Association of FcγRIIa and FcγRIIa polymorphisms with clinical outcome in metastatic colorectal cancer patients (mCRC) treated with cetuximab and irinotecan
11004 Background: Cetuximab, a chimeric monoclonal IgG1 targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated clinical efficacy in mCRC patients refractory to Irinotecan, mainly in wild type KRAS tumors. Besides the inhibition of the EGFR pathway, Cetuximab may exert anti-tumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). This phenomenon is an important anticancer mechanism in which antibody Fc portion interacts with Fc receptors (FcγRs) expressed by immune effector cells. ADCC is influenced by two FcγRs (FcγRIIa and FcγRIIIa), whose polymorphisms (FcγRIIa-H131R and FcγRIIIa- V158F) could affect their affinity for IgG1. We wondered whether these two polymorphisms could impact the clinical outcome of mCRC patients treated with Cetuximab and Irinotecan. Methods: We examined FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms and KRAS tumor mutational status in 69 mCRC patients by direct sequencing, multiplex allele-specific PCR and SnaPshot assay, respectively. DNA from normal and tumor tissues was extracted from paraffin-embedded samples. All patients were initially refractory to Irinotecan and received Cetuximab associated with Irinotecan. Clinical response was evaluated using RECIST criteria (Complete Response, Partial Response (PR), Stable or Progressive Disease). Results: KRAS mutations were significantly associated with the absence of response (1 PR among 27 mutated patients vs 10 PR among 37 wild type patients, p=0.021; Fisher’s exact test). Patients with HH and/or VV homozygous genotypes have a longer median progression free survival (PFS) than those carrying R and F alleles (5.5 vs 3 months, p=0.005; log-rank test). In KRAS mutated patients, HH and/or VV homozygous genotypes were also associated with a longer PFS than those with R and F alleles (3.2 vs 2.8 months, p=0.015). Conclusions: Our study shows that FcγRIIa131 HH and/or FcγRIIIa158 VV genotypes have a favorable impact on the clinical outcome of mCRC patients treated with Cetuximab and Irinotecan. Moreover, these polymorphisms are clinically relevant in KRAS mutated patients, suggesting the important role of ADCC in Cetuximab efficacy. No significant financial relationships to disclose.