DNA mismatch repair status and site of tumor recurrence in stage II and III colon cancers treated in 5-fluorouracil-based adjuvant therapy trials.

Abstract

3519 Background: DNA mismatch repair (MMR) status has been shown to confer prognostic and predictive information in colon cancer patients. We analyzed site of recurrence data in relation to MMR status and adjuvant treatment. Methods: TNM stage II and III colon carcinoma patients (n = 2,141) were treated in 13 randomized, 5-FU-based trials conducted by U.S., Canadian, and European groups. Tumors were analyzed for microsatellite instability (MSI) and/or MMR protein expression. Deficient MMR (n = 347; 16.2%) was defined as MSI-H or loss of an MMR protein (IHC). Treatment was categorized as effective (n = 1,382) or none/ineffective (n = 759). Site-of-recurrence (n = 601) was categorized as local, intra-abdominal, and distant sites. An Italian case series (n = 404; 110 MSI-H) was also analyzed. Association of MMR and treatment with survival was analyzed using a Cox model, and with site of recurrence using Chi-square or Fisher's Exact tests. Results: Deficient (vs. proficient) MMR was associated with reduced tumor recurrence (20% vs. 32%; p < 0.0001). However, patients with MMR deficient tumors receiving effective adjuvant therapy had a significant increase in local (12% vs. 8%) and intra-abdominal recurrence rates (31% vs. 17%), and a reduction in distant metastases (overall p = 0.026). Among patients receiving observation/ineffective treatment, MMR status was not associated with site of recurrence. Site of recurrence was prognostic for OS with local having better OS compared to intra-abdominal or distant sites (HR 0.62 [95% CI 0.43-0.90]; p = 0.0275). The impact of 5-FU-based treatment was significantly predictive for DFS and OS in proficient MMR cases, but not in deficient MMR tumors (ASCO 2008; 26: abstr 4008). In a separate case series, deficient (vs. proficient) MMR was associated with reduced rates of recurrence (16 vs. 33%; p = 0.001), higher local vs. distant spread (p = 0.0549), and more favorable OS (p = 0.0016). Conclusions: Colon cancers with deficient MMR have significantly reduced rates of recurrence and show higher rates of local and intra-abdominal recurrence after 5-FU-based adjuvant therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health