases and was associated with high histological grade and nuclear. Follow-up was possible in 55 cases and a trend for shorter disease-free survival was observed in AKT-positive and AR-negative tumors. CONCLUSIONS: Our results confirmed that HER-2-positive breast cancers are heterogeneous and indicate that differences in at least two cellular signaling pathways PI3K/AKT and androgen pathway might underliy such a heterogeneity

This thesis concerns a melanoma-derived growth regulatory factor that inhibited proliferation of several malignant human cell lines, and, in particular, a line designated UCT-BR-1, which was derived from a human breast cancer metastasis. The work is presented in four chapters. Chapter 1 provides a review of the relevant literature at the time of writing; Chapters 2 and 3 describe the experimental work that was done; and in Chapter 4 I discuss the implications of my results for current and future work in growth factors. Experimental results are presented as Charts (which may be Figures or Tables) and the methods and experimental protocols that I used are described in the Chart legends and not in the main text of the thesis. The Appendix contains details of the tissue culture techniques and descriptions of the cell lines that were used. Sources of the various laboratory materials as well as the methods that were employed for the more routine procedures are also described in the appendix.

Introdução: Os sítios mais comuns de metástases de câncer de mama são pulmões, ossos, fígado e cérebro. Sítios menos comuns incluem trato gastrointestinal, pâncreas, baço, tireoide, adrenais, rins, coração e trato genital feminino (TGF). As metástases no TGF de sítios primários distantes são incomuns, mas quando se apresentam, tendem a estar envolvidas com os ovários ou o endométrio. O relato deste estudo retrata a ocorrência de neoplasia maligna metastática paratubária em paciente com carcinoma primário de mama. Objetivos: Relatar o caso de uma paciente com metástase de carcinoma de sítio primário de mama para o TGF e revisar na literatura disponível tal ocorrência. Material e Métodos: As informações do caso foram obtidas a partir da revisão de prontuário, registro fotográfico diagnóstico da paciente e revisão de literatura. A revisão foi realizada na base de dados do PubMed, em estudos publicados nos últimos 20 anos (2000‒2020), com os termos “breast cancer” AND “metastasis” AND “female genital tract”. Os artigos selecionados foram estudos meta-analíticos, casos clínicos e revisões na língua inglesa. Resultados e Conclusão: Paciente, sexo feminino, 70 anos, G1P1. Há 20 anos submetida à mastectomia esquerda apresentando carcinoma ductal invasor (CDI), com RE e RP positivo e Human Epidermal growth factor Receptor-type 2 (HER2) negativo. Realizou histerectomia com anexotomia profilática com diagnóstico de neoplasia maligna metastática em tuba esquerda com 1:1 cm no maior eixo. Exame imuno-histoquímico apresentando GATA3 negativo, CK7, Mamoglobina, PAX8, RP e RE positivos. Exames laboratoriais e de imagem pré-operatórios negativos para neoplasia. O CDI é o tipo mais comum de câncer de mama invasivo, seguido pelo carcinoma lobular invasivo (CLI). Contudo, metástases para o TGF são mais frequentemente associadas ao CLI do que ao CDI. Estima-se que mais de 80% dos cânceres de mama que metastatizam para o TGF são CLI. Um estudo realizado em mulheres com metástase ginecológica (n=54) demonstrou que 42,6% tinham câncer de mama correspondente a CLI; 48,1%, carcinoma invasor sem tipo específico; e 9,3%, outros. Além disso, o estudo revelou que os sítios de metástases ginecológicas mais envolvidos foram os ovários, seguido das tubas e do útero. A respeito da expressão de biomarcadores de tumores primários que se espalharam para sítios ginecológicos, 93,5% expressou RE positivo; 65,7%, RP positivo; e 0%, HER2 positivo. Uma avaliação de 13 casos mostrou que, enquanto a expressão de RE e FOXA1 foi mantida ou aumentada durante a progressão para órgãos ginecológicos, a expressão de proteínas acessórias envolvidas com a regulação hormonal diminuiu. Conforme o aumento do tumor, as células que expressam RP, RA e GATA3 em metástases distantes diminuíram em 69,2, 38,5 e 46% dos casos, respectivamente. O relato em questão confirma os resultados obtidos nos estudos, já que apresenta semelhança na expressão gênica de carcinomas primários de mama com metástase para o TGF. No entanto, apresenta um histotipo incomum para metástases ginecológicas.