Trastuzumab Efficacy In Breast Cancer Linked To FCγ Gene Variants

Gene polymorphisms may predict ERBB2/HER2-positive breast cancer disease-free survival with trastuzumab

medwireNews: Variations in the genes encoding the FCγ receptors (FCGR) that bind to trastuzumab may influence response to the drug in patients with early-stage ERBB2/HER2-positive breast cancer, suggests research published in JAMA Oncology.

Trastuzumab-treated patients who carried the high affinity V/V or V/F alleles of FCGR3A-158 derived significantly greater benefit from trastuzumab than those who were homozygous for the low-affinity F allele, with hazard ratios (HRs) against patients not given the anti-ERBB2/HER2 treatment of 0.31 versus 0.71.

“These findings provide convincing evidence that antibody-dependent immune effects, such as ADCC [antibody-dependent cell-mediated cytotoxicity], are probably the main mediators of the efficacy of adjuvant trastuzumab in patients with ERBB2/ HER2–positive breast cancer”, says Riccardo Dolcetti, from The University of Queensland Diamantina Institute in Brisbane, Australia, in a comment accompanying the study.

The secondary analysis of the phase III, National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial included 1251 patients with surgically resected, node-positive breast cancer who were given doxorubicin plus cyclophosphamide followed by paclitaxel alone (ACT) or with 1 year of weekly trastuzumab (ACTH).

After a median of 8.2 years, the 3-year disease-free survival probability was 74% for ACT-treated patients and 86% for those given ACTH, with corresponding 5- and 8-year rates of 66% versus 82%, and 58% versus 78%.

Thus, the addition of trastuzumab significantly improved patient outcome, with a hazard ratio of 0.46, report Kay Pogue-Geile, from the NSABP in Pittsburgh, Pennsylvania, USA, and study co-authors.

genotype analysis suggested that patients with the high-affinity H/H genotype of FCGR2A-131 received more benefit from treatment than those with the H/R genotype, who in turn had more benefit than those with the low-affinity R/R genotype. But unlike the correlation between FCGR3A-158 polymorphism and trastuzumab efficacy, treatment interaction tests failed to show a significant correlation between FCGR2A-131 genotype and trastuzumab benefit.

The authors note that around 15% of the patients were homozygous for the low-affinity alleles of both FCGR3A-158 and FCGR2A-131, and trastuzumab showed a trend towards being less effective in these patients, but the treatment interaction tests were not significant.

“This study supports the hypothesis that ADCC activity plays an important role in the efficacy of trastuzumab”, Kay Pogue-Geile et al write.

“However, a great number of different molecules are involved in determining ADCC activity, therefore it may be useful to collect peripheral blood monocytes from patients in future clinical trials so that functional ADCC activity can be assessed and associated with treatment efficacy of trastuzumab and other therapeutic monoclonal antibodies”, they suggest.

Riccardo Dolcetti agrees that the current research “reaffirms the complexity of the field and the difficulty to predict clinical outcomes when immunologic markers are considered” and awaits further large clinical trial results to see if FCGR polymorphisms could be used to stratify patients for treatment.

“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”, he cautions.

“The use of complementary immunomodulating or immunotherapeutic approaches, such as immune checkpoint modulators, could improve the rate of clinical responses induced by trastuzumab also in patients with a less favorable FCGR immunogenetic background.”

Reference

Gavin PG, Song N, Kim SR, et al. 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. JAMA Oncol; Advance online publication 3 November 2016. doi:10.1001/jamaoncol.2016.4884

Dolcetti R. Predictive value of FcR polymorphisms. A further step on the long and winding road to application. JAMA Oncol; Advance online publication 3 November 2016. doi:10.1001/jamaoncol.2016.4905

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