FcγRIIa and FcγRIIIa Polymorphisms and Cetuximab Benefit in the Microscopic Disease
A partir d'échantillons de sang périphérique prélevés sur 164 patients atteints d'un cancer du rectum de stade localement avancé, cette étude évalue l'association entre deux polymorphismes du gène Fc-gammaR et la réponse au cétuximab
Purpose: FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in high-risk, locally advanced rectal cancer.
Experimental Design: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analysed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.
Results: Genotyping was successfully performed in 105/164 (64%) patients (CAPOX=54, CAPOX-C=51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumour RAS status was observed. FcγRIIa-131R (HR 0.38, p=0.058) and FcγRIIIa-158F alleles (HR 0.21, p=0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5-yrs 78.4%, HR 0.22, p=0.002) and overall survival (OS) (5-yr 86.4%, HR 0.24, p=0.018) when compared to patients homozygous for 131H and/or 158V (5-yr PFS 35.7%, 5-yrs OS 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (p=0.017) and remained significant after adjusting for prognostic variables (p=0.003).
Conclusions: This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in early stage colorectal cancer patients treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.
Clinical Cancer Research , résumé, 2014