KRAS and BRAF Mutations in Stage II/III Colon Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Vincenzo Formica ◽  
Francesco Sera ◽  
Chiara Cremolini ◽  
Silvia Riondino ◽  
Cristina Morelli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Statistical Tests ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Phase Iii ◽  
Braf Mutations ◽  
The Impact

Abstract Background KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer, however their impact in the adjuvant setting has not yet been established. Methods We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS/BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS/OS (so-called ‘multivariate’) meta-analysis was performed. All statistical tests were 2-sided. Results Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled HR = 1.36, 95% CI = 1.15–1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03–1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00–1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31–1.70, P < .001). MSI adjustment enhanced the effect of the mutations on outcome in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15–1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03–1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22–2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37–2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (P interaction = 0.02). This interaction was even more pronounced in the DFS/OS multivariate meta-analysis. Conclusions Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.

Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4010-4010 ◽  
Author(s):  
N. A. Jackson McCleary ◽  
J. Meyerhardt ◽  
E. Green ◽  
G. Yothers ◽  
A. de Gramont ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Recurrence ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Phase Iii ◽  
Cox Models ◽  
Time To Death ◽  
Time To Recurrence ◽  
Clinically Meaningful Outcomes ◽  
The Impact

4010 Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age <70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts <70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age<70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts <70 but not those >70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts >70 do not receive the same benefit from combination and/or oral FU as those <70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age [Table: see text] [Table: see text]

Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07

2007 ◽  
Vol 25 (16) ◽  
pp. 2198-2204 ◽  
Author(s):  
J. Philip Kuebler ◽  
H. Samuel Wieand ◽  
Michael J. O'Connell ◽  
Roy E. Smith ◽  
Linda H. Colangelo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Phase Iii ◽  
Wall Thickening ◽  
Free Survival ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact ◽  
Disease Free

Purpose This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. Patients and Methods Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Results A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. Conclusion The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3557-3557
Author(s):  
Robin Park ◽  
Laércio Lopes da Silva ◽  
Sunggon Lee ◽  
Anwaar Saeed
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Braf Mutation ◽  
Meta Analysis ◽  
Stage Iv ◽  
Stage I ◽  
Prognostic Impact ◽  
Braf Mutations ◽  
Mutation Status ◽  
The Impact

3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]

Cochrane systematic review and meta-analysis of adjuvant chemotherapy for stage II colon cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3548-3548
Author(s):  
Brandon Matthew Meyers ◽  
Humaid Obaid Al-Shamsi ◽  
Alvaro Tell Figueredo
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Cochrane Systematic Review ◽  
Free Survival ◽  
Stage Ii Colon Cancer ◽  
Disease Free

3548 Background: Colon cancer is potentially curable by surgery in the early stages of the disease. Adjuvant chemotherapy improves disease-free and overall survival in patients with stage III disease, but the magnitude of benefit in stage II colon cancer is less clear. A previous Cochrane systematic review and meta-analysis (SR/MA) found improved disease-free, but not overall survival (Figueredo et al., 2008). An updated SR/MA was performed to determine the effects of adjuvant chemotherapy on disease-free and overall survival in patients with stage II colon cancer. Methods: Relevant databases (MEDLINE, EMBASE, and Cochrane) were independently searched by all authors, using the same search strategy employed in the original study (1/1988 to 9/2012). Randomized trials containing data on stage II colon cancer patients undergoing adjuvant 5-fluorouracil (5FU) chemotherapy versus observation were included. Pooled results were expressed as hazard ratios (HR) whenever possible, or risk ratios (RR), with 95% confidence intervals (95%CI) using a random effects model. Results: Seven studies were identified, and included in the final SR/MA. Six of the 7 studies were included in the disease-free survival analysis (n=4587). Adjuvant 5FU was associated with better disease-free survival (RR 0.84 (95%CI 0.75-0.94)). All 7 studies (n=5353) were included in the overall survival analysis showing an improvement with adjuvant 5FU (HR 0.87 (95%CI 0.78-0.97)). There was no evidence of heterogeneity across the studies (I2 = 0% for all analyses). Conclusions: In stage II colon cancer, adjuvant 5FU chemotherapy statistically improves both disease-free and overall survival. Our SR/MA demonstrates, for the first time, an overall survival advantage with adjuvant chemotherapy in stage II colon cancer.

Neurotoxicity From Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: NSABP C-07

2007 ◽  
Vol 25 (16) ◽  
pp. 2205-2211 ◽  
Author(s):  
Stephanie R. Land ◽  
Jacek A. Kopec ◽  
Reena S. Cecchini ◽  
Patricia A. Ganz ◽  
H. Samuel Wieand ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Disease Free Survival ◽  
Adverse Event Reporting ◽  
Stage Ii ◽  
Phase Iii ◽  
Low Grade ◽  
Group V ◽  
Patient Reported ◽  
Assessment Time

Purpose The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments. Patients and Methods Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up. Results A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, “quite a bit” of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group. Conclusion Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.

Adjuvant Therapy for Stage II Colon Cancer: A Systematic Review From the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group

2004 ◽  
Vol 22 (16) ◽  
pp. 3395-3407 ◽  
Author(s):  
Alvaro Figueredo ◽  
Manya L. Charette ◽  
Jean Maroun ◽  
Melissa C. Brouwers ◽  
Lisa Zuraw
Keyword(s):  
Systematic Review ◽  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Therapy ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Free Survival ◽  
Stage Ii Colon Cancer ◽  
Disease Free

Purpose To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy? Methods A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation. Results Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P = .07). Conclusion There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.

Smoking status and prognosis in patients with stage III colon cancer: A correlative analysis of NCCTG phase III trial N0147.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3526-3526
Author(s):  
Amanda I. Phipps ◽  
Qian Shi ◽  
Paul J. Limburg ◽  
Garth D. Nelson ◽  
Daniel J. Sargent ◽  
...  
Keyword(s):  
Physical Activity ◽  
Colon Cancer ◽  
Alcohol Consumption ◽  
Braf Mutation ◽  
Smoking Status ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Stage Iii ◽  
Smoking History ◽  
Mutation Status

3526 Background: Prior observational studies have suggested that smoking is associated with poorer overall survival after colon cancer (CC) diagnosis. Using data from N0147, a phase III randomized adjuvant trial of patients with stage III CC, we assessed the relationship between smoking status and cancer outcomes (disease-free survival (DFS) and time to recurrence (TTR)), accounting for possible heterogeneity by patient and tumor characteristics. Methods: Patients completed a risk factor questionnaire at baseline prior to randomization to FOLFOX or FOLFOX+cetuximab (N=1968). Information was collected on smoking and other lifestyle factors, including alcohol consumption, body mass index (BMI), and physical activity. Multivariate Cox models assessed the association between smoking history and the primary trial outcome of DFS, as well TTR, adjusting for other lifestyle and clinical factors. The median follow-up was 3.5 years. Results: Overall, 52% of patients were former or current smokers. Compared to never smokers, ever smokers experienced significantly shorter DFS [3-year DFS: 70% vs 74%, hazard ratio (HR)=1.21, 95% confidence interval (CI): 1.02-1.42]. This association persisted after adjusting for age, sex, tumor subsite, number of nodes involved, T-stage, mismatch repair deficiency, BRAF mutation status, performance score, physical activity, BMI, and alcohol consumption (HR=1.23, 95% CI: 1.02-1.49). There was significant interaction in this association by BRAF mutation status (p=0.02): smoking was associated with shorter DFS in BRAF wildtype CC patients (HR=1.25, 95% CI: 1.04-1.51) but not in BRAF mutant CC patients (HR=0.72, 95% CI: 0.47-1.10). Patterns of association with smoking, overall and by BRAF status, were identical in analyses of TTR. Conclusions: Overall, smoking was significantly associated with shorter DFS and TTR in CC patients. These adverse relationships were most evident in patients with BRAF wildtype CC.

Phase III Study Comparing a Semimonthly With a Monthly Regimen of Fluorouracil and Leucovorin As Adjuvant Treatment for Stage II and III Colon Cancer Patients: Final Results of GERCOR C96.1

2007 ◽  
Vol 25 (24) ◽  
pp. 3732-3738 ◽  
Author(s):  
Thierry André ◽  
Emmanuel Quinaux ◽  
Christophe Louvet ◽  
Philippe Colin ◽  
Erik Gamelin ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
International Study ◽  
Stage Ii ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Metastatic Relapse ◽  
Significant Difference

PurposeThis randomized, 2 × 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer.Patients and MethodsLV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m2) as a 2-hour infusion, followed by 400 mg/m2FU bolus and a 600-mg/m2FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m2FU 15-minute infusion. The primary end point was disease-free survival (DFS).ResultsBetween September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, ≥ 2 years; log-rank test for trend P, .0497).ConclusionDFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study

2015 ◽  
Vol 33 (35) ◽  
pp. 4176-4187 ◽  
Author(s):  
Thierry André ◽  
Armand de Gramont ◽  
Dewi Vernerey ◽  
Benoist Chibaudel ◽  
Franck Bonnetain ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Disease Free Survival ◽  
International Study ◽  
Stage Ii ◽  
Stage Iii ◽  
Formalin Fixed Paraffin Embedded ◽  
Resected Stage

Purpose The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. Methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. Results After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. Conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.

Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial

2010 ◽  
Vol 28 (3) ◽  
pp. 466-474 ◽  
Author(s):  
Arnaud D. Roth ◽  
Sabine Tejpar ◽  
Mauro Delorenzi ◽  
Pu Yan ◽  
Roberto Fiocca ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Multivariate Analysis ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Tumor Stage ◽  
Stage Ii ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutation Status

Purpose Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10−4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

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