Outcomes and Immunogenicity of pancreatic cancer stratified by the HRDetect score.

Abstract

4630 Background: The HRDetect score uses whole genome sequencing (WGS) to incorporate patterns of substitution base signatures and structural variation to identify tumours deficient in homologous recombination repair (HRD). HRD-tumours, with a higher mutational burden, may be more immunogenic. Methods: We applied HRDetect to 182 resected pancreatic cancers (PDA) and 233 advanced PDA enrolled on the COMPASS trial; both cohorts underwent WGS after tumour enrichment. Patients were classified as high(hi) or low(lo) according to the published score threshold of 0.7; clinical characteristics and survival outcomes were determined. Immunogenicity of the cohorts was explored by analyzing cytolytic activity (CYT) as measured by RNA expression of perforin and granzyme A. Results: 14% of resected (25/182) and 14% of advanced cases (32/233) were considered HRDetecthi . The median age at PDA diagnosis was younger in HRDetecthi vs HRDetectlo (61 vs 66 years, p = 0.005), with no difference in sex between groups. Of the 57 cases identified, 37 (65%) were considered true HRD-PDA with inactivation of BRCA1, BRCA2, PALB2, RAD51C and XRCC2. The remaining 20 cases, were considered false positives for HRD; of these 7 had evidence of a tandem duplicator phenotype with duplications ranging from 10Kbp to 1Mbp in size and 13 had no defining genomic characteristics of the HRD-subtype. In resected PDA, the HRDetect score after adjusting for stage, was not prognostic. In contrast in a multivariable analysis of advanced cases, both HRDetect (HR 0.51, 95% CI 0.30-0.87, p = 0.01) and the Moffitt RNA classifier were highly prognostic (HR 1.99, 95% CI 1.32-3.00, p = 0.0001) with improved survival in HRDetecthi and classical PDA. Of patients receiving platinum in advanced disease (n = 128) HRDetecthi PDA had longer survival compared to the HRDetectlo (15.6 vs. 9.9 months, p = 0.02) although the interaction term between chemotherapy regimen (gemcitabine vs. platinum) and HRDetect score was not significant in this cohort. HRDetecthi tumours had increased cytolytic activity than HRDetectlo PDA; furthermore, within the cohort of HRDetecthi PDA, higher CYT scores were evident in primary lesions compared to metastatic sites sequenced. Conclusions: A high HRDetect score is prognostic in advanced PDA where patients treated with platinum have longest survival. HRDetecthi tumours have increased cytolytic activity with differences observed between primary and metastatic lesions.