Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Abstract

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes

“…Our data are partially consistent with the recently published analyses that demonstrated inconsistent results of predictive value of other HR/FA genes mutations as biomarkers of platinum response. 37 In contrast, in our study, ATM mutations were rather common (18/543 – 3.3%). Moreover, ATM inhibitors are currently in clinical trials.…”

“… 44 However, other studies did not confirm the role of family history as a surrogate marker of platinum efficacy. 37 Although the role of family history as a predictor of higher risk of mutations in HR/FA genes cannot be denied, our study failed to confirm this issue. We assume that the results of our study are related to the insufficient knowledge of family history by patients in our population.…”

“…Our results confirm recently published data that personal history of prior cancer is a surrogate marker of higher risk of germline BRCA1/2 mutations. 37 Nevertheless, the clinically meaningful rate of BRCA1/2 or PALB2 mutations in patients with PC without a personal history of prior cancer points at the importance of genetic testing beyond this marker. The National Comprehensive Cancer Network guidelines also recommend genetic testing for all the patients with PC.…”

The Homologous Recombination Deficiency Scar in Advanced Cancer: Agnostic Targeting of Damaged DNA Repair

“…Reduced, DNA-damaged, induced nuclear RAD51 foci have been associated with BRCA1 or BRCA2 gene defects and PARPi responses [ 110 , 111 ]. This approach is currently under investigation, and functional assays have not yet been validated for pancreatic cancer [ 112 ].…”

The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways

“…Retrospective and systematic analyses have found that 15–25% of PDAC have mutations in genes associated with HRD and that there were no significant differences between somatic and germline mutations [ 114 , 115 , 116 ]. Historically, sensitivity of cancers with HRD to platinum chemotherapy have been well characterized, specifically owing to the inability for HRR-deficient cells to resolve DNA damage induced by platinum therapy [ 117 ].…”