TY - JOUR
T1 - Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy
AU - Sinicrope, Frank A.
AU - Mahoney, Michelle R.
AU - Smyrk, Thomas C.
AU - Thibodeau, Stephen N.
AU - Warren, Robert S.
AU - Bertagnolli, Monica M.
AU - Nelson, Garth D.
AU - Goldberg, Richard M.
AU - Sargent, Daniel J.
AU - Alberts, Steven R.
N1 - Funding Information:
Supported by a National Cancer Institute Senior Scientist Award (Grant No. K05CA-142885 to F.A.S) and the North Central Cancer Treatment Group Biospecimen Resource National Institutes of Health Grant No. CA-114740. Support for correlative studies was also provided by unrestricted funds from Bristol-Myers Squibb, ImClone Systems, sanofi-aventis, and Pfizer.
Funding Information:
Supported by a National Cancer Insti tute Senior Scientist Award (Grant No. K05CA-142885 to F.A.S) and the North Central Cancer Treatment Group Biospecimen Resource National Insti tutes of Health Grant No. CA-114740. Support for correlative studies was also provided by unrestricted funds from Bristol-Myers Squibb, ImClone Systems, sanofi-aventis, and Pfizer.
Publisher Copyright:
© 2013 by American Society of Clinical Oncology.
PY - 2013/10/10
Y1 - 2013/10/10
N2 - Purpose: The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown. Patients and Methods: Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used. Results: dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600E or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction = .009) and lymph node category (N1 v N2; Pinteraction = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction = .037). Conclusion: The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.
AB - Purpose: The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown. Patients and Methods: Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used. Results: dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600E or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction = .009) and lymph node category (N1 v N2; Pinteraction = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction = .037). Conclusion: The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.
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U2 - 10.1200/JCO.2013.48.9591
DO - 10.1200/JCO.2013.48.9591
M3 - Article
C2 - 24019539
AN - SCOPUS:84891619188
SN - 0732-183X
VL - 31
SP - 3664
EP - 3672
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 29
ER -