Some common single-nucleotide polymorphisms (SNP) in the coding regions of the FcγRIIIa and FcγRIIa genes have been associated with differential mAb-binding affinities and clinical outcomes. In their study (1), Liu and colleagues performed a validation of these polymorphisms in a randomized trial of cetuximab (anti-EGFR mAb) monotherapy in metastastic colorectal cancer (mCRC). Study results confirmed previous reported data showing that cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying the “high binding affinity” FcγRIIa H/H genotype (1). Interestingly, and somewhat paradoxically, the authors also observed that among patients in the best supportive care arm, who were not treated with cetuximab, the “low binding affinity” FcγRIIa R/R and H/R genotypes were associated with improved overall survival (OS). According to these data, in our retrospective analysis of 86 mCRC patients treated with cetuximab therapy (2), a statistically significant difference in OS was observed in favor of FcγRIIa R/R carriers (17.5 months) in comparison with both FcγRIIa H/R and H/H genotypes (9.4 and 9.9 months, respectively). We also observed that peripheral mononuclear blood cells (PBMC) of individuals bearing the favorable prognostic genotype (FcγRIIa R/R) showed a significantly worse cetuximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) than other FcγRIIa variants.
A possible explanation for the apparently paradoxical effect of the FcγRIIa R/R genotype on cetuximab activity and OS can be hypothesized. Affinity of Fc portion of immunoglobulins to FcγRs does not influence only ADCC (3). Monocytes/macrophages express both FcγRIIIa and FcγRIIa, while neutrophils express FcγRIIa but not FcγRIIIa (3). Therefore, FcγRIIa variants might affect not only monocyte/macrophage function, which is responsible for ADCC activity of mAbs, but also the function of other immune cells such as tumor-associated neutrophils, which have been associated with unfavorable overall survival (4). The differences of identified FcγRIIa genotypes according to either cetuximab activity or prognosis may, thus, reflect the different functions of FcγRIIa expressed on various immune effector cells.
We agree with the authors that the prognostic role of FcγR polymorphisms, unrelated to mAb administration, remains, to date, exploratory. Further investigation is warranted in a prospectively accrued population.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.