Germline Genetic Variants in GATA3 and Breast Cancer Treatment Outcomes in SWOG S8897 Trial and the Pathways Study

Victoria Larsen, William E. Barlow, J. J. Yang, Qianqian Zhu, Song Liu, Marilyn L. Kwan, Isaac J. Ergas, Janise M. Roh, Laura F. Hutchins, Susan A. Kadlubar, Kathy S. Albain, James M. Rae, I. Tien Yeh, Peter M. Ravdin, Silvana Martino, Alan P. Lyss, C. Kent Osborne, Gabriel N. Hortobagyi, Lawrence H. Kushi, Daniel F. HayesChristine B. Ambrosone, Song Yao

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2 Scopus citations

Abstract

Introduction: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer. Patients and Methods: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study. Results: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue. Conclusions: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted. In an ancillary study to a completed clinical trial, we identified GATA3 genotypes predictive of survival after adjuvant chemotherapy, particularly among those subsequently treated with tamoxifen. Although the replication effort in a second cohort proved to be futile owing to substantial differences between the discovery and the replication cohorts, mechanistic exploration of the identified variants supported their functional significance.

Original languageEnglish (US)
Pages (from-to)225-235.e2
JournalClinical breast cancer
Volume19
Issue number4
DOIs
StatePublished - Aug 2019

Keywords

  • Chemotherapy
  • Pharmacogenetics
  • Recurrence
  • SNPs
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Larsen, V., Barlow, W. E., Yang, J. J., Zhu, Q., Liu, S., Kwan, M. L., Ergas, I. J., Roh, J. M., Hutchins, L. F., Kadlubar, S. A., Albain, K. S., Rae, J. M., Yeh, I. T., Ravdin, P. M., Martino, S., Lyss, A. P., Osborne, C. K., Hortobagyi, G. N., Kushi, L. H., ... Yao, S. (2019). Germline Genetic Variants in GATA3 and Breast Cancer Treatment Outcomes in SWOG S8897 Trial and the Pathways Study. Clinical breast cancer, 19(4), 225-235.e2. https://doi.org/10.1016/j.clbc.2019.02.010