Lilyquist, Jenna

Abstract Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% 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. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)>4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the >50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM, CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection of individuals in the general population who may benefit from genetic testing and associated risk management strategies. Citation Format: Couch FJ, Hu C, Hart SN, Gnanaolivu RD, Lilyquist J, Lee KY, Gao C, Eckloff B, Samara R, Klebba J, Auer P, Bernstein L, Gaudet M, Haiman C, Palmer JR, Yao S, Domchek SM, Weitzel JN, Goldgar DE, Nathanson KL, Kraft P, Polley EC. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-01.

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.

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)>5.0) and moderate risk (OR>2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [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 PD1-02.

Abstract Background: Clinical panel testing has become routine practice for patients that are diagnosed with breast cancer at a young age and/or have a personal or family history of cancer. Associations with known breast cancer genes and breast cancer subtypes have been previously identified, such as BRCA1 associations with estrogen receptor negative (ER-) and triple negative (ER-/PR-/HER2-) breast cancers. However, the cancer predisposition genes associated with each of the four clinical subtypes of breast cancer have not been fully defined. We evaluated 24,901 Caucasian female breast cancer cases receiving clinical panel testing for 23 cancer predisposition genes and assessed associations between mutations in each gene and breast cancer subtypes. Methods: Germline hereditary cancer multigene panel testing results for cancer predisposition genes were obtained for 24,901 Caucasian female breast cancer cases evaluated by a clinical testing laboratory. Information on tumor histology, personal and family history of cancer, age at diagnosis, and previous genetic testing was provided by clinical care providers of patients receiving clinical cancer genetic testing. Breast cancer cases were classified into clinical breast cancer subtypes based on estrogen/progesterone hormone receptor status (HR) and HER2 status: Luminal A (HR+/HER2-), Luminal B (HR+/HER2-), HER2 subtype (HR-/HER2+), and Triple Negative (HR-/HER2-). The frequency of pathogenic or likely pathogenic mutations observed in each subtype was compared against the Exome Aggregation Consortium (ExAC) non-TCGA non-Finnish European population to estimate risks. Results: ATM was associated with moderate risks (odds ratio (OR)>2.0) of Luminal A, Luminal B, and HER2 subtypes of breast cancer, but was not associated with the Triple Negative subtype. PALB2 was associated with moderate risk for Luminal B subtype, but high risk (OR>5.0) for Luminal A, HER2, and triple negative subtypes. TP53 was associated with high risks for Luminal B and HER2 tumors. NBN, MRE11A, and RAD50 were not associated with any subtype of breast cancer. Conclusions: Identifying associations between inherited mutations (odds ratio (OR)>2.0) and breast cancer subtypes can inform clinical risk management, treatment options, and therapeutic development efforts. Citation Format: Lilyquist J, Laduca H, Hu C, Na J, Polley EC, Hart SN, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS, Couch FJ. Associations between hereditary cancer panel predisposition genes and breast cancer histological subtypes [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 P6-09-02.