Sahin, Ibrahim Halil

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

e16486 Background: Allele-specific KRAS G12C inhibitors have revolutionized lung and colorectal cancer treatment, yet the biology of G12C in other gastrointestinal (GI) malignancies remains undefined. We aimed to elucidate the clinicopathologic and genomic landscape of KRAS G12C-mutated tumors compared to other G12 variants in a large non-colorectal GI cohort. Methods: We queried cBioPortal for pancreatic, esophagogastric, hepatobiliary, ampullary, and appendiceal adenocarcinomas. Following data quality control, the final cohort (n = 6,352) was stratified into KRAS wild-type (n = 3,293), G12C (n = 63), and other G12 variants (n = 2,996). Clinicopathologic features, tumor mutational burden (TMB), microsatellite instability status, and co-alteration in 96 key genes across 11 signaling pathways were compared. Statistical significance was assessed using Fisher’s exact or Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. The Benjamini-Hochberg method was applied to correct for multiple hypothesis testing. Results: KRAS G12C prevalence was 1.0% overall, with significant heterogeneity across cancer subtypes (p < 0.001). Appendiceal adenocarcinoma demonstrated the highest G12C prevalence at 5.71% (10/175), followed by ampullary (1.44%, 2/139), pancreatic (1.17%, 34/2906), hepatobiliary (0.88%, 12/1360), and esophagogastric cancers (0.28%, 5/1772). G12C patients were significantly older than wild-type patients (64.8±11.2 vs 62.5±12.9 years, mean±SD, p < 0.001) but younger than other G12 variant carriers (65.8±10.4 years). G12C tumors demonstrated intermediate genomic instability, with a TMB of 4.82±6.17 compared to 4.98±10.55 in wild-type tumors and 3.67±10.12 in other G12 variants (p < 0.001). Notably, G12C tumors were universally microsatellite stable (0% MSI-H vs 4.0% wild-type vs 0.9% other G12, p < 0.001). Genomic analysis revealed that AKT1 mutations were significantly enriched in the G12C cohort (6.3% vs 0.4%; q = 0.025) as compared to other G12 variants. A trend of increased mutation frequency in HRAS was observed specifically in pancreatic cancers in G12C tumors as compared to other variants (8.8% vs 0.7%; q = 0.083). In pancreatic adenocarcinoma, G12C tumors were enriched for chromatin modifiers, notably ARID1A (17.6% vs 7.7%, p = 0.045) and SETD2 / SETD26 (8.8% vs 1.1%, p = 0.006), though these did not reach FDR significance. Notably, the immunotherapy-resistance drivers STK11 and KEAP1 were absent (0%) in the whole G12C cohort. Conclusions: KRAS G12C represents a biologically distinct subgroup of exon 2 KRAS mutations compared to other KRAS G12 pathogenic variants. The absence of resistance markers and enrichment of actionable AKT1 and chromatin-modifier mutations suggest distinct therapeutic vulnerabilities in non-colorectal KRAS G12C-mutated GI cancers.

TPS256 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-4-2025): 967/1,912. Drs. Lieu and Dasari contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

210 Background: ERBB2/HER2 amplification defines a rare but clinically distinct subtype of colorectal cancer (CRC), associated with favorable responses to HER2-targeted therapies. In contrast, ERBB2/HER2 -mutant CRCs show limited therapeutic benefit, and their clinical and molecular features remain poorly defined. This study investigated the molecular and clinical features of ERBB2/HER2 -mutant CRCs to provide insight into the molecular basis of their differential therapeutic vulnerabilities compared to amplified CRC. Methods: CRC cases were identified from cBioPortal studies with available clinical and ERBB2/HER2 genomic data. After quality control and deduplication, the cohort included 4407 unique cases: 97 with driver mutation(s) only (2.2%), 86 with amplification only (2%), and 4224 wild-type (95.9%). Demographic, clinical, and molecular features, including microsatellite instability (MSI), tumor mutational burden (TMB), and alterations in 94 oncogenic pathway genes, were compared across groups. Statistical analyses used chi-square/Fisher’s exact tests for categorical data, Kruskal-Wallis tests for continuous variables, and the Benjamini-Hochberg correction for multiple comparisons. Odds ratios and FDR-adjusted p-values were calculated to assess associations. Results: Across groups, the distributions of gender, race, and primary cancer site (colon or rectal cancer) were comparable. However, significant differences were observed in age (mean 58.7 ± 15.0 years for ERBB2/HER2 -mutant, 55 ± 13.9 for amplified, and 59 ± 14.8 for wild-type; p = 0.035) and tumor sidedness (among ERBB2/HER2 -mutant cases: right-colon 30.8%, left-colon 15.2%; among ERBB2/HER2 -amplified: right-colon 12.1%, left-colon 37.9%, p = 0.011). KRAS alterations were significantly more common in ERBB2/HER2 -mutant CRCs (50.5%) compared with both amplified (19.8%) and wild-type (37.6%). MSI-H was detected in 34.5% of ERBB2/HER2 -mutant cases, whereas no MSI-H was observed among amplified tumors (p < 0.001). Expectedly, ERBB2/HER2 -mutant tumors exhibited a hypermutated phenotype, with significantly higher TMB (30.3 ± 45.5) and total mutation count (232.8 ± 926.0), compared to amplified (6.1 ± 9.7 and 15.3 ± 28.4) and wild-type (10.5 ± 20.3 and 126.3 ± 424.5; both p < 0.001). Conversely, ERBB2/HER2 -amplified tumors had the highest fraction of overall genomic alterations including chromosomal changes (0.24 ± 0.17 in amplified vs 0.14 ± 0.17 in mutants and 0.20 ± 0.16 in wild-type; p < 0.001). Hierarchical clustering demonstrated that ERBB2/HER2 -mutant tumors form a distinct molecular cluster, whereas amplified tumors cluster closely with wild-type CRC. Conclusions: ERBB2/HER2 - mutant and amplified CRCs show highly distinct genomic and clinical features, supporting the need for tailored treatment approaches.