The impact of HRD in patients with pancreatic adenocarcinoma undergoing surgical resection: An updated analysis.

Abstract

4132 Background: Limited data is available regarding which mutations in the homologous recombination repair (HRR) pathway beyond BRCA can be targeted with platinum-based chemotherapy in the perioperative setting in patients with pancreatic ductal adenocarcinoma (PDAC). In this updated analysis, we assess the outcome of patients with homologous recombination deficiency (HRD) in response to platinum vs. non-platinum based perioperative chemotherapy in resected PDAC and have included additional variants linked to HRD. Methods: Patients with resectable PDAC, diagnosed between 1999-2020 from the participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Patient’s germline and somatic whole exome sequencing (WES) data were analyzed for known pathogenic and likely pathogenic variants according to ClinVar for the following HRR pathway genes: BRCA1, BRCA2, PALB2, BRIP1, BRAD1, BLM, BAP1, ATM, RAD51C, RAD51, RAD50, RAD54B, CHECK2, NBN, FANCA/B/C/D2/E/F/G, ARID1A, MRE11 and XRCC2. The Kaplan Meier method was used to compare median overall survival (mOS) between patients with and without HRR pathway mutations in response to perioperative platinum vs non-platinum-based chemotherapy. Multivariate cox proportional hazard model was used to calculate HR and 95% CIs adjusting for age, sex and pathologic stage. Results: The ORIEN cohort included 311 patients with resectable PDAC and available WES data. A total of 22 patients (7%) had an HRR pathway mutation. Of these, 8 (36%) received perioperative platinum-based chemotherapy and 9 (41%) a non-platinum based regimen, 4 patients (23%) received no perioperative systemic treatment. Frequency of HRR variants detected: BRCA2 n=8 (2.6%), BRCA1 n=3 (1%), ATM n=2 (0.6%), ARID1A n=1 (0.3%), BRIP1 n=1 (0.3%), CHECK2 n=1 (0.3%), FANCG n=1 (0.3%), PALPB2 n=1 (0.3%), RAD50 n=4 (1.3%), RAD51C n=1 (0.3%). The mOS for patients with HRR mutations exposed to perioperative platinum-based chemotherapy was 3.5 years (95% CI 3.4-NA), patients with HRR mutation but no platinum exposure had a mOS of 1.2 years (CI 0.9-NA). In patients with no HRR mutation exposed to platinum-based chemotherapy mOS was 2.7 years (CI 2.3-3.9) and in those without exposure mOS was 2.9 years, p=0.43. Comparison of risk of death between the 4 groups is demonstrated in the table. Conclusions: There was a trend towards improved survival in patients with PDAC who harbored a HRR pathway mutation and were treated with perioperative platinum-based chemotherapy compared to those with no platinum exposure. Our results highlight the importance of identifying patients with HRD beyond BRCA and the need for large prospective studies in the perioperative setting to further assess their predictive role. [Table: see text]