Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value

Abstract

Purpose The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer. Experimental Design Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). Results BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P S: 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. Conclusions This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP.

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

“…However, this eff ect may principally be manifest in metastatic disease. Th e lack of BRAF predictive eff ect in our data is consistent with recent fi ndings from Gavin et al ( 40 ) who showed that in stage II / III CRC, BRAF mutation is principally an indicator of poor prognosis aft er relapse and is hence associated with overall, but not DFS, survival.…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…However, only limited data from prospective RCTs is available (Des Guetz et al, 2010;Kim et al, 2010). Gavin et al, in an analysis of 2299 stage II and stage III CRC patients from National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 [5-FU plus leucovorin (LV) ± oxaliplatin] and C-08 (FOLFOX ± bevacizumab) adjuvant studies showed that dMMR was prognostic for recurrence in CRC patients treated with FOLFOX (time to relapse [TTR] HR = 0.58; 95 % CI: 0.35-0.96; P = 0.03) compared to MSS CRC, however, the MMR status was not predictive of oxaliplatin efficacy (Gavin et al, 2012). Andre et al and colleagues in an analysis of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study evaluated MMR status in 986 of the 2240 enrolled patients.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…77 BRAF V600E mutation status and MMR proficiency were both prognostic factors associated with shorter overall survival times. 77,81 Other studies using multi-gene expression tests have not been able to show predictive value.…”

“…77 BRAF V600E mutation status and MMR proficiency were both prognostic factors associated with shorter overall survival times. 77,81 Other studies using multi-gene expression tests have not been able to show predictive value. Thus, identifying the molecular characteristics of colon tumors most likely to benefit from chemotherapy and the development of targeted agents remain high priorities for clinical trial design.…”

“…The most commonly occurring mutations in colon cancer are KRAS, PIK3CA, BRAF, and NRAS, with mutation frequencies of 38%, 20%, 14% and 3%, respectively. 77 Reported mutation frequencies can vary somewhat, depending upon detection methods . KRAS and NRAS mutations are known to be predictive for lack of response to EGFR-targeting antibody therapy for patients with advanced disease.…”