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Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2–M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathologic complete response, higher chromosomal instability index (CIN), and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC preclinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications. Significance: Proteogenomic analysis of triple-negative breast tumors revealed a complex landscape of chemotherapy response associations, including a 19q13.31–33 somatic deletion encoding genes serving lagging-strand DNA synthesis (LIG1, POLD1, and XRCC1), that correlate with lack of pathologic response, carboplatin-selective resistance, and, in pan-cancer studies, poor prognosis and CIN. This article is highlighted in the In This Issue feature, p. 2483

Management of triple negative breast cancer (TNBC) that is resistant to chemotherapy remains a challenge. Many studies have investigated the unconventional approach of concurrent chemotherapy with radiation in management of TNBC that is resistant to neoadjuvant anthracycline and taxane containing chemotherapy. Various chemotherapies have been used as radiosensitizers. In this report we summarize the published literature and highlight clinical trials that pertain to management of TNBC.

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2–M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathologic complete response, higher chromosomal instability index (CIN), and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC preclinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications.Significance:Proteogenomic analysis of triple-negative breast tumors revealed a complex landscape of chemotherapy response associations, including a 19q13.31–33 somatic deletion encoding genes serving lagging-strand DNA synthesis (LIG1, POLD1, and XRCC1), that correlate with lack of pathologic response, carboplatin-selective resistance, and, in pan-cancer studies, poor prognosis and CIN.This article is highlighted in the In This Issue feature, p. 2483

Supplementary Figure from Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer

Supplementary Table from Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer

Background: Patients with higher socioeconomic status (SES) are overrepresented in NCI-sponsored cancer clinical trials (CCT). Inadequate access, social and cultural barriers have been described as reasons for poor accrual of patients with low SES into clinical trials. Racial minorities including African Americans (AA) and Hispanics are underrepresented in CCT and often experience issues related to lack of access. On the other hand, survey studies throughout United States suggest equal willingness for participation in CCT among all racial categories. When access to CCT is not a barrier to enrollment, the rate of CCT participation by Racial and Ethnic minorities with low SES is not well studied. Methods: We performed a retrospective review of the database of new patients screened for breast CCT at Dan L Duncan Comprehensive Cancer Center (DLDCCC). DLDCCC is an ideal venue for studies on clinical trial diversity because it provides cancer care to two very different patient demographics: 1) Smith Clinic is a Harris Health System (HHS) cancer clinic where a majority of the patients are of low SES; half of our patients earn less than $25,000 annually, 60% are uninsured using a county financial assistance program called “Gold Card”, 65% are unable to speak proficient English, and 52% are Hispanic, 25% AA, 9% Caucasian and 5% Asian, 2) Baylor St Luke’s Medical Center (BSLMC) serves predominantly Caucasian patients with >95% of the patients having federal or commercial insurance. Cancer clinical trials are available at both sites, and all patients across the two clinics have equal opportunity for enrollment. The database dates back to 5/2015 and includes 3,084 patients. Using the chi-squared test, we compared the rate of trial availability, trial eligibility and enrollment for breast CCT between two patient populations receiving care at Smith clinic vs. BSLMC. We tabulated the rate of trial participation decline at each clinic per year from 5/2015 to 6/2021. The study had IRB approval from Baylor College of Medicine.Results: Among the 3,084 new-to-practice patients, 1,664 patients were seen at BSLMC and 1,420 were seen at Smith Clinic. Clinical trials were available for 758 (53.4%) patients at Smith clinic and 742 (44.6%) patients at BSLMC, p Citation Format: Maryam Nemati Shafaee, Emily L Podany, Katherine Sanchez, Nicole Higashiyama, Valentina Hoyos, Liz Binu Micheal, Kristen Otte, Anne Pavlick, Julie Nangia, Alphi Kuriakose, Kent C Osborne, Maria Jibaja-Weiss, Matthew J Ellis, Shaun Bulsara, Mothaffar Rimawi. Breast cancer clinical trial participation rate among patients of low socioeconomic status at a comprehensive cancer center [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-02.

Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.

Background: Following the declaration of the COVID-19 national emergency, screening mammograms (SM) abruptly dropped across the United States. Stay-at-home orders discourage cancer patients from seeking care, and cancer screenings and surgeries were postponed. Upon resumption of screening services, rates of screening were slow to recover. At Baylor St. Luke’s CHI (BSL), one of the largest tertiary care centers providing comprehensive cancer screening in Houston, we investigated patient level predictors, including comorbidities and area deprivation index (ADI), and the risk of skipping SM in the first year of the COVID-19 Pandemic. Methods: We used the local PENRAD database to retrieve the monthly gross number of SM performed at all BSL sites from 02/2018 to 01/2021. We obtained patient level data through EPIC, including address and demographics, comorbid conditions e.g., diabetes, hypertension, obesity (BMI30), chronic kidney disease and cardiovascular diseases (CVD). We identified ADI associated with patient addresses. We included patient who received at least one SM between 02/2018 to 01/2020. We compared patients did not get a mammogram in the first year of the pandemic; 02/2020 to 01/2021, to those who maintained screening during the pandemic. We performed a logistic regression analysis to assess the influence of age, 0 to +3 comorbid conditions, and ADI in quartiles on the odds ratio of skipping SM in the first year of the pandemic. Statistical significance was set at p< 0.05. The study was IRB approved. Results: Out of the 4591 women that screened in 2018 and/or 2019, only 1628 came back for SM in 2020 (35.5%). Women who obtained SM during the pandemic vs those who did not were slightly older, mean age 58 vs 56 (P< 0.001), were less likely to be living in the most deprived neighborhood, Q4 of ADI, 23.8% vs. 25.6%, more likely to be obese 39% vs. 35% (P< 0.001), more likely to have diabetes 48% vs. 41% (P< 0.001), more likely to have CVD, 16% vs. 13% (P< 0.001), and more likely to have hypertension 80% vs. 71% (P< 0.001). On multivariate logistic regression, living in Q4 ADI was associated with 22% higher risk of skipping SM in 2020 (95% CI 1.02-1.42), having one vs. two vs. three comorbid conditions increased the likelihood of obtaining SM in 2020 by 25% (95% CI 0.62-0.91) vs. 30% vs (95% CI 0.58-0.85), 42% (95% CI 0.48-0.7) compared to no comorbid conditions. Conclusion: Women living in Q4 of the ADI (most deprived neighborhood) were more likely to miss 2020 screening when compared with the Q1 women (least deprived neighborhood). The more chronic diseases women had, the less likely they were to skip 2020 screening when compared with those that had no chronic disease. This could because women with many health issues have to frequent health facilities at higher rates and thus less likely to miss mammograms. Citation Format: Maryam Nemati Shafaee, Omar Rosales, Randall Parker Kirby, Tamara Ortiz-Perez, Luke Gilman, Ashley Hardeman, Preeya Bhavsar Bhakta, Chris Amos, Abiodun Oluyomi. Patient-level predictors of skipping screening mammograms during the COVID-19 pandemic at a large tertiary care center in Texas [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 P4-03-25.

Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown.This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004 and 2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow-up was 11.5 years. Risk of CBC was evaluated as time to event.935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs 6.5% (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p = 0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC.This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

100 Background: In an ideal world, the populations studied in cancer clinical trials (CCT) would be representative of the patients seen in clinic. Unfortunately, significant disparities exist in trial enrollment. Patients who are white, male, insured, or of high socioeconomic status (SES) are overrepresented in NCI-sponsored CCT. Despite data indicating equal willingness for participation in CCT across all racial groups, lack of access, cultural barriers, and social determinants of health contribute to poor accrual rates among racial and ethnic minority patients. The Dan L. Duncan Comprehensive Cancer Center (DLDCCC) provides equal access to breast CCT at Smith Clinic (SC) within the safety-net Harris Health system and Baylor St. Luke’s Medical Center (BSLMC). The patient populations differ greatly at these two sites, with BSLMC serving > 95% insured, largely Caucasian patients, and SC serving 60% uninsured, mostly low SES patients, with > 80% racial and ethnic minorities. Despite equal access, patients at SC have a significantly higher CCT refusal rate. Methods: We performed a retrospective review of a prospectively maintained database of new patients seen at DLDCCC dating from 5/2015 to 9/2021, which included 3043 patients screened for breast CCT. 366 patients were found to be eligible for CCT. Some patients were eligible for multiple CCT, so there were 431 total offers of CCT. We performed logistic regression to evaluate whether differences in age, clinic, race, trial type, and primary language may be underlying the observed differences in CCT enrollment rates. Results: In the BSLMC cohort, 61% (116/204) of eligible patients enrolled in a CCT, while in the SC cohort only 39% (74/227) of eligible patients elected to enroll in CCT. This difference was significant on univariate but not multivariate analysis. There were significant differences when comparing race and trial type in the overall patient set. On univariate analysis, SC patients, African American (AA) patients, Hispanic/Latino patients, and Spanish speaking patients were significantly more likely to decline CCT participation. However, on multivariate analysis, only the AA patient category was associated with enrollment refusal (odds ratio 0.261, 95% CI 0.116-0.563, p < 0.001). On both univariate and multivariate analyses, patients were significantly more likely to accept biobanking trials (multivariate: odds ratio 12.799, 95% CI 3.777-61.403, p < 0.001). Conclusions: Based on these findings, it is likely an oversimplification to assume that equal access will lead to a complete elimination of CCT disparities. Our AA patients were significantly less likely to agree to participate in clinical trials, challenging the commonly held view that lack of access is a major barrier. We are exploring interventions designed to improve our AA patient population’s views of trial enrollment.

104 Background: Patient education has been shown to improve clinical trial participation. Medically underserved, racial, and ethnic minorities have a lower participation rate in cancer clinical trials (CCT) than patients of high socioeconomic status (SES). Our comprehensive cancer center is notable for providing equal access to breast CCT (BCCT) through a private system (McNair) and a public safety net hospital system, Smith Clinic (SC). Our prior research has shown that SC cancer patients, who are 60% uninsured, predominantly low SES, and >80% racial minorities, are 40% less likely to enroll into BCCT compared to McNair patients who are > 95% insured and largely White. Methods: We developed a 7-minute video with testimonies of our current patients (who are of diverse racial and linguistic backgrounds) about their BCCT experience and testimonies of our research team discussing misconceptions surrounding BCCT and biospecimen collection. The video was designed to be culturally sensitive and used simplified terms in English, Spanish, and Vietnamese. We modified a validated questionnaire by UT Health San Antonio, Institute for Health Promotion Research to assess participants’ attitudes towards CCT participation before and after watching the video. We used a Wilcoxon Signed Rank test to measure the effect of the video on a 5-point Likert scale with 5 indicating “Extremely likely”, 3 “Moderately Likely” and 1 “Not Likely at all”. The primary outcome was a shift in likelihood of participation in a CCT by 1. Other outcomes included assessing the effects of English proficiency, residing in United States (US) for at least 10 years, race, stage of breast cancer diagnosis (high risk vs. early stage vs. metastatic disease) using Chi-squared tests. With 200 survey respondents, the study had 97% power to detect the desired primary outcome. The project was supported by a Pfizer education grant. Results: A total of 200 patients (73 at McNair and 127 at SC) watched the video and completed the surveys. 93 identified as Hispanic, 50 as African American, 14 as Asian, 47 as White, and 7 as other races. The mean pre-intervention score for likelihood of willingness to participate in a CCT was 3.34 (SD 1.45) at McNair and 2.81 (SD 1.28) at SC. The mean post-intervention score was 3.89 (SD 1.28) at McNair and 3.44 (SD 1.22) at SC. While the pre- and post-intervention scores were significantly different across the two sites (p = 0.01 and p = 0.015 respectively), the study did not meet its primary objective. English proficiency, residing in US for at least 10 years, race, and stage of breast cancer diagnosis were not significantly associated with the outcome. Conclusions: Our patient education video did not improve our patients’ willingness to participate in BCCT as much as we had hoped. This suggests that a comprehensive approach is required to improve our community’s engagement and close the disparity gap in BCCT enrollment.

e12583 Background: For women with certain high risk germline mutations, preventive surgical procedures (PSP) have been shown to reduce the risk of cancer. Uptake of these PSP, however, is highly variable among the population at risk. Rate of contralateral mastectomies is reported to be lower among African American (AA) and Asian women compared to Whites. Low socioeconomic status (SES) is reported to impact decision making concerning PSP, but the data remains scant due to associated low healthcare access. Our comprehensive cancer center is notable for providing state of the art care at a public safety net hospital, Harris Health System (HHS), where the population is > 80% racial and ethnic minorities, 60% uninsured and predominantly of low SES. Patients who meet the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing are provided with the opportunity for counseling and testing. We therefore evaluated the likelihood of PSP among our patients with known germline mutations. Methods: We performed a retrospective chart review of a prospectively maintained database of patients who were offered genetic counseling and testing at HHS. We included patients diagnosed with high-risk mutations in BRCA1, BRCA2, PALB2, ATMand CHEK2 between 10/1/2009-09/30/2019 . We abstracted data on date of birth, race and ethnicity, history of breast cancer, breast cancer subtype, family history of breast or ovarian cancers. We collected data on whether the patients had undergone any PSP: bilateral or contralateral mastectomy, salpingectomy, or BSO. We used descriptive statistics to compare patient profiles in each mutation category. We performed univariate and multivariate logistic regression to evaluate whether differences in race, ethnicity, family history of breast or ovarian cancer, or personal history of breast cancer contributed to the likelihood of undergoing PSP. Results: Our dataset identified a total of 202 patients who had a pathogenic mutation in one of the genes above. This included 108 BRCA1, 57 BRCA2, 26 PALB2, 8 ATM and 4 CHEK2 mutation carriers. Sixty-one percent of the mutation carries identified as Hispanic, 18% as AA, 10% as White and 3% as Asian, 31% of the population never had a history of breast cancer. Sixty-three percent of the patients underwent at least one PSP. The results of the regression analysis identified personal history of breast cancer as the only predictor of undergoing PSP, OR 2.77, p = 0.002, which remained significant on the multivariate analysis with OR 4.4, p < 0.001. There were no statically significant findings with regards to race, ethnicity or family history of breast or ovarian cancers. Conclusions: Among our population racially diverse patients with low SES, history of breast cancer significantly increases the likelihood of opting to have prophylactic PSP. We will use this information to tailor our approach towards patient education and future quality improvement projects.

e18532 Background: Patient education has been shown to improve clinical trial participation. Medically underserved, racial, and ethnic minorities have lower participation rate in cancer clinical trials (CCT) than patients of high socioeconomic status (SES). Our comprehensive cancer center is notable for providing equal access to breast CCT through a private system (Baylor McNair) and a public safety net hospital (Harris Health Smith Clinic). Our prior research has shown that breast cancer patients at Smith Clinic (SC) who are 60% uninsured, predominantly of low SES, and 80% racial and ethnic minorities are 40% less likely to enroll compared to McNair patients where patients are > 95% insured and largely Caucasian. Methods: We developed a 7-minute video consisting of current patients’ testimonies of their CCT experience along with the research team discussing misconceptions regarding CCT and biospecimen collection. The video was designed to be culturally sensitive and used simplified terms in English, Spanish, and Vietnamese. We modified a validated questionnaire by UT Health San Antonio, Institute for Health Promotion Research to assess participants attitudes towards CCT participation before and after watching the video. We used a Wilcoxon Signed Rank test for measuring the effect of the video on a 5-point Likert scale with 5 indicating “Extremely likely”, 3 “Moderately Likely” and 1 “Not Likely at all”. The primary outcome was a shift in stated likelihood of participation in a CCT by 1 point. Using Chi-squared test, we assessed whether English proficiency or residing in the United States (US) for more than 10 years affected the results. Patients’ reason for refusing CCT was documented. With 200 survey responders, the study had 97% power to detect the desired primary outcome. The project was supported by a Pfizer education grant. Results: A total of 200 patients (73 at McNair and 127 at SC) watched the video and completed the surveys. The mean pre-intervention score for likelihood of willingness to participate in a CCT was 3.34 (SD 1.45) at McNair and 2.81 (SD 1.28) at SC. The mean post-intervention score was 3.89 (SD 1.28) at McNair and 3.44 (SD 1.22) at SC. While the pre- and post- intervention scores were significantly different across the two sites (p = 0.01 and p = 0.015 respectively), the study did not meet its primary objective. There were also no significant differences in the willingness to participate in CCT with regards to time spent in the US or English proficiency. Most frequent reasons for refusal were concern about extra costs, extra time commitment and the need to discuss the trial with family members. Conclusions: Our in-house developed patient education video did not improve patients’ willingness to participate in CCT as much as we had hoped. This suggests that a comprehensive approach is required to improve our community’s engagement and close the disparity gap in the treatment and outcomes of breast cancer.

e18679 Background: There has been growing concern regarding the impact of the COVID-19 pandemic on health care delivery and disruption of care to cancer patients. Reductions in cancer surgeries, delays in administration of life saving chemo and radiation therapies, and lower rates of cancer-related hospitalizations have been reported. While cancer patients with COVID-19 infection have poor hospitalization outcomes, less is known about the outcomes of hospitalized cancer patients without the infection. This study aimed to describe the impact of the COVID-19 pandemic on outcomes of the most common cancer-related hospital admissions for patients without COVID-19 infection at a national level using insurance claims. Given the concern for disruptions in their care, we hypothesized that hospitalized cancer patients may have worse outcomes. Methods: We used the Optum Clinformatics Data Mart, consisting of claims records linked to electronic health records, including an average of 8 million adult Americans per year enrolled for at least 6 months. We identified cancer-related hospitalizations from 02/2018-05/2021 and included patients with at least of one of these cancer types: breast, prostate, bladder, ovarian, cervical, lung, colorectal, esophageal, liver, small intestine, gastric, or gallbladder cancer. Patients with cancer-related hospitalization who had COVID-19 infection were excluded. The main outcome was “severe adverse outcome” and included at least one of the following: mortality during or within 30 days of hospitalization, mechanical ventilation during hospitalization, intensive care unit admission, or discharge to hospice. We used Poisson regression to compare the number of hospitalizations before (2/1/2018-1/30/2020) and during (2/1/2020-5/30/2021) the pandemic and a Chi-squared test to compare the proportion of cancer-related hospitalizations with severe adverse outcomes over that time period in 4-month intervals and across cancer types, gender, (male vs female) and geography (the 9 Census Bureau regions). Results: There were 82,796 cancer-related hospitalizations in the period 2/2018-05/2021. A slightly higher proportion of cancer-related hospitalizations resulted in a severe adverse outcome during the pandemic as compared to prior to the pandemic (41.8% vs 40.9%; p = 0.012). There were no differences by cancer site, gender, or geography. The number of hospitalizations was lower during vs prior to the pandemic (p < 0.0001). Conclusions: The number of cancer-related hospitalizations during the pandemic was lower compared to before the, and a slightly higher proportion of those hospitalized experienced severe adverse outcomes among insured U.S. cancer patients without COVID-19 infection. The lower number of cancer-related hospitalizations during the pandemic warrants further investigation.

e18547 Background: In an ideal world, the populations studied in cancer clinical trials (CCT) would be representative of the patients seen in clinic. Unfortunately, significant disparities exist in trial enrollment. Patients who are white, male, insured, or of high socioeconomic status (SES) are overrepresented in NCI-sponsored CCT. Despite data indicating equal willingness for participation in CCT across all racial groups, lack of access, cultural barriers, and social determinants of health contribute to poor accrual rates among racial and ethnic minority patients. The Dan L. Duncan Comprehensive Cancer Center (DLDCCC) notably provides equal access to breast CCT at Smith Clinic (SC) within the Harris Health system and Baylor St. Luke’s Medical Center (BSLMC). The patient populations differ greatly at these two sites, with BSLMC serving > 95% insured, largely Caucasian patients, and SC serving 60% uninsured, mostly low SES patients, with > 80% racial and ethnic minorities. Despite equal access, patients at SC have a significantly higher CCT refusal rate. This retrospective cohort study aims to identify predictors of CCT refusal. Methods: We performed a retrospective review of a prospectively maintained database of new patients seen at DLDCCC dating from 5/2015 to 9/2021, which included 3043 patients screened for breast CCT. 366 patients were found to be eligible for CCT. Some patients were eligible for multiple CCT, so there were 431 total offers of CCT. We performed logistic regression to evaluate whether differences in age, clinic, race, trial type, and primary language may be underlying the observed differences in CCT enrollment rates. Results: In the BSLMC cohort, 61% (116/204) of eligible patients enrolled in a CCT, while in the SC cohort only 39% (74/227) of eligible patients elected to enroll in CCT. This difference was significant on univariate but not multivariate analysis. There were significant differences when comparing race and trial type in the overall patient set. On univariate analysis, SC patients, African American (AA) patients, Hispanic/Latino patients, and Spanish speaking patients were significantly more likely to decline CCT participation. However, on multivariate analysis, only the AA patient category was associated with enrollment refusal (odds ratio 0.261, 95% CI 0.116-0.563, p < 0.001). On both univariate and multivariate analyses, patients were significantly more likely to accept biobanking trials (multivariate: odds ratio 12.799, 95% CI 3.777-61.403, p < 0.001). Conclusions: Based on these findings, it is likely an oversimplification to assume that equal access will lead to a complete elimination of CCT disparities. Our AA patients were significantly less likely to agree to participate in clinical trials, challenging the commonly held view that lack of access is a major barrier. We are exploring interventions designed to improve our AA patient population’s views of trial enrollment.

Background Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. Methods We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp’s Women’s Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. Results One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. Conclusion Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. Impact Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient's hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase Activating Protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not impact ER binding. Consequently, neurofibromin-depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin-loss in endocrine therapy-treated ER(+) breast cancer. Neurofibromin-deficient ER(+) breast cancer cells initially retain sensitivity to selective estrogen receptor degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER(+) breast tumors.

BACKGROUND: Inherited BRCA gene mutations (pathogenic variants) cause 10% of breast cancers. BRCA pathogenic variants predispose carriers to triple-negative breast cancer (TNBC); around 30% of patients with TNBC carry BRCA pathogenic variants. The 2018 NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend genetic counseling referrals for patients with TNBC diagnosed at age ≤60 years. This study sought to describe genetic counseling referral patterns among long-term TNBC survivors at The University of Texas MD Anderson Cancer Center. METHODS: This single-institution retrospective analysis of female long-term (disease-free for ≥5 years) TNBC survivors sought to determine the rate of genetic counseling referral among patients diagnosed at age ≤60 years between 1992 and 2008. Patients who underwent treatment and surveillance visits at our institution and were followed until 2017 were included. We collected BRCA pathogenic variant status among tested patients. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. RESULTS: We identified 646 female long-term TNBC survivors with a median age at diagnosis of 47 years. Of these, 245 (38%) received a recommendation for a genetic counseling referral. Among those referred, 156 (64%) underwent genetic testing, and 35% of those tested had BRCA pathogenic variants. Interestingly, among those referred, 20% declined genetic testing. The rate of genetic referrals improved over time, from 25% among TNBC survivors whose last surveillance visit was between 2011 and 2013 to 100% among those whose last surveillance visit was between 2014 or later. Younger age and premenopausal status at diagnosis and a family history of breast or ovarian cancer were associated with an increased rate of referral for genetic counseling. CONCLUSIONS: Among long-term TNBC survivors, the rate of referral to genetic counseling increased over time, and among those tested, 35% carried a BRCA pathogenic variant. Survivorship care provides an excellent opportunity to refer eligible patients for genetic counseling.

e13067 Background: Recently, next generation sequencing (NGS) has been used with increasing frequency to guide therapy decisions for patients with metastatic solid tumors. NGS is a DNA sequencing technology that detects somatically acquired mutations. If an actionable mutation is identified, it may affect prognosis and guide therapy. At our institution we serve a large proportion of minority and underserved patients and analyzed their NGS results to determine if there was a change in management. Methods: Patients with metastatic breast cancer treated at one of two sites at Baylor College of Medicine who underwent NGS via Tempus between 2018-2020 were included. Tempus provided access to the variant database for these patients. We analyzed the charts of 43 patients who underwent NGS via Tempus on tissue, blood or both. In those patients with clinically actionable mutations, we noted if there was a change in management. Utilizing Redcap, we extracted demographics, sites of metastasis, biomarker activity and site, genomic sequencing, and duration and sequencing of therapies given along with clinical trial information. Results: Of the 43 patients included in this analysis, the mean age was 55 years, 33% were African American, 30% were Hispanic, 21% were white/non-Hispanic, 12% were Asian, 4% were other. Two thirds of patients were treated in the Harris Health System (a safety net hospital with a unique and diverse population) while one third was treated at the Baylor St. Luke’s Medical Center (a private academically affiliated institution). Of the 43 patients, 14 had PIK3CA mutations and 3 had a change in management. 2 patients had microsatellite instability (MSI) and received immunotherapy, and 1 patient had a HER2 mutation and entered a clinical trial with Neratinib. Additionally, 2 patients were incidentally found to have MUTYH germline mutation which is associated with polyposis. Conclusions: With increasing frequency, patients with metastatic malignancy undergo NGS in order to determine if there is an actionable mutation that can guide their next line of treatment. However, this technology could be cost prohibitive for many underserved patients. Our study analyzes a unique and diverse population of patients, many of whom are underserved. We were able conduct this testing in our cohort, study the frequency of somatic mutations and monitor for change in treatment. Of the variants analyzed, PIK3CA mutations are actionable and patients can receive Alpelisib + Fulvestrant- however many did not. There was not a large shift in management based on the incorporation of this DNA sequencing technology which suggests that, unlike the case of other solid tumors, there aren’t yet as many actionable targets for patients with metastatic breast cancer. Shared decision making along with consideration of cost is paramount for these patients as we shift into an era of highly personalized medicine.

Purpose Resource limitations in low- and middle-income countries make the management of CNS tumors challenging, particularly in Brazil, a country with major disparities in socioeconomic status and access to health care. We aimed to evaluate cancer-related neurosurgical procedures in the public health care system. Methods On the basis of Brazil’s public health system database, we collected data for neurosurgical procedures related to CNS tumors performed between January 2008 and November 2013. Information about the number of procedures, costs, length of stay, and number of inpatient deaths were analyzed for each state and then correlated to the state-specific population, gross domestic product per capita, and number of procedures. Results In all, 57,361 procedures were performed, the majority of them in the Southeast region. The mean length of hospital stay was 14.4 days, but longer hospital stay was reported for patients treated in the North. The inpatient mortality rate was 7.11%. Mortality rates decreased as the number of procedures ( P < .001), gross domestic product per capita ( P < .001), or state population increased ( P < .001). On multivariate analysis, only the number of procedures (odds ratio, 0.93; 95% CI, 0.91 to 0.96; P < .001) and state population (odds ratio, 1.25; 95% CI, 1.13 to 1.38; P < .001) had an independent association with mortality. Conclusion To the best of our knowledge, this is the first study to evaluate disparities in CNS tumor surgery in a middle-income country, confirming that regional disparities exist and that clinical and economic outcomes correlate with income level, number of procedures, and state population.

Background: The third most populous county in the United States, the Harris Country, has some of the worst outcomes of breast cancer in the country. In this county, 27% of mammogram eligible women, ages 40-64 are uninsured, compared to about 11% the national average. Harris Health (HH) is a state funded network of SafetyNet hospitals and clinics that provide comprehensive care, including breast cancer screening to the uninsured and underinsured residents of the Harris county. The population who receives care at the HH sites is majority of racial and ethnic minorities and generally lower socioeconomic status than the county average. The number of screening mammograms abruptly dropped by 94% across the United States following the declaration of the COVID-19 national emergency. Currently there is no data on how breast cancer screening rates have been affected during the pandemic across Houston, and specifically in Harris County where health disparities gap already existed. We hypothesized that the population across HH sites have lower rates of screening mammograms following the COVID-19 pandemic declaration compared to the rest of the population across Houston who visit Baylor St. Luke’s Health- Texas (SLH) catchment area. Methods: We retrieved the monthly gross number of screening mammograms performed at all HH sites and SLH sites from February to October for both 2019 and 2020 on the PENRAD database. We then used the Independent-Samples Mann-Whitney U Test to assess differences in the distribution of percent change in mammogram between HH sites and SLH sites. First, we compared the total mammogram numbers for February to October (2020 vs. 2019). We then compared only the numbers for each month (e.g., May 2020 vs. May 2019). Beyond basic descriptive counts, statistical analysis was limited to mammogram among women ages 40 – 69. Statistical significance was set at p Citation Format: Maryam Nemati Shafaee, Luke Gilman, Abiodun Oluyomi, Melissa Bondy, Tamara Ortiz-Perez, Chris Amos, Mothaffar Rimawi. Disparities in breast cancer screening and the impact of COVID-19 in Houston, Texas [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P33.

Fulvestrant is a steroidal selective estrogen receptor degrader that was approved by the US FDA in 2002 for treatment of ER-positive metastatic breast cancer (ER + MBC) post-progression on aromatase inhibitors. In 2017, the label was updated to include endocrine therapy naive ER + MBC. While initially fulvestrant was thought to be equivalent to aromatase inhibitors with monthly dose of 250 mg intramuscular injection, several postmarketing trials challenged this understanding. Subsequently, the recommended dose changed to 500 mg monthly plus loading dose, and this was proven to be superior to anastrozole in efficacy. Most recently the results of FALCON trial have further challenged the way fulvestrant is viewed and used. This report provides a historical perspective on this compound, its evolving role in management of ER + MBC and what the future may hold for this drug.

Background Patients with sarcomatoid renal-cell carcinomas (sRCC) have poor outcomes and limited treatment options. Preclinical and clinical data suggest susceptibility to cytotoxic agents and vascular endothelial growth factor–targeted therapies. We designed a phase 2 trial to evaluate the efficacy and safety of capecitabine, gemcitabine, and bevacizumab in sRCC. Patients and Methods Patients with metastatic or unresectable sRCC were eligible for inclusion. Patients received oral capecitabine 800 mg/m2 twice daily on days 1 to 21 of a 28-day cycle, intravenous gemcitabine 900 mg/m2 on days 1 and 15, and intravenous bevacizumab 10 mg/kg on days 1 and 15. Primary end points were progression-free survival and time to treatment failure (TTF). Secondary end points were safety, objective response rate, and overall survival. Results Thirty-four patients were enrolled onto the trial. One patient was excluded from survival analysis and 4 from response analysis as a result of missing data. Median progression-free survival was 5.5 months (95% confidence interval [CI], 3.4-7.7), median TTF was 4.2 months (95% CI, 2.4-6.0), and median overall survival was 12 months (95% CI, 10.6-13.4). Objective response rate was 20% (5 partial responses, 1 complete response), and disease control rate was 73%. Thirty-one (91%) of the 34 patients discontinued treatment. The most common reason for treatment discontinuation was progressive disease, which occurred in 24 patients (71%). The most common grade 3 toxicity was rash (including hand–foot syndrome) in 24% patients. Conclusion The combination of capecitabine, gemcitabine, and bevacizumab is an option for patients with sRCC; however, response rates are low. Novel therapies are needed to improve outcomes in patients with sRCC.

NF1 has been best known as a GAP (GTPase Activating Protein) that inactivates Ras. However, we are now finding evidence that it also functions as an ER co-repressor, whose loss leads to endocrine therapy resistance. Sequencing tumor DNA from >600 ER+ breast cancers treated by tamoxifen adjuvant monotherapy, we found that frameshift (FS) and nonsense (NS) NF1 mutations, which can create an NF1-null state, strongly correlate with relapse risk (HR=2.6, submitted). Surprisingly, no recurrent missense NF1 mutations inactivating GAP activity were found in our cohort, and such mutations are rare in primary cancers in general. We thus posulated that complete loss of NF1 protein (e.g., caused by NS/FS mutations), but not GAP inactivation alone, is required to drive endocrine therapy resistance. Here we demonstrate that NF1 loss (by gene silencing) in ER+ breast cancer cells greatly enhances ligand-dependent ER transcriptional activity in vitro and in vivo, causing estradiol (E2) hypersensitivity and tamoxifen agonism. Mechanistically we show that NF1 can bind directly to ER, an interaction enhanced by tamoxifen but not by E2. Binding is mediated by leucine/isoleucine-rich motifs in NF1, analogous to other ER co-repressors. Mutations in these motifs (some of which are targeted by somatic mutation in cancer) inhibit ER binding and transcriptional activity without impacting GAP activity; conversely, inactivating GAP activity does not impact ER binding and repression. To validate NF1 as an ER co-repressor, we examined proteomic data from >100 breast cancer patients in the CPTAC data base and found that proteins whose levels are positively correlated with NF1 are highly enriched with factors known to bind nuclear receptors; by contrast, levels of another GAP, p120, which lacks ER binding sites, are negatively correlated with these molecules. Importantly, preclinical treatment studies indicate that while NF1-deficient ER+ breast cancer should not be treated by tamoxifen or aromatase inhibitors, fulvestrant, which degrades ER, remains effective. However, fulvestrant monotherapy can activate the Ras-MAP pathway, which may promote cell survival and acquired fulvestrant resistance unless combined with dabrafinib and trametinib to inhibit Raf and MEK —a clinical trial for this combination is in development. Our data suggest that NF1 is a dual negative regulator at the intersection of two potent oncogenic signaling pathways, Ras and ER. Combination therapy targeting both the ER and the Ras-Raf pathways should be investigated for NF1-deficient cancers driven by ER. Citation Format: Eric C. Chang, zeyi Zheng, Meenakshi Anurag, Jin Gao, Burcu Cakar, Xinhui Du, Jing Li, Philip Lavere, Jonathan T. Lei, Purba Singh, Sinem Seker, Wei Song, Jianheng Peng, Tiffany Nguyen, Doug Chan, Xi Chen, Kimberly C. Banks, Richarad B. Lanman, Maryam Shafaee, Susan Hilsenbeck, Charles Foulds, Matthew J. Ellis. NF1 as an estrogen receptor-α co-repressor in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1814.

The estrogen receptor (ER) has been targeted for breast cancer treatment for over a century, but many challenges persist. ER-positivity identifies the largest breast cancer subgroup, and ER-directed therapies prolong survival and improve symptoms in the advanced setting with a very favorable side effect profile. Treatment strategies have included decreasing estrogen synthesis and modulating or degrading the ER. However, ER+ breast cancer once diagnosed in the advanced setting still represents an incurable condition. Many efforts are ongoing to circumvent resistance mechanisms with a few strategies already incorporated into clinical practice such as the combination of endocrine agents with drugs that interfere with other signaling pathways and cell-cycle progression. Important questions remain as how best to select each available strategy, how to sequence them and ultimately how to extend benefits to the largest number of patients in need.

Inactivating germline mutations in the NF1 gene (encoding neurofibromin) cause neurofibromatosis type 1. In addition to peripheral nervous system tumors, NF1 patients are at higher risk for other cancers, including breast cancer. Tumor exome-sequencing studies demonstrate that approximately 20% of all human cancers have somatic NF1 mutations. NF1 has been best known for its ability to inactivate Ras as a GAP (GTPase Activating Protein). However, this function is served by a small GAP domain in a very large protein. Recurrent missense mutations inactivating the GAP activity are infrequent. In contrast, it is common to detect frameshift (FS) and nonsense (NS) NF1 mutations, which can create an NF1-null state deleting not only GAP, but also, potentially, undefined NF1 functions whose loss could also drive tumorigenesis. As we reported at SABCS previously, in 600+ patients treated by tamoxifen adjuvant monotherapy, we found that FS/NS NF1 mutations independently correlate with relapse risk (HR=2.6, p=0.03). To explore this finding, we silenced NF1 in preclinical models of ER+ breast cancer, which markedly enhanced ER transcriptional activities, causing estradiol (E2) hypersensitivity and converted tamoxifen into an agonist (in vitro and in vivo). Most important, these activities depend on ER, but not on NF1's GAP activity. These findings readily explain the poor patient outcomes associated with NS/FS NF1 mutations, and reveal a previously unrecognized function for NF1 in ER regulation. In the presence of an agonist, liganded ER repels co-repressors and recruits co-activators, while the reverse is true with an antagonist such as tamoxifen. Many co-regulators contain leucine/isoleucine rich motifs, which bind directly to the ligand-binding domain (LBD) in ER. NF1 has several of these motifs that are much more highly conserved in species with a functional ER pathway, and some of these are mutated in cancers (e.g., in our patient cohort). Furthermore, we found that NF1 canbind directly to ER, and that this binding is mediated between the ER LBD and the NF1 leucine-rich regions. Like a classic co-repressor, wildtype NF1 (but not mutants lacking GAP activity or the Leu-rich motif) binds to ER, and is recruited by ER to the ERE in the presence of tamoxifen, but not E2. Further preclinical treatment studies indicate that while NF1-deficient ER+ breast cancer should not be treated by tamoxifen or AIs, fulvestrant remains effective. Furthermore, when fulvestrant is combined with dabrafinib and trametinib to inhibit Ras effectors Raf and MEK, apoptosis is induced in vitro, and tumor regression is observed in vivo. In conclusion, we have demonstrated that NF1 is a dual negative regulator at the intersection of two potent oncogenic signaling pathways, Ras and ER, and that NF1-deficient ER+ breast cancer patients may be more effectively treated by co-targeting the Ras and ER signaling. These patients, up to 10% of those with advanced ER+ breast cancer, can be readily identified for treatment by ctDNA analysis. A clinical trial is under development. Citation Format: Chang EC, Zheng Z, Philip L, Burcu C, Lei J, Singh P, Anurag M, Chan D, Li JD, Du XP, Shafaee MN, Banks K, Sacker S, Song W, Nguyen T, Cao J, Chen X, Haricharan S, Kavuri M, Kim B-J, Zhang B, Gutmann DH, Lanman RB, Foulds C, Ellis M. Direct regulation of estrogen receptor-α (ER) transcriptional activity by NF1 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS2-02.

e12065Background: While Oncotype-Dx testing has become the standard of care in early stage ER positive BC, its role in the management of BRCA associated breast cancer is not well defined. Inherited mutations in the BRCA gene are responsible for 5-10% of breast cancers. BRCA2 mutation predisposes to ER positive BC 50% of the time, while BRCA1 mutation is more commonly associated with ER negative tumors. In this report, we sought to evaluate the role of Oncotype Dx in a population of patients (pts) with known BRCA status. Methods: We performed an IRB approved single institution retrospective analysis of women with known BRCA status diagnosed with stage I-II BC (T0-T3, N0-N1). We included women diagnosed with ER and/or PR positive, Her2 neu normal BC between years 1974-2015. Tumor grade and Oncotype –Dx scores were retrieved. We evaluated the relationship between BRCA and Oncotype-Dx scores. Results: 691 pts were included in this study. 133 (19%) were BRCA1 or 2 positive and 558 (81%) were negative. 65 of th...

1095Background: Inherited mutations in the BRCA gene are responsible for 5-10% of breast cancers. These mutations, predominantly BRCA 1, predispose to TNBC. Around 20% of women with TNBC are BRCA m...

3 Background: Contralateral breast cancer (CBC) risk in BRCA1 & 2 mutations is up to 64%. Patients (pts) with estrogen receptor positive (ER+) breast cancer (BC) are offered tamoxifen (TAM) or Aromase inhibitors (AI) adjuvantly. Reports suggest that TAM may reduce the risk of CBC in BRCA mutation; however there is no such data on the effect of AIs. Here, we evaluate the effect of TAM and AI as potential CBC risk reducers in a cohort of women with known BRCA status. Methods: 1043 BC pts receiving genetic counseling and BRCA testing were included. 13 had metastasis, 168 had a variant BRCA, and 50 had synchronous BC, and were excluded. Of the 812 remaining pts, 153 had a deleterious BRCA 1 or 2 mutations. Pts were followed from the diagnosis of BC until CBC, death, or last follow-up. The study had IRB approval. Univariate analyses were performed to test the significance of each variable in relation to BRCA status using chi-square tests for categorical variables and t tests for continuous variables. Results: The median age at diagnosis of BC was 42.3 years (range: 21-84). Median follow up was 8.6 years. 86% (700) had ER+ tumors, 80% were diagnosed with T1-2, and 81% had N0-N1. 76% (622) received TAM, and 37% (304) received AI. A total of 68 (8.7%) CBCs occurred of which 14% (21/153) occurred in BRCA carriers vs 7% (47/659) in BRCA non-carriers. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC. Specifically, compared with BRCA negative, pts with BRCA1+ or BRCA2+ had larger hazard of developing CBC, Hazard Ratio (HR) (95% confidence interval (CI)) = 2.49 (1.21, 5.10), p = 0.013 for BRCA1+ vs Negative. HR (95%CI) = 1.97 (1.05, 3.73), p = 0.036 for BRCA2+ vs Negative. Compared to pts who did not receive AI, those who received AI had smaller hazard of developing CBC, HR (95%CI) = 0.42 (0.22, 0.81), p = 0.01. The interaction between AI and BRCA status was not significant (p = 0.4), hence all pts benefited from AI use in terms of CBC risk reduction. TAM use did not show significant effect on the risk of CBC in univariate and multivariate analyses (p > 0.13). Conclusions: This is the first report showing that AIs can reduce risk of CBC in women with BC who have a BRCA mutation. This finding should be validated in larger independent cohorts.