No abstract

PURPOSE Germline mutations in the homologous recombination genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in homologous recombination genes are sensitive to DNA-damaging agents. We retrospectively studied patients with resected PDAC and a pathogenic germline mutation in one of these three genes. The planned analyses included overall survival (OS) and changes therein when platinum chemotherapy was used in the perioperative setting. MATERIALS AND METHODS Thirty-two individuals with pathogenic germline mutations in BRCA1, BRCA2, or PALB2 and resected PDAC (mutation positive) were matched in a 1:2 fashion to patients who were noncarriers or untested (mutation negative) by age, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at University of Pennsylvania: the Basser Center for BRCA Registry or the electronic medical record. The primary outcome was OS. RESULTS Patients in the mutation-positive group had a median OS (mOS) of 46.6 months; those in the mutation-negative group had an mOS of 23.2 months (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.88). With platinum exposure in the perioperative setting, mOS in the mutation-positive group had not yet been met versus a mOS of 23.1 months in the mutation-negative group (HR, 0.12; 95% CI, 0.01 to 1.00). When neither group was treated with platinum, there was no significant OS difference between groups (HR, 0.52; 95% CI 0.12 to 2.24). Patients in the mutation-positive group who received perioperative treatment with platinum had a trend toward improved mOS compared with those who did not (HR, 0.15; 95% CI, 0.02 to 1.23; P = .07). CONCLUSION Platinum-based chemotherapy may confer a survival benefit in patients with resected PDAC and a pathogenic germline BRCA1, BRCA2, or PALB2 mutation. Knowledge of a germline mutation may be important to determine best choice of perioperative chemotherapy.

1506 Background: Germline genetic testing (GT) for cancer susceptibility is recommended for pancreatic and advanced prostate cancer patients, due to potential implications for targeted therapies and risk assessment of family members. Traditional cancer GT programs may create barriers for certain patient populations. To more effectively integrate testing into standard oncology care POC GT was introduced in early 2018 in a joint protocol with Memorial Sloan Kettering Cancer Center. Here we report pre and post POC referral and testing numbers at the University of Pennsylvania. Methods: Patients with metastatic prostate or pancreatic cancer were ascertained through their GU/GI oncologist onto an IRB approved protocol and shown an educational video about GT by research staff who obtained informed consent and facilitated biospecimen collection. Genetic counselors returned results and provided post-test counseling by phone. To evaluate the impact of this model on the uptake of GT services, the number of patients who were referred to and proceeded with GT was compared before and after study initiation. Results: In 2017, 77 patients were referred to genetics of which 45 underwent genetic counseling and testing. Twenty-nine (38%) did not complete genetic counseling or testing, and 3 later underwent testing through the POC study. Since the study launched in 2018, 407 patients were referred and underwent testing through the study. This represents a ten-fold increase in patients who underwent GT. Conclusions: Comparing uptake of GT services before and after study initiation suggests that a POC model with abbreviated pre-test education and post-test genetic counseling by phone is a possible solution to barriers of traditional genetic counseling, increasing physician referrals and uptake of testing by patients. This approach allows for more timely access to genetic information that may impact treatment strategies and medical management of family members. Clinical trial information: pending. [Table: see text]

1578 Background: Barriers to population screening for BRCA mutations include access, availability of counseling, and readiness of care providers to participate in this process. The BRCA Founder OutReach (BFOR) study evaluates a digital approach to genetic testing of a defined population using a medical model and risk-adapted follow-up. Methods: The BFOR study (Bforstudy.com) includes web-based enrollment open to individuals in four US cities who are age 25 or older and have at least one grandparent of Ashkenazi Jewish (AJ) ancestry. Participants receive web-based education, provide consent, complete questionnaires, and note their preference for receiving results either from their primary care provider (PCP) or BFOR staff. BRCA AJ founder mutation results are disclosed by (e)mail or phone, depending on need for additional counseling/genetic testing. Participants will be surveyed by email for up to 5 years; a subset of PCPs is also being surveyed. Results: From March 2018 to January 2019, 2562 participants enrolled: 78% female; < 30 years old, 8%; 30-50 years, 39%; > 50 years, 53%. At enrollment, 33% requested disclosure of results by PCP. Among 847 PCPs invited to disclose results, 45% accepted, 50% declined and 5% have yet to respond. 69 (3.2%) participants tested positive for a BRCA founder mutation, of whom 8 (12%) had no significant family history. 2087 participants tested negative, of whom 6% reported a known family mutation, 38% reported a family history of breast/ovarian cancer, and 56% no such history. The most common reason for study participation was referral by a friend. One individual with a distant history of breast cancer tested positive for a BRCA2 mutation and underwent risk reducing surgery that identified an early stage fallopian tube carcinoma. Her daughter then tested positive and underwent prophylactic surgeries. Conclusions: Population screening of individuals at higher risk for cancer-predisposing mutations is feasible and identifies individuals who would not have been tested using clinical criteria. Preliminary findings reveal challenges for engaging PCPs and at-risk individuals, particularly men. Ongoing follow-up and a second phase of the study will address these barriers to testing. Clinical trial information: NCT03351803.