Do polymorphisms in FCγ receptors affect trastuzumab efficacy?
In this secondary analysis of 1251 patients with early-stage ERBB2/HER2–positive breast cancer enrolled in a randomized clinical trial, patients homozygous for FCGR3A-158 F benefited less from the addition of trastuzumab to chemotherapy than did patients with F/V or V/V genotypes.
Significant association between polymorphisms of FCGR3A and trastuzumab benefit suggests that antibody-dependent cell-mediated cytotoxic effect plays a role in determining the efficacy of trastuzumab in the adjuvant treatment of ERBB2/HER2–positive breast cancer.
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.
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.
Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab.
Main Outcomes and Measures
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.
clinicaltrials.gov Identifier: NCT00004067
Gavin PG, Song N, Kim SR, Lipchik C, Johnson NL, Bandos H, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP, Swain SM, Wickerham DL, Geyer CE, Jeong J, Costantino JP, Wolmark N, Paik S, Pogue-Geile KL. Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2–Positive Breast CancerAnalysis of the NSABP B-31 Trial. JAMA Oncol. 2017;3(3):335-341. doi:10.1001/jamaoncol.2016.4884