FCGR3A Polymorphisms Predict Trastuzumab Benefit in HER2-Positive Breast Cancer

Polymorphisms in the FCGR3A gene are correlated with degree of benefit from trastuzumab in women with ERBB2/HER2-positive breast cancer, according to a new analysis.

Trastuzumab’s efficacy has several underlying mechanisms, but one is its ability to trigger the immune system to kill tumor cells. “This immune response, known as antibody-dependent cell-mediated cytotoxic effect (ADCC), is initiated when the FCγ receptor on natural killer cells binds to the Fc portion of trastuzumab,” wrote study authors led by Kay L. Pogue-Geile, PhD, of NRG Oncology in Pittsburgh. Earlier preclinical work has suggested that the genes encoding those FCγ receptors are related to the strength of the immune response.

The new study was a retrospective analysis of 1,251 patients included in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, a phase III trial of women with ERBB2/HER2-positive breast cancer conducted from 2000 to 2005. Patients were randomized to either doxorubicin and cyclophosphamide followed by paclitaxel (ACT), or the same regimen followed by a year of weekly trastuzumab (ACTH). The researchers compared outcomes based on single-nucleotide polymorphisms (SNPs) in FCGR3A and FCGR2A; the results were published in JAMA Oncology.

Only SNPs on FCGR3A-158 were found to be significantly associated with treatment response. For that gene, 46% of patients had F/F alleles, 42% had F/V, and 12% had V/V.

Patients with the V/V or F/V genotype fared worse than others with the ACT regimen, and derived significantly more benefit from the addition of trastuzumab with regard to disease-free survival. On multivariate analysis, the hazard ratio (HR) for disease-free survival was 0.31 (95% CI, 0.22–0.43; P < .001). For patients with the F/F genotype, the difference was less pronounced between treatment groups, with an HR of 0.71 (95% CI, 0.51–1.01; P = .05).

“Genotype by treatment-interaction test indicates an association between FCGR3A-158 and benefit from trastuzumab (P < .001),” the authors wrote. The V/V homozygous patients derived the most benefit according to an exploratory analysis, with an HR of 0.12 (95% CI, 0.05–0.28; P < .001), followed by heterozygous F/V patients and then homozygous F/F patients.

Similar trends were seen with SNPs with the FCGR2A gene, but the treatment-interaction test showed no significant difference in trastuzumab efficacy.

“These results indicate that ADCC may play a substantial component in the efficacy of trastuzumab for the treatment of breast cancer in the adjuvant setting,” the authors concluded, noting that the difference was likely not strong enough to justify the use of genotyping for the selection of patients. Other biomarkers may be necessary to further refine this assessment of ADCC activity.