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Taieb J.,University of Paris Descartes | Zaanan A.,University of Paris Descartes | Zaanan A.,French Institute of Health and Medical Research | Julie C.,Ambroise Pare Hospital | And 15 more authors.
JAMA Oncology | Year: 2016

IMPORTANCE The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status. OBJECTIVE To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab. DESIGN, SETTING, AND PARTICIPANTS This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial. Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015. INTERVENTION Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer. MAIN OUTCOMES AND MEASURES Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status). RESULTS Among the 2559 patients enrolled in the PETACC-8 trial (42.9%female; median [range] age, 60.0[19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAFV600E mutationswere detected in, respectively, 9.9%(177 of 1791), 33.1%(588 of 1776), and 9.0%(148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95%CI,0.73-1.64], P = .67;HR for OS: 1.02 [95%CI,0.61-1.69], P = .94) and BRAFV600Emutation (HR for DFS: 1.22 [95%CI,0.81-1.85], P = .34;HRfor OS: 1.13 [95%CI,0.64-2.00], P = .66)were not prognostic, whereas KRAS mutationwas significantly associated with shorter DFS (HR, 1.55 [95%CI, 1.23- 1.95]; P < .001) and OS (HR, 1.56 [95%CI, 1.12-2.15]; P = .008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95%CI, 1.29-2.08], P < .001;HRfor OS: 1.71 [95%CI, 1.21-2.41], P = .002) and BRAFV600Emutation (HR for DFS: 1.74 [95%CI, 1.14-2.69], P = .01;HR for OS: 1.84 [95%CI, 1.01-3.36], P = .046)were independently associated withworse clinical outcomes. In patients with MSI tumors, KRAS statuswas not prognostic, whereas BRAFV600Emutationwas associated with significantly longer DFS (HR, 0.23 [95%CI,0.06-0.92]; P = .04) but not OS (HR,0.19 [95%CI,0.03-1.24]; P = .08). CONCLUSIONS AND RELEVANCE BRAF V600E and KRAS mutationswere significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification. © 2016 American Medical Association. All rights reserved.

Atallah V.,Bergonie Institute | Honore C.,CNRS Gustave Roussy Institute | Orbach D.,University Pierre and Marie Curie | Helfre S.,University Pierre and Marie Curie | And 12 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2016

Purpose To identify the prognostic role of adjuvant abdominal radiation therapy (RT) on oncologic outcomes as a part of multimodal treatment in the management of desmoplastic small round cell tumor (DSRCT) and to determine its impact according to the quality of surgical resection. Methods and Materials All patients treated for primary abdominal DSRCT in 8 French centers from 1991 to 2014 were included. Patients were retrospectively staged into 3 groups: group A treated with adjuvant RT after cytoreductive surgery, group B without RT after cytoreductive surgery, and group C by exclusive chemotherapy. Peritoneal progression-free survival (PPFS), progression-free survival (PFS), and overall survival (OS) were evaluated. We also performed a direct comparison between groups A and B to evaluate RT after cytoreductive surgery. Radiation therapy was also evaluated according to completeness of surgery: complete cytoreductive surgery (CCS) or incomplete cytoreductive surgery (ICS). Results Thirty-seven (35.9%), thirty-six (34.9%), and thirty (28.0%) patients were included in groups A, B, and C, respectively. Three-year OS was 61.2% (range, 41.0%-76.0%), 37.6% (22.0%-53.1%), and 17.3% (6.3%-32.8%) for groups A, B, and C, respectively. Overall survival, PPFS, and PFS differed significantly among the 3 groups (P<.001, P<.001, and P<.001, respectively). Overall survival and PPFS were higher in group A (RT group) compared with group B (no RT group) (P=.045 and P=.006, respectively). Three-year PPFS was 23.8% (10.3%-40.4%) for group A and 12.51% (4.0%-26.2%) for group B. After CCS, RT improved PPFS (P=.024), but differences in OS and PFS were not significant (P=.40 and P=.30, respectively). After ICS, RT improved OS (P=.044). A trend of PPFS and PFS increase was observed, but the difference was not statistically significant (P=.073 and P=.076). Conclusions Adjuvant RT as part of multimodal treatment seems to confer oncologic benefits for patients treated for abdominal DSRCT after cytoreductive surgery and perioperative chemotherapy. © 2016 Published by Elsevier Inc.

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