Defining homologous recombination deficiency status in pancreatic ductal adenocarcinoma: Clinical implications for evaluating response to platinum chemotherapy

Aims

Pancreatic ductal adenocarcinoma (PDAC) remains a daunting malignancy with limited therapeutic options; effective biomarkers are needed to improve its treatment decision-making. The aim of this study is to evaluate the role of homologous recombination deficiency (HRD) in assessing the response to platinum chemotherapy in PDAC.

Methods

A retrospective analysis was conducted on 264 patients diagnosed with PDAC. Tumor tissue samples were subjected to next-generation sequencing (NGS) to assess DNA damage repair (DDR) gene mutation landscape and HRD score. The integrated HRD score was calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) scores. The associations between HRD status and clinical outcomes in patients receiving platinum treatment were systematically analyzed.

Results

Patients with BRCA1/2 biallelic loss-of-function (BILOF) status and/or an HRD score ≥ 42 were predefined as HRD-positive. According to this HRD status definition, 4.9 % (n = 13) of the 264 patients were identified as HRD-positive, identifying a broader population than using BRCA1/2 BILOF alone (1.9 %, n = 5). Patients with BRCA1/2 mutations (BRCA1/2 ^m), presented a lower frequency of alteration in genes related to non-homologous end joining (NHEJ) and mismatch repair (MMR) genes than those with BRCA1/2 wild-type (BRCA1/2 ^wt), with mutations observed in 46.15 % (6/13) of BRCA1/2 ^m versus 72.91 % (183/251) of BRCA1/2 ^wt patients. The median HRD score (23) in patients with DNA damage repair (DDR) gene BILOF mutations was notably higher than that in those with non-BILOF mutations in DDR genes (9). HRD-positive patients demonstrated markedly longer progression-free survival (PFS) (median PFS 44.1 months) than HRD-negative patients (median PFS 12.2 months) when the patients received first-line platinum-based adjuvant treatment (P = 0.035). Specifically, patients with BRCA1/2 BILOF exhibited a substantial clinical benefit from platinum therapy, with none of these patients experiencing disease progression or death during follow-up.

Conclusions

BRCA1/2 BILOF plays a crucial role in identifying PDAC patients for first-line platinum-based adjuvant treatment, and HRD positive status, defined by BRCA1/2 BILOF and/or an HRD score ≥ 42, broadens the pool of eligible patients, and helps avoid ineffective treatment due to intrinsic drug resistance.