Molecular characteristics and outcomes of early-onset pancreatic cancer: 10-year retrospective from a single-center cohort.

Abstract

e16416 Background: Pancreatic cancer (PC) incidence continues to increase globally. Early-onset PC (eoPC), defined variably as PC diagnosed < = 50 vs < = 55 yrs, represents < 15% of annual PC diagnoses in the US, but the rate of increase remains higher than late onset PC (loPC). eoPC manifests distinct pathologic and clinical features that may support improved understanding of the genetic and environmental risks driving this diagnosis. Here we sought to define molecular and clinical characteristics of eoPC cases evaluated at a tertiary care cancer center. Methods: We conducted a retrospective, EHR based 10-year (2015-2024) analysis of eoPC patients (age < = 55 yrs). Demographics, medical history, presentation, treatment, germline/somatic genetic testing results, and outcomes were collected and presented as descriptive statistics. (IRB 25-9013). Results: 106 patients with eoPC met inclusion criteria. Median age at diagnosis was 49 years (range 22–55), with 49% female. Reported ethnicity included Caucasian (55%), African American (32%), and Hispanic (7%). 30.2% (32/106) had a history of DM2/hyperlipidemia or NAFLD, and 3 had a history of pancreatitis. Smoking history was reported by 52.8%, while 62.3% reported alcohol use. Family history of PC was reported in 19% (20/106) patients. Germline testing (available for 71%) revealed pathogenic variants in ATM(x5), BRCA1/2(x5), CFTR(x3), PALB2(x2), MUTYH(x3), MSH6, TP53, RAD51D, and CDKN2A, as well as a VUS in ATM, NBN(x3), RAD50(x2), CHEK2, FANCC, MLH1, MSH6 and PMS2. Somatic testing (available for 84%) detected KRAS PV most commonly, with KRAS G12D (n = 16) associated with the shortest median survival (16.5 months), compared to KRAS G12V (n = 6) and KRAS G12R (n = 5), the latter was linked to the most favorable outcomes (median 25 months). 31.5% (25/89) were KRAS WT (compared to ~10% in loPC). Other somatic PVs included TP53, CDKN2A, SMAD4, and Wnt-pathway genes such as RNF43 and FBXW7. Notably, patients aged ≤45 had more KRAS wild-type tumors compared to those aged 46–55 (58% vs 39%), fewer somatic mutations (68% vs 79%) but a higher prevalence of germline PVs (40% vs 28.3%). Several patients were enrolled in clinical trials, including a young woman with a germline ATM mutation who remains on ATR inhibitor therapy for > 1 yr with stable disease, and 3 others with gBRCA1/2 PVs on PARP +/- IO therapy (POLO and TAPUR trials), one pt achieving CR. Notably, 1 patient with a MSI-H eoPC (germline negative) achieved disease control for > 30 months on single-agent IO. Conclusions: Early onset pancreatic cancer represents a unique subset of PC with rising incidence and distinct molecular patterns. Younger patients are more likely to harbor germline mutations and KRAS wild-type tumors and as targeted therapies continue to expand, early and comprehensive genetic testing will be increasingly critical to guide treatment decisions and improve outcomes for these patients.