bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ED2-3: Hormonal exposure and risk in BRCA1/2 carriers
Authors: Kotsopoulos Joanne
Published: March 2023

Women who inherit a pathogenic variant (mutation hereafter) in the BRCA1 or BRCA2 geneface extremely high lifetime risks of developing breast and ovarian (or fallopian tube) cancer. More than two decades since the discovery of these genes, and primary prevention with bilateral mastectomy and salpingo-oophorectomy remain the most effective options to manage cancer risk in this population. Understanding the impact of exogenous hormone use is important for both the clinical management of high-risk women and for furthering our knowledge of the pathogenesis of BRCA-associated disease. In this session, I will review the current epidemiologic data surrounding the role of exogenous (anti)hormone use on BRCA-cancer risk. Specifically, I will discuss the role of tamoxifen in preventing BRCA-associated breast cancer and I will describe whether use of oral contraceptives or hormone replacement therapy (HRT) increase the risk of breast cancer. Where possible, I will present data by gene mutation. Potential associations with the risk of ovarian cancer will also be referred to, given that managing BRCA-cancer risks is a balancing act. Finally, I will review how the epidemiologic information has contributed to the discovery of novel targets for the non-surgical prevention of BRCA1-associated breast cancer and gaps in the literature to be addressed in future research.

Citation Format: Joanne Kotsopoulos. Hormonal exposure and risk in BRCA1/2 carriers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED2-3.
Abstract ED5-3: Financial toxicity
Authors: Chino Fumiko
Published: March 2023

People with cancer spend more out of pocket for medical care than others with chronic diseases, a pattern that persists years after initial cancer diagnosis and treatment. Patients and their families are at risk for financial toxicity including problems paying medical bills, increased stress and/or symptom burden, and delaying or forgoing care due to costs. In this talk, Dr. Fumiko Chino provides an overview of financial toxicity in cancer care and its real-life impact on people with cancer. Factors contributing to financial toxicity are addressed as well potential solutions.

1. Define financial toxicity as a negative consequence of cancer diagnosis/treatment

2. Describe effects of financial toxicity on quality of life, adherence, and outcomes

3. Name potential solutions to financial toxicity on a health system, provider, and patient level

Citation Format: Fumiko Chino. Financial toxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED5-3.
Abstract ED9-2: The contribution of the tumor microenvironment to cancer dormancy
Authors: Bravo-Cordero Jose Javier
Published: March 2023

In this seminar I will discuss how breast cancer DTCs modify the metastatic microenvironment to favor seeding and dormancy. In order to extravasate efficiently and form metastasis, cancer cells have to become migratory and coordinate both invasive and proliferative programs at distant organs. High-resolution lattice light-sheet with adaptive optics imaging in living cells revealed that DTCs extravasate from the blood vessels by forming actin-rich invadopodium protrusions. We have identified a population of breast cancer DTCs with pro-invasive and pro-dormancy capacities. These cells downregulate srGAP1, a GTPase regulator, favoring dissemination and dormancy at metastatic organs. Our findings describe a novel mechanism mediating the shift from a proliferative to an invasive/dormant phenotype in breast cancer cells in vivo. srGAP1 is a new regulator of dormancy that regulates the formation of dormancy-permissive microenvironments through increased secretion of TGFb2 and SMAD2 activation.

Citation Format: Jose Javier Bravo-Cordero. The contribution of the tumor microenvironment to cancer dormancy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED9-2.
Abstract OT3-33-01: Prospective, Multi-Center, Artificial Intelligence Study for Early Prediction of Serious Events under Treatment Is Now Open for Recruitment in Breast Cancer - OMCAT Trial in Progress
Authors: Schinköthe Timo , Tonk Christian Horst , Kates Ronald , Küemmel Sherko , Cardoso Fatima , Harbeck Nadia , Staib Peter , Schmidt Annette
Published: March 2023

Background: Aim of the OMCAT trial (‘One Million CAncer Treatment months’, NCT04531995) is improvement of cancer patient care and safety by developing artificial intelligence (AI)-based, incident prediction algorithms. Incident detection allows early notification of treatment teams, enabling timely management changes or interventions. Ultimately the algorithms can also support improved health resource allocation. This trial in progress aims to provide learning databases in breast cancer comprising both electronic patient reported outcome (ePRO) data using the mobile medical device ‘CANKADO PRO-React’ and ground truth outcome data, which provide disease-specific events of interest (“incidents”) verified by the physician (e.g., during patient examinations). Methods: Incident prediction is posed as an application of stochastic time series analysis using AI and knowledge engineering technology. The learning process begins by fitting individualized and disease-specific stochastic process models to “incident-free” intervals extracted from the ePRO data series. Incidents produce detectable deviations from “ordinary” ePRO fluctuations. The algorithms are trained on CANKADO PRO-React data to produce real-time risk functions for predicting incidents on a clinically specified time horizon. Results: Considering the heterogeneity and combinatorics of diseases, stages, therapies, and types of events considered in this study, ultimately the AI algorithms aim to discover about 360 distinct predictive relationships. The estimate of one million treatment months is derived from statistical power analysis of this target, considering estimated median documentation time of six months per patient and estimated 400-500 patients per predictive relationship. To date, 45 centers in Germany have expressed interest in participating. This participation level will enable proof of principle. Ethics votes are already available in most regions. Other centers are invited to participate in this trial. Conclusions: OMCAT opens a whole new path towards evidence-trained AI and a novel combination of patient observation and predictive care. The goals of OMCAT are ambitious and will therefore require many more supporters.

Citation Format: Timo Schinköthe, Christian Horst Tonk, Ronald Kates, Sherko Küemmel, Fatima Cardoso, Nadia Harbeck, Peter Staib, Annette Schmidt. Prospective, Multi-Center, Artificial Intelligence Study for Early Prediction of Serious Events under Treatment Is Now Open for Recruitment in Breast Cancer - OMCAT Trial in Progress [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-33-01.
Abstract P1-05-24: DELAYS in DIAGNOSIS of Adolescent and Young Adult BREAST CANCER and LACK OF BREAST HEALTH EDUCATION, Community Based Research
Authors: Peters Missy , Tubman Steph
Published: March 2023

INTRO) The average AYA breast cancer patient is diagnosed at a higher stage and has a higher mortality rate compared to their 40+ counterparts [1,2,3]. Ruddy et al. (2014) establish a higher prevalence of delayed diagnosis in AYA patients [4]. Delays in treatment of just 6 weeks have been linked to poorer 5-year survival rates [5]. In this study, we attempt to confirm the findings of Ruddy et al. and further define factors affecting delays in diagnosis. METHODS) We distributed an online survey via social media outlets to women diagnosed < 40 years old in the USA. We interpreted 455 responses. RESULTS) Our findings determined that 70% of respondents (n=320) made extra efforts after detecting an abnormality and taking steps to obtain a diagnosis. This includes those with prompt and delayed diagnosis. 36% of survivors faced delays in diagnosis (defined by 8+ weeks duration from detection to diagnosis). 62% of survivors say that a physician never educated them on breast health prior to diagnosis. 54% have not heard of breast self-awareness (BSA) and 54% incorrectly defined breast self-exams (BSE), suggesting confusion in this distinction. DISCUSSION) These data confirm earlier findings that 1) women under 40 face a significant rate of delayed diagnosis; and 2) patient perceptions and medical provider perceptions contribute to these delays. We propose that earlier diagnosis of breast cancer in young women will initiate quicker treatment interventions which have been shown to increase 5-year survival rates and lower long-term mortality rates in the AYA breast cancer population [5,6]. CONCLUSION) Greater efforts should be made to educate young women on breast health, and the medical community should be made aware of these challenges so they can properly evaluate and assist young women to receive a prompt diagnosis.

Young Breast Cancer Project

Summary of poster presented at AACR summarizing our community based research and advocacy efforts for AYA breast cancer in the US.

Citation Format: Missy Peters, Steph Tubman. DELAYS in DIAGNOSIS of Adolescent and Young Adult BREAST CANCER and LACK OF BREAST HEALTH EDUCATION, Community Based Research [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-24.
Abstract P1-05-34: MicroRNAs as Prognostic Markers in Breast Cancer
Authors: Nguyen Anh Q. , Cunningham Colin , Okpechi Samuel , Yousefi Hassan , McKinney Shawn , Boulmay Brian , Garcia Agustin , Alahari Suresh
Published: March 2023

Background: Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. BC disproportionally affects women of ethnic minorities, especially Black and Hispanic. While this disparity has been acknowledged and social determinations of health remains an important contributor, BC pathophysiology is yet to be elucidated in minorities. MicroRNAs (miRNA), including but not limited to let-7, 125-3p, 192-5p, 451a, play regulatory roles in cancer pathobiology and progression in many cancer types, including but not limited to BC. In our lab, in vitro and in vivo studies on mouse models demonstrated that miR-23b and miR-27b had crucial roles in cancer progression in BC via mechanisms that involves nischarin, an integrin-binding protein, and were associated with worse outcome. Moreover, miRNAs can be detected and are stable in blood samples, and thus the detection has a profound clinical impact on diagnosis. Study Design: Between April 2021 and May 2022, 30 newly diagnosed patients with BC and 30 patients without any cancer diagnosis at University Medical Center- New Orleans were enrolled on the study (IRB# 936). 86% of patients are African American or Hispanics. Plasma samples were collected before any medical intervention for BC. Plasma miRNAs were isolated and miRNA expression were performed utilizing RT-PCR. Results: Expressions of let-7 and 125a miRNAs are two times higher in plasma of patients with BC compared to patients without a diagnosis of cancer. There was no difference in miRNA expression in circulatory 23b, 27b, 192-5p, and 451a. Among breast cancer types, there are two-fold decreased expression of 192-5p and 451a in triple negative compared to hormone positive BC. Conclusion: This project will add to the body of knowledge on roles of miRNAs as prognostic markers in patients with BC, more importantly, triple negative BC, and elucidate pathophysiologic mechanism contributing to racial disparity in breast cancer treatment and recurrence. In the near future, we aim to examine effects of chemotherapy and surgery on the expression of circulatory microRNAs.

Citation Format: Anh Q. Nguyen, Colin Cunningham, Samuel Okpechi, Hassan Yousefi, Shawn McKinney, Brian Boulmay, Agustin Garcia, Suresh Alahari. MicroRNAs as Prognostic Markers in Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-34.
Abstract P1-05-36: AI-Based Smartphone App Using a Single-Lead ECG for Automated QTc Diagnostics in Oncology
Authors: Schinköthe Timo , Tonk Christian Horst , Harbeck Nadia , Carmelo Vanda , Feliciano Joana Gomes , Wuerstlein Rachel , Küemmel Sherko , Schmidt Annette
Published: March 2023

Introduction: Long QT syndrome is a common cardiotoxic side effect of various anti-tumor drugs. Previous cardiological monitoring of oncological patients is primarily complex and requires for non-internal oncologists a consultation. Therefore, the QTc-Tracker smartphone APP was developed, which enabled a tele-cardiological diagnosis of the QTc time with standard single-lead ECG devices. As a result, diagnosis times could already be reduced by 99%. The further development examined an automatic determination of the QT time using the smartphone APP. However, since single-lead ECG devices are significantly more susceptible to interference, the determination of the QT time is more complex than with 12-lead ECGs. Methods: The QTc-Tracker smartphone APP was developed to determine the QT time. Self-tracker single-lead ECG devices were used to record the lead I signal. The ECG recordings were analyzed in the APP and passed on to an external cardiologist as reference. The APP used artificial intelligence and was trained in the first phase and validated in the second phase. The first phase aimed to improve QT time detection. The results of the APP were compared with the findings of the external cardiologist. In both phases, ECGs from breast cancer patients receiving ribociclib were used. Results: A total of 1889 single-lead ECGs were carried out. 248 of these could not be evaluated (13%). QTc prolongation, according to CTCAE, was diagnosed in 41 cases (2.5%). 878 of the evaluable ECGs were used for the training phase and 763 for the evaluation phase. In the first group (before the improvement), the sensitivity to automatically detect a prolongation of the QT time was 36%, and the specificity was 96%. In the evaluation collective (after the training), the sensitivity went up to 85%, and the specificity was unchanged at 96%. Conclusions: The trained method of the QTc tracker is able to reliably detect a QT time lengthening even without a cardiological diagnosis only by using single-lead self-tracker ECG’s. In the rare cases in which an elongation was not detected, the cardiac diagnosis was only a few milliseconds above the threshold value. This artificial intelligence-based smartphone APP is not intended to replace the cardiological diagnosis, but it can simplify routine processes and help to decide which patients need a cardiological examination more urgently.

Citation Format: Timo Schinköthe, Christian Horst Tonk, Nadia Harbeck, Vanda Carmelo, Joana Gomes Feliciano, Rachel Wuerstlein, Sherko Küemmel, Annette Schmidt. AI-Based Smartphone App Using a Single-Lead ECG for Automated QTc Diagnostics in Oncology [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-36.
Abstract P1-09-07: Omission of Axillary Surgery for Ipsilateral Breast Tumor Recurrence with Negative Nodes after Previous Breast-Conserving Surgery: Is It Oncologically Safe?
Authors: Qu Feilin , Lin Caijin , Li Jun-Jie , Shao Zhi-Ming
Published: March 2023

Background: Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of the previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR.

Methods: We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS). Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the loco-regional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups.

Results: A total of 154 IBTR patients were eligible for final analysis. Compared to no SAS group, SAS group was less likely to undergo ALND (15.1% vs 73.3%, p <  0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p=0.03), and were more likely to have discordant molecular subtype with primary tumor (35.8% vs 12.9%, p=0.001). However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. Pathologic analysis revealed pathologically uninvolved nodal status in approximately 85% of patients receiving SAS at time of IBTR in the overall population and the subgroup (Table 1). No significant differences were observed in LRRFS, DMFS and OS between the two groups (Table 2).

Conclusion: For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS, but comparable LRRFS, DMFS, and OS. These results support wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.

Table 1. Pathologic axillary staging in patients receiving axillary surgery at time of IBTR.

Table 2. Cox regression analysis of LRRFS, DMFS, and OS after IBTR.

Citation Format: Feilin Qu, Caijin Lin, Jun-Jie Li, Zhi-Ming Shao. Omission of Axillary Surgery for Ipsilateral Breast Tumor Recurrence with Negative Nodes after Previous Breast-Conserving Surgery: Is It Oncologically Safe? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-09-07.
Abstract P2-06-01: Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial
Authors: Carpenter Catherine L. , Master Aashini K. , Julian Olivia , Ben-Nissan Dina , Rakoff Michele , Thames Gail , Li Zhaoping
Published: March 2023

Background: In spite of aromatase inhibitors reducing risk of recurrence and mortality, painful side effects often cause women to discontinue use of the drug. Side effects of aromatase inhibitors include joint and muscle pain, loss of bone mineral density, and impairment of heart functioning. Discontinuation of aromatase inhibitors due to these side effects occur in up to 40% of breast cancer survivors, and consequently risks of recurrence and mortality increase. Objective: We developed two interventions designed to reduce inflammation, alleviate pain and stabilize bone mineral density. Methods: We are currently conducting a pilot parallel intervention trial that is targeted toward alleviating side effects from aromatase inhibitors through dietary and exercise controlled interventions lasting for three months. The dietary intervention is an anti-inflammatory Mediterranean diet designed to decrease inflammation and lessen joint and muscle pain. Participants randomized to the Mediterranean dietary intervention are exclusively consuming food provided by Territory Foods®, an outside food preparation and delivery service, local to Los Angeles. Our exercise intervention is designed to mobilize the joints, and strengthen and reduce bone loss. Participants are visiting the UCLA Kinross gym for three days per week and are undergoing tailored exercise sessions delivered from personal trainers following our bone strengthening intervention protocol. Anthropometric measures, muscle strength, DXA scanning of bone mineral density, peripheral arterial tonometry, pulse wave velocity and biomarkers of inflammation, bone turnover and heart functioning are conducted at baseline, mid- and end of intervention. Results: Our trial is targeted to accrue 20 participants. Thus far we enrolled six participants, with three participants completing the trial. Analysis is ongoing and preliminary results will be presented at the San Antonio Breast Cancer Symposium in December, 2022. Post intervention reports from participants have noted a reduction in pain symptoms, moderate weight loss and increase in muscle strength.

Citation Format: Catherine L. Carpenter, Aashini K. Master, Olivia Julian, Dina Ben-Nissan, Michele Rakoff, Gail Thames, Zhaoping Li. Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-01.
Abstract P2-24-07: Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression
Authors: Parisian Alison D. , Palanisamy Gopinath S. , Ortega Fabian , Sapugay Judevin L. , Bodell William J. , Kulp David , Kushner Peter , Harmon Cyrus
Published: March 2023

OP-1250, a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), is currently in Phase I/II clinical trials for the treatment of estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. OP-1250 has previously demonstrated efficacy in both estrogen receptor 1 (ESR1) wild-type and Y537S mutant breast cancer xenograft models. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are a standard first-line treatment for ER+ advanced or metastatic breast cancer in combination with endocrine therapy. To characterize OP-1250 efficacy in this setting, we explored the combination of OP-1250 with CDK4/6 inhibitors palbociclib and ribociclib in ER+/HER2- breast cancer preclinical models, and profiled the transcriptional changes associated with single agent and combination therapy. OP-1250 and CDK4/6 inhibitors were tested alone and in combination in ESR1 wild-type MCF7 and ESR1 Y537S mutant ST941 xenograft models. Higher doses of OP-1250 and either CDK4/6 inhibitor, when given as a monotherapy, suppress tumor growth and increase animal survival, while lower doses of the compounds display a modest or minimal effect on tumor growth or survival. In combination, lower doses of OP-1250 and either CDK4/6 inhibitor result in significantly greater tumor growth suppression (both xenograft models), tumor regression (MCF7) and animal survival (ST491) than each compound individually. RNA sequencing revealed substantially more gene expression changes with combination treatment than monotherapy. In particular, pathways associated with cell cycle progression displayed greater changes with combination treatment, similar to what was observed with a much higher dose of monotherapy. This study supports the clinical evaluation of OP-1250 in combination with CDK4/6 inhibitors (palbociclib or ribociclib) and provides additional context to mechanisms of combination efficacy. OP-1250 is currently being evaluated in a Phase Ib clinical trial in combination with palbociclib and a study including evaluation of the combination of OP-1250 with ribociclib is planned to initiate in Q3 2022.

Citation Format: Alison D. Parisian, Gopinath S. Palanisamy, Fabian Ortega, Judevin L. Sapugay, William J. Bodell, David Kulp, Peter Kushner, Cyrus Harmon. Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-07.
Abstract P2-26-13: Gene deletion of insulin receptor in MCF-7L breast cancer cells by CRISPR gene editing
Authors: Zhang Xihong , Monteiro Marvis , Yee Douglas
Published: March 2023

The type I insulin-like Growth Factor Receptor (IGF-IR) plays important roles in breast cancer cell proliferation and metastasis. However, preclinical and clinical research targeting IGF-IR also revealed the potential for insulin receptor (IR) to compensate for IGF-1R inhibition. IR is expressed as two isoforms (IRA and IRB) through alternative splicing. The IRB is expressed in adult tissues and thought responsible for cell metabolism while IRA is expressed in fetal development to enhance cell growth. Since breast cancer cells usually express both IGF-IR and IRA/IRB, differential signaling by IRA and IRB has not been clearly demonstrated. To further define the role for IR, we used CRISPR technology for gene editing in exon 2 of IR in MCF-7L cells to delete IR. Cells were selected for absent IR expression by flow cytometry and Sanger sequencing confirmed that one of the clones (CL35) had the targeted 4 base pair deletions in exon 2. Immunoblotting using an antibody to the  subunit of IR showed no expression in CL35. Unexpectedly, 10 nM insulin exposure resulted in downstream AKT and Erk1,2 phosphorylation. Immunoprecipitation showed that IGF-IR was activated by the insulin in CL35 cells. Insulin signaling in CL35 through IGF-IR was inhibited by huEM164, an anti IGF-IR monoclonal antibody. Compared to MCF-7L parental cells, CL35 was more sensitive to IGF-I and less sensitive to insulin as demonstrated by downstream AKT phosphorylation and MTT monolayer growth assay. Insulin stimulated monolayer growth of CL35 measured by MTT was not affected in testing serum free media (SFM) unless transferrin was deleted from the media. These data suggest IGF-IR can function to activate signaling in response to insulin. To ensure that our clone does not contain alternate splicing products resulting in aberrant IR proteins, we are further sequencing IR mRNA in CL35. In conclusion, we have established an IR null breast cancer cell line with reduced sensitivity to insulin and increased sensitivity to IGF-I. This cell line can be used to express the IRA and IRB isoforms to characterize their function in breast cancer cells.

Citation Format: Xihong Zhang, Marvis Monteiro, Douglas Yee. Gene deletion of insulin receptor in MCF-7L breast cancer cells by CRISPR gene editing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-13.
Abstract P3-03-03: Risk factors associated with chemotherapy-induced nausea and vomiting among breast cancer patients receiving highly emetogenic chemotherapy
Authors: Yeo Winnie , Ngai Nicole , Yip Christopher , Yeo Victoria , Ko Jonathan , Yip Claudia , Mo Frankie
Published: March 2023

Purpose: Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by prior studies, there are only few studies evaluating risk factors associated with the contemporary antiemetic prophylaxis, including that of olanzapine/aprepitant- or NEPA- containing regimens. The present study aimed to identify the risk factors related to CINV development in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide chemotherapy. Methods: Data from 304 patients who were enrolled to 3 previously reported prospective antiemetic studies were included. Multivariate logistic regression models were used to predict risk factors associated with the occurrence of CINV. Additionally, likelihood of treatment failure in relation to number of risk factors of individual patient was evaluated. Results: Multivariate analysis of the entire study group revealed that obese status (defined as body mass index >/= 25.0 kg/m2) and the use of olanzapine/aprepitant- or NEPA- containing antiemetic regimens were associated with high likelihood, while history of motion sickness was associated with lower likelihood, of complete response (CR) and ‘no nausea’ in the overall phase. History of vomiting in pregnancy was also associated with lower likelihood of overall CR. Patients with increasing number of risk factors had higher likelihood of treatment failure as well as shorter time to first vomiting. Those who did not achieve CR and ‘no nausea’ in the first cycle were less likely to achieve these parameters in the subsequent cycle of chemotherapy. Conclusions: This present study confirmed the previously reported risk factors to be important for CINV in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide. Further optimization of CINV control is required for patients with identifiable risk factors; olanzapine/aprepitant- or NEPA- containing prophylaxes are the preferred contemporary antiemetics regimens for Chinese breast cancer patients undergoing doxorubicin and cyclophosphamide chemotherapy.

Citation Format: Winnie Yeo, Nicole Ngai, Christopher Yip, Victoria Yeo, Jonathan Ko, Claudia Yip, Frankie Mo. Risk factors associated with chemotherapy-induced nausea and vomiting among breast cancer patients receiving highly emetogenic chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-03.
Abstract P3-03-15: Physical Activity and Risk of Death in Breast Cancer Survivors: A Prospective Study
Authors: Chen Lie Hong , Irwin Michael R. , Olmstead Richard , Haque Reina
Published: March 2023

BACKGROUND. Strong evidence exists supporting the protective effect of physical activity on the risk of developing breast cancer; however, its impact on survival after breast cancer diagnosis remains controversial with limited research in long-term survivors. The aim of the current study was to evaluate the association of physical activity and risk of all-cause mortality in long-term breast cancer survivors.

METHODS. We conducted a prospective cohort of 315 post-menopausal breast cancer survivors who were at least 2 years post their initial diagnosis (median 6 years of survivorship). They initially were diagnosed with early stage (AJCC TNM Stages 0-II) breast cancer between January 1996-December 2012. Baseline interviews were conducted between August 2013 and March 2015, and participants were followed until date of death or study’s end (April 2022). Subjects were queried on physical activity and fatigue using validated questionnaires, Godin Leisure Physical Activity Scale (GLPAS) and Fatigue Symptom Inventory (FSI). Physical activity was defined in 3 levels (active, moderately active, insufficiently active). Cox proportional hazards regression model was used to estimate the association of physical activity with risk of all-cause mortality, adjusted for age at baseline, breast cancer stage, Charlson comorbidity index (CCI), years since cancer diagnosis, fatigue, race/ethnicity, lifetime history of insomnia and depression, and adjuvant cancer treatments (endocrine, chemotherapy and radiation).

RESULTS. Of the 315 women, mean age at interview was 71 years (range: 57-86). The cohort included 30% women of color, mainly African American/Black and Asian/Pacific Islander women. Over a maximum follow-up of 8.7 years (median:7.8, IQR:7.3-8.3) after their baseline interview, 45 subjects (14.3%) died due to all causes. The mortality rates were: 12.9 per 1000 person years (PY) for active; 13.4 per 1000 PY for moderately active; and 32.9 per 1000 PY for insufficiently active. In multivariable analysis, compared to insufficiently active women, those who were active or moderately active had a markedly 60% decreased risk of death (active: HR=0.42, 95% CI: 0.21-0.85; moderately active: HR=0.40, 95% CI:0.17-0.95).

CONCLUSION: We found that even moderate physical activity was associated with a significantly decreased risk of all-cause death in long-term breast cancer survivors. Survivorship care plans should consider incorporating physical activity because even moderate activity is vital for extending survival as well as health-related quality of life.

Citation Format: Lie Hong Chen, Michael R. Irwin, Richard Olmstead, Reina Haque. Physical Activity and Risk of Death in Breast Cancer Survivors: A Prospective Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-15.
Abstract P3-07-01: Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe
Authors: Yan Ying , Baranowska-Kortylewicz Janina , Graff Brendan
Published: March 2023

Metastatic breast cancer (mBC) is still an incurable disease and is responsible for the majority of breast cancer-related death, despite tremendous efforts spent on developing better regimens for mBC. Microtubule-targeting chemotherapy agents (MTAs) have been on the front lines of treating mBC. However, many of these drugs become ineffective following treatment, as a consequence of either primary or acquired resistance, which leads to refractory disease. Furthermore, failures of the first-line MTA treatment will negatively affect the effectiveness of the second- and third-line agents in the patients, as the overall response rates of the subsequent treatments are in a range of only ~12% to 35%. Thus, there is an urgent need for alternative MTAs that are significantly different in biological characteristics from those currently used MTAs for mBC therapy. For this purpose, we investigated Mebendazole (methyl 5-benzoyl-2-benzimidazole-carbamate (MEB), which binds different sites on the α/β-tubulin remote from the binding sites of other MTAs, for its potential against mBC cells. MEB has much lower in vivo toxicity than the other MTAs used to treat mBC and it can be orally administrated. We explored MEB for its effectiveness in anti-mBC cells with a panel of human breast normal and mBC cell lines. The data from clonogenic survival studies indicate that MEB delivers < 10-fold greater cytotoxicity toward mBC cells compared to normal mammary epithelial (HME) or benign breast tumor cells. Furthermore, the cytotoxicity in detected in mBC cells was attributed to the induction of mitotic catastrophe, as demonstrated by the increased mitotic cell population (cells with 4N-DNA content and Histon-H3-Ser10 phosphorylation) and concurrent nuclear fragmentation. In contrast, under the same dose range, MEB did not cause mitotic catastrophe in HME cells. In addition, our data also show that MEB is much more efficient in killing p53-deficient mBC cells than p53-proficient mBC cells for the same reason, induction of mitotic catastrophe, which suggest the protective function of p53 against MEB-induced mitotic catastrophe. Collectively, our data support a great potential for MEB as an innovative regimen for improving mBC treatment.

Citation Format: Ying Yan, Janina Baranowska-Kortylewicz, Brendan Graff. Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-01.
Abstract P4-02-09: Evaluation of the Automated Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC-005 Prospective Trial
Authors: Visvanathan Kala , Cope Leslie , Fackler Mary Jo , Considine Michael , Carey Lisa , Forero-Torres Andres , Ingle James N. , Lin Nancy U. , Nanda Rita , Storniolo Anna Maria , Tulac Suzana , Wu Natalie C. , Marla Sudhakar , Venkatesan Neesha R. , Wolff Antonio C. , Sukumar Saraswati
Published: March 2023

Purpose: We previously demonstrated that high levels of circulating methylated DNA are associated with subsequent disease progression in women with metastatic breast cancer (MBC). In this study, we validated the clinical utility of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) prototype assay using the GeneXpert® cartridge system for early assessment of disease progression in MBC. Study Design: The 9-marker, LBx-BCM prototype assay was evaluated in TBCRC-005, a prospective biomarker study, using plasma collected at baseline, week 4 and week 8 from 144 MBC patients. Results: At week 4 MBC patients with high cumulative methylation (CM) had a significantly shorter median PFS (2.88 months v 6.60 months, p = 0.001) and OS (14.52 months v 22.44 months, p=0.005) compared to those with low CM. In a multivariable model, high versus low CM was also associated with shorter PFS (HR = 1.90, 95%CI 1.20-3.01; p =0.006). Change in CM from baseline to week 4 (OR = 4.60, 95%CI 1.77, 11.93; p = 0.002) and high levels of CM at week 4 (OR = 2.78, 95%CI 1.29, 5.99; p = 0.009) were associated with progressive disease at the time of first restaging. A robust risk model (AUC = 0.733) based on week 4 circulating CM levels was developed to predict disease progression as early as 3 months after initiating a new treatment. Conclusion: The easy to perform and automated LBx-BCM prototype assay is a promising clinical tool for detecting disease progression early after initiating treatment in women with MBC. Further validation in larger clinical datasets is needed.

Citation Format: Kala Visvanathan, Leslie Cope, Mary Jo Fackler, Michael Considine, Lisa Carey, Andres Forero-Torres, James N. Ingle, Nancy U. Lin, Rita Nanda, Anna Maria Storniolo, Suzana Tulac, Natalie C. Wu, Sudhakar Marla, Neesha R. Venkatesan, Antonio C. Wolff, Saraswati Sukumar. Evaluation of the Automated Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC-005 Prospective Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-09.
Abstract P4-03-08: Breast cancer incidence rates in Japan turned into bimodal age distribution in this decade
Authors: Uchida Ken , Ohashi Hitoshi , Nogi Hiroko , Kinoshita Satoki , Nosaka Ryouko , Kamio Makiko
Published: March 2023

BACKGROUND: Japan is the globe’s fastest ageing country: 32.0 % of the female population are 65 or older in 2021. The birth rate was 1.30 children per woman in 2021. Japan’s population has been constantly shrinking since 2011 with aging. The number of breast cancer cases has increased rapidly in the course of low birth rate and aging population. Breast cancer has increased and accounted for the first place of all of cancers in Japanese women. OBJECTIVES; Number of breast cancer has increased recently and accounted for the first place of all of female cancers in Japan. Detailed analytics of the increase and aging of breast cancer are not studied. We elucidate the transformation of Japanese breast cancer by ages at diagnosis over the past decade. MATERIALS: We used the registry data of Japanese Breast Cancer Society and Statistics Bureau of Japan in 2018. Female breast cancer new cases were 59,389 patients in 2008 and 93,858 patients in 2018, respectively. The total female population was 65.441 million in 2008 and 64.911 million in 2018, respectively. 65 years and older women accounted for 23.4% in 2008 and 31.0 % in 2018, respectively. METHODS: We compared incidences and incidence rates of breast cancer by ages in 2008 and 2018, respectively. We used the statistical method of Ameijeiras-Alonso et al for mode assessment. RESULTS; Total number of incidences and incidence rates of breast cancer in 2018 were higher than those in 2008 among all ages. Difference of number of incidences were maximum in age of 60-69 in both years. Difference of incidence rates in both years reached maximum in age of 75-79. Incidence rates in 2008 showed unimodal age distribution with the gentle peak. Incidence rates in 2018 showed bimodal age distribution with two peaks of 45-49 and 65-69. CONCLUSIONS; Incidences and incidence rates of breast cancer increased rapidly among all ages in this decade in Japan. The incidence rates increased most in ages of 75-79 and turned into bimodal age distribution in 2018.

Citation Format: Ken Uchida, Hitoshi Ohashi, Hiroko Nogi, Satoki Kinoshita, Ryouko Nosaka, Makiko Kamio. Breast cancer incidence rates in Japan turned into bimodal age distribution in this decade. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-08.
Abstract P4-03-26: Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort
Authors: Wu HuiChen , Castano Angelica , Liao Yuyan , Santella Regina , Brenner David , Terry Mary Beth , Tycko Benjamin
Published: March 2023

Breast cancer has increased dramatically in young women < 50 years in the US over the past decade. DNA methylation is a type of epigenetic change that plays an important role in cancer etiology by silencing tumor suppressor genes or DNA repair-related genes through hypermethylation or activating oncogenes through hypomethylation. Previous genome-wide association studies have suggested DNA methylation in blood is a potential epigenetic markers of breast cancer risk. In this study, we applied targeted methyl-seq to examine the DNA methylation profile in regulatory sequences of 57 known DNA repair pathway genes, together with 123 other genes, located in immune-related loci and genome-wide association peaks for breast cancer. We used a nested case-control design within the Breast Cancer Prospective Family Study Cohort (FroF-SC) and examined DNA methylation profile in DNA from the blood of breast cancer cases (N=293) and age-matched controls (N=327). In the preliminary data analysis, we observed that the methylation levels in 5 genes were statistically significantly different between cases and controls using Wilcoxon Rank Sum Test (Table 1). Some candidate loci show methylation values spanning a wide range (Std Dev) in both cases and controls, suggesting the presence of genotype-dependent allele-specific methylation (ASM). We then conducted generalized estimating equations (GEE model) adjusting for age at blood draw and calculated the odds ratios (ORs) and 95%CI for the association between methylation levels in the 90th and 10th percentiles of differentially methylated genes (90% vs 10% methylation) and breast cancer risk. The ORs (95% CI) from the GEE models were 1.26 (0.97, 1.63, p=0.08) for CD6, 1.27 (0.85, 1.91, p=0.24) for SDCCAG3, 1.12 (0.85, 1.48, p=0.40) for DCLRE1B, 1.29 (0.88, 1.90, p=0.20) for IP09, and 1.63 (1.08, 2.45, p=0.02) for GNPDA1 (Table 2). The associations were not different by age group. Our preliminary results suggest that DNA methylation measured in blood may be a biomarker of breast cancer susceptibility.

Citation Format: HuiChen Wu, Angelica Castano, Yuyan Liao, Regina Santella, David Brenner, Mary Beth Terry, Benjamin Tycko. Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-26.
Abstract P4-03-37: The characteristics of male breast cancer by molecular subtypes: a population-based study
Authors: Wang Min , Liu Deyue , Zhu Li
Published: March 2023

Background: To explore the characteristics of molecular subtype in male breast cancer. Methods: A retrospective study was conducted to investigate the characteristics and prognosis of patients with male breast cancer using the data recorded in the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2014. Results: A total of 1597 cases were enrolled, including 1373 cases with HR+/HER2- (86%), 182 cases with HR+/HER+ (11.4%), 13 cases with HR-/HER2+ (0.8%) and 29 cases with Triple Negative (1.8%), respectively. There were significant differences in distributions in age, race, grade, tumor size and AJCC stage between the molecular subtypes. The molecular subtypes differed significantly in 5 years overall survival and 5 years cause specific survival, establishing the following sequence with HER2-/HR+ > HER2+/HR+ > HER2+/HR- > Triple negative. According to Cox regression, age>65y, ER negative, PR negative, TN subtype, advanced AJCC stage, larger tumor size, stage T3 and M1 were independent prognostic factors for poorer survival. Conclusion: The prognosis of male breast cancer varied by molecular subtypes. Age, ER and PR, status, stage as well as tumor size were independent prognostic factors.

Citation Format: Min Wang, Deyue Liu, Li Zhu. The characteristics of male breast cancer by molecular subtypes: a population-based study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-37.