Somatic profiling of the epidermal growth factor receptor pathway in tumours from patients with advanced colorectal cancer, treated with chemotherapy ± cetuximab
Menée sur 1 976 échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal avancé et inclus dans un essai clinique (COIN) d'évaluation du cetuximab en complément d'une chimiothérapie, cette étude évalue l'association entre des mutations de gènes impliqués dans la voie de signalisation EGFR et la réponse thérapeutique
Purpose To study the somatic molecular profile of the epidermal growth factor receptor (EGFR) pathway in advanced CRC (aCRC), its relationship to prognosis, the site of the primary and metastases, and response to cetuximab.
Experimental Design We used Sequenom and Pyrosequencing for high-throughput somatic profiling the EGFR pathway in 1,976 tumours from patients with aCRC from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy ±cetuximab). Correlations between mutations, clinico-pathological, response and survival data were carried out.
Results Sequenom and Pyrosequencing had 99.0% (9961/10063) genotype concordance. We identified thirteen different KRAS mutations in 42.3% of aCRCs, two BRAF mutations in 9.0%, four NRAS mutations in 3.6% and five PIK3CA mutations in 12.7%. 4.2% of aCRCs had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations co-occurred (P=8.9x10-4) as did MSI and BRAF mutations (P=5.3x10-10). KRAS mutations were associated with right colon cancers (P=5.2x10-5) and BRAF mutations with right (P=7.2x10-5) and transverse colon (P=9.8x10-6) cancers. KRAS mutations were associated with lung-only metastases (P=2.3x10-4), BRAF mutations with peritoneal (P=9.2x10-4) and nodal-only (P=3.7x10-5) metastases, and MSI (BRAFWT) with nodal-only metastases (P=2.9x10-4). MSI (BRAFWT) was associated with worse survival (HR=1.89, 95% CI 1.30-2.76, P=8.5x10-4). No mutations, subsets of mutations, or MSI-status were associated with response to cetuximab.
Conclusions Our data support a functional co-operation between KRAS and PIK3CA in colorectal tumourigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN.
Clinical Cancer Research , résumé, 2013