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

• DOI: 10.1038/tpj.2016.51
• Publication Date: 2016-07-05T10:03:59Z
• Authors: A Musolino; N Naldi; M V Dieci; D Zanoni; A Rimanti; D Boggiani; P Sgargi; D G Generali; F Piacentini; M Ambroggi; K Cagossi; L Gianni; S Sarti; G Bisagni; A Ardizzoni; P F Conte; V Guarneri
• Keywords: Adult; Genotype; Pharmacogenomic Variants; Molecular Medicine; Genetics; Pharmacology; Breast Neoplasms; Disease-Free Survival; 03 medical and health sciences; Clinical Trials, Phase II as Topic; 0302 clinical medicine; Genetic; Gene Frequency; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Mastectomy; Aged; Pharmacology; Lapatinib; Middle Aged; Neoadjuvant Therapy; Pharmacogenomic Testing; 3. Good health; Phenotype; Chemotherapy, Adjuvant; Pharmacogenetics; Molecular Medicine; Female

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.