O6-Methylguanine-DNA Methyltransferase (MGMT) Promoter Methylation-Guided Irinotecan-Based Therapy in Metastatic...

The management of metastatic colorectal cancer (mCRC) has evolved toward precision oncology, integrating molecular biomarkers to guide therapeutic selection. While RAS status remains a key determinant of response to anti-epidermal growth factor receptor (anti-EGFR) therapy, emerging alterations in DNA repair pathways, including O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation, may reveal additional, biologically relevant therapeutic vulnerabilities. We describe a 45-year-old female patient with a prior history of breast carcinoma who presented with metastatic high-grade colorectal adenocarcinoma involving the sigmoid colon and liver. Immunohistochemistry (IHC) confirmed colorectal origin. Comprehensive molecular profiling demonstrated KRAS wild-type status, microsatellite stability, low tumor mutational burden (TMB), and canonical alterations in adenomatous polyposis coli (APC) and tumor protein p53 (TP53). First-line capecitabine and oxaliplatin (CAPOX) resulted in disease progression following initial disease stabilization. Subsequent circulating tumor DNA (ctDNA) analysis identified MGMT promoter methylation, suggesting impaired DNA repair capacity. In the absence of actionable genomic targets, second-line therapy with capecitabine and irinotecan (CAPIRI) and cetuximab was initiated. This approach yielded a durable partial response, with significant reduction in hepatic metastatic burden and the preservation of functional status. While established treatment sequencing remains the cornerstone of mCRC management, ctDNA-detected MGMT promoter methylation offers an additional biologically informed stratification marker, suggesting underlying DNA repair deficiency and potential sensitivity to irinotecan-based therapy.