Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

Abstract

Pancreatic cancer is a highly lethal malignancy which tends to present with late stage disease.To date, identification of oncogenic drivers and aberrations has not led to effective targeted therapy.Approximately 5-15% of pancreatic cancer has an inheritable component. In fact, pancreatic adenocarcinoma is now recognized as a BRCA1/2-related cancer. Germline BRCA1/2 mutations can be found in up to 3.6-7% of unselected pancreatic cancer patients although the rates are significantly higher amongst patients with Ashkenazi Jewish ancestry. Germline mutations of other components of DNA repair and homologous recombination have also been identified although at much lower frequency. Large sequencing efforts have further identified somatic mutations in these genes in a small subset of pancreatic cancers. Small series and case reports have suggested that pancreatic cancers harboring BRCA1/2 or other homologous repair gene mutations demonstrate enhanced response to platinum-based chemotherapy although this has not been prospectively validated. Clinical trials with poly (ADP-ribose) polymerase (PARP) inhibitors as monotherapy or in combination with chemotherapy in different clinical settings are currently on-going. A subtype of pancreatic adenocarcinoma as characterized by deficiency in homologous recombination exists although the optimal management strategy remains to be fully elucidated.

Genetic mapping of pancreatic cancer by targeted next-generation sequencing in a cohort of patients managed with nab-paclitaxel-based chemotherapy or agents targeting the EGFR axis: a retrospective analysis of the Hellenic Cooperative Oncology Group (HeCOG)

“…In our study, 13.5% of the patients harboured pathogenic mutation in one of the HR genes ( BRCA1, BRCA2, CHEK, PALB2, NBN and BAP10 ) in their tumours, while in 8.8% mutations could be identified in BRCA1 or BRCA2 genes. In any case, alterations in HR component genes result in HR deficiency and there are data pointing towards improved outcomes for the carriers when cisplatin-based chemotherapy is administered or with the use of DNA intercalating agents 19 20. Ongoing research is currently investigating the role of poly ADP ribose polymerase (PARP) inhibitors alone or in combination with cytotoxic regimens for patients with pancreatic cancer found to have HR deficiency 21.…”

Exceptional response to FOLFIRINOX in a patient with pancreatic cancer and a germline RAD51C mutation

“…There are reports of RAD51C mutations in patients with GIST and head and neck cancers (7,8). The patient's remarkable response to platinum-based therapy supports the hypothesis that the RAD51C mutation contributed to the development of his pancreatic cancer (9,10). Platinum agents exert their antineoplastic activity by causing DNA crosslinking.…”

Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality?

“…DNA damage repair deficits, specifically homologous recombination deficits secondary to BRCA1/2, PALB2, ATM and RAD51 mutations, may be efficacious biomarkers for enhanced sensitivity to platinum and poly ADP-ribose polymerase (PARP) inhibitors in PDAC. BRCA1/2 is the most common mutation with approximately 3.6–7% of PDAC patients having germline BRCA 1/2 mutations and up to 12.1% of PDACs in Ashkenazi Jews (42, 43). Homologous recombination is required for repair of double stranded DNA breaks caused by platinum agent mediated DNA crosslinks.…”