Polley, Eric C.

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.

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.

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.

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

11599 Background: It is unclear whether survival varies among breast cancer molecular subtypes without systemic and locoregional therapy. This study aims to evaluate the survival profile by molecular subtypes after surgery. Methods: In total, we evaluated 301 women with invasive breast cancer with stage I, II or III disease. Patients were classified into four major breast cancer subtypes by immunohistochemistry/FISH classifiers: luminal-A (ER+ and/or PR+/HER2-), luminal-B (ER+ and/or PR+/HER2+), HER2-enriched (HER2+/ER-/PR-) or basal-like (ER-/PR-/HER2-; triple-negative). Overall survival (OS) was analyzed by Kaplan-Meier analysis, and log-rank test for differences. Association between clinical outcome and subtype adjusting for breast cancer prognostic factors was assessed by multivariable Cox proportional hazards model. Results: All patients did not receive systemic chemotherapy and hormone therapy as well as radiation therapy. Luminal A was the most common subtype (N = 224), followed by basal-like (N = 43), luminal B (N = 21) and HER2-enriched (N = 13). Median follow-up for OS was 197 months (range: 1 – 273 months). Age at diagnosis was statistically different among the subtypes, with basal-like and luminal B having high proportions less than 50 years (P = 0.047). Patients with basal-like and HER2-enriched had more high grade tumors (P < 0.001). Notably, there was no difference in OS among the four subtypes (log-rank P = 0.983). In multivariable analysis, the adjusted hazard ratio (HR) was 1.1 for luminal A vs. luminal B (P = 0.781), 0.62 in luminal A vs. HER2-enriched (P = 0.273), or 0.67 in luminal A vs. basal-like (P = 0.158). In contrast, the adjusted HR were 2.2 in age less than 50 years (P = 0.0017), and 1.1 for number of positive nodes (P = 0.00074). Conclusions: OS, through long-term clinical follow-up, is not significantly different among molecular subtypes if not controlling for other prognostic factors in patients who only received surgery. Age and number of positive nodes are independent prognostic factors in patients with no systemic and locoregional treatments.

Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population. Methods Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed. Results The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer. Conclusion These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.