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

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

doi:10.1038/tpj.2016.51

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

Pharmacogenomics J. 2016 Oct;16(5):472-7. doi: 10.1038/tpj.2016.51. Epub 2016 Jul 5.

Authors

A Musolino¹, N Naldi¹, M V Dieci², D Zanoni³, A Rimanti¹, D Boggiani¹, P Sgargi¹, D G Generali⁴, F Piacentini⁵, M Ambroggi⁶, K Cagossi⁷, L Gianni⁸, S Sarti⁹, G Bisagni¹⁰, A Ardizzoni¹¹, P F Conte², V Guarneri²

Affiliations

¹ Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
² Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
³ Department of Oncology, Guastalla Hospital, Guastalla, Italy.
⁴ U.O. Multidisciplinare di Patologia Mammaria, A.O. Istituti Ospitalieri di Cremona, Cremona, Italy.
⁵ Medical Oncology Unit, Modena University Hospital, Modena, Italy.
⁶ Medical Oncology Unit, Hospital of Piacenza, Piacenza, Italy.
⁷ Medical Oncology Unit, Ramazzini Hospital, Carpi, Italy.
⁸ Medical Oncology Unit, Ospedale Infermi, Rimini, Italy.
⁹ Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
¹⁰ Medical Oncology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
¹¹ Division of Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy.

PMID: 27378608
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.

MeSH terms

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Biomarkers, Tumor* / analysis
Biomarkers, Tumor* / genetics
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / genetics
Breast Neoplasms / immunology
Chemotherapy, Adjuvant
Clinical Trials, Phase II as Topic
Disease-Free Survival
Female
Gene Frequency
Genotype
Humans
Lapatinib
Mastectomy
Middle Aged
Neoadjuvant Therapy*
Pharmacogenetics
Pharmacogenomic Testing
Pharmacogenomic Variants*
Phenotype
Polymorphism, Single Nucleotide*
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / therapeutic use*
Quinazolines / adverse effects
Quinazolines / therapeutic use*
Randomized Controlled Trials as Topic
Receptor, ErbB-2 / analysis*
Receptors, IgG / genetics*
Retrospective Studies
Time Factors
Trastuzumab / adverse effects
Trastuzumab / therapeutic use*
Treatment Outcome

Substances

Biomarkers, Tumor
FCGR3A protein, human
Fc gamma receptor IIA
Protein Kinase Inhibitors
Quinazolines
Receptors, IgG
Lapatinib
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab