Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2-Positive Breast Cancer: Analysis of the NSABP B-31 Trial

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: NCT00004067.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mamounas is a consultant for the Genentech/Roche speakers board. Dr Swain has received honoraria, uncompensated steering committees, and research grants to her institution from Genentech/Roche. Dr Geyer is a consultant for Genentech. No other conflicts are reported.

Figures

Figure 1. Treatment Effect According to FCGR Polymorphism

ACT indicates doxorubicin and cyclophosphamide followed by paclitaxel; ACTH, doxorubicin and cyclophosphamide followed by paclitaxel with the addition of 1 year of weekly trastuzumab; DFS, disease-free survival; HR, hazard ratio; M, multivariable; U, univariable.

Figure 2. Cox Models Examining Treatment Affect According to Genotype

The box size is proportional to the precision. ACTH, doxorubicin and cyclophosphamide followed by paclitaxel with the addition of 1 year of weekly trastuzumab; HR, hazard ratio.

Figure 3. Combined Genotypes

ACT indicates doxorubicin and cyclophosphamide followed by paclitaxel; ACTH, doxorubicin and cyclophosphamide followed by paclitaxel with the addition of 1 year of weekly trastuzumab; DFS, disease-free survival; HR, hazard ratio; M, multivariable; U, univariable.