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.
OBJECTIVE
Preclinical models and studies in the metastatic and neoadjuvant settings suggest that single nucleotide polymorphisms in FCGR3A and FCGR2A may be associated with differential response to trastuzumab in the treatment of ERBB2/HER2-positive breast cancer, by modulating antibody-dependent cell-mediated cytotoxic effects.


OBJECTIVE
To evaluate the effect of FCGR2A and FCGR3A polymorphisms on trastuzumab efficacy in the adjuvant treatment of ERBB2/HER2-positive breast cancer.


METHODS
This is a retrospective analysis of patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, a phase 3 cooperative group study conducted between 2000 and 2005. The NSABP B-31 trial randomized 2119 women with surgically resected node-positive, ERBB2/HER2-positive breast cancer to treatment with doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. Patients were accrued at cooperative group sites across the United States and Canada. This analysis was performed between 2013 and 2016.


METHODS
Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab.


METHODS
Disease-free survival.


RESULTS
The genotyped cohort (N = 1251) resembled the entire B-31 cohort based on clinical variables and the degree of benefit from trastuzumab. Median follow-up time was 8.2 years in the genotyped samples. The disease-free survival probability at 3, 5, and 8 years was 74% (95% CI, 71%-79%), 66% (95% CI, 62%-71%), and 58% (95% CI, 54%-63%) in patients who received ACT and 86% (95% CI, 83%-89%), 82% (95% CI, 79%-85%), and 78% (95% CI, 74%-81%) in patients who received ACTH. Addition of trastuzumab significantly improved patient outcome (hazard ratio [HR], 0.46; 95% CI, 0.37-0.57; P < .001). The expected trend for interaction between polymorphisms and trastuzumab was observed for both genes, but only FCGR3A-158 polymorphism reached statistical significance for interaction (P < .001). As hypothesized, patients with genotypes FCB3A-158V/V or FCB3A-158V/F received greater benefit from trastuzumab (HR, 0.31; 95% CI, 0.22-0.43; P < .001) than patients who were homozygous for the low-affinity allele (HR, 0.71; 95% CI, 0.51-1.01; P = .05).


CONCLUSIONS
The FCGR3A-158 polymorphism is predictive of trastuzumab efficacy in this cohort of patients with early ERBB2/HER2-positive breast cancer. Patients who are homozygous for phenylalanine at this position represent a considerable proportion of the population and, in contrast to previously reported analyses from similarly designed trials, our results indicate that trastuzumab may be less efficacious in these patients.


BACKGROUND
clinicaltrials.gov Identifier: NCT00004067.
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Patrick G
PG
Gavin
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Nan
N
Song
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
S Rim
SR
Kim
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Corey
C
Lipchik
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Nicole L
NL
Johnson
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Hanna
H
Bandos
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Melanie
M
Finnigan
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania3University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Priya
P
Rastogi
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania4Kaiser Permanente, Northern California, Vallejo, California.
Louis
L
Fehrenbacher
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania5UF Cancer Center at Orlando Health, Orlando, Florida.
Eleftherios P
EP
Mamounas
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania6Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC7Georgetown University Medical Center, Washington, DC.
Sandra M
SM
Swain
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania8Allegheny Health Network Cancer Institute, Pittsburgh, Pennsylvania.
D Lawrence
DL
Wickerham
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania9Virginia Commonwealth University, Massey Cancer Center, Richmond.
Charles E
CE
Geyer
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania2Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jong-Hyeon
JH
Jeong
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania2Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Joseph P
JP
Costantino
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania8Allegheny Health Network Cancer Institute, Pittsburgh, Pennsylvania.
Norman
N
Wolmark
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania10Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea.
Soonmyung
S
Paik
National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, Pennsylvania.
Kay L
KL
Pogue-Geile
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics*; D016019:Survival Analysis; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C445323:FCGR2A protein, human; C496124:FCGR3A protein, human; C508053:ERBB2 protein, human