Patients with DDR-related pancreatic cancer had significantly improved survival in our cohort. This contrasts sharply with historical landmark studies of pancreatic cancer where survival ranges between of 6-11 months13. Response duration was also significantly longer compared to what has been reported, likely secondary to increased sensitivity to DNA-damaging drugs. The increased survival is comparable to previous research on DDR-related pancreatic cancer cohorts3,12.
Patient 11 was the only individual in this population to pass away before the general population median survival time for a similarly staged tumor. Unfortunately, at the time of her pancreatic cancer diagnosis, she had other significant co-morbidities, including end-stage renal disease requiring dialysis. At the time of her passing, there was no evidence of cancer recurrence on MRI or CT.
Estimates vary, but around 5-15% of all patients with pancreatic cancer have a detectable pathogenic DDR-related gene variant, and around 5% have a BRCA1/2 variant specifically14-16. The National Comprehensive Cancer Network (NCCN) recommends BRCA1/2 analysis for all diagnosed with pancreatic adenocarcinoma17. The significant, potential impact for the patient has led to this approval.
Even with potential, personal benefit, cost can still be a prohibitive factor. Patient 2 had not been able to complete germline testing initially due to high personal cost despite young diagnosis and family history of pancreatic, prostate and uterine cancer in first degree relatives. Results of circulating tumor DNA (ctDNA) testing and an additional testing platform that reported somatic/ germline status confirmed his BRCA1 variant.
It is less well studied whether other DDR-related gene variants would respond to platinum based chemotherapies and/or PARP-inhibitors in same way as BRCA1/2. BRCA1/2 and PALB2 are known to be associated with an increased risk for pancreatic cancer18-21. Evidence supports that risk for pancreatic cancer may be elevated as well in those with a pathogenic ATM variant22, and BRCA1 is a downstream target of the ATM gene23. FANCC is less well characterized and associated with lower penetrance for hereditary cancer risk17; limited research suggests an association with pancreatic cancer24,25. The FANCC gene is a DDR-related gene in the Fanconi anemia pathway26. Decisions regarding chemotherapy should be weighed and discussed on an individual basis preferably in a molecular tumor board setting. Further research should include these other DDR-related cohorts to explore if they derive similar benefit. It is also important to note that most experts would suggest that cisplatin may be superior as compared to other platinum drugs. Furthermore, irinotecan, which is part of FOLFIRINOX combination chemotherapy, is a DNA-damaging drug (topoisomerase inhibitor). Therefore, the benefit derived in patients who are exposed to FOLFIRINOX is likely from both the irinotecan and the platinum part of the combination chemotherapy.
The relatively small sample size, large number of resectable tumors, and the retrospective, single-institutional nature of this study with selection bias are all limitations. However, our study corroborates previous studies and expands the literature with inclusion of non-BRCA1/2 genes.
This case series does suggest that patients with pancreatic cancer due to DDR-related genes may have better overall outcomes than the general population with pancreatic cancer. Their response to platinum based or other DNA-damaging chemotherapies may be the driving factor. Similar results are being reported from pooled large cohorts from other major academic centers. With universal germline testing now endorsed for pancreatic cancer, data regarding DDR-related pancreatic cancer will significantly increase. For the time being, with platinum-based therapies already approved for these patients, if there is a choice, it would be reasonable to choose a DNA-damaging based therapy and/or participation in some of the PARP-inhibitor trials.