ABSTRACT
Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cetuximab/administration & dosage , Chemotherapy, Adjuvant/methods , Colonic Neoplasms/drug therapy , Adenocarcinoma/genetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/adverse effects , Colonic Neoplasms/genetics , DNA Mutational Analysis , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Middle Aged , Mutation , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Young Adult , ras Proteins/geneticsABSTRACT
CONCLUSIONS: A pretreatment neck dissection in a chemoradiation regimen for pyriform sinus carcinoma provides no delay for radiation, low complication rates, optimal radiation doses and a high nodal disease control. OBJECTIVES: The aims of this study were to evaluate the clinical feasibility, therapeutic consequences and neck nodes control of a pretreatment neck dissection in a chemoradiation regimen for organ preservation strategy for pyriform sinus carcinoma. PATIENTS AND METHODS: Seventy-six patients with untreated stage III and IV squamous cell carcinoma of the pyriform sinus were included in this study. Eighty neck dissections were performed according to the N status. Dose of radiotherapy was delivered according to the pathologic finding of neck dissections. RESULTS: The mean time between neck dissection and the chemoradiation was 24 days (+/-12 days). Only two patients (2.5%) experienced wound complications. A 'boost' radiation of 14 Gy was delivered after 49 neck dissections (61%) in patients with extracapsular spread. The rate of disease control within the regional nodes was 90%. The Kaplan-Meier 1- and 2- year overall survival rates were 78% and 43%, respectively, and specific survival rates were 88% and 67%, respectively.
