Overall survival result and outcomes by KRAS, BRAF, and DNA mismatch repair in relation to primary tumor site in colon cancers from a randomized trial of adjuvant chemotherapy: NCCTG (Alliance) N0147.

En el presente trabajo presentado en ASCO 2014 se analizan los resultados negativos de asociar el Cetuximab al Folfox6 en adyuvancia de colon, estadío III.

Author(s): Frank A. Sinicrope, Harry H. Yoon, Michelle R. Mahoney, Garth D. Nelson, Stephen N. Thibodeau, Richard M. Goldberg, Daniel J. Sargent, Steven R. Alberts, Alliance for Clinical Trials in Oncology; Mayo Clinic, Rochester, MN; Mayo Clinic College of Medicine, Rochester, MN; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH

Abstract:

Background: We report mature overall survival (OS) data in stage III colon cancers from a phase III trial of adjuvant mFOLFOX6 ± cetuximab. Biomarkers were analyzed in relation to primary tumor site and OS, and include additional non randomized patients (pts) with KRASmutant tumors. Methods: Cancers (N= 3,018) were analyzed prospectively forBRAF^V600E (exon 15) and KRAS (exon 2;codons 12, 13) mutations, and expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6). Loss of an MMR protein indicated deficient (d) MMR. Tumor site was categorized as proximalvsdistal (inclusive of the splenic flexure). Median follow-up was 4.9 yrs. Cox proportional hazards models were adjusted for covariates including treatment. Results: Consistent with our previously reported DFS data, the addition of cetuximab was associated with worse OS in pts with wild type KRAS (p=.0073). Activating BRAF^V600E or KRAS mutations were detected in 346/2831 (12.2%) and 1042/2905 (35.9%) tumors, respectively; dMMR was found in 329/2906 (11.3%). dMMR or mutations in BRAF^V600E or KRAS were more likely to occur in proximal vs distal tumors [all p<.0001]. BRAF^V600E mutations were associated with older age, female sex, high grade histology, dMMR, and higher T and N stage (all p< 0.01). A tumor site interaction was observed for OS with KRAS (p=.0435) and MMR (p=.0097), but not BRAF. KRAS mutations [HR 1.98 (1.49-2.63); p<.0001] and dMMR [HR 1.85 (0.99-3.46); p=.054] were each associated with worse OS in distal (vs proximal) cancers. dMMR predicted favorable OS in proximal tumors [HR 0.71 (0.53-0.97); p=.030]. Tumors with wild type copies of both BRAFand KRAS showed better OS within proximal [HR 0.74 (0.59-0.93); p=.009] and distal [HR 0.51 (0.39-0.67); p<.0001] cancers compared to those with a BRAF^V600E or KRASmutation. Conclusions: The addition of cetuximab to mFOLFOX6 resulted in significantly poorer OS. The prognostic impact of biomarkers on OS differed significantly by tumor site. Novel findings include poor OS of KRAS mutant tumors that was restricted to the distal colon, and a divergent prognosis for dMMR by primary tumor site.