FcγRIIa and FcγRIIIa polymorphisms and cetuximab benefit in the microscopic disease

F. Sclafani, D. Gonzalez de Castro, D. Cunningham, S. Hulkki Wilson, C. Peckitt, J. Capdevila, B. Glimelius, S. Roselló Keränen, Andrew Wotherspoon, Gina Brown, D. Tait, R. Begum, Janet Thomas, J. Oates, I. Chau

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

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 randomized 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 analyzed 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 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation from the Hardy–Weinberg equilibrium or association of these polymorphisms with tumor 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 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year 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).

Conclusion: This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.
Original languageEnglish
Pages (from-to)4511-4519
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number17
DOIs
Publication statusPublished - 01 Sep 2014

Keywords

  • Antibodies, Monoclonal, Humanized
  • Cetuximab
  • Colorectal Neoplasms
  • Disease-Free Survival
  • Genotype
  • Humans
  • Prognosis
  • Receptor, Epidermal Growth Factor
  • Receptors, IgG
  • Treatment Outcome

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