Homologous recombination deficiency (HRD) profiling in Chinese pancreatic ductal adenocarcinoma: Implications for platinum-based chemotherapy.

Abstract

4165 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis. While platinum-based therapies have demonstrated some therapeutic benefits, their associated toxicity underscores the need to identify patients who are most likely to respond. Homologous recombination deficiency (HRD) has been linked to improved sensitivity to platinum-based therapies, but its role in PDAC, particularly beyond BRCA1 and BRCA2 ( BRCA1/2 ) mutations, remains poorly understood. Methods: A retrospective analysis was conducted on 264 Chinese patients diagnosed with PDAC. Genomic data were obtained using a targeted next-generation sequencing (NGS) panel, which included: (1) 28 canonical homologous recombination repair (HRR) genes ( BRCA1, BRCA2, PALB2, ATM, ATR, BAP1, BARD1, BRIP1, CDK12, CHEK1, CHEK2, EMSY, FAM175A, FANCA, FANCC, FANCD2, FANCL, FANCI, MRE11, NBN, PPP2R2A, PTEN, RAD50, RAD51B, RAD51C, RAD51D, RAD54B, and RAD54L ), along with their bi-allelic loss-of-function (BILOF) status; (2) 8 genes associated with other DNA damage repair (DDR) pathways ( TP53, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS2, and STK11 ); and (3) an integrated HRD score, calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST). HRD score ≥ 38 and/or BRCA1/2 BILOF was predefined as HRD positive. The association between HRD status and clinical outcomes in patients treated with first-line platinum-based therapies was systematically analyzed. Results: Among the 264 PDAC patients, 6.4% (n = 17) were classified as HRD-positive, a larger group compared to the 1.9% (n = 5) with BRCA1/2 BILOF. Overall, 19.3% (51/264) of patients harbored mutations in HRR genes. Among these, 4.9% (n = 13) had BRCA1/2 mutations, with 38.5% (n = 5) exhibiting BILOF. The most frequently mutated HRR genes included ATM (4.2%) and BRCA2 (3.8%), followed by CHEK2 (1.5%), BRCA1 (1.5%), ATR (1.5%), and FANCA (1.5%). The median HRD score was notably higher in patients with HRR gene BILOF (25.5) compared to those with non-BILOF (14). In the first-line platinum chemotherapy cohort (n = 133), HRD-positive patients exhibited significantly improved progression-free survival (PFS), with a median PFS of 20.5 months, compared to 11.3 months in HRD-negative patients (HR = 0.385, 95% CI: 0.177-0.84, P = 0.012). Notably, patients with BRCA1/2 BILOF derived substantial clinical benefit from first-line platinum-based therapies, with no instances of disease progression or death during the treatment period. Conclusions: HRD profiling, defined by an HRD score threshold of ≥38 and/or BRCA1/2 BILOF status, is a valuable biomarker for predicting response to platinum-based chemotherapy in PDAC. This study suggests that scar-based HRD marker and gene BILOF status could serve as predictive markers for PDAC personalized therapy. Clinical trial information: [2024]138 .