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 forBRAFV600E (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 BRAFV600E 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 BRAFV600E or KRAS were more likely to occur in proximal vs distal tumors [all p<.0001]. BRAFV600E 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 BRAFV600E 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.
