bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PS16-18: Inhibition of mTOR signaling by rapamycin abrogates mammary stem/progenitor cell activity in aged mice
Authors: Broome Larry E. , Bouamar Hakim , Nelson James F. , Sun Lu-Zhe
Published: February 2021

Previous studies have shown an altered physiology in the mammary gland of aged mice, with mammary ducts displaying increased tertiary branching along with an enriched myoepithelial population compared to younger mice. It is the population of myoepithelial cells residing in the basal layer of mammary ducts that is thought to be responsible for the development of the mammary gland. These qualities have been attributed to the mammary stem cells (MaSCs) that reside in this population and are capable of regenerating the mammary gland when implanted in an empty mammary fat pad, indicating their bipotent nature. It is not known however, if these stem cells are responsible for the aging mammary gland phenotype and the increased risk of cancer seen in aging mammals. Our preliminary studies showed that rapamycin could be utilized as a MaSC inhibitor and clinical trials are currently under way investigating the role of rapamycin in inhibiting MaSC function and abrogating biomarkers associated with invasive BC progression. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates growth, proliferation, and survival in cells and is often upregulated in cancer. Rapamycin is an extremely selective inhibitor of mTORC1 function and its downstream signaling. In this study, aged mice fed ad lib with microencapsulated rapamycin showed decreased mTOR activity in the mammary ducts as shown by immunohistochemistry in aged mice. Treated mouse breast tissue also displayed a decreased population of Lin- CD24low CD49fhi myoepithelial/basal cells along with decreased tertiary branching in the ductal morphology, effectively reversing the aged mammary gland phenotypes. MaSC inhibition by rapamycin was also shown using sphere formation efficiency (SFE) assays after sorting the luminal (Lin- CD24hi CD49flow) and basal (Lin- CD24low CD49fhi) epithelial cells using Florescence Activated Cells Sorting (FACS) in a free suspension culture. Together, these findings show a possible use in regulating MaSCs by rapamycin and its potential in preventing age-related diseases such as breast cancer.

Citation Format: Larry E. Broome, Hakim Bouamar, James F. Nelson, Lu-Zhe Sun. Inhibition of mTOR signaling by rapamycin abrogates mammary stem/progenitor cell activity in aged mice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-18.
Abstract PS17-24: Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism
Authors: Lai Shu-Chin Alicia , Gundlapalli Harika , Ekiz Huseyin A , Welm Alana L
Published: February 2021

Metastatic breast cancer is the overwhelming cause of breast cancer mortality and is still incurable. The rapid development of immunotherapy is an exciting new area of research in metastatic breast cancer. However, the extreme immunosuppressive tumor environment poses a major challenge. A better understanding of how the immune system can be harnessed against metastatic cancer is required to improve patient outcomes. We previously showed that expression of the receptor tyrosine kinase Ron in the host, rather than Ron's tumor expression, contributed to tumor-associated immunosuppression and duo inhibition of Ron and CTLA-4 significantly reduced metastatic outgrowth. However, the actual mechanism remains unclear.

The present study provides evidence that the N-terminal truncated isoform, short-form Ron (SF-Ron), is the major contributor in suppressing the anti-tumor immune responses and promoting metastatic outgrowth. Genetic deletion of host SF-Ron nearly eliminated breast cancer metastasis in mice, lead to systemic immune-activation, increased recruitment of lymphocytes to the site of metastasis, and augmented tumor-specific T-cell responses. Lack of SF-Ron also leads to the accumulation of CD4+ T-cells in the metastatic lungs and endowed with anti-tumor potential. Importantly, mice treated with small molecule Ron kinase inhibitor that targets both Ron and SF-Ron, produced significantly higher, active, tumor-specific CD8+ T-cells. Our study indicates that blocking Ron, especially the SF-Ron, remodels the metastatic lung microenvironment to enhance anti-tumor immunity. This study sheds light on the potential non-redundant roles of full-length and SF-Ron isoforms in mediating breast cancer metastasis and anti-tumor immune responses; and highlights the relevance of combining Ron inhibitors with immunotherapeutic agents to potentially improve treatment efficacy for metastatic breast cancer patients.

Citation Format: Shu-Chin Alicia Lai, Harika Gundlapalli, Huseyin A Ekiz, Alana L Welm. Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-24.
Abstract PS17-29: Surgically induced weight loss corrects obesity associated tumor progression and improves responsiveness to immunotherapy
Authors: Sipe Laura , Chaib Mehdi , Korba Emily B , Lovely Mary C , Clements Jared C , John Neena A , Pingili Ajeeth K , Pierre Joseph F , Makowski Liza
Published: February 2021

Background: Obesity leads to a higher risk of cancer invasion, metastases, recurrence, mortality, and impaired therapeutic response through various mechanisms. One of these mechanisms is microenvironment dysfunction, where changes in immune cells, microbes, metabolites, and growth factors contribute to tumor aggressiveness. We study obesity-induced changes to the tumor microenvironment in Triple Negative Breast Cancer (TNBC), an aggressive subtype associated with obesity. The goal to compare tumor progression in lean vs. obese vs. weight loss manipulations to identify causal and targetable pathways associated with reprogramming the tumor microenvironment. Clinically, bariatric surgery induced weight loss reduced the risk of BC, with the greatest benefit detected in pre-menopausal patients with ER- tumors, like TNBC. We hypothesize surgically-induced weight loss will diminish obesity-associated tumor progression. Methods: To study weight gain and loss that best mimics human adiposity, we utilized obesogenic C57BL/6 females with a syngeneic orthotopic transplant of TNBC cells. Female mice placed on a high fat diet (HFD) at weaning became obese compared to mice on a low fat diet (LFD). After 16 weeks on an HFD diet, mice underwent the bariatric surgery Vertical Sleeve Gastrectomy (VSG). The VSG resulted in reduced body weight, adiposity, and correction of metabolic profiles compared to obese mice. Two weeks post-surgery, TNBC cells were OT into the mammary fat. Results: As expected, tumor growth was increased in obese mice compared to lean. Importantly, surgical weight loss rescued obese tumor progression. We identified key changes in tumor infiltrating of immune cells that could be responsible for the beneficial effects of bariatric surgery on tumor progression. We then exploited these changes with immunotherapy, which was uniquely effective in mice that underwent bariatric surgery. Conclusions: In conclusion obesity promotes a pro-tumor microenvironment, that can be corrected through surgically induced weight loss.

Citation Format: Laura Sipe, Mehdi Chaib, Emily B Korba, Mary C Lovely, Jared C Clements, Neena A John, Ajeeth K Pingili, Joseph F Pierre, Liza Makowski. Surgically induced weight loss corrects obesity associated tumor progression and improves responsiveness to immunotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-29.
Abstract PS17-38: Comprehensive association analysis of 21-gene recurrence score and overweight in breast cancer patients
Authors: Tong Yiwei , Gao Weiqi , Wu Jiayi , Zhu Siji , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Shen Kunwei , Chen Xiaosong
Published: February 2021

Background: The association between 21-gene recurrence score (RS) and host factors such as overweight remains unclear for breast cancer patients. The objectives of the current study are to comprehensively analyze the distribution, single gene expression, and prognostic predictive value of RS between overweight or non-overweight patients.Patients and methods: Luminal-like patients receiving surgery between January 2009 and December 2018 in the Comprehensive Breast Health Center, Shanghai Ruijin Hospital, with 21-gene RS results were retrospectively retrieved. Association and subgroup analysis between BMI and 21-gene RS were conducted. Single-gene expression in 21-gene RS panel was compared between overweight and non-overweight groups. Recurrence-free survival (RFS) and overall survival (OS) were calculated according to RS category and BMI status.Results: Among 1876 patients included, 442 (23.56%), 995 (53.04%) and 439 (23.40%) were classified into low, intermediate and high risk groups. RS category was significantly differently distributed between overweight and non-overweight patients (P=0.035). Overweight patients had a trend of lower RS score than patients with normal weight (25.13 vs 26.17, P=0.080). The effect of BMI on RS significantly varied according to age (P=0.012) and menstruation status (P<0.001). Compared to non-overweight patients, overweight ones presented with higher ER (P<0.001), PR (P<0.001), CEGP1 (P=0.017), Ki67 (P=0.020) and STMY3 (P=0.026) mRNA expression levels. Regarding menstrual status, postmenopausal women with BMI≥24 kg/m2 were associated with higher ER group score (P<0.001), with higher ER (P=0.041), PR (P<0.001), CEGP1 (P=0.005), as well as GRB7 (P=0.015) expression, which was not significant in premenopausal women. After a median follow-up of 39.40 months (range 1.67-119.53), overweight patients had similar RFS (P=0.670) and OS (P=0.077) to non-overweight ones. Moreover, RS category could significantly predict RFS in the whole population (P<0.001), in either those overweight (P=0.003) or non-overweight (P=0.019).Conclusion: 21-gene RS was differently distributed between overweight and non-overweight patients, which interacted with age and menopausal status. ER, PR, CEGP1, Ki67 and STMY3 genes were more expressed in overweight patients. RS category could predict RFS regardless of BMI status, which warranted further validation.

Citation Format: Yiwei Tong, Weiqi Gao, Jiayi Wu, Siji Zhu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen, Xiaosong Chen. Comprehensive association analysis of 21-gene recurrence score and overweight in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-38.
Abstract PS17-55: Reactive oxygen species scavengers in triple negative breast cancer
Authors: Duhoux Francois P , Capelôa Tânia , Sonveaux Pierre , Derouane Francoise
Published: February 2021

Reactive oxygen species (ROS) are well known to play important roles in cancer. In particular, ROS of mitochondrial origin (mtROS) promote DNA mutations and cell death when produced at high levels, but rather stimulate autophagy and metastatic spread when produced at subcytotoxic levels [1]. Multiple metabolic pathways and oncogenic regulators linked to ROS have been studied in cancer cells, including MAPK/ERK, PI3K/AKT, PTEN, PKD, BREF2, HIF-1, NF-κB and p53 [2]. Abnormalities in these pathways can contribute to tumor development.By producing mtROS, mitochondria control and could even trigger metastatic spread, meaning that the use of specific mitochondria-targeted superoxide inhibitors/scavengers, such as mitoquinol mesylate (MitoQ), could reduce and/or prevent metastatic dissemination. This has been studied and reported with the use of MitoTempo, which prevents metastasis of naturally metastatic MDA-MB-231 human breast cancer cells implanted in mice [1]. Here, we show that MitoQ impairs MDA-MB-231 and SkBr3 human breast cancer cell migration and invasion in vitro, and MDA-MB-231 metastasis to the lungs in mice in vivo. In metastatic take assays, tail vein-injected MDA-MB-231 cells pretreated with MitoQ formed significantly less metastases after 4 weeks compared to vehicle. In spontaneous metastatic assays, mice bearing orthotopic MDA-MB-231 tumors were treated with ± 20 mg/kg MitoQ (per os) for 6 weeks. Primary tumors were surgically removed to allow metastatic outgrowth. In this model, MitoQ decreased primary tumor recurrence as well as the number of lung micro-metastases. Additionally, RNAseq studies in two human breast cancer cell lines identified that MitoQ significantly modulated a common set of metabolic genes in vitro and in vivo. They can be used as biomarkers of response. These results, together with a successful Phase I clinical trial and the fact that MitoQ does not interfere with the cytotoxic effects of chemotherapy, confirm that MitoQ is a potential candidate to be clinically tested in triple negative breast cancer patients.

References:

1.Porporato PE et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8(3):754-66.2.Payen VL, et al. Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev. 2019;38(1-2):189-203.

Citation Format: Francois P Duhoux, Tânia Capelôa, Pierre Sonveaux, Francoise Derouane. Reactive oxygen species scavengers in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-55.
Abstract PS18-22: Association of molecular biomarkers heterogeneity and treatment pattern, disease outcomes in multifocal or multicentric breast cancer patients
Authors: Li Shuai , Wu Jiayi , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Chen Xiaosong , Shen Kunwei
Published: February 2021

Background: To evaluate the rates of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 heterogeneity in multifocal or multicentric breast cancer (MMBC) and its association with treatment pattern and disease outcomes.Methods: MMBC patients with ER, PR, HER2, and Ki67 results for each tumor focus were retrospectively analyzed. Patients with concordant ER, PR, HER2, and Ki67 status among all invasive tumor foci were categorized into the Homo group, while the rest were defined as the Hetero group. Chi-square or Fisher test were performed to compare the treatment options between the Hetero and Homo groups. Disease-free survival (DFS) and overall survival (OS) rates were estimated from Kaplan-Meier curves and compared between two groups.Results: A total of 330 patients were included. Concordance rates of ER, PR, HER2, Ki67, and molecular subtype were 97.0%, 93.9%, 96.5%, 91.2%, and 88.2%, respectively (all P values < 0.001). There were 53 (16.1%) and 287 (83.9%) patients classified into the Hetero and Homo groups. Adjuvant endocrine therapy was more frequently assigned for patients in the Hetero group than in the Homo group (84.9% vs. 71.7%, P = 0.046). There was no difference in terms of adjuvant anti-HER2 therapy (28.3% vs. 19.6%, P = 0.196) and chemotherapy (69.9% vs. 69.8%, P = 0.987) usage between two groups. At a median follow-up of 36 months, DFS rates were 81.2% for the Hetero group and 96.5% for the Homo group (HR = 2.81, 95% CI: 1.00-7.88, P = 0.041). The estimated 3-year OS rates for these two groups were 95.8% and 99.5%, respectively (HR = 4.31, 95% CI: 0.83-22.46, P = 0.059).Conclusion: Heterogeneity of ER, PR, HER2, or Ki67 was present in 16.1% patients with MMBC. Biomarkers heterogeneity influenced adjuvant endocrine therapy usage and was associated with worse disease outcomes, indicating further clinical evaluation.

Citation Format: Shuai Li, Jiayi Wu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen. Association of molecular biomarkers heterogeneity and treatment pattern, disease outcomes in multifocal or multicentric breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-22.
Abstract PS18-32: Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases
Authors: Nagalingam Arumugam , Muniraj Nethaji , Siddharth Sumit , Avtanski Dimiter , Parida Sheetal , Kuppusamy Pajamurthy , Saxena Neeraj K , Muniraj Nethaji
Published: February 2021

Background and Aim: Obese state is associated with increased breast cancer growth, metastasis, and poor overall survival. In this study, we seek to decipher the underlying molecular mechanisms by which obesity/hyperleptinemia reduces the efficacy of tamoxifen. Methods: The impact of obesity on tamoxifen was evaluated utilizing clonogenicity, high-fat-diet- induced obese mice and leptin-treated xenograft-models. Mechanistic studies involved immunoblotting, real-time PCR, immunocytochemistry, chromatin immunoprecipitation assay, phosphokinase array and in silico analysis. Results: Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT and Mi2. Further, we found that coactivator Med1 potentially associates with 48 (out of 75) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205 and increases its functional activation via phosphorylation that is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. Additionally, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improve tamoxifen efficacy in hyperleptinemic state.Conclusion: In conclusion, these studies show the molecular mechanisms by which obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin’s negative effect on tamoxifen.

Citation Format: Arumugam Nagalingam, Nethaji Muniraj, Sumit Siddharth, Dimiter Avtanski, Sheetal Parida, Pajamurthy Kuppusamy, Neeraj K Saxena, Nethaji Muniraj. Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-32.
Abstract PS18-49: A transcriptome approach to reveal CTDP1 knockdown induced G1 cell cycle arrest in triple negative breast cancer cells
Authors: Law Henry Chun Hin , Woods Nicholas
Published: February 2021

CTDP1 (C-terminal domain phosphatase 1) is the only phosphatase domain with a BRCT-domain and known to be associated with transcription and mitosis in eukaryotic systems. Our previous research showed that CTDP1 participates in the DNA damage response by mediating interstrand DNA repair through the Fanconi anemia pathway. This study also revealed that CTDP1 is an essential gene in breast cancer cell lines but not in normal breast derived epithelial MCF10A cells. This project aims to identify the changes in transcripts, kinases and interactors leading to the cell death induced by CTDP1 knockdown in the triple-negative breast cancer cell lines. Since RNA Pol II is one of the major targets of CTDP1 phosphatase activity, we initially hypothesized that the cellular changes were mediated by transcriptional regulation. The global transcriptomic profiling of shCTDP1 MDA-MB-231 cells detected more than 29000 gene products, where 1000 and 616 genes were found consistently up- and down-regulated, respectively. The downregulation of cell cycle-associated genes CCNA2, TOP2A and POLA1 in the MDA-MB-231 cells were confirmed with q-RT-PCR. While the upregulated genes did not show enrichment in the Reactome pathway database, the downregulated genes were significantly associated with DNA damage response, mitosis and transcription, which is consistent with the known functions of CTDP1. The transcription factor binding motifs analysis with iRegulon reveals that the E2F1 transcription activity decreased as CTDP1 was knocked down in MDA-MB-231. The subsequent cell cycle analysis supports this prediction and showed G1 arrest as CTDP1 is knocked down in MDA-MB-231 and MDA-MB-453, but not in MCF10A. A kinase array analysis was also conducted to further identify kinases activated or deactivated as CTDP1 is knocked down. A nested network analysis of the predicted transcription factors, kinases and CTDP1 interactors is used to identify potential pathways contributing to cell death of the triple-negative breast cancer cells upon loss of CTDP1 expression.

Citation Format: Henry Chun Hin Law, Nicholas Woods. A transcriptome approach to reveal CTDP1 knockdown induced G1 cell cycle arrest in triple negative breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-49.
Abstract PS2-25: Cell-free DNA based detection of mono-allelic versus bi-allelic loss of function for essential genes in breast cancer
Authors: Xie Feng , Tang Haoran , Zhang Yue , Huang Yong
Published: February 2021

Background: Breast cancer is the top cancer in women, accounting for over 30% of new cancer cases in women worldwide. Breast cancer is a highly heterogenous disease. Treatment of breast cancer is a very active area in cancer research with significant progresses in recent years. Despite of recent progress in liquid biopsy molecular profiling, blood-based detection of mono-allelic versus bi-allelic loss of function for essential genes such as BRCA, PTEN etc. remains an unmet clinical need for targeted therapy in breast cancer.

Methods: We tested over 1000 plasma samples of breast cancer patients using PredicneCARE, a proprietary cell-free DNA (cfDNA) assay, which covered the DNA Damage Repair (DDR) genes in addition to most genes under research in cancer pathways. This blood-based cfDNA assay has a well-tuned capability to reliably detect copy number gain and loss, discriminating bi-allelic versus mono-allelic gene deletions. The assay also has an HRD (Homologous Recombination Deficiency) add-on for the generation of HRD score.

Results: PredicineCARE was used to test over 1000 breast cancer patients. The most frequently mutated genes include TP53(59.7%), PIK3CA(47.6%), BRCA2(16.1%), ATM(12.9%), ESR1(12.1%), and ARID1A(10.1%), with cancer variant detection capability down to 0.1% for hotspots; for copy number gain at ≥2.23 and for copy number loss at ≤1.75; and for rearrangements at 0.375%. Interestingly, cfDNA-based gene amplifications were founded in ERBB2, PIK3CA, FGFR1, MYC, etc. and gene deletions were found in important genes such as PTEN, RB, BRCA1/2 etc. Interestingly, we observed significant difference in mutations of key driver genes such as PIK3CA in Chinese versus Caucasian mBC cohorts.

Conclusion: The PredicineCARE assay detects blood-based cancer alterations including copy number loss, fusion detection and somatic status evaluation, providing a non-invasive approach to profile important targets including HER2, EGFR, VEGFR, DNA damage repair (BRCA1/2), cell cycle and growth regulations (CDK4/6-RB and PTEN/PI3K/AKT/mTOR), and TRK/ROS1/RET fusions for the treatment of breast cancer.

Citation Format: Feng Xie, Haoran Tang, Yue Zhang, Yong Huang. Cell-free DNA based detection of mono-allelic versus bi-allelic loss of function for essential genes in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-25.
Abstract PS2-27: Benefits of a rapid diagnostic centre for breast cancer care during the COVID-19 pandemic
Authors: Ko Gary , Sarvanantham Sharmy , Sequeira Sangita , Prajapati Vrutika , McCready David R. , Freitas Vivianne , Cil Tulin D.
Published: February 2021

BACKGROUND: Changes in access to breast imaging and suspension of mammographic screening during the COVID-19 pandemic had the potential to significantly delay breast cancer diagnostic pathways. The Gattuso Rapid Diagnostic Centre (GRDC) is an innovative clinic that provides a patient-centered approach for investigation of suspicious breast abnormalities and sees approximately 1200 patients per year. The aim of this study was to assess the impact of the pandemic on patient volumes and imaging at this high-volume breast rapid diagnostic centre.

METHODS: A retrospective review of consecutive patients who presented to the GRDC from the start of the pandemic (March 12, 2020) until May 31, 2020 was performed. The number of patients, reason for referral, cancer detection rate (CDR), and waiting time from appointment to diagnosis were evaluated and compared to a corresponding time period in 2019.

RESULTS: A total of 168 new patients presented to the GRDC during the study period, corresponding to a 32.3% decrease in the number of patients compared to 2019 (n=248). Seventy-eight patients (46.4%) were referred due to the presence of a clinical palpable abnormality, which represented an increase of 13.8% (n=81 [32.7%] in 2019; p=0.005). Out of 168 patients, 69 were diagnosed with a breast malignancy, yielding a CDR of 41.1% during the pandemic versus 111 patients in 2019 (CDR of 44.8%; p= 0.456). The average time from appointment at GRDC to diagnosis was lower at 0.76 days vs 1.21 days in 2019. The rate of same day diagnosis was significantly higher at 39.5% vs 27.0% in 2019 (p=0.008). Twenty-five patients (14.9%) received neoadjuvant systemic therapy compared to 16 patients (6.5%) in 2019 (p=0.005). CONCLUSION: There were fewer patients presenting for breast investigations during the pandemic period and a significant increase in the percentage of patients with palpable masses as the cause for referral with no appreciable change in the CDR. The presence of a rapid diagnostic breast center enabled patients with concerning breast symptoms to access and receive expedited assessment. This ensured patients did not undergo diagnostic delays despite the health care restrictions that emerged during the COVID-19 pandemic.

Citation Format: Gary Ko, Sharmy Sarvanantham, Sangita Sequeira, Vrutika Prajapati, David R. McCready, Vivianne Freitas, Tulin D. Cil. Benefits of a rapid diagnostic centre for breast cancer care during the COVID-19 pandemic [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-27.
Abstract PS2-43: Innovating a magnetic experience on wirral peninsula in the United Kingdom- our experience with magseed localisation of impalpable breast tumours and axillary node for therapeutic surgery and staging
Authors: Arif Tahera , Absar Mohammed Shameem , Lund Jonathan Michael
Published: February 2021

INTRODUCTION Magseed is a novel localization technology in which a tiny seed is inserted to accurately mark the site of breast tumour. These can be detected intra-operatively by sentimag localization system. These can be implanted days prior to surgery and do not require use of radioactive material. It aids localization of impalpable breast lesions improving margin clearance rates. METHODS A study was undertaken of 50 patients undergoing Magseed localization of non-palpable breast lesions in rural and urban areas of Wirral Peninsula in the UK. Data including age, mode of localization (Stereo-guided/ Ultrasound guided), presentation (Symptomatic/Screen detected), and time to surgery after localization, size and weight of specimen, histology and re-excision rates was collected between June 2019 and November 2019. RESULTS A total of 50 patients had 52 Magseed inserted. n=14 were symptomatic, n=35 were screen detected and n=1 was an incidental finding on surveillance mammogram for a B3 lesion. All 50 patients had therapeutic surgery. 30 seeds were inserted on the right and 22 were inserted on the left (two were bilateral). 44 seeds were inserted under Ultrasound guidance and the rest were targeted under stereo guidance (n=8).Deployment of 2 Magseed resulted in malposition requiring wire localization. Mean age of subjects was 59.76 (range 31-81) years. Mean time to surgery after Magseed insertion was 8.04 (range 1-27) days. Mean weight of the specimen was 48.57(range 10-264) gm. Mean size of the lesions was 20.32 (range 8-65) mm. Redo surgery for margin clearance was performed bringing the re-excision rate to 15.38% (n=8). CONCLUSION We conclude that Magseed localization of breast tumours is a safe and reliable technique in terms of accuracy, localization and clearance of margins without any radiation concerns. Our re-excision rate for margin clearance is comparable to the national average. The only caveat we observed was localization of impalpable lesions prior to surgery in bulky breasts where we had to utilize wire guided localization on the day of surgery. Large scale data are lacking to compare Magseed localization with other localization techniques for non-palpable breast lesions.

Citation Format: Tahera Arif, Mohammed Shameem Absar, Jonathan Michael Lund. Innovating a magnetic experience on wirral peninsula in the United Kingdom- our experience with magseed localisation of impalpable breast tumours and axillary node for therapeutic surgery and staging [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-43.
Abstract PS3-30: Peri-operative diagnostic accuracy of magnetic resonance imaging and ultrasonography in breast cancer: A meta-analysis
Authors: Mouabbi Jason A , Sako Zeyad , Abdalla Ahmed , Hadid Tarik , Rimawi Mothaffar F
Published: February 2021

Background: Accurate determination of the extent of tumor is essential when a breast-conserving therapy (BCT) is considered. Due to its high sensitivity, breast magnetic resonance imaging (MRI) is increasingly used for the accurate diagnosis and surgical planning of breast cancers. However, a recent meta-analysis showed that peri-operative evaluation with MRI leads to higher mastectomy rates in patients that could have potentially underwent BCT.

Objective: The aim of this study is to compare the pre-operative diagnostic accuracy of MRI to ultrasonography (US) in breast cancer.

Methods: We identified eligible studies that examined peri-operative tumor size using MRI and US and compared it to its pathological counterpart. Databases of PubMed, Embase and Google Scholar were reviewed. To keep the study homogenous, only studies evaluating invasive ductal carcinoma were included and studies evaluating ductal carcinoma in-situ and lobular ductal carcinoma were excluded. An accurate tumor estimation by MRI or US was defined as within 10 mm from the pathological tumor size. An overestimation was defined as imaging tumor size more than 10 mm larger than its pathological counterpart. Odds ratios (ORs) were calculated using a random-effects model with 2-sided p-value of 0.05 set as the significance level.

Results: Twenty-five studies with 3,562 patients were included in the final analysis. MRI was 1.6-fold more accurate than US in preoperative diagnostic evaluation of breast cancer (OR 1.65; 95% confidence interval (CI) 1.24-2.18, p-value <0.00001). However, MRI was 20 folds more likely to overestimate the tumor size compared to US (OR 20.25; 95% CI 9.46-43.33; p-value <0.0001).

Conclusion: MRI remains the most accurate modality for the diagnosis of breast cancer. However, it is highly likely to overestimate tumor size and can result in unnecessary mastectomies. US is a reasonable diagnostic option for most patients with breast cancer.

Citation Format: Jason A Mouabbi, Zeyad Sako, Ahmed Abdalla, Tarik Hadid, Mothaffar F Rimawi. Peri-operative diagnostic accuracy of magnetic resonance imaging and ultrasonography in breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-30.
Abstract PS4-39: Efficacy of combined CDK4/6 inhibitor and PARP inhibitor in the treatment of BRCA1 mutant triple negative breast cancer
Authors: Zhu Xiuzhi , Chen Li , Wang Zhonghua
Published: February 2021

Background: PARP inhibitors (PARPi) benefit only a fraction of breast cancer with BRCA mutation, and are even more limited in triple negative breast cancer (TNBC), due to clinical primary and acquired resistance. Here we found that the efficacy of PARPi in TNBC can be expanded with CDK4/6 inhibitors (CDK4/6i). Methods: We screened sensitive and resistant PARPi cell lines from existing TNBC cell lines and cultured PARPi-resistant strains by gradient concentration increase method. The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on TNBC cells lines were examined in vitro and in vivo. Combination index (CI) was used to evaluate the synergistic effects of drug combination. Results: We screened out the cell line MDA-MB-436, which was the most sensitive to PARPi, and the cell lines HCC1937 and SUM149, which were relatively resistant to PARPi, all of which were BRCA1 mutants. We demonstrated for the first time that the combination of PARPi and CDK4/6i has synergistic effects against some TNBCs both in vitro and in vivo, and was verified by CI<0.9. Further experiments confirmed that PARPi combined with CDK4/6i inhibited cell proliferation and migration, and increased apoptosis and DNA damage. In the PARPi sensitive BRCA-/TNBC cell (MDA-MB-436), the inhibitory effect of monotherapy PARPi was obvious; In the PARPi resistant BRCA-/TNBC cells (HCC1937 and SUM149), CDK4/6i was added to achieve significant growth inhibition. In the timing of medication, PARPi followed by CDK4/6i had better inhibitory effect.Conclusions: In some BRCA-/ TNBCs, PARPi combined with CDK4/6i had a synergistic effect. Even in PARPi-resistant cells, combined treatment could enhance the efficacy and might reverse the drug resistance to some extent.

The combination index index of HCC1937 at different drug concentrations (uM)The combination index index of HCC1937 at different drug concentrations (uM)OlaparibPalbociclib25.0016.6711.117.414.943.292.191.460.980.65P-25.000.459110.668320.866540.869640.993450.989890.97841.003221.073741.00809P-20.000.537090.851131.022651.149561.231561.270271.189071.145021.14811.25795P-15.000.594121.018141.134481.056960.928140.955670.889760.842040.81060.81348P-10.000.475540.860580.77190.717480.62330.615880.561390.52960.510250.49752P-5.000.509450.762230.746560.683340.56030.499410.467390.41490.390670.37502P-2.500.573130.706410.714750.661230.519270.455960.350980.29340.319310.2756

Citation Format: Xiuzhi Zhu, Li Chen, Zhonghua Wang. Efficacy of combined CDK4/6 inhibitor and PARP inhibitor in the treatment of BRCA1 mutant triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-39.
Abstract PS5-39: Tumour cellularity size as a biomarker to predict response after neoadjuvant endocrine therapy: Correlation analysis between Ki67 expression and PEPI score
Authors: Velazco Joanna Ines Lopez , Otaño María , Larburu Lide , Lahuerta Ainhara , Elorriaga Kepa , Segur Virginia , Irizabal Juan Carlos , Martínez Ana , Jáuregui Lourdes , Caffarel Maria M. , Urruticoechea Ander
Published: February 2021

Background: Neoadjuvant endocrine therapy (NET) is an approach that allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. This evaluation is mainly performed in surgical specimens after NET and it has been used as a research tool to obtain prognostic and predictive information using tumour response to decide adjuvant treatment. In this setting, there are not many validated biomarkers to predict response beyond Ki67 expression and Preoperative Prognostic Index (PEPI score) in NET. The aim of this study is to determine if the tumour cellularity size (TCS) in surgical specimen after NET correlates with PEPI score and Ki67 expression. Methods: Retrospective study of postmenopausal patients with estrogen receptor (ER) positive/HER2 negative resectable breast cancer, treated with an aromatase inhibitor for at least 4 months prior to surgery. Pathological characterization of tumour specimens: Evaluation of the percentage of residual tumour cellularity of formalin fixed paraffin embedded surgical specimens and immunohistochemistry characterization of ER and Ki67. Tumour cellularity size: calculated by combining the percentage of residual tumour cellularity and tumour pathological size. Results: N=104. Tumour characteristics at surgery and breakdown for the calculated PEPI score: table 1. Correlation between the percentage of Ki67 positive cells at surgery and TCS: (r=0.2503) p=0.04 (95% CI, 0.0014 to 0.4700). Correlation between TCS and PEPI score: (r=0.2582) p=0.05 (95% CI, -0.0131 to 0.4940).

Conclusions: Tumour cellularity size is a promising biomarker to determine response and prognosis after NET. There is a need to find other biomarkers to predict response after NET.

Table 1Pathology/Biomarker statusPEPI score RFS pointsNo. of patientspTNot available (NA)1pT1/T20102pT3/T431pNNA7Negative075Positive322KI67 levelNA10%-2.7%039>2.7%-7.3%131>7.3%-19.7%119>19.7%-53.1%213>53.1%31ER-status Allred scoreNA120-2303-8092PEPI scoreNA190281342533495561PEPI groupNot calculated19I (0 score)28II (1-3 score)42III (≥4 score)15

Citation Format: Joanna Ines Lopez Velazco, María Otaño, Lide Larburu, Ainhara Lahuerta, Kepa Elorriaga, Virginia Segur, Juan Carlos Irizabal, Ana Martínez, Lourdes Jáuregui, Maria M. Caffarel, Ander Urruticoechea. Tumour cellularity size as a biomarker to predict response after neoadjuvant endocrine therapy: Correlation analysis between Ki67 expression and PEPI score [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-39.
Abstract PS6-59: Impact of Cholecystectomy in Breast Cancer Recurrence
Authors: Madeka Isheeta , Gawdi Rohin , Cook Katherine L , Chiba Akiko
Published: February 2021

Background: Several published studies demonstrate that bile acid metabolites may influence the growth of breast cancer cells in vitro. Our group has shown reduced plasma concentrations of cholic acid and chenodeoxycholic acid (primary bile acids) and deoxycholic acid and lithocholic acid (secondary bile acids) in breast cancer patients that later on develop tumor recurrence. Cholecystectomy reduces the circulating bile acid pool. In patients with prior cholecystectomy, changes in bile acid metabolites may contribute to breast cancer tumorigenesis and recurrence. This study investigates our institutional rate of cholecystectomy in women diagnosed with breast cancer and its impact on breast cancer recurrence.

Methods: A retrospective review of patients with an invasive breast cancer diagnosis between 2014-2015 was conducted. Demographics, preoperative variables, surgical history and clinical outcome data was collected. 5-year disease-free survival (DFS) was compared using a Log-rank (Mantel-Cox) test.

Results: The study included 264 patients with mean age of 60.9. Most were Caucasian (83.5%). The majority were diagnosed at Stage II or lower (80.3%) and had hormone receptor positive, HER2 negative breast cancer (72.9%). Approximately 22.7% of patients had prior cholecystectomy surgery. The only statistically significant heterogeneity in demographic data between patients with and without cholecystectomy was body mass index (BMI). Patients with cholecystectomy had a mean BMI of 33.3, versus 29.1 in patients with intact gallbladders. The 5-year DFS in breast cancer patients with cholecystectomy was 91.6%, versus 97.1% in patients with intact gallbladders (p=0.06).

Conclusion: Women with breast cancer who had a history of cholecystectomy had increased rates of breast cancer recurrence over a 5-year period compared to women with breast cancer with intact gallbladders. Although this result was not statistically significant, a trend was seen. Future study of a larger patient sample size sample may lead to a statistical significant difference. The statistically significant difference in BMI between the two patient groups is likely a confounding factor, given increased BMI is a known risk factor for developing cholecystitis and breast cancer. This data supports existing in vitro studies that bile acids may influence the growth of breast cancer cells. There may be utility in closer follow-up of women with breast cancer and a history of cholecystectomy given the increased rate of breast cancer recurrence in this population.

Citation Format: Isheeta Madeka, Rohin Gawdi, Katherine L Cook, Akiko Chiba. Impact of Cholecystectomy in Breast Cancer Recurrence [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-59.
Abstract PS7-05: Estrogen-based hormone replacement therapy [E-HRT] reduces all-cause, breast cancer, and Alzheimer's dementia mortality
Authors: Ragaz Joseph , Shakeraneh Shayan , Qian Hong , Wong Hubert , Spinelli John J. , Wilson Kenneth S.
Published: February 2021

OBJECTIVES. To evaluate the long-term population-level impact of E-HRT on cause-specific and all-cause mortality in postmenopausal women in the USA, using the results of the 2017 Women’s Health Initiative HRT Trial 2 update.1 Of particular interest was the significantly reduced Breast Cancer [BrCa] mortality rates [RR=0.55, 95% C.I.=0.33-0.92].1

METHODOLOGY. In the WHI HRT Trial 2, women were randomized to receive estrogen (E) or placebo (P).1 For our analyses, the Annualized mortality rates (AR) were extracted for women aged 50-59, 60-69, 70-79, for breast cancer, Alzheimer's dementia, and all-cause mortality. The Median follow-up was 18 years. The Annualized Mortality Rate Difference (ARD) between the two groups was calculated as a difference of the AR between the P vs. E (AR in P - [minus] AR in E), expressed per 100,000 person-years. Subsequently, the Number of Avoided Deaths per year (NAD/year) was calculated using the number of women in each age group from the 2010 US census data.

RESULTS. The annualized number of deaths avoided by the use of E-HRT in the US population was estimated as follows: BrCa, 9,292; Alzheimer’s dementia: 18,966; and all cause-mortality: 50,008 (Table).

CONCLUSIONS. These data show a major beneficial impact of E-HRT, with over 50,000 deaths/year prevented in the USA alone. While these gains, sustained throughout the follow-up, represent undoubtedly major multi-organ metabolic benefits of estrogen, the most striking and unexpected findings involve BrCa, with over 9,000 BrCa deaths potentially avoided each year, just in the USA alone.

RECOMMENDATION. Adoption and implementation of E-based HRT to the current HRT medical guidelines, to extend the health benefits to millions of women, and to prevent thousands of deaths each year in the USA alone.

REFERENCE.1.Manson JE et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. J Am Med Assoc 2017; 318(10): 927-938.

AgesAge 50 – 59(N=21,506,008)Age 60 – 69(N=15,323,140)Age 70 – 79(N=9,169,601)ALL ages(N=45,998,749)ARD / 100,000NAD / YearARD / 100,000NAD / YearARD / 100,000NAD / YearNAD / YearBreast Cancer204,301233,524161,4679,292Alzheimer’s Dementia00406,12914012,83718,966All-Cause Mortality15032,259507,66211010,08750,008

Citation Format: Joseph Ragaz, Shayan Shakeraneh, Hong Qian, Hubert Wong, John J. Spinelli, Kenneth S. Wilson. Estrogen-based hormone replacement therapy [E-HRT] reduces all-cause, breast cancer, and Alzheimer's dementia mortality [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-05.
Abstract PS7-27: Trends in breast cancer mortality in Brazil - a 14-year registry-based study
Authors: Marta Guilherme Nader , Testa Laura , Guindalini Rodrigo Santa Cruz , Marta Gustavo Nader , Del Pilar Estevez Diz Maria , Hoff Paulo M.
Published: February 2021

Background: Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. BC mortality rates have been decreasing over the past decades in the developed countries. In the United States, BC mortality declined on average 1.5% each year over 2008-2017. Given the paucity of BC mortality data in Brazil, we sought to characterize BC mortality trends in southeastern Brazil and its relationship with demographic variables.

Methods: A cross-sectional registry-based analysis was conducted to describe BC mortality trends in the State of Sao Paulo (Brazil) from 2004 to 2017. Sao Paulo is the most populous state in Brazil, with 45.5 million inhabitants, corresponding to 21.8% of the country's total population. BC-related death records, including gender and age were collected from SEADE Foundation’s database, an official entity charged with generating statistical data for the State of Sao Paulo. Mortality rates are expressed in units of deaths per 100,000 individuals per year. The annual percentage change (APC) was calculated to identify mortality trends over the period. Trend analysis was carried out by linear regression and an increase or decrease in trend was considered statistically significant when p-value < 0.05.

Results: From 2004 to 2017, 52,005 deaths from BC were recorded in the State of São Paulo, Brazil. Average annual mortality was 8.96/100,000 (17.38/100,000 for females and 0.11/100,000 for males). Average mortality rates were higher in the age group over 65 years-old (46.47/100,000). BC mortality rates remained stable during the period analyzed (APC 0, 95%CI -0.2% to +0.3%, P = 0.9) for both females (APC 0, 95%CI -0.3% to +0.2%, P = 0.7) and males (APC +2.4%, 95%CI -1.7% to +6.6%, P = 0.2). Among females, an increasing BC mortality trend was detected for patients under 40 years-old (APC +2.4%, 95%CI +1.6% to +3.2%, P < 0.0001) and remained stable for the age groups between 40 - 65 years-old (APC -0.3%, 95%CI -0.7% to +0.1%, P = 0.1) and over 65 years-old (APC -0.1%, 95%CI -0.4% to +0.2%, P 0.5).

Conclusion: In contrast with data from other developing countries, a stable BC mortality has been demonstrated in southeastern Brazil over a 14-year period for the general population. However, a significant increase in BC mortality rates has been demonstrated among patients under 40 years-old.

Citation Format: Guilherme Nader Marta, Laura Testa, Rodrigo Santa Cruz Guindalini, Gustavo Nader Marta, Maria Del Pilar Estevez Diz, Paulo M. Hoff. Trends in breast cancer mortality in Brazil - a 14-year registry-based study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-27.