Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer.

Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.

Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.

PURPOSE: The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS: Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS: Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION: Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.