Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2–Positive Breast Cancer

Abstract

IMPORTANCE Preclinical models and studies in the metastatic and neoadjuvant settings suggest that single nucleotide polymorphisms in FCGR3A and FCGR2A may be associated with differential response to trastuzumab in the treatment of ERBB2/HER2–positive breast cancer, by modulating antibody-dependent cell-mediated cytotoxic effects. OBJECTIVE To evaluate the effect of FCGR2A and FCGR3A polymorphisms on trastuzumab efficacy in the adjuvant treatment of ERBB2/HER2–positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective analysis of patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, a phase 3 cooperative group study conducted between 2000 and 2005. The NSABP B-31 trial randomized 2119 women with surgically resected node-positive, ERBB2/HER2–positive breast cancer to treatment with doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. Patients were accrued at cooperative group sites across the United States and Canada. This analysis was performed between 2013 and 2016. INTERVENTIONS Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. MAIN OUTCOMES AND MEASURES Disease-free survival. RESULTS The genotyped cohort (N = 1251) resembled the entire B-31 cohort based on clinical variables and the degree of benefit from trastuzumab. Median follow-up time was 8.2 years in the genotyped samples. The disease-free survival probability at 3, 5, and 8 years was 74% (95%CI, 71%–79%), 66%(95%CI, 62%–71%), and 58%(95%CI, 54%–63%) in patients who received ACT and 86%(95%CI, 83%–89%), 82%(95%CI, 79%–85%), and 78%(95%CI, 74%–81%) in patients who received ACTH. Addition of trastuzumab significantly improved patient outcome (hazard ratio [HR], 0.46; 95%CI, 0.37–0.57; P < .001). The expected trend for interaction between polymorphisms and trastuzumab was observed for both genes, but only FCGR3A-158 polymorphism reached statistical significance for interaction (P < .001). As hypothesized, patients with genotypes FCB3A-158V/V or FCB3A-158V/F received greater benefit from trastuzumab (HR, 0.31; 95%CI, 0.22–0.43; P < .001) than patients who were homozygous for the low-affinity allele (HR, 0.71; 95%CI, 0.51–1.01; P = .05). CONCLUSIONS AND RELEVANCE The FCGR3A-158 polymorphism is predictive of trastuzumab efficacy in this cohort of patients with early ERBB2/HER2–positive breast cancer. Patients who are homozygous for phenylalanine at this position represent a considerable proportion of the population and, in contrast to previously reported analyses from similarly designed trials, our results indicate that trastuzumab may be less efficacious in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifier for NSABP B-31: NCT00004067

FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125

“…The role of FCGR3A -V158F polymorphism on ADCC and clinical outcome remains controversial. The V allele having higher affinity has been reported to be associated with better outcome in a clinical study with rituximab [Weng and Levy, 2003] and trastuzumab [Gavin et al, 2017], while other independent studies found no genotype association using rituximab or alemtuzumab in lymphoma trials [Farag et al, 2004;Lin et al, 2005;Dornan et al, 2010]. More confounding are the contradictory findings reported by Zhang et al [2007] where the V allele correlated with a negative clinical outcome in colorectal cancer patients treated with cetuximab.…”

Enhanced expression of FCER1G predicts positive prognosis in multiple myeloma

“…[47]. The polymorphisms of FCGR3A play an important role in First-Relapsed ovarian cancer, metastatic breast cancer, and metastatic colorectal cancer [48][49][50][51]. Early research also found that FCGR3A was associated with infections of MM patients [52].…”

Key genes with prognostic values in suppression of osteosarcoma metastasis using comprehensive analysis

“…Ekmekcioglu et al found that CD74 is associated with overall survival and recurrence-free survival in stage III melanoma, and could be a useful prognostic tumor marker [38]. Furthermore, FCGR2A is reportedly associated with the pharmacodynamics of monoclonal antibodies in different cancer types, such as colorectal cancer [39], breast cancer [40], and metastatic squamous cell head and neck cancer [41]. However, a search of the published literature revealed that there are few studies about the candidate genes for osteosarcoma.…”