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

Patrick G. Gavin, Nan Song, S. Rim Kim, Corey Lipchik, Nicole L. Johnson, Hanna Bandos, Melanie Finnigan, Priya Rastogi, Louis Fehrenbacher, Eleftherios P. Mamounas, Sandra M. Swain, D. Lawrence Wickerham, Charles E. Geyer, Jong Hyeon Jeong, Joseph P. Costantino, Norman Wolmark, Soonmyung Paik, Kay L. Pogue-Geile

Research output: Contribution to journalArticle

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Abstract

Importance: 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.

Design, Setting, and Participants: 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.

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

Main Outcomes and Measures: 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 and Relevance: 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.

Trial Registration: clinicaltrials.gov Identifier: NCT00004067.

Original languageEnglish (US)
Pages (from-to)335-341
Number of pages7
JournalJAMA oncology
Volume3
Issue number3
DOIs
StatePublished - Mar 1 2017

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Breast
Breast Neoplasms
Therapeutics
Paclitaxel
Doxorubicin
Cyclophosphamide
Disease-Free Survival
B 31
Trastuzumab
Phenylalanine
Adrenocorticotropic Hormone
Canada
Single Nucleotide Polymorphism
Alleles
Genotype
Outcome Assessment (Health Care)
Antibodies
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / Gavin, Patrick G.; Song, Nan; Kim, S. Rim; Lipchik, Corey; Johnson, Nicole L.; Bandos, Hanna; Finnigan, Melanie; Rastogi, Priya; Fehrenbacher, Louis; Mamounas, Eleftherios P.; Swain, Sandra M.; Wickerham, D. Lawrence; Geyer, Charles E.; Jeong, Jong Hyeon; Costantino, Joseph P.; Wolmark, Norman; Paik, Soonmyung; Pogue-Geile, Kay L.

In: JAMA oncology, Vol. 3, No. 3, 01.03.2017, p. 335-341.

Research output: Contribution to journalArticle

Gavin, PG, Song, N, Kim, SR, Lipchik, C, Johnson, NL, Bandos, H, Finnigan, M, Rastogi, P, Fehrenbacher, L, Mamounas, EP, Swain, SM, Wickerham, DL, Geyer, CE, Jeong, JH, Costantino, JP, Wolmark, N, Paik, S & Pogue-Geile, KL 2017, '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', JAMA oncology, vol. 3, no. 3, pp. 335-341. https://doi.org/10.1001/jamaoncol.2016.4884
Gavin, Patrick G. ; Song, Nan ; Kim, S. Rim ; Lipchik, Corey ; Johnson, Nicole L. ; Bandos, Hanna ; Finnigan, Melanie ; Rastogi, Priya ; Fehrenbacher, Louis ; Mamounas, Eleftherios P. ; Swain, Sandra M. ; Wickerham, D. Lawrence ; Geyer, Charles E. ; Jeong, Jong Hyeon ; Costantino, Joseph P. ; Wolmark, Norman ; Paik, Soonmyung ; Pogue-Geile, Kay L. / 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. In: JAMA oncology. 2017 ; Vol. 3, No. 3. pp. 335-341.
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title = "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",
abstract = "Importance: 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.Design, Setting, and Participants: 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.Interventions: Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab.Main Outcomes and Measures: 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 and Relevance: 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.Trial Registration: clinicaltrials.gov Identifier: NCT00004067.",
author = "Gavin, {Patrick G.} and Nan Song and Kim, {S. Rim} and Corey Lipchik and Johnson, {Nicole L.} and Hanna Bandos and Melanie Finnigan and Priya Rastogi and Louis Fehrenbacher and Mamounas, {Eleftherios P.} and Swain, {Sandra M.} and Wickerham, {D. Lawrence} and Geyer, {Charles E.} and Jeong, {Jong Hyeon} and Costantino, {Joseph P.} and Norman Wolmark and Soonmyung Paik and Pogue-Geile, {Kay L.}",
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TY - JOUR

T1 - Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2-Positive Breast Cancer

T2 - Analysis of the NSABP B-31 Trial

AU - Gavin, Patrick G.

AU - Song, Nan

AU - Kim, S. Rim

AU - Lipchik, Corey

AU - Johnson, Nicole L.

AU - Bandos, Hanna

AU - Finnigan, Melanie

AU - Rastogi, Priya

AU - Fehrenbacher, Louis

AU - Mamounas, Eleftherios P.

AU - Swain, Sandra M.

AU - Wickerham, D. Lawrence

AU - Geyer, Charles E.

AU - Jeong, Jong Hyeon

AU - Costantino, Joseph P.

AU - Wolmark, Norman

AU - Paik, Soonmyung

AU - Pogue-Geile, Kay L.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Importance: 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.Design, Setting, and Participants: 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.Interventions: Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab.Main Outcomes and Measures: 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 and Relevance: 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.Trial Registration: clinicaltrials.gov Identifier: NCT00004067.

AB - Importance: 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.Design, Setting, and Participants: 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.Interventions: Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab.Main Outcomes and Measures: 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 and Relevance: 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.Trial Registration: clinicaltrials.gov Identifier: NCT00004067.

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