Abstract 2032: Germline genetic variants in GATA3 and breast cancer treatment outcomes in SWOG 8897 trial

Purpose: GATA3 is involved in estrogen signaling and mammary cell differentiation, and is frequently mutated in breast cancer. Germline variations of GATA3 are prognostic in childhood acute lymphoblastic leukemia (ALL). Thus, we sought to examine their prognostic and predictive role in breast cancer. Methods: SWOG S8897 comprised two groups of breast cancer patients. In the first high-risk group, women were randomly assigned to CAF vs. CMF, and secondarily randomized to tamoxifen or not. In the second low risk group, women did not receive any adjuvant therapy after surgery. Germline DNA was extracted from uninvolved axillary lymph nodes and 12 candidate GATA3 SNPs were genotyped. Associations of genotypes with treatment outcomes were evaluated in 441 women in the treated and 799 in the untreated groups separately. Hazard ratio (HR) for disease free (DFS) and overall survival (OS) for each SNP was estimated using multivariate Cox hazard regression. Further stratified analyses by tamoxifen were performed in the treated group. Results: After correcting for multiple testing, we identified significant associations of two variants (rs3802604 and rs568727) with DFS and OS for patients who received adjuvant chemotherapy. Women carrying the variant GG genotype at rs3802604 had significantly poorer DFS (HR = 1.95, 95% CI: 1.27-2.99, p = 0.002) and OS (HR = 2.45, 95% CI: 1.48-4.05, p = 0.0005), compared to women carrying the common AA genotype. Associations of similar magnitude were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analysis suggested that these two SNPs more strongly influenced treatment outcomes in the patients who also received tamoxifen. Seven additional variants were also associated with OS and DFS in the tamoxifen treated group. Only 3 of the 12 SNPs analyzed in GATA3 were not associated with survival in this subgroup; however, these three SNPs (rs3781093, rs3824662, and rs3802600) associated with OS in the group not treated with tamoxifen. Functional annotation revealed that several GATA3 SNPs, e.g., rs3802604, rs369421, and rs3824662, are likely to function by affecting transcription factor binding and/or altering regulatory chromatin states at this locus. Conclusions: GATA3 harbors common germline genetic variants that are related to survival following adjuvant chemotherapy and endocrine therapy in breast cancer patients. Citation Format: Victoria L. Larsen, William E. Barlow, Jun J. Ya