Abstract A046: Pre-diagnostic clinical-trajectory signatures of early-onset pancreatic cancer
Early-onset pancreatic cancer (EOPC; age <50 y at diagnosis) is rare (≈1.3/100,000), biologically distinct, and germline-enriched (BRCA1/2, PALB2, ATM, CDKN2A, Lynch). Despite NCCN and CAPS Consortium recognition, its pre-diagnostic electronic health record (EHR) trajectory is uncharacterized. We sought reproducible signatures to guide subtype-aware surveillance for this under-screened young-adult population, where conventional guidelines do not apply. We assembled an EOPC cohort from Mayo Clinic (3 sites, 2001–2023; n=169 EOPC, n=3,162 older-onset PDAC), identified by ICD-10 C25.0–C25.3, C25.7, C25.9 or ICD-9 157.x with age <50 at first diagnosis. For each patient, 3-year pre-diagnostic trajectories of 10 routine laboratory analytes (bilirubin, CA 19-9, CEA, lipase, amylase, glucose, HbA1c, ALT, AST, alkaline phosphatase) were summarized over 30/90/180/365-day windows (mean, slope, delta; 1,706 features total; 131 retained at ≥10% non-zero). Features were winsorized (1–99 pct), standardized, and projected onto 15 PCA components capturing 81.7% variance. K-means clustering (k=2–6, min cluster fraction ≥10%) was assessed by silhouette and 100-resample bootstrap Adjusted Rand Index (ARI). Cluster signatures were compared against the older-onset PDAC cohort projected into the same component space. Two reproducible pre-diagnostic clusters emerged (k=2; silhouette 0.469; bootstrap ARI 0.440). Cluster A: "occult prodrome" (87.0%; n=147; mean age 44.9 y) showed no clear signal across the 10 monitored analytes, with all analyte z-scores near zero through the 3-year window. Cluster B: "metabolic-biliary active" (13.0%; n=22; mean age 44.4 y) was characterized by elevated mean HbA1c (z=+1.08), rising bilirubin slope (z=+0.54), and rising ALT/alkaline phosphatase slopes (z=+0.51 each), consistent with combined diabetic-onset and biliary-obstructive prodrome. The two-cluster structure reproduced in older-onset Mayo PDAC at 87.3% / 12.7%, nearly identical to the EOPC distribution, indicating a fundamental pre-diagnostic dichotomy of pancreatic cancer rather than an age-specific phenomenon. The dominant occult phenotype across age strata indicates that lab-trajectory–anchored surveillance can only address the active minority and motivates complementary genetic-, demographic-, or imaging-anchored pathways for the occult majority. EOPC pre-diagnostic trajectories partition into a dominant occult prodrome (∼87%) without detectable signal in the 10 routine labs evaluated and a minority metabolic-biliary active prodrome (∼13%) with combined diabetic and obstructive features. The high occult prevalence motivates germline-guided active surveillance for genetically at-risk young adults rather than symptom-driven workup, anchoring next-generation surveillance trial designs in rare and hereditary pancreatic malignancies. External validation in independent institutional cohorts (Mayo Clinic Platform / MERCI, or comparable EHR networks) is the planned next step. Jianfu Li Li, Yingyun Yang, Wallace MIchael, Yan Bi. Pre-diagnostic clinical-trajectory signatures of early-onset pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A046.