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백철. "Commercial Consciousness of San yan er pai." Journal of Chinese Language and Literature ll, no. 75 (June 2016): 251–75. http://dx.doi.org/10.26586/chls.2016..75.010.
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Ham, Eun Sun. "Analysis on the Behavior Motivation of the Matchmakers in “San yan” and “Er pai”." Journal of Chinese Studies 86 (November 30, 2018): 61–77. http://dx.doi.org/10.35982/jcs.86.3.
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SoJung kim. "The two different perspectives on Women, a male narrative in San-Yan(三言) & Er-Pai(二拍) & Huan-Xi-Yyuan-Jia(歡喜寃家)." Journal of the research of chinese novels ll, no. 28 (September 2008): 215–36. http://dx.doi.org/10.17004/jrcn.2008..28.012.
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Ouyang, Quchang, Huihua Xiong, Min Yan, Jincai Zhong, Li Ran, Ting Luo, Liping Liu, et al. "Abstract P2-13-32: Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–13–32—P2–13–32. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-13-32.
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Abstract Background: HER2-targeted agents combined with endocrine therapy (ET) has been recommended as an optional therapeutic strategy for hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) co-positive metastatic breast cancer (MBC). Pyrotinib is an oral irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting EGFR, HER2 and HER4, with proven efficacy in combination with chemotherapy in HER2-positive MBC. This multicenter, single-arm phase 2 trial aimed to investigate the efficacy and safety of pyrotinib plus letrozole in patients with estrogen receptor (ER)-positive, HER2-positive MBC (NCT04407988). Methods: Pre-/perimenopausal or postmenopausal women with histologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with fluorescence in situ hybridization positive) and ER-positive (the percentage of ER+ cells ≥ 10% by IHC) MBC were enrolled. Prior treatment for metastatic disease was not allowed. Eligible patients received pyrotinib (400 mg, po, qd) plus letrozole (2.5 mg, po, qd) until disease progression or unacceptable toxicity. For pre-/perimenopausal patients, additional treatment with ovarian function suppression (OFS) was required. The primary endpoint was clinical benefit rate (CBR), defined as the rate of patients with complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks per RECIST 1.1. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 3, 2019 and April 2, 2021, 26 patients were enrolled. As of July 5, 2021, CBR was 76.9% (20 of 26; 95% CI 56.4% to 91.0%) and ORR was 57.7% (15 of 26; 95% CI 36.9% to 76.6%). One of the 26 patients (3.8%) had CR, 14 (53.8%) had PR, 5 (19.2%) had SD, 5 (19.2%) had progressive disease, and 1 (3.8%) had not evaluable disease. The benefits in CBR and ORR were observed across all subgroups. The most common any grade AEs were diarrhea (25 of 26, 96.2%), vomiting (8 of 26, 30.8%), nausea (6 of 26, 23.1%), and oral ulceration (6 of 26, 23.1%). Diarrhea was the only reported grade 3 AE that occurred in 5 patients (19.2%). No grade 4 or 5 AEs occurred during this study. Conclusions: Pyrotinib combined with letrozole showed an encouraging antitumor activity with good tolerance in patients with ER/HER2 co-positive MBC, promising as an alternative treatment option for this disease. The study is ongoing. Citation Format: Quchang Ouyang, Huihua Xiong, Min Yan, Jincai Zhong, Li Ran, Ting Luo, Liping Liu, Jing Li, Xiaohong Yang, Huawu Xiao, Ning Xie, Hui Wu, Jianxiang Gao, Jun Lu, Xuming Hu, Zheyu Hu, Can Tian, Zhengrong Shui, Min Cao. Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial [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 P2-13-32.
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Tseng, Chu-Yao, Ching-Wen Huang, Hsin-Chia Huang, and Wei-Chen Tseng. "Utilization Pattern of Traditional Chinese Medicine among Fracture Patients: A Taiwan Hospital-Based Cross-Sectional Study." Evidence-Based Complementary and Alternative Medicine 2018 (September 30, 2018): 1–9. http://dx.doi.org/10.1155/2018/1706517.
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Traditional Chinese medicine (TCM) divides fracture treatment into three stages. Many TCM herbs and formulas have been used to treat fractures for thousands of years. However, research regarding the Chinese herbal products (CHPs) that should be used at different periods of treatment is still lacking. This study aims to identify the CHPs that should be used at different periods of treatment as well as confirm the TCM theory of fracture periods medicine. We used prescriptions of TCM outpatients with fracture diagnoses analyzed using the Chang Gung Research Database (CGRD) from 2000 to 2015. According to the number of days between the date of the fracture and the clinic visit date, all patients were assigned to one of three groups. Patients with a date gap of 0-13 days were assigned to the early period group; those with a date gap of 14-82 days were assigned to the middle period group; and those with a date gap of 83-182 days were assigned to the late period group. We observed the average number of herbal formulas prescribed by the TCM doctor at each visit was 2.78, and the average number of single herbs prescribed was 6.47. The top three prescriptions in the early fracture period were Zheng-gu-zi-jin-dang, Shu-jing-huo-xue-tang, and Wu-ling-san. In the middle fracture period, the top three formulas were Zheng-gu-zi-jin-dang, Shu-jing-huo-xue-tang, and Zhi-bai-di-huang-wan. In the late fracture period, the top three formulas were Shu-jing-huo-xue-tang, Gui-lu-er-xian-jiao, and Du-huo-ji-sheng-tang. The main single herbs used in the early fracture period were Yan-hu-suo, Gu-sui-bu, and Dan-shen. From the middle to the late period, the most prescribed single herbs were Xu-duan, Gu-sui-bu, and Yan-hu-suo. We concluded that the results showed that the CGRD utilization pattern roughly meets the TCM theory at different fracture periods.
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Oshi, Masanori, Shipra Gandhi, Yoshihisa Tokumaru, Rongrong Wu, Li Yan, Akimitsu Yamada, Takashi Ishikawa, Itaru Endo, and Kazuaki Takabe. "Abstract P5-03-01: Conflicting roles of EGFR expression by subtypes in breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–03–01—P5–03–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-03-01.
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Abstract Epidermal growth factor receptor (EGFR) is one of the receptors that belongs to the epidermal growth factor family of receptor tyrosine kinases (ErbBs). Several malignancies including breast cancer that express EGFR have poor prognosis. Our study examined the EGFR expression among 5176 breast cancer patients from multiple independent breast cancer cohorts and its contribution to tumor immune microenvironment in different subtypes. We found that, EGFR expression in triple negative breast cancer (TNBC) was the highest among breast cancer subtypes in GSE96058 and METABRIC cohorts when compared to other subtypes (both p < 0.001), which is in agreement with the existing literature. High EGFR expression was significantly associated with improved survival in ER-positive/HER2-negative breast cancer in both cohorts (both p < 0.001) and also significantly associated with high level of intratumor heterogeneity and homologous recombination deficits (HRD) (both p < 0.001) in the TCGA cohort. Furthermore, high EGFR expression tumor enriched not only several pro-cancer-related gene sets, but also immune-related gene sets, including Allograft rejection, inflammatory response, IL2/STAT5 signaling, IL6/JAK/STAT3 signaling, coagulation and complement pathway in both cohorts. On the other hand, low EGFR tumor enriched cell proliferation-related gene sets, including E2F targets, G2M checkpoint MYC targets v1 and v2, and DNA repair, which may explain the observed worse survival (all normal enrichment score < -0.50). However, these findings were not observed in TNBC. Interestingly, high EGFR ER-positive/HER2-negative breast cancers were infiltrated with anti-cancer immune cells (CD8+ T cell, CD4+ T cell, and dendritic cell), and associated with high level of cytolytic activity (CYT) (p < 0.001). On the other hand, a lower fraction of immune cells was observed in high EGFR TNBC along with low level of CYT (p < 0.001). In the single cell sequence data, tumor cells have significantly higher EGFR expression compared to immune cells (p < 0.001). High EGFR expression among ER-positive/HER2-negative breast cancer was significantly associated with higher expression of immune checkpoint molecules (PD-1, PD-L1 and PD-L2, CTLA4, IDO1, and BTLA; all p < 0.001), while, on the other hand, there was lower immune checkpoint molecule expression in high EGFR TNBC. Finally, high EGFR metastatic tumor was associated with worse survival, but there was no association with infiltrating immune cells. In conclusion, EGFR expression was found to have different characteristics depending on breast cancer subtype. Especially, high EGFR ER-positive/HER2-negative breast cancer was significantly associated with better survival and immunity in tumor immune microenvironment. Citation Format: Masanori Oshi, Shipra Gandhi, Yoshihisa Tokumaru, Rongrong Wu, Li Yan, Akimitsu Yamada, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Conflicting roles of EGFR expression by subtypes in 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 P5-03-01.
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Oshi, Masanori, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, and Kazuaki Takabe. "Abstract P4-07-29: Reactive Oxygen Species (ROS) pathway is associated with aggressive cancer biology, elevated immune response, and with worse survival in ER-positive/HER2-negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–07–29—P4–07–29. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-07-29.
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Abstract Background: Reactive oxygen species (ROS) in tumor microenvironment are known to promote many aspects of cancer progression. On the other hand, excessive accumulation of ROS can induce cancer cell apoptosis. To our knowledge, clinical relevance of ROS response signaling in breast cancer has never been studied in multiple large patient cohorts. Here, we hypothesized that the high ROS pathway score reflect tumor aggressiveness, thus, it predicts worse survival in breast cancer patients. Methods: A total of 6245 breast cancer patients from three independent cohorts (GSE96058, METABRIC, and TCGA) were analyzed. We defined the ROS pathway score by the degree of enrichment by Gene Set Variant Analysis (GSVA) and median was used to divide high vs low score groups in each cohort. Results: The ROS score was significantly associated with aggressive clinical factors, such as triple-negative breast cancer (TNBC) subtype, Nottingham histological grade, American Joint Committee on Cancer (AJCC) Stage and lymph node metastasis consistently in both GSE96058 and METABRIC (all p < 0.001). High ROS score was significantly associated with worse overall survival (OS) in the GSE96058 (hazard ratio (HR) = 3.59, 95% confidence interval (CI); 2.47-5.20, p < 0.001), as well as OS (HR = 1.55, 95%CI; 1.16-2.07, p = 0.002), disease-free survival (HR = 1.63, 95%CI; 1.10-2.43, p = 0.016), and disease-specific survival (HR = 2.57, 95%CI; 1.75-3.77, p < 0.001) in the METABRIC cohort. Subgroup analysis revealed that a high ROS score was significantly associated with worse OS in ER-positive/HER2-negative breast cancer in both cohorts. High ROS ER-positive/HER2-negative breast cancer was significantly associated with high level of intratumor heterogeneity (p = 0.013), homologous recombination deficient (HRD) (p < 0.001), and mutation-related score (silent and non-silent mutation rate (p = 0.003 and 0.011, respectively), fraction altered (p = 0.038), and single-nucleotide variant (SNV) neoantigens (p = 0.006)) in the TCGA cohort. In agreement, high ROS ER-positive/HER2-negative breast cancer significantly enriched cell proliferation-related gene sets; E2F targets, G2M checkpoint, and MYC targets v1 and v2 consistently in both GSE96058 and METABRIC cohorts (all false discovery rate (FDR) < 0.25). On the other hand, high ROS ER-positive/HER2-negative tumors were associated with elevated infiltration of multiple immune cells, including anti-cancer immune cells (CD8+ T cell, CD4+ memory T cell, M1 macrophage, dendritic cell, gamma-delta T cell), as well as pro-cancer immune cells (regulatory T cell, T helper type2 cell, and M2 macrophage) and with high level of cytolytic activity (CYT) consistently in both cohorts (all p < 0.001). Those tumors also enriched immune-related pathway (Interferon (IFN)-α response, IFN-γ response, allograft rejection, complement, IL6/JAK/STAT3 signaling, and inflammatory response) consistently in both cohorts (all FDR < 0.25). Finally, high ROS ER-positive/HER2-negative breast cancer was significantly associated with high expression of immune checkpoint molecules including PD-1, PD-L1 and PD-L2, CTLA4, IDO1, LAG3, BTLA, HLA-A, and TIGIT, in (all p < 0.005). Conclusion ROS pathway is associated with cancer aggressiveness, elevated immune response, and with worse survival in ER-positive/HER2-negative breast cancer. Citation Format: Masanori Oshi, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Reactive Oxygen Species (ROS) pathway is associated with aggressive cancer biology, elevated immune response, and with worse survival in ER-positive/HER2-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 P4-07-29.
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LEE, Wing-yi. "明代婦女自殺——倫理學研究的進路." International Journal of Chinese & Comparative Philosophy of Medicine 3, no. 2 (January 1, 2001): 77–119. http://dx.doi.org/10.24112/ijccpm.31399.
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LANGUAGE NOTE | Document text in Chinese; abstract also in English.現代人對於自殺的討論，普遍地從科學的觀點剖析，視之為與疾病有關。從科學的觀點而言，當事人是在受制於心理或生理的疾病影響下作出自殺的行為。他們的自殺，是處於“不由自主”、“無力選擇”下的自殺，當事人其實是“受害者”，需要的是心理輔導、醫治以預防自殺，而非對其背後所包含的價值觀予以討論。然而，有一些自殺卻不能歸納為與疾病有關。當事人的自殺，是處於自主的狀態之中，是經過深思熟慮，有其充分道德理據下的自主行為。當事人自殺的理據，是與同時代，同一社群的人所認同的道德價值觀，有著密切的關係。對當事人的自殺子以道德價值上的探討，則屬於倫理學上的討論。本文以明代的婦女自殺為例，試從倫理學研究的進路，探究古代中國人的自殺。Modern people usually discuss suicide from scientific views and treat it as a kind of disease. Suicidal behavior occurs under the influence of psychological or physiological illness; it is an involuntary behavior. People who commit suicide are deemed the "victims" of their illnesses. All what we should do is to prevent, to intervene and to postvent their suicidal behavior.However, some cases of suicide are not due to illness. They are the result of voluntary and deliberate moral choice. The reasons of committing suicide are associated with the ethical values of people in the same period of time and in the same community. For example, the moral principle of "zhen" played an important role in woman suicide of Ming Dynasty. In Ming Dynasty, " zhen" was manifested in three ways: (1) "Congi er yongzhong", women should commit suicide after the death of their husbands in order to express loyalty. (2) "Daili er zhengshi", women should commit suicide if they have inappropriate sexual relations with other people, such as pre-marital sex, in order to express their regret and to cover up their sinful behavior. (3) "Sijie", women should commit suicide in order to avoid being raped.Although the government and some intellectuals in Ming Dynasty encouraged women to commit suicide for "men", the suicide and suicide attempt cases in San Yan show that women should consider other moral principles and other values of life and death before they commit suicide. We found that the moral principle of "xiao" overrode the moral principle of "men" in some cases of woman suicide and suicide attempt in San Yan. In Chinese society, "xiao" was manifested in three ways: (l) "Fengyang shuangqin", women should keep their lives for supporting and serving their parents. (2) "Fengyang sizi", women should keep their lives for bringing up their children. (3) "Wei Jiaren Baochou", women should keep their lives for avenging their dead family members. Under the moral principle of "xiao", women should give up suicide. The purpose of this paper is to uncover the underlying values of woman suicide in Ming Dynasty and give an ethical analysis on it.DOWNLOAD HISTORY | This article has been downloaded 68 times in Digital Commons before migrating into this platform.
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Chen, Grace, Stacy W. Blain, Irina Jilishitz, Allison Vanlnwegen, Lingyue Yan, and Yun Wu. "Abstract P5-16-18: Developing IpY: A novel inhibitor for the treatment of ER+ CDK4i-resistant breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–16–18—P5–16–18. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-16-18.
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Abstract Almost 270,000 US women will be diagnosed with breast cancer (BC) this year, anddespite advances in treatment, ~40,000 women will die. ER/PR+ (endocrineresponsive), Her2- tumors occur in approximately 40% of breast cancer patients andare candidates for drugs targeting estrogen responsiveness, such as letrozole orfulvestrant. CDK4 targeting drugs (CDK4i) like palbociclib, abemaciclib, or ribociclib arenow approved in combination with letrozole or fulvestrant as a front- and second-linetherapy for metastatic ER/PR+, Her2- patients. However, while combined ER andCDK4i treatment significantly extends Progression Free Survival (PFS), those treatedinvariably develop resistance. Thus, drug resistance remains an urgent unmet need, as current treatments only marginally improve Overall Survival (OS) for these patients.Resistance to palbociclib develops because of compensation by another kinase, CDK2, suggesting that to be effective, therapies must be developed to inhibit both CDK4 andCDK2. Concarlo has taken a different approach to inhibit CDK4 and CDK2 by targetingp27Kip1 (p27). p27 interacts specifically with CDK4/6 and CDK2, and is responsible forturning these kinases ON and OFF. This transition from ON to OFF is mediated by aspecific modification to p27 itself, by the tyrosine kinase BRK (breast tumor relatedkinase). Published work has shown that a naturally occurring ALTernatively splicedform of BRK, ALT, can bind to p27, blocking BRK's association, and preventing BRK'sphosphorylation of p27. This locks CDK4 and CDK2 into the OFF conformation andsimultaneously inhibits activities of both kinases. As the naked 144 aa ALT peptidedoes not enter cells, it was formulated within a lipid nano-particle (NP), and called IpY.1.IpY.1 inhibits proliferation of HR+ and triple negative (TN) BC cells, but not non-cancerous breast cells MCF10A. IpY.1 arrests CDK4i-resistant and endocrine-resistantBC cells and it is both cytostatic and cytotoxic, demonstrating that p27 is a viabletherapeutic target to combat drug resistance. In vivo, IpY reduces tumor volumes and increase OS in cell line-derived xenografts (CDX). In order to convert manufacturing of the therapeutic peptide portion of IpY from recombinant to synthetic production, Concarlo truncated the large ALT peptide and bioengineered it to a more stable form. IpY.20 has a comparable IC50 as IpY.1 in HR+and TNBC cells and does not cause growth arrest in non-cancerous MCF10A cells. Using the fluorescent-labeled variant of IpY.20 (fluo-IpY.20) injected into tumor-bearingsyngeneic CDX model, followed by IVIS imaging, we could detect fluo-IpY.20 in tumorsas early as 15 min and up to 24h post injection. 6-10% of the total fluorescent signal isallocated to tumor at all timepoints. In addition, fluo-IpY.20 inhibits the activation of itstarget in tumors within 24h, suggesting fluo-IpY.20 not only reaches tumors but alsoengages with its target. IpY.20 induces tumor regression in CDX models and animmunocompetent genetically engineered model that overexpresses the potent Erbb2oncogene. Overall, repeated dosing of IpY.20 does not exhibit significant adverseeffects and is well tolerated in immunocompetent mice. However, in these treated mice, there was an increase in platelets and production of some cytokines compared to vehicle-treated mice, suggesting that an immune response may have been initiated. By targeting p27 instead of the conserved CDK4 or CDK2 active sites, IpY.20 will bemore selective and have fewer off-target effects than the ATP-competitive smallmolecule CDK4is currently in use. As the majority of the drug resistance seen withCDK4 inhibitory drugs is a result of compensatory CDK2 activity, IpY.20 preventsacquired drug resistance by hitting both CDK4 and CDK2 simultaneously, resulting in amore durable response to the drug. Concarlo is currently in manufacturing with IpY.20. Citation Format: Grace Chen, Stacy W Blain, Irina Jilishitz, Allison Vanlnwegen, Lingyue Yan, Yun Wu. Developing IpY: A novel inhibitor for the treatment of ER+ CDK4i-resistant 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 P5-16-18.
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Oshi, Masanori, Shipra Gandhi, Michelle R. Huyser, Yoshihisa Tokumaru, Li Yan, Rongrong Wu, Akimitsu Yamada, Itaru Endo, and Kazuaki Takabe. "Abstract P1-08-17: Melk expression is associated with immune cell infiltration and pathological compete response (pcr) after neoadjuvant chemotherapy in breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–08–17—P1–08–17. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-08-17.
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Abstract In experimental settings, maternal embryonic leucine zipper kinase (MELK), an apical member of the snf1/AMPK serine-threonine kinases family, is highly expressed in several malignancies, and plays a role in cell cycle and proliferation in cell culture settings. However, there is no clear insight on the underlying mechanism or association of MELK expression with several key players in the tumor microenvironment (TME) in regulating cancer progression and response to several drugs in the human tumor. We investigated the clinical relevance of MELK expression by performing silico analyses of 7,135 breast cancer patients using multiple independent large cohorts in this study. We found that MELK expression was significantly correlated with tumor growth assessed by American Joint Committee Cancer (AJCC) stage (p < 0.001), Nottingham histological grade (both p < 0.001), MKI67 expression (spearman rank correlation (r) = 0.704 and 0.888, respectively, both p < 0.001), triple-negative breast cancer (TNBC) subtype (both p < 0.001) and also with cell proliferation-related gene sets (all normalized enrichment score (NES) > 1.70, all false discovery rate (FDR) < 0.01) using gene set enrichment analysis (GSEA), in two large cohorts METABRIC and GSE96058. Furthermore, we observed worse patient survival (both p < 0.001), high mutation rate (all p < 0.03), and enhanced cancer cell survival pathways, including MTORC1 signaling, DNA repair and unfolded protein response (all NES > 1.50) in high MELK expression breast cancer. Additionally, breast cancer with high MELK expression was significantly enriched in immune-related gene sets, including allograft rejection, interferon (IFN)-α response and IFN-γ response (all NES > 1.30). Furthermore, infiltration of anti-cancer immune cells (CD4+ memory T cells, T helper type1 cells, CD8+ T cells, M1 macrophages, gamma-delta T cells, and dendritic cells) and pro-cancer (T helper type 2 cells and regulatory T cells), calculated by xCell algorithm, was associated with high MELK expression. High immune cell killing activity (CYT) was also significantly associated with high MELK expression. Although MELK expression did not correlate with sensitivity of any drug tested in cell lines, high MELK was significantly associated with high pathological complete response (pCR) rate after neoadjuvant chemotherapy (NAC) not only in TNBC (area under the curve (AUC) = 0.78, 0.81, and 0.93, respectively), the aggressive breast cancer subtype known to be associated with around 30-40% pCR, but also in ER-positive plus HER2-negative breast cancer (AUC = 0.62, 0.75, and 0.80, respectively), a subtype of breast cancer where pCR rates are very low, in three cohorts GSE25066, GSE20194 and HESS cohorts. In conclusion, our study shows that high MELK expression is significantly associated with cell proliferation, immune cell infiltration, and higher incidence of response to NAC both in ER-positive/HER2-negative and TNBC. Citation Format: Masanori Oshi, Shipra Gandhi, Michelle R Huyser, Yoshihisa Tokumaru, Li Yan, Rongrong Wu, Akimitsu Yamada, Itaru Endo, Kazuaki Takabe. Melk expression is associated with immune cell infiltration and pathological compete response (pcr) after neoadjuvant chemotherapy in 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 P1-08-17.
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Oshi, Masanori, Shipra Gandhi, Rongrong Wu, Li Yan, Akimitsu Yamada, Takashi Ishikawa, Itaru Endo, and Kazuaki Takabe. "Abstract P3-10-01: Mir-150 expression is associated with immune cell infiltration and immune response in breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–10–01—P3–10–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-10-01.
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Abstract MicroRNA (miRNA) are known as a key player in tumor growth, and is shown to epigenetically regulate a large number of protein-coding genes, including tumor-related genes. MiR-150, a hematopoietic cell-specific miRNA, has been suggested to have various effects on cell proliferation, differentiation, apoptosis, migration, and invasion. However, there has been no study that investigated the role of miR-150 in the tumor microenvironment (TME) of breast cancer patients. We studied the clinical relevance of miR-150 expression by performing in silico analyses of 1961 breast cancer patients using multiple independent large cohorts. We found that miR-150 expression was strongly correlated with immune-related gene set scores, Allograft rejection, IL6/JAK/STAT3 signaling, Interferon (IFN)-γ response, Inflammatory response, IL2/STAT5 signaling, and complement, in Hallmark collection of gene set variation analyses consistently in both METABRIC and TCGA cohorts (all spearman’s rank correlation coefficient (r) > 0.50, all p < 0.01). MiR-150 expression was also strongly correlated with cytolytic activity (CYT) score in both cohorts (r = 0.824 and 0.786, respectively, both p < 0.01). Furthermore, miR-150 expression was significantly correlated with infiltrating fraction of CD8+ T cells (r = 0.799 and 0.525, respectively), CD4+ memory T cells (r = 0.759 and 0.656, respectively), dendritic cells (r = 0.735 and 0.696, respectively), and B cells (r = 0.759 and 0.576, respectively), as well as mRNA expression of major immune checkpoint molecules, including PD-1, CTLA4, IDO1, TIGIT, BTLA, and LAG3, in both cohorts (all r > 0.50, and all p < 0.01). MiR-150 expression in triple negative breast cancer (TNBC) was the highest when compared to other subtypes (both p < 0.001). A high miR-150 was significantly associated with high Nottingham grade (both p < 0.001). MiR-150 high tumor enriched not only immune-related gene sets but also apoptosis, KRAS signaling up, MTORC1, and p53 pathway by gene set enrichment analysis in both cohorts. A high miR-150 was significantly associated with better overall survival (OS) in both cohorts (p < 0.001 and p = 0.030, respectively). Subgroup analysis revealed that a high miR-150 was associated with better OS in ER-positive/HER2-negative breast cancer in both cohorts (p = 0.002 and 0.044, respectively), and in TNBC in the METABRIC cohort (p = 0.006). In conclusion, miR-150 expression is associated with immune cell infiltration and immune response, as well as with better survival in breast cancer patients. Citation Format: Masanori Oshi, Shipra Gandhi, Rongrong Wu, Li Yan, Akimitsu Yamada, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Mir-150 expression is associated with immune cell infiltration and immune response in 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 P3-10-01.
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Khan, Mustafa Tamim Alam, Christian Cervantes, Suryavathi Viswanadhapalli, Yan Hui, Ratna Vadlamudi, and Zhenming Xu. "Abstract P1-04-11: Pd-l1-expressing b-cells promote murine breast cancer development and mediate the response to anti-pd-l1 immune checkpoint inhibitor." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–04–11—P1–04–11. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-04-11.
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Abstract B cells promote tumor development in murine models of breast cancer (BCa), including - as we have shown - by producing pleiotropic cytokine IL-27, which upregulates expression of the PD-L1 immune checkpoint in BCa cells and tumor-infiltrating B cells (TIL-Bs). Paradoxically, B cell activation has been shown to predict the positive response to immune checkpoint inhibitors (ICIs) by murine BCa tumors and melanoma, sarcoma and kidney cancer in patients. Here, we have addressed the role of B cell-expressed PD-L1 in BCa development and responses to ICIs by generating conditional knockout (KO) mice in which Cd274 (encoding PD-L1) was ablated only in activated B cells (AicdacreCd274fl/fl). Tumor development in AicdacreCd274fl/fl mice from engrafted syngeneic ER+ E0071 BCa cells was significantly delayed, albeit not abolished (as occurring in mice lacking B cells), in association with increased B-cell expression of CD86, a key agonistic ligand for T cell-expressed CD28, a co-stimulatory receptor whose function is inhibited by the PD-L1/PD-1 immune checkpoint in exhausted tumor-infiltrating CD8+ T cells. The heightened B-cell CD86 expression in AicdacreCd274fl/fl mice was recapitulated in AicdacreCd274fl/fl B cells stimulated in vitro by CD154, a T helper cell stimulus critical for B cell activation and differentiation as well as the antibody response. Accordingly, AicdacreCd274fl/fl mice displayed an increased antibody response to a T-dependent antigen. Likewise, treatment with the anti-PD-L1 (αPD-L1) ICI boosted wildtype B cells stimulated with CD154 in vitro to express CD86 and differentiate into potentiated plasma cells. It also effectively regressed the growth of pre-developed E0071 tumor in C57 and AicdacreCd274+/fl mice by rejuvenating tumor-infiltrating CD8+ T cells, likely through activation of previously dampened CD28 signaling. By contrast, residual tumors that had eventually developed in AicdacreCd274fl/fl mice failed to respond to αPD-L1 and continued to grow at a pace comparable to tumors treated with an isotype-matched control antibody, showing that the full anti-tumor efficacy of αPD-L1 was mediated mainly by PD-L1-expressing B cells, but not other immune cell types. Thus, PD-L1+ TIL-Bs use PD-L1 to impose a “brake” on the host anti-tumor activity, but are directly targeted by αPD-L1 to relieve the brake, “jump-start” the CD86:CD28 signaling and potentiate the anti-tumor response, thereby providing a mechanistic explanation for the opposing roles of B cells in murine BCa development and ICI responses. Our findings also provide a strong rationale to investigate the activation of PD-L1-expressing TIL-Bs by Atezolizumab® (αPD-L1) in BCa patients to underpin the patient response to this ICI. Citation Format: Mustafa Tamim Alam Khan, Christian Cervantes, Suryavathi Viswanadhapalli, Yan Hui, Ratna Vadlamudi, Zhenming Xu. Pd-l1-expressing b-cells promote murine breast cancer development and mediate the response to anti-pd-l1 immune checkpoint inhibitor [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 P1-04-11.
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Jiang, Zefei, Min Yan, Li Bian, Tao Wang, Xichun Hu, Qingyuan Zhang, Quchang Ouyang, et al. "Abstract PD8-05: Overall survival (OS) results from the phase III PHENIX trial of HER2+ metastatic breast cancer treated with pyrotinib plus capecitabine." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD8–05—PD8–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd8-05.
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Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2, and HER4) plus capecitabine previously demonstrated a statistically significant improvement in progression-free survival (PFS) over placebo plus capecitabine for HER2-positive local relapsed or metastatic breast cancer after prior trastuzumab and taxanes in the interim analysis of the PHENIX trial (NCT02973737; Jiang Z et al. Oral presentation at ASCO 2019, Abstract 1001). It is shown that patients also benefit from subsequent pyrotinib monotherapy after progressed on capecitabine alone. Here we present an updated OS from a follow-up period with a median of 42.1 months. Methods: This PHENIX trial enrolled patients with HER2-positive local relapsed or metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for relapsed or metastatic disease. Eligible patients were randomized 2:1 to receive pyrotinib (400 mg orally once daily) in combination with capecitabine (1000 mg/m2 orally twice daily on days 1-14 for 21-day cycles; P+C group) or placebo plus capecitabine followed by pyrotinib monotherapy upon disease progression (C-P group). Randomization was stratified by the presence of visceral disease (yes vs. no) and the hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative). The primary endpoint was the independent review committee-assessed PFS. The data cutoff for the updated OS analysis was January 15, 2021. Results: A total of 279 eligible patients were randomized, with 185 to P+C group and 94 to C-P group. As of data cutoff, the median duration of follow-up was 41.7 months (95% CI 40.2-42.4) in P+C group and 43.1 months (95% CI 38.8-44.5) in C-P group. 71 out of 94 patients who progressed on placebo plus capecitabine received pyrotinib monotherapy as the first subsequent anti-cancer therapy according to protocol. Excluding the protocol prespecified pyrotinib monotherapy, 129 (69.7%) patients in the P+C group and 74 (78.7%) patients in the C-P group received anti-cancer therapy after discontinuing study treatment, and 107 (57.8%) patients and 61 (64.9%) patients received post-discontinuation anti-HER2 drugs, respectively. 98 (53.0%) of the 185 patients in P+C group and 59 (62.8%) of the 94 patients in C-P group died by the time of data cutoff. Kaplan-Meier estimated median OS was 34.9 months (95% CI 28.4-42.1) in P+C group and 23.6 months (95% CI 19.3-34.4) in C-P group (HR 0.74, 95% CI 0.54-1.02; p=0.068). The 2-year OS rate was 65.2% (95% CI 57.6%-71.8%) versus 48.9% (95% CI 38.1%-58.7%), respectively. Subgroup analyses of OS were generally consistent with the overall result (Table 1). Conclusion: The updated OS analysis highlighted the long-term efficacy of pyrotinib plus capecitabine in pretreated HER2-positive local relapsed or metastatic breast cancer. We did not observe a statistically significant difference in OS between pyrotinib plus capecitabine group and capecitabine group followed by subsequent pyrotinib monotherapy upon disease progression. Table 1.Subgroup analysis of OS.Pyrotinib plus capecitabine (n=185)Placebo plus capecitabine (n=94)HR (95% CI) *Brain metastasesPresentEvents14/21 (66.7)8/10 (80.0)Median OS22.9 (19.7-35.0)17.3 (1.6-34.4)0.77 (0.32-1.84)AbsentEvents84/164 (51.2)51/84 (60.7)Median OS36.7 (30.7-43.0)23.6 (21.5-40.4)0.72 (0.51-1.02)Previous chemotherapyNoneEvents29/60 (48.3)12/22 (54.5)Median OS37.5 (34.2-NA)32.6 (18.9-NA)0.75 (0.38-1.47)1 lineEvents34/70 (48.6)27/47 (57.4)Median OS35.6 (25.9-NA)31.6 (18.0-NA)0.73 (0.44-1.21)2 linesEvents30/44 (68.2)13/18 (72.2)Median OS21.1 (13.6-33.4)15.9 (5.4-44.0)0.77 (0.40-1.49)Data are n/N (%) or median (95% CI). NA, not available. *HRs are from unstratified analyses. Citation Format: Zefei Jiang, Min Yan, Li Bian, Tao Wang, Xichun Hu, Qingyuan Zhang, Quchang Ouyang, Jifeng Feng, Yongmei Yin, Tao Sun, Zhongsheng Tong, Xiaojia Wang, Herui Yao, Shuping Jiang, Xiaoyu Zhu, Jianjun Zou. Overall survival (OS) results from the phase III PHENIX trial of HER2+ metastatic breast cancer treated with pyrotinib plus capecitabine [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 PD8-05.
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Xiang, Kui, Wang Yan, Hua Yanshan, Yi Xiaojia, Zhao Chunmei, and Guo Minmin. "Abstract P3-06-06: Pg5 promotes breast cancer metastasis by activatingpi3k/akt/mtor signaling pathways." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–06–06—P3–06–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-06-06.
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Abstract Background: Breast cancer is the most common malignancy and the leading cause of cancer death among women. Glycoprotein V (GP V) is involved in thrombin-induced platelet activation and in other platelet responses. However, its roles and underlying mechanisms in the pathogenesis of breast cancer are still unclear. This study aimed at assessing GP V expression in breast cancer, its subsequent effects on cancer cell apoptosis, proliferation, invasion, and migration, and the underlying molecular mechanisms. Methods: GP V mRNA expression was analysed in total RNA samples obtained from tumor and adjacent normal tissue of 41 breast cancer patients and cell lines (MDA-MB-231, MCF-7 and MCF-10A). The correlation between the expression of GP V and clinicopathological features was analyzed by immunohistochemical (IHC) staining. Stable knockdown and overexpression MDA-MB-231 cell lines were generated by using the lentiviral system. Then, the cells were harvested for CCK-8 assay, flow cytometry, scratch healing experiments, and western blotting. Two samples each from the Stable knockdown and control groups were used for transcriptome sequencing and pathway analysis. Finally key molecules associated with the related signaling pathways were analyzed by RT-PCR and western blot. Results: The results showed that the mRNA (P<0.0001) and protein expression (P<0.001) of GP V in the breast cancer tissues was significantly increased compared with in the adjacent non-tumor tissues. The protein and mRNA expression of GP V were significantly higher in MDA-MB-231 and MCF-7cell lines compared with human normal breast epithelial cells (MCF-10A) (P<0.01). GP V expression was positively correlated with higher histological grade and advanced TNM stage. (P<0.05), but was not related to gender, age, menopausal status, tumor size, vascular invasion, ER, PR, Ki-67 and lymph node metastasis (P>0.05). CCK-8 assay showed that cell viability was enhanced after GP V upregulation compared to the control group (P<0.05). The in vitro scratch assay showed that the number of GP-V-overexpressing cells migrating to the scratch area was significantly higher than that of the control group at 24 h and 48 h, respectively (P<0.001). Flow cytometric analysis demonstrated there was no significant difference in cell cycle distribution and apoptosis. Differential gene expression analysis showed 13 significantly down- and 141 upregulated mRNAs. The mRNA expression levels of PI3K and AKT were significantly increased after GP V upregulation compared with those in the control group (P<0.001). N-cadherin, Vimentin and MMP2/9 were up-regulated after GP V upregulation compared with those in the control group (P<0.05).Conclusion: GP5 is highly expressed in breast cancer tissues and may play an important role as a cancer-promoting gene in breast cancer. The high expression of GP5 was significantly associated with higher nuclear grade, TNM stage and Her-2 negativity. GP5 can promote the proliferation, invasion, and metastasis of breast cancer cells. GP5 may promote the proliferation, invasion, and metastasis by activating PI3K/AKT signaling pathway to upregulate MET, and is expected to become a potential target for clinic diagnosis and treatment. Citation Format: Kui Xiang, Wang Yan, Hua Yanshan, Yi Xiaojia, Zhao Chunmei, Guo Minmin. Pg5 promotes breast cancer metastasis by activatingpi3k/akt/mtor signaling pathways [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 P3-06-06.
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Xu, Binghe, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, et al. "Abstract GS3-02: Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): GS3–02—GS3–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-gs3-02.
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Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2 and HER4) plus capecitabine significantly improved progression-free survival (PFS) compared with that for lapatinib plus capecitabine in women with HER2-positive metastatic breast cancer after treatment with trastuzumab and taxanes in the interim analysis of the PHOEBE trial (NCT03080805; Xu et al. Lancet Oncology, 2021). In this report, we present an updated analysis of the overall survival data from this trial. Methods: This PHOEBE trial enrolled patients with HER2-positive metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) to receive either oral pyrotinib 400 mg or lapatinib 1250 mg once daily, combined with oral capecitabine 1000 mg/m² twice daily on days 1-14 of each 21-day cycle. Stratification factors were hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative) and previous lines of chemotherapy for metastatic disease (≤1 vs 2). The primary endpoint was PFS assessed by masked independent central review. Data cutoff for the updated overall survival analysis was March 31, 2021. Results: Between July 31, 2017 and October 30, 2018, 267 eligible patients were enrolled and randomized to either pyrotinib plus capecitabine (pyrotinib group) or lapatinib plus capecitabine (lapatinib group). 134 patients in pyrotinib group and 132 in lapatinib group started the assigned treatment. At data cutoff, the median follow-up duration was 33.2 months (95% CI 31.4-34.2) in the pyrotinib group and 31.8 months (95% CI 31.2-34.1) in the lapatinib group. 78 (58.2%) patients in the pyrotinib group and 98 (74.2%) patients in the lapatinib group received post-discontinuation therapy, with trastuzumab (60 [44.8%] in the pyrotinib group and 65 [49.2%] in the lapatinib group) being the most common. As of data cutoff date, 54 (40.3%) of 134 patients randomly assigned to the pyrotinib group and 69 (52.3%) of the 132 patients randomly assigned to lapatinib group had died. Median OS was not reached (95% CI 34.0-not reached) in the pyrotinib group and 26.9 months (22.4-not reached) in the lapatinib group (HR 0.69 [95% CI 0.48-0.98]; P=0.019). Kaplan-Meier estimated OS at 24 months was 66.6% (95% CI 57.7-74.0) and 58.8% (95% CI 49.7-66.7), respectively. 99 (73.9%) patients in the pyrotinib group and 121 (91.7%) in the lapatinib group had disease progression or had died. Pyrotinib plus capecitabine significantly improved PFS assessed by investigator compared with that for lapatinib plus capecitabine (12.5 months [95% CI 9.8-13.8] vs 5.6 months [95% CI 5.5-7.0]; HR 0.48 [95% CI 0.37-0.63]; P<0.0001). The benefits of pyrotinib plus capecitabine were observed in most clinically relevant subgroups for the updated analysis of both OS and PFS (Table 1). Conclusion: With extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant OS improvement compared with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. This updated analysis of overall survival in the PHOEBE trial reaffirmed pyrotinib plus capecitabine as an established treatment option in this patient population. Table 1.Subgroup analysis of OS and PFS per investigator.HR for OSHR for PFSAll Patients0.69 (0.48-0.98)0.48 (0.37-0.63)Trastuzumab therapy for metastatic disease<3 months0.67 (0.33-1.35)0.34 (0.17-0.69)3-6 months0.78 (0.34-1.76)0.66 (0.32-1.34)≥3 months0.79 (0.37-1.66)0.44 (0.26-0.75)Trastuzumab resistanceNo0.60 (0.39-0.91)0.44 (0.32-0.61)Yes0.94 (0.48-1.85)0.58 (0.35-0.98)HER2 amplification by FISH0.76 (0.39-1.51)0.57 (0.35-0.92)Pathological gradingII0.65 (0.33-1.28)0.51 (0.31-0.85)III0.82 (0.41-1.65)0.51 (0.31-0.83)Unknown0.70 (0.41-1.21)0.45 (0.29-0.70)Visceral lesionsVisceral0.59 (0.40-0.88)0.45 (0.33-0.62)Non-visceral1.28 (0.55-2.95)0.57 (0.31-1.04)ECOG performance status00.72 (0.40-1.29)0.42 (0.26-0.66)10.67 (0.43-1.04)0.50 (0.36-0.71)Estrogen and progesterone receptor statusPositive0.74 (0.44-1.25)0.58 (0.39-0.86)Negative0.64 (0.39-1.04)0.41 (0.28-0.60)Previous lines of chemotherapy for metastatic disease00.72 (0.38-1.35)0.47 (0.30-0.74)10.73 (0.44-1.22)0.49 (0.32-0.73)20.56 (0.24-1.32)0.56 (0.28-1.08)Data are median (95% CI). HRs are from unstratified analyses. Citation Format: Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic 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 GS3-02.
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Sarode, Venetia, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, and Barbara Haley. "Abstract P1-02-14: A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–02–14—P1–02–14. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-02-14.
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Abstract A comparative analysis of clinical and pathologic characteristics of HER2 positive breast cancer patients treated with adjuvant versus neoadjuvant antiHer2 therapy: an analysis of 397 cases. Introduction: Currently there are several anti-HER2 therapy options for patients with HER2 positive breast cancer. Surgery as an initial treatment is usually performed in patients with smaller, node negative tumors. Neoadjuvant therapy (NAT) is the treatment of choice for patients with higher stage disease. Detailed analysis of clinical and pathologic characteristics of patients who received adjuvant versus NAT anti-HER2 therapy has not been well elucidated. Objectives: A comparative analysis of clinical and pathologic findings including biomarker expression (ER, PR, HER2 and Ki67) was performed to determine if there were differences in tumor characteristics and clinical outcome in the two groups.Methods:We retrospectively analyzed data on HER2+ breast cancer patients treated with adjuvant and NAT anti-HER2 therapy from 2011 to 2017. Clinical and pathologic parameters including biomarker expression prior to the start of therapy were obtained from the electronic database after IRB approval. In the adjuvant group, patients were treated with initial surgery followed by anti-HER2 therapy plus chemotherapy. In the NAT group, anti-HER2 therapy plus chemotherapy was administered prior to definitive surgery. Types of anti-HER2 therapies and follow-up information were obtained from the electronic medical record. Results:We identified 258 (64.9%) patients who received NAT and 139 (35.0%) received adjuvant anti-HER2 therapy. Table 1.VariablesNeoadjuvant groupAdjuvant groupp-valueAgeBelow 40 years42 (16.2%)11(7.9%)0.02940 years and above Total216 (83.7%) 258128 (92.0%) 139Menopausal statusPremenopausalPostmenopausal Total113 (45.3%)136 (54.6%) 24935 (25.1%)104 (74.8%) 139<0.001Nodal status on biopsyNegativePositive Total31 (18.1%)140 (81.8%) 17117 (53.1%)15 (46.8%) 32<0.001Tumor size by imaging (cm)Mean + SD3.87+2.832.24+1.76<0.001Tumor grade123 Total5 (2%)78 (31.3%167 (66.8%) 2507 (5.3%)49 (37.6%)74 (56.9%) 1300.068HER2 by IHC0 and 1+ (FISH +)2+ (FISH+)3+ Total11 (4.2%)61 (23.8%)184 (71.8%) 2564 (3.5%)41 (36.6%)67 (59.8%) 1120.042HER2 FISH copy no.Mean +SD15.44 ± 8.2512.64 ± 6.470.007HER2 ratioMean SD6.35 ± 3.445.57 ± 3.560.046ER statusNegativePositive Total113 (43.9%)144 (56.0%) 25745 (35.1%)83 (64.8%) 1280.122Percent positive71.38 ± 33.3778.74 ± 29.040.042ER intensity1+2+3+ Total24 (16.9%)38 (26.7%)80 (56.3%) 1422 (2.6%)26 (34.2%)48 (63.1%) 760.001PR statusNegative Positive Total147 (57.1%)110 (42.8%) 25766 (51.9%)61 (48.0%) 1270.389Percent positive42.33 ± 34.5444.72 ± 32.890.645PR intensity1+2+3+ Total20 (18.5%)41 (37.9%)47 (43.5%) 10810 (17.5%)30 (52.6%)17 (29.8%) 570.012KI67 indexPercent positive49.44 ± 22.6638.56 ± 22.36<0.001Anti-HER2 therapyHerceptinHerceptin+ Perjeta Total72 (31.0)160 (68.9%) 23291 (89.2%)11 (10.7%) 102<0.001SurgeryTotal Partial BilateralModified radicalOther Total SurvivalAlive. Dead116 (44.95)75 (29.0%)25 (9.6%)38 (14.7%)04 (1.5%) 258 239 (92.6%) 19 (7.3%)55 (40.4%)56 (41.1%)18 (13.2%)5 (3.6%)02 (1.4%) 136 125 (89.9%) 14 (10.0%)0.002 0.458Conclusions:Patients who received NAT were significantly younger, premenopausal with more aggressive tumor biology (higher Ki67, HER2 expression). Recent advances in anti-HER2 therapy has improved the outcome of these patients despite having higher stage disease. Breast conserving surgery was higher in the adjuvant group since the tumors were smaller in size. There was no significant difference in overall survival when compared to the adjuvant group (p=0.458) Citation Format: Venetia Sarode, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, Barbara Haley. A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases [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 P1-02-14.
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Rastogi, Aditi, Jerome Lin, Yan Hong, Darlene Limback, Hanan S. Elsarraj, Haleigh Harper, Haley Haines, et al. "Abstract P5-01-03: Mouse-intraductal (MIND): An in vivo model for studying the underlying mechanisms of DCIS malignancy." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–01–03—P5–01–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-01-03.
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Abstract Background: Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. Methods: To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), by which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. The source of DCIS samples reflected clinical practice as predominantly high grade (70%), but also included intermediate grade (27%) and low grade (3%). Thirty-seven patient samples were injected into 202 mouse mammary glands and evaluated for invasive progression at a median duration of 9 months. The expression of clinically relevant biomarkers (ER, PR, Ki-67, HER2 and p53) on patient DCIS FFPE sections and xenografts’ extent of in vivo growth were evaluated for their utility in predicting DCIS invasive progression in the xenografts. Targeted DNA sequencing using Tempus XT oncology assay was used on patient DCIS in order to find a unique pattern of cancer related gene mutations that predicted DCIS invasiveness in the xenografts. Results: Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression while 17 (46%) samples injected into 107 xenografts remained noninvasive. Among the 20 samples that showed invasive progression in the MIND model, 9 patient samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained noninvasive. The mean duration of follow-up was not significantly different among the progressed, non-progressed or mixed groups (ANOVA; p-value=0.44). Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and extent of in vivo growth in xenografts predicted an invasive outcome in the xenografts. Tempus XT oncology assay was used on 16 patient DCIS FFPE sections including eight patient DCIS that showed invasive progression (P), five patient DCIS that remained non-invasive (NP) and three patient DCIS that showed a mixed pattern (M) in the xenografts. Variant severity was called using SnpSift which is a program for identifying phenotype-relevant variants and predicts the severity of SNPs based on their effect on gene expression and function. COSMIC database was also used to identify mutations with pathogenic scores >0.5. Analysis of the frequency of cancer related pathogenic mutations showed no significant differences (P=27, NP=79, M=43, Kruskal-Wallis: P value=>0.05). There were also no differences in the frequency of low, moderate or high severity mutations (P= 25 highly severe, 120 moderately severe and 50 low-severity; NP=9 highly severe, 58 moderately severe and 28 low severity; M=3 highly severe, 33 moderately severe and 14 low severity; Kruskal-Wallis; P value >0.05). Conclusions: Highly severe and pathogenic variants in the patient’s DCIS were not associated with whether the DCIS developed into invasive lesions or remained non-invasive in the MIND models. These results are in agreement with previous studies that showed no significant differences in frequency of non-synonymous mutations and CNAs when comparing pure DCIS with synchronous IDC-DCIS. The MIND models are in immunocompromised mice, so the contribution of the immune system to DCIS progression may not recapitulate cancer progression in an immunocompetent state. However, the MIND model suggests that genetic changes in the DCIS are not the primary driver for the development of invasive disease. Citation Format: Aditi Rastogi, Jerome Lin, Yan Hong, Darlene Limback, Hanan S. Elsarraj, Haleigh Harper, Haley Haines, Hayley Hansford, Michael Ricci, Carolyn Kaufman, Emily Wedlock, Mingchu Xu, Jianhua Zhang, Lisa May, Terri Cusick, Marc Inciardi, Mark Redick, Jason Gatewood, Onalisa Winblad, Allison Aripoli, Ashley Huppe, Christa Balanoff, Jamie Wagner, Amanda Amin, Kelsey E. Larson, Lawrence Ricci, Ossama Tawfik, Hana Razek, Ruby O Meierotto, Rashna Madan, Andrew K. Godwin, Jeffrey Thompson, Susan G. Hilsenbeck, Andy Futreal, Alastair Thompson, E. Shelley Hwang, Fang Fan, Nicholas Navin, Fariba Behbod, Grand Challenge PRECISION Consortium. Mouse-intraductal (MIND): An in vivo model for studying the underlying mechanisms of DCIS malignancy [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 P5-01-03.