Homologous recombination deficiency (HRD) scoring in pancreatic ductal adenocarcinoma (PDAC) and response to chemotherapy.

Abstract

741 Background: Whole genome sequencing (WGS) can reveal patterns of substitution base signatures and structural variation consistent with tumours deficient in homologous recombination repair. We evaluated the published HRDetect score and a novel HRD hallmark score (HS) in patients receiving combination chemotherapy (cCT) on the COMPASS trial for advanced PDAC. Methods: The HRD-HS incorporates 10 genomic characteristics of HRD-PDAC with a score ≥ 4 defining HRD. HRD-HS and an HRDetect score ≥0.7 were applied to WGS data and overall survival (OS) and response (ORR) evaluated. Sensitivity and specificity were ascertained. Results: As of 05/19, 205 eligible patients (pts) were enrolled and 186 received cCT including modified FOLFIRINOX n = 108 (58%) or cisplatin/gemcitabine n = 2 (1%) and gemcitabine/nab-paclitaxel n = 76 (41%). HRD-HS had a sensitivity of 87.5% and specificity of 100% in detecting HRD-PDAC. In contrast, HRDetect (≥0.7) had sensitivity of 51.9% and specificity of 100%; sensitivity increased to 73.7% when using a cutoff score of ≥0.99. 23/186 (12%) pts were classified as HRdetecthi and median OS was 15.3months (mo) vs 8.7mo in HRDetectlo pts (HR 0.44 95% CI 0.27-.70, p = 0.009). In platinum treated pts, median OS was 18.1mo (HRDetecthi) vs 9.3mo (HRDetectlo) (HR 0.38 95%CI 0.21-0.69, p = 0.02). HRD-HS predicted the longest median OS for platinum of 21.0mths. ORR in HRDetecthi was not different to HRDetectlo pts treated with cCT, however in those receiving platinum the ORR was 50% vs 19% respectively (p < 0.001). Of the false positives by HRDetect, 46% had a non-BRCA1 tandem duplicator phenotype (TDP). The TDP group comprised 8% of all patients enrolled. HRD-PDAC was caused by inactivation of BRCA1/2, PALB2, RAD51C and XRCC2; all germline variants were pathogenic. Pathogenic ATM and CHEK2 germline variants were present in 3 pts with evidence of a second somatic hit or LOH, none of these identified as HRD by either classifier nor considered a TDP. Conclusions: HRD-HS most correctly identified HRD-PDAC however the HRDetect score classifies additional patients sensitive to cCT, especially platinum. The TDP cohort may be responsive to DNA damaging agents warranting further evaluation. Clinical trial information: NCT02750657.