Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy, with a 5-year survival of less than 10%.1-3 Despite recent diagnostic and therapeutic advances, overall survival has only marginally improved.3-6 Known risk factors for PDAC include cigarette smoking, obesity, environmental and chemical exposures, and alcohol.1 The role of genetic abnormalities, however, has become increasingly important as genetic testing platforms, and our knowledge of genetic risk factors, have improved.
Genetic Testing in PDAC
Pathogenic germline variants for pancreatic cancer are identified in more than 10% of patients with PDAC.7,8 Both the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recently updated recommendations to include genetic testing for all patients with newly diagnosed pancreatic cancer.1,9,10 Given the lack of any single driver mutation in PDAC, but rather numerous tumorigenic pathways, patients require broad genetic testing.
The most common genetic drivers of pancreatic cancer are genes that play a role in DNA damage repair. These include mutations in BRCA1 and BRCA2 (Breast Cancer gene 1 and 2), but also less well-known genes such as ATM, PALB2, and CDKN2A, among others.11,12 Specifically, these gene mutations (whether germline or somatic) lead to homologous recombination deficiency (HDR) and hindrance of double-stranded DNA break repair.12-16 Such mutations leave these tumors susceptible to specific therapies, including platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARP).17,18 Platinum agents work by binding and cross-linking DNA, causing DNA damage and cell death, while PARP are theorized to inhibit the repair of single-strand DNA breaks, although the exact mechanism remains unclear. When PARP are combined with preexisting mutations affecting double-stranded DNA break repair, tumor cell death occurs via a process known as synthetic lethality.19,20
These effects translate to meaningful improvements in patient outcomes.17,18 In one study conducted by Park and colleagues, patients with somatic or germline HDR stage III/IV PDAC had a significantly prolonged progression-free survival (PFS) when treated with first-line platinum chemotherapy (HR 0.44, p<0.01) compared with patients without an HRD mutation; this effect was not observed among patients treated with a non-platinum regimen.21
Importantly for surgeons, these findings may have implications in the neoadjuvant setting. As neoadjuvant therapy is increasingly used in treatment of nonmetastatic PDAC, mutation status should be defined at the time of diagnosis to ensure that patients with germline or somatic HRD mutations are considered for upfront platinum therapy.22 This is specifically relevant when a gemcitabine-based regimen is chosen over FOLFIRINOX (fluorouracil, leucovorin calcium [folinic acid], irinotecan hydrochloride, and oxaliplatin). In this situation, combination with cisplatin rather than the more common gemcitabine-nab-paclitaxel should be considered, particularly for patients with BRCA/PALB2 mutations.1
These patients also may be candidates for PARP therapy.18 In the Pancreas Cancer Olaparib Ongoing (POLO) trial, a phase-3 randomized controlled trial comparing PFS in patients with BRCA1/2 germline mutations and metastatic disease without progression on platinum therapy, patients receiving the PARP olaparib had significantly longer PFS compared with placebo (7.4 versus 3.8 months, p = 0.004).23 Combination strategies and use of PARP in the adjuvant setting are being actively investigated.18,20,24 For example, the phase 2-APOLLO* trial—which aims to investigate the benefits of adjuvant olaparib versus placebo on relapse-free survival in patients with resected pancreatic cancer with BRCA1/2 or PALB2 pathologic mutations after platinum-based chemotherapy—is currently recruiting and projected to conclude in 2024 (NCT04858334). The role of PARP in the neoadjuvant setting is not yet defined but also is being studied.18
Genomic Testing
In addition to germline testing, tumor molecular profiling is recommended to identify actionable somatic mutations in patients with locally advanced or metastatic disease who are candidates for anti-cancer therapy.1 While relatively rare in PDAC, patients with mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) mutations may be responsive to PD-1 blockade with the immune checkpoint inhibitor pembrolizumab, which now is recommended as a second-line option in dMMR/MSI-H positive tumors.18,25-28 There is potential for targeting KRAS mutations, which may be found in approximately 90% of pancreatic cancers.29 Preliminary results investigating the efficacy of KRAS inhibitors in solid tumors including pancreatic cancer, such as sotorasib in the CodeBreaK 100 trial, are highly promising.30-32 Variants such as neurotrophic tyrosine receptor kinase (NTRK) fusions, though found in an extremely small subset of patients, also are important to recognize and target.18
What All Surgeons Should Know
Increasing attention is directed to genetic and genomic drivers of PDAC. With potentially actionable mutations being found in up to 25% of patients, genomic sequencing is recommended for locally advanced or metastatic disease, and genetic testing for newly diagnosed PDAC or when suspicion exists for inherited risk.1,8,18 Long-term survival of patients with PDAC remains poor, but there is reason for optimism following the discovery of HDR mutations and the potential for more targeted treatment regimens.18 Because surgeons often are the first clinicians to see a patient after a diagnosis of pancreatic cancer, it is critical for surgeons to be aware of the recommendation for genetic testing and to understand the implications of identifying targetable alterations.
Disclosures
The views expressed herein are those of the authors and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the Department of the Army, Department of the Air Force, Department of Defense, or the US government.
*A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Curative Intent Therapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation.
