Pancreatic Cancer in Young Adults: Can Innovative Approaches Lead to Better Outcomes?

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the United States, accounting for 7.8% of all cancer-related mortality in 2020 (1). Despite improvements in imaging, surgical techniques, and therapeutics, the 5-year survival for PDAC is still only 10%, reflecting the multifaceted challenges in treating this recalcitrant tumor. Cytotoxic chemotherapy has improved outcomes, but it is apparent that to make huge strides in improving survival, we will likely need to reevaluate our current approach. Sung et al. (2) and others have observed a rising incidence in multiple gastrointestinal malignancies in younger patients over time, and unfortunately, this trend is seen for PDAC as well, with Tavakkoli et al. (3) describing an increase in incidence of 44% and 55% among Black and White patients, respectively, ages 30-39 years (3). The analysis by Varghese et al. (4) in this issue of the Journal is, to date, one of the largest molecular analyses reported and shines a light on this important subgroup of patients within PDAC, providing insight into the unique molecular and demographic characteristics as well as outcomes in a cohort of younger individuals with PDAC (defined as age at diagnosis of 50 years or younger) in the United States. In this retrospective review, 450 patients were identified who met criteria and had been seen in consultation at Memorial Sloan Kettering between 2008 and 2018, with baseline demographic and clinical characteristics and outcomes categorized (4). Similar to what we see in a broader population, 49.1% presented with metastatic disease and 23.6% were deemed potentially resectable. Approximately one-third of this group underwent somatic testing, and 15.9% of these patients were found to be RAS wild-type, with 8 of these patients harboring highly actionable alterations (NTRK fusions, NRG1 fusions, IDH mutation, MMR deficiency, etc.). Of this cohort, 31% also underwent germline testing with one-third of these displaying a pathogenic germline variant (PGV), including BRCA1 and BRCA2, APC, and ATM, and patients with a PGV had improved survival over the non-PGV group. Although the number of patients with highly actionable mutations is small, finding cohorts with unique molecular characteristics is the first step to personalizing care. This important analysis emphasizes the need to ensure that all patients, and especially the early onset pancreatic cancer (EOPC) cohort, have access to comprehensive testing for somatic and germline mutations. This is imperative because this article suggests a higher proportion of young patients harbor RAS wildtype tumors, as well as a higher rate of PGVs and actionable mutations within this cohort (4). Given that outcomes may be improved for patients with actionable genetic alterations and a treatment plan that includes targeted therapies, we must not miss this opportunity within this subgroup. It is important to note that fewer than half of these patients had somatic testing done, and this highlights issues with tissue adequacy in these patients, because fine needle aspirates of the primary tumors are often the initial source of tissue obtained for diagnosis, and these often provide a low yield of viable tumor cells compared with surrounding stroma, making additional procedures necessary for patients to have adequate tissue for analyses. There is a subset of patients who may have locally advanced tumors for whom obtaining adequate specimens for sequencing is impossible. Pishvaian et al. (5) showed a low concordance between cell-free DNA-based and tumor tissue sequencing assays, so this approach will not currently solve the issue of inadequate tissue. We have previously discussed (6) the rising PDAC incidence across populations and with a call to action with ideas for how we could make substantive gains in survival for patients with this disease. We are heartened by this analysis by Varghese and colleagues (4) because it provides evidence for what our experience would predict—that finding subpopulations with actionable mutations can potentially improve the overall survival of our patients. Although progress also has been made over this time with the approval of new agents and combinations, for the majority of our patients, the lack of highly effective therapeutics combined with rising incidence makes this a growing problem for our health-care system and the patients we care for. What ED IT O R IA L