Genetic variants in FCGR2A and FCGR3A and disease-free survival in patients with HER2 positive breast cancer treated with trastuzumab in the SUCCESS A trial

M Wunderle; A Hein; B Rack; L Häberle; L Li; AB Ekici; A Reis; MP Lux; JM Cunningham; M Rübner; A Schneeweiss; H Tesch; JU Blohmer; T Fehm; G Heinrich; M Rezai; MW Beckmann; W Janni; RM Weinshilboum; L Wang; PA Fasching

doi:10.1055/s-0038-1651824

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2018; 15(02): e53-e54
DOI: 10.1055/s-0038-1651824

Abstracts

Georg Thieme Verlag KG Stuttgart · New York

Genetic variants in FCGR2A and FCGR3A and disease-free survival in patients with HER2 positive breast cancer treated with trastuzumab in the SUCCESS A trial

M Wunderle

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

,

A Hein

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

,

B Rack

²Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Deutschland

,

L Häberle

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

³Department of Gynecology and Obstetrics, Biostatistics Unit, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Deutschland

,

L Li

⁴Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Vereinigte Staaten von Amerika

⁵Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

,

AB Ekici

⁶Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Deutschland

,

A Reis

⁶Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Deutschland

,

MP Lux

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

,

JM Cunningham

⁷Department of Laboratory Medicine & Pathology, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, Vereinigte Staaten von Amerika

,

M Rübner

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

,

A Schneeweiss

⁸Division of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Deutschland

,

H Tesch

⁹Department of Oncology, Onkologie Bethanien, Frankfurt am Main, Deutschland

,

JU Blohmer

¹⁰Department of Gynecology and Obstetrics, Charité University Hospital, Berlin, Deutschland

,

T Fehm

¹¹Department of Gynecology and Obstetrics, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Deutschland

,

G Heinrich

¹²Department of Gynecologic Oncology, Schwerpunktpraxis für Gynäkologische Onkologie, Fürstenwalde, Deutschland

,

M Rezai

¹³Department of Breast Diseases, Breast Center of Düsseldorf, Luisenkrankenhaus, Düsseldorf, Deutschland

,

MW Beckmann

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

,

W Janni

¹⁴Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Deutschland

,

RM Weinshilboum

¹⁵Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, Vereinigte Staaten von Amerika

,

L Wang

⁴Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Vereinigte Staaten von Amerika

,

PA Fasching

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Deutschland

¹⁶Department of Medicine, Division of Hematology/Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, Vereinigte Staaten von Amerika

› Author Affiliations

Abstract

Full Text

Background:

The anti-HER2 antibody trastuzumab acts by different mechanisms, one of which is antibody-dependent cellular cytotoxicity of immune effector cells via Fcγ receptors (FCGRs). Lower affinity to trastuzumab has been described for the minor alleles in FCGR2A (H131R, rs1801274) and in FCGR3A (V158F, rs396991). These genotypes were previously associated with poorer response to trastuzumab in metastatic breast cancer. This study investigates the association of these genetic polymorphisms with disease-free survival (DFS) in HER2 positive breast cancer patients from the adjuvant SUCCESS A trial.

Patients and Methods:

Whole genome SNP genotyping was performed from germline DNA of 654 HER2 positive patients treated with chemotherapy and trastuzumab within the SUCCESS A trial. The influence of rs1801274 (FGR2A, originally on the chip) and rs396991 (FCGR3A, imputed) on DFS was analyzed using two multiple Cox regression models with these predictors: SNP (ordinal, count of minor alleles), age at diagnosis, body mass index, tumor stage, nodal status, ER status, PgR status, and grading.

Results:

rs1801274 in FCGR2A (minor allele frequency (MAF), 0.44) was associated with DFS in HER2 positive patients. The adjusted hazard ratio (HR) was 1.80 (95% confidence interval (CI), 1.25 to 2.60; p < 0.01) per minor allele. rs396991 in FCGR3A was not associated with DFS (adjusted HR, 0.74; 95% CI, 0.44 to 1.26; p = 0.27).

Conclusion:

We demonstrate for the first time that genetic variants in FCGR2A are associated with DFS in HER2 positive breast cancer patients adjuvantly treated with trastuzumab.