Landscape of <i>GATA3</i> mutations identified from circulating tumor DNA clinical testing and their impact on disease outcomes in estrogen receptor-positive (ER+) metastatic breast cancers treated with endocrine therapies.
Authors: Marko Velimirovic, Lorenzo Gerratana, Andrew A. Davis, Charles Sichao Dai, Ju Cheng, A. John Iafrate, Bruce Allan Chabner, Massimo Cristofanilli, Aditya Bardia
Journal: Journal of Clinical Oncology (2021)

1065 Background: The GATA3 gene encodes for a transcription factor (TF) that plays a pivotal role in the development of breast tissue. Breast tumors with lower GATA3 expression have worse prognosis compared to tumors with higher expression. However, the consequences of somatic GATA3 mutations ( GATA3 mut ) on clinical outcomes in metastatic breast cancer (MBC) remain poorly understood. Further, GATA3 TF interferes with FOXA1 and ER to enhance transcription of ER-responsive genes, but the role of GATA3 mut in altering downstream transcriptional activity and its effects on response to anti-estrogens remains unclear. Methods: We retrospectively identified ctDNA next-generation sequencing results from 101 ER+/HER2- patients with MBC treated with either selective estrogen receptor degraders (SERDs) alone or a combination of SERDs and CDK4/6 inhibitors at Massachusetts General Hospital (Boston, MA) and Northwestern University (Chicago, IL). Associations between GATA3 mut , patient and tumor characteristics, and prior treatments were assessed using logistic regression. Clinical outcomes were estimated through Cox proportional hazards regression. Results: GATA3 mut were observed in 13 patients (13%), each with a single GATA3 variant. These mutations were detected in exon 4 (M294K), exon 5 that includes Zn-finger-2 motif (T327fs, R331fs, N334K, D336fs, c.925-3_925-2del splice acceptor variant), and exon 6 (K358fs, P409fs, M416fs, G431fs, M439fs, V440fs). All mutations except for M294K were insertion/deletion frameshift mutations that result in either elongation or truncation of the protein, potentially with heterogenous downstream effects. GATA3 mut were the only detectable alteration in 4 patients. The most commonly co-occurring mutations with GATA3 mut were ESR1 mut in 7/13 (53.8%) and PIK3CA mut in 6/13 (46%) patients. Presence of GATA3 mut was associated with prior exposure to chemotherapy (OR = 1.09, 95%CI [1.01 - 1.10], p = 0.03). Patients with GATA3 mut tumors had shorter PFS compared to GATA3 w ild tumors (4.1 vs. 6.7 months, in both univariate and multivariate analysis controlled for presence of ESR1 mut : HR = 2.22 95%CI [1.12 – 4.38], p = 0.02). OS was also significantly shorter in patients harboring GATA3 mut compared to GATA3 wild (14.1 vs. 27.1 months, multivariate analysis: HR = 2.30 95%CI [1.04 – 5.11], p = 0.04). Conclusions: GATA3 mut in breast cancer tend to be grouped within exons 5 and 6, and they likely contribute to acquired resistance to endocrine-based therapies in MBC. Our study showed that patients with GATA3 mut ER+ MBC have worse prognosis compared to those who were GATA3 wild . Larger studies are needed to further stratify and ascertain functional effects of different GATA3 mutations and explore GATA3 gene or its translational product as a possible druggable target.