Predictive Value of FcR Polymorphisms: A Further Step on the Long and Winding Road to Application.

The addition of the ERBB2/HER2 protein–targeting trastuzumab antibody to standard chemotherapy is a consolidated treatment for patients with ERBB2/HER2–overexpressing breast cancer. Nevertheless, the clinical benefit of trastuzumab is still limited to a proportion of patients with advanced disease (26%)1 or undergoing adjuvant treatment (50%). 2 Identification of suitable biomarkers of predictive value is therefore a pressing medical need to improve patient stratification. To this end, several studies focused on the immunerelated effects of trastuzumab mediated by its binding to the Fcγ receptor (FCGR) expressed by macrophages and natural killer cells, particularly antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxic effects, and antibody–mediated cellular phagocytosis. The strength of these responses was shown to correlate with the antibodybinding affinity of FCGR, which is dictated by some common single-nucleotide polymorphisms (SNPs) in the coding region of the FCGR genes.3 Functionally relevant FCGR SNPs affecting affinity for human immunoglobulins (IgG) have been demonstrated for FCGR2A and FCGR3A, with a histidine (H)/ arginine (R) polymorphism at position 131 for FCGR2A and a valine (V)/phenylalanine (F) polymorphism for FCGR3A at position 158.3 Available preclinical evidence supports the functional relevance of FCGR SNPs in modulating the efficacy of immune effects mediated by therapeutic antibodies, and several studies reported a significant correlation between FCGR2A H131R and/or FCGR3A V158F and improved clinical outcomes in patients with ERBB2/HER2–positive breast cancer treated with trastuzumab. These positive findings are consistent with those reported for patients with lymphoma treated with rituximab and for patients with colon cancer receiving cetuximab. Nevertheless, negative results have been also reported, highlighting the complexity to unequivocally validate SNP data for their possible clinical application. In particular, 2 large studies of patients enrolled in the NCCTG-N9831 and BCIRG-006 clinical trials failed in confirming the predictive value of FCGR2A and FCGR3A SNPs in patients with ERBB2/HER2– positive breast cancer treated with trastuzumab in the adjuvant setting.4,5 Although carried out with rigorous methodological approaches, these studies suffered from sampling biases that may have reduced the power to detect genotypetreatment interactions. In this issue of JAMA Oncology, Gavin and colleagues6 report on a retrospective analysis of FCGR genotypes carried out in 1251 surgically resected, nodepositive, ERBB2/HER2–positive breast cancer patients treated with doxorubicin and cyclophosphamide followed by paclitaxel with or without the addition of 1 year of weekly trastuzumab (NSABP B-31 clinical trial). It is worth noting that the clinical variables and the degree of benefit induced by trastuzumab in the genotyped cohort were similar to those observed in the whole B-31 cohort, thus limiting the possible confounding effects of sampling biases. The study disclosed a significantly greater benefit from trastuzumab in patients with the FCGR3A-158V/V or V/F genotypes than in patients homozygous for the low-affinity allele F/F. These findings provide convincing evidence that antibody-dependent immune effects, such as ADCC, are probably the main mediators of the efficacy of adjuvant trastuzumab in patients with ERBB2/ HER2–positive breast cancer. The recent observation that the effects of trastuzumab as single agent on the gene expression profile of peripheral blood mononucleated cells were more prominent in patients with the high-affinity FCGR2A and FCGR3A alleles further supports the contribution of these polymorphisms to the systemic immune response triggered by trastuzumab.7 While these positive results are encouraging in the long search of reliable predictive markers in this setting, the study by Gavin and colleagues also reaffirms the complexity of the field and the difficulty to predict clinical outcomes when immunologic markers are considered. In fact, the study also reported the unexpected finding that the FCGR3A-158 lowaffinity allele was associated with a better prognosis than the high-affinity allele in patients treated with chemotherapy alone. This could be a chance finding or the result of immune effects triggered by chemotherapy and involving effector cells expressing different sets of FCGRs. Our knowledge on the functional relevance of FCGR polymorphisms has certainly improved in the last years and carefully performed studies are providing convincing evidence that these SNPs may be of potential clinical relevance. Nevertheless, a reliable clinical application of these immunogenetic biomarkers still awaits additional supporting evidence. Large, prospective, carefully controlled clinical trials should be performed to confirm the possible predictive value of FCGR polymorphisms in patients treated with trastuzumab. Analysis of these immunogenetic biomarkers should be coupled with assessment of the functional ADCC activity mediated by peripheral blood mononucleated cells of the same patients and results normalized for the number of circulating immune effectors. The possible immunomodulating activity of drugs used in combination with trastuzumab should be also taken into account. If these studies are successful, FCGR polymorphisms could help stratify patients for different treatments according to their immunogenetic background. Nevertheless, considering that the subgroup of patients with less favorable genotypes still derive some treatment benefit from trastuzumab, it would be inappropriate and unethical to deny the drug to these patients. The use of complementary immunomodulating or immunotherapeutic Related article Predictive Value of FcR Polymorphisms Invited Commentary