Deleterious alterations in DNA-damage repair (daDDR) genes as a predictive biomarker for platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).

Abstract

266 Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.