Tumor mutation profiles and circulating tumor DNA detection across gastrointestinal and hepatobiliary cancers.

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Background: This study aimed to compare tumor mutation landscapes and ctDNA detection across 9 types of gastrointestinal (GI) and hepatobiliary (HPB) cancers. Methods: We retrospectively analyzed 1638 tumor- and 1381 blood- samples of patients diagnosed with stage I-IV GI cancers: esophageal (49), colorectal (CRC) (547), gastric (488), GIST (185); and HPB cancers: hepatocellular carcinoma (HCC) (61), cholangiocarcinoma (73), gallbladder (19), pancreatic (202), ampulla of vater (AoV) (14). Tumor profiling and ctDNA detection were performed using the 155-gene panel and tumor-informed approach, respectively (K-TRACK, Gene Solutions). Longitudinal ctDNA status was correlated with clinical outcomes in 325 early-stage CRC, HCC, gastric cancer patients. Results: The most frequently mutated genes across all tumors were TP53 (29-86%), APC (11-70%), KRAS (9-76%), TERT promoter (7-47%), and KIT (5-75%). While TP53 and APC mutations were predominant in GI cancers (>80%), KRAS and TERT promoter mutations were more prevalent in HPB cancers (47-76%). ctDNA shedding rates varied significantly by cancer types. At early stage, pre-treatment ctDNA detection rates were the highest in HCC (95%) and CRC (86%), and dropped to 43-58% in other types. At metastatic stage, for GI, detection rate was higher in esophageal (83%) and CRC (96%), but lower in gastric (76%) and GIST (43%) cancers. For most HPB cancers, the rate was high (>80%), except in gallbladder (67%) and AoV (60%). The overall ctDNA shedding rates significantly increased (p<0.001) when tumors had either KRAS (OR=286.1), TP53 (OR=165.3) or APC (OR=89.7) mutations. For longitudinal ctDNA monitoring, surveillance ctDNA outperformed standard-of-care biomarkers to predict recurrence. The sensivitiy-specificity for CRC: ctDNA 91%-97% vs. CEA 39%-91%; HCC: ctDNA 83%-96% vs. WAKO 83%-76%; gastric cancer: ctDNA 70%-89% vs. CEA 30%-60%. Post-operative ctDNA positivity was an independent prognostic factor (p<0.001) that increased recurrence risk in CRC (HR=91.0, 11.3-736.9), HCC (HR=17.9, 5.9-54.1), and gastric cancer (HR=3.9, 2.0-7.7). Conclusions: This study directly compared tumor mutation landscape across GI and HPB cancers using the same technology and platform. It also delineated the ctDNA shedding dynamics specific to each cancer type for optimal utilization and interpretation of ctDNA results.