Couch, Fergus J.

Abstract Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. Pathogenic mutations in cancer predisposition genes are associated with established risks of breast cancer and are actively used for risk management of breast cancer for women qualifying for genetic testing because of a family history of breast and/or ovarian cancer or young age of diagnosis. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study was to estimate breast cancer risks associated with mutations in hereditary cancer panel genes. Germline DNA from 32,298 breast cancer patients and 31,869 matched unaffected controls enrolled in cohorts and population-based case-control studies were sequenced to identify pathogenic mutations in 37 cancer predisposition genes.The average age at diagnosis was 61.2 years and the average age of last follow-up was 62.1 years. DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions in 37 predisposition genes. Products from 768 samples were pooled and sequenced in a single lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Vardict.High quality sequence data was obtained for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified in 6.2% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. In case-control association analyses adjusted for age at diagnosis or last follow up and family history of breast and ovarian cancer, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR)>4.0). Mutations in CHEK2 and BARD1 were associated with moderate risks of breast cancer (OR>2.0), whereas mutations in ATM had lower clinical relevance (OR=1.6). Stratification by ER, PR, and HER2 status of tumors found that BRCA1, BRCA2, PALB2 and TP53 were associated with high risks of studies of triple negative breast cancer (TNBC), and that BARD1, BRIP1, FANCM, and RAD51C were associated with moderate risks of TNBC. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in high-risk families. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform on the use of cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J. Couch, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Jenna Lilyquist, Kun Y. Lee, Chi Gao, Bruce Eckloff, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia Gaudet, Christopher Haiman, Julie Palmer, Amy Tentham-Dietz, Song Yao, Susan Domchek, Jeffrey N. Weitzel, David E. Goldgar, Katherine L. Nathanson, Peter Kraft, Eric C. Polley. Population-based breast cancer risk estimates associated with cancer predisposition gene mutations from 32,298 breast cancer patients and 31,869 matched unaffected controls from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4169.

e23111 Background: Acupuncture has been shown to reduce aromatase inhibitor-induced arthralgias, as well as possibly hot flashes and fatigue, but research has been limited. The purpose of this study was to evaluate real world perceived benefit of acupuncture for commonly experienced symptoms among breast cancer survivors. Methods: Breast cancer survivors who had used acupuncture for cancer- or treatment-related symptoms were identified using an ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) cohort. In addition, Mayo Clinic electronic health records (EHR) were queried to identify additional participants. All identified patients were mailed a survey with acupuncture-related questions. Respondents were also asked to recall their severity of arthralgia, myalgia, post-surgical pain, hot flashes, nausea/vomiting, fatigue, depression, anxiety, insomnia, lymphedema, headache, and neuropathy from 1 to 5 (1 = mild, 5 = severe) before and after acupuncture treatment. Results: Acupuncture use was reported among 413 participants in MCBDR (12% of all enrollees) and 73 patients were identified in the Mayo EHR. 241 eligible women returned surveys (median age at diagnosis 50 yrs). Mean symptom severity scores decreased from before to after acupuncture by at least 1 point for all queried symptoms (Table). Conclusions: Acupuncture is frequently used by patients for a variety of breast cancer-related symptoms. Those who do pursue acupuncture usually perceive few toxicities and substantial benefits. Cost may be a barrier to treatment for some. [Table: see text]

e23089 Background: Taxanes (paclitaxel and docetaxel) are commonly administered as part of chemotherapy for breast cancer, but long-term data on chemotherapy-induced peripheral neuropathy (CIPN) are limited in this population. We aimed to assess CIPN approximately three years after an initial exposure to paclitaxel or docetaxel. Methods: In a cross-sectional observation study, which surveyed consented enrollees annually after receipt of care at Mayo Clinic for a new breast cancer diagnosis over age 18, we collected patient-reported EORTC CIPN20 data by mailed questionnaire at baseline and three years after a breast cancer diagnosis. We then confirmed patient-reported chemotherapy data by chart abstraction and only included those who had received a standard course of docetaxel-based or paclitaxel-based chemotherapy, but had not had other neurotoxic treatment for cancer. CIPN20 overall and sensory scale raw scores were converted to a 0-100 linear scale with lower scores indicating more severe symptoms. Results: 84 women who received a taxane for breast cancer completed the survey. 82 were treated in the adjuvant or neo-adjuvant setting, while 2 received a taxane for metastatic breast cancer. 67 women received paclitaxel, while 17 received docetaxel. The median age at diagnosis was 51.5 years (range 31-86). 37 had estrogen receptor (ER) and/or progesterone receptor (PR) positive and human epidermal growth factor receptor-2 (Her2) negative, 31 Her2 positive, and 16 triple negative breast cancer. The median CIPN20 score was 92.98 (range 33.33-100). The median sensory CIPN score was 92.59 (range 25.94-100). 81% of women had an overall CIPN20 score of less than 100, and 68% had a sensory score of less than 100. Conclusions: The majority of women who received a taxane based chemotherapy regimen for breast cancer reported at least mild neuropathic symptoms three years out from treatment. Additional research is needed to help tailor chemotherapy decisions to toxicity risks and to reduce the likelihood of long-term CIPN, which can impair quality of life.

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.

1501 Background: Despite BC risk reduction of 50-65% by preventive endocrine therapy (ET), very few at-risk women choose to take them. A woman’s perceived BC risk correlates with uptake of ET. A PRS comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP) improves the accuracy of risk prediction for BC. We examined the impact of the addition of individualized PRS BC risk prediction to standard risk calculator estimates on intent to take BC prevention medication. Methods: Eligible women had ≥5% 10 yr BC Tyrer-Cuzick risk (IBIS) or 5 year Gail score ≥3%, with no history of BC or hereditary BC syndrome. Standard BC risk estimates (IBIS or Gail) were incorporated into the counselling on BC preventive ET. A self-reported questionnaire at baseline quantified intention to take ET and explored factors associated with this decision. Blood samples were obtained and genotyped for 77 SNPs, individualized PRS were calculated then incorporated into IBIS and Gail predictions for 5 yr, 10 yr, & lifetime BC risk. At a second visit, PRS risk & prevention recommendations were revisited. Post visit questionnaires assessed change in intent to take ET. Multivariable linear regression was performed to assess impact of baseline variables on change in intent to take medication. Results: From 2016 to 2017, 151 women in Canada & USA were enrolled, median age: 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian. Median 5yr, 10yr, & lifetime IBIS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). PRS increased BC risk estimates in 84 (55.6%) and reduced BC risk estimates in 67 (44%) women. After PRS risk counselling, intention to take ET significantly changed (p<0.001): 41.9% of those with increased PRS were more inclined, and 46.7% of women with decreased PRS were less inclined to take ET. On multivariable regression, increase in PRS (p<0.0001) and less concern about ET side effects (p<0.0001) were associated with greater intent to take ET. Conclusions: In high risk women, PRS significantly changed BC risk estimates & intent to take preventive ET. Further assessments of the impact of PRS scores on compliance with ET are warranted. Clinical trial information: NCT02517593.

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.

104 Background: The identification of pathogenic mutations in breast cancer susceptibility genes through clinical genetic testing leads to focused screening and prevention strategies for women at increased risk of cancer. However, the frequency of mutations and the risks of cancer associated with breast cancer predisposition genes has not been established for the African American population. Methods: Germline DNA samples from African American women (5,054 breast cancer cases and 4,993 age-matched unaffected controls) from 10 U.S. studies were tested for mutations in 20 established breast cancer predisposition genes using a QIAseq multiplex amplicon panel as part of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study. The frequency of mutations in each gene and associations between mutations and breast cancer risk, adjusted for study design, age, and first-degree family history of breast cancer, were evaluated. Results: The mean age at diagnosis of breast cancer cases was 54.4 years and the mean age of controls was 55.2 years. 18.2% of cases and 10.8% of controls reported a first-degree family history of breast cancer. Pathogenic mutations in any of the 20 breast cancer predisposition genes were identified in 7.6% of breast cancer cases and 2.4% of controls. In multivariable analyses, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR) > 5.0). Mutations in CHEK2 were associated with moderate risks of breast cancer (OR > 2.0), whereas mutations in ATM had lower clinical relevance (OR = 1.8). Mutations in BRCA1, BRCA2, PALB2, and RAD51D, but not CHEK2 or ATM, were associated with increased risks of estrogen receptor negative breast cancer. Conclusions: Cancer predisposition genes confer similar risks of breast cancer in the African American population as in non-Hispanic Whites. These studies provide important insights into the risks of breast cancer associated with predisposition gene mutations in the African American population.

The field of germline genetic testing for breast cancer (BC) risk has evolved substantially in the last decade. The introduction of multigene panel testing (MGPT) led to an urgent need to understand the cancer risk associated with several genes included in the panels. Although the research on understanding the cancer risk associated with mutations in several genes continues, there is also a need to understand the modifying effects of race and ethnicity, family history, and BC pathology on the prevalence of germline mutations and associated BC risk. Furthermore, polygenic risk scores (PRSs) to predict BC risk in patients with or without germline mutations in cancer-predisposition genes are now available for clinical use, although data on the clinical utility of PRSs are lacking. In patients with advanced BC associated with BRCA1/2 mutation, olaparib and talazoparib are now approved for treatment. In addition, molecular profiling studies are being used to clarify the BC tumor biology in mutation carriers to identify potential therapeutic options. In this article, we discuss these advances in the field of germline genetic testing and highlight current limitations and implications for clinical care.