Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

A Musolino,D Boggiani,A Rimanti,M V Dieci,P Sgargi,F Piacentini,A Ardizzoni,N Naldi,L Gianni,S Sarti,P F Conte,D G Generali,K Cagossi,D Zanoni,V Guarneri,G Bisagni,M Ambroggi

doi:10.1038/tpj.2016.51

Abstract

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Highlights

HER2 (Her-2/neu, c-erbB-2) is a 185-kDa transmembrane tyrosine kinase protein giving higher aggressiveness in breast cancers (BCs)
Results of the present study indicate an association between FcγRIIIa polymorphism and pathological complete response (pCR) to the combination of trastuzumab and lapatinib in pts with operable HER2-positive BC enrolled in the neoadjuvant randomized phase II CHER-LOB trial
FcγRIIIa V allele carriers included in the trastuzumab plus lapatinib arm obtained a significant increase in pCR rate than FcγRIIIa V carriers treated with either trastuzumab or lapatinib

Summary

Introduction

HER2 (Her-2/neu, c-erbB-2) is a 185-kDa transmembrane tyrosine kinase protein giving higher aggressiveness in breast cancers (BCs). HER2 overexpression occurs in 15–20% of primary breast tumors, and is associated with diminished diseasefree (DFS) and overall survival (OS).[1] The anti-HER2 monoclonal antibody (mAb) trastuzumab in combination with chemotherapy is an effective treatment for all stages of HER2-positive BC.[2]. Following adjuvant trastuzumab, relapse can occur up to 25.4% of patients (pts) at 10 years of follow-up.[3] What is more, only 25–30% of HER2-positive metastatic BC (MBC) pts will respond to trastuzumab and most of them will experience disease progression during the first year of treatment.[4] All these findings are consistent with the occurrence of intrinsic or acquired drug resistance in the majority of pts.[4,5]

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