Comparative analysis of potentially actionable genomic alterations in early-onset versus later-onset gastrointestinal cancers.

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846 Background: There is an alarming rise in early-onset (EO) gastrointestinal (GI) cancers, which may have distinct genomic profiles compared with later-onset (LO) cases. OncoKB is a validated database that provides evidence-based annotation of genomic alterations with therapeutic relevance. Utilizing the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v18.0 and OncoKB annotator, we performed a comprehensive analysis of OncoKB-actionable alterations across all GI tumors. Methods: The AACR GENIE v18.0 database was used to select GI cancers samples by OncoTree code, which were classified by tumor group. We utilized OncoKB to annotate all samples and their somatic mutations, copy number alterations, and structural variants by therapeutic level of evidence (Levels 1-4). We considered a tumor sample to have a potentially actionable alteration if there was at least one Level 1-3B alteration present. We defined EO as age < 50 and LO as age ≥ 50, and excluded samples without age. Chi-square testing compared frequency of actionable alterations between EO and LO tumor groups, and Benjamini-Hochberg procedure controlled for false discovery rate (statistical significance for q<0.05). Results: 43748 samples were analyzed with 19.2% EO and 80.8% LO samples. There were decreased potentially actionable alterations in EO colorectal (43.0% vs 46.3%, q<0.001), gastrointestinal stromal tumor (78.6% vs 93.4%, q<0.001), pancreatic (59.1% vs 67.2%, q<0.001), and stomach/esophagus tumors (50.8% vs 57.2%, q=0.001). No significant differences were observed in other GI tumor groups. The most frequent potentially actionable alterations were in KRAS , PIK3CA , and ERBB2 . Conclusions: To our knowledge, this study represents the largest molecular analysis of actionability of GI tumors. EO GI cancers have decreased frequency of potentially actionable genomic alterations compared to respective LO GI cancers in numerous GI tumor groups. These findings suggest that several EO GI cancers have more limited precision oncology targets, highlighting the need for novel therapeutic strategies. Tumor Group EO samples (n) LO samples (n) EO samples with potentially actionable alterations (n, %) LO samples with potentially actionable alterations (n, %) Most common potentially actionable altered gene q-value Appendix 222 624 103 (46.4%) 282 (45.2%) KRAS 0.85 Colorectal 5274 13989 2270 (43.0%) 6474 (46.3%) PIK3CA <0.001 Gastrointestinal stromal tumor 322 1554 253 (78.6%) 1451 (93.4%) KIT <0.001 Hepatobiliary 589 3995 344 (58.4%) 2274 (56.9%) KRAS 0.64 Neuroendocrine 345 1219 161 (46.7%) 534 (43.8%) ATM 0.52 Other 77 544 37 (48.1%) 295 (54.2%) PTEN 0.52 Pancreatic 614 7874 363 (59.1%) 5290 (67.2%) KRAS <0.001 Small bowel 85 480 62 (72.9%) 351 (73.1%) KRAS 0.97 Stomach/Esophagus 861 5080 437 (50.8%) 2904 (57.2%) ERBB2 0.001

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