Improving the clinical risk score: An analysis of molecular biomarkers in the era of modern chemotherapy for resectable hepatic colorectal cancer metastases

摘要

Background: The prognostic relevance of variations in expression of specific tumor genes in colorectal cancer liver metastases (CRCLMs) in patients treated with resection and modern chemotherapy is not known. Methods: Patients submitted to liver resection for CRCLM between January 2000 and October 2007 were studied. A clinical risk score (CRS; range, 0-5) was calculated for each patient. RNA was extracted from histologically confirmed tumor isolates, and using real-time polymerase chain reaction (PCR) studies, we assessed the quantitative expression of 12 genes with potential importance in chemotherapy resistance and tumor progression, including thymidylate synthase (TS; 5-fluorouracil), excision repair cross complementing gene-1, and xeroderma pigmentosum groups A through G (oxaliplatin), topoisomerase-I (irinotecan), c-met, and hepatocyte growth factor. Primary outcomes were recurrence-free survival (RFS) and disease-specific survival (DSS) after hepatic resection. Results: One-hundred fifty-five patients with good quality tumor mRNA were identified. Median follow-up was 32 months for survivors, and the median CRS was 2. Eighty-seven patients (56%) received preoperative chemotherapy, and 124 (80%) received postoperative chemotherapy. Median RFS for all patients was 13 months, and 3-year DSS was 69%. Median RFS and 3-year DSS for patients with an increased CRS (3-5) was lower (7 vs 18 months [P <.0001] and 50% vs 80% [P <.0001], respectively). Of the 12 genes studied, only increased TS expression was associated with a lower RFS (hazard ratio, 1.16; 95% confidence interval, 1.0-1.3; P =.03) and DSS (hazard ratio, 1.25; 95% confidence interval, 1.0-1.5; P =.03). Median RFS and 3-year DSS for patients with increased TS expression was decreased (9 vs15 months [P =.03] and 48% vs 82% [P =.001], respectively). TS expression had prognostic value that was independent of CRS on multivariate analysis. Conclusion: In patients with hepatic CRCLM treated with resection and modern chemotherapy, increased expression of TS improves outcome stratification and appears to be a useful biomarker.