Landscape of GATA3 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: Velimirovic Marko , Gerratana Lorenzo , Davis Andrew A. , Dai Charles Sichao , Cheng Ju , Iafrate A. John , Chabner Bruce Allan , Cristofanilli Massimo , Bardia Aditya 
Published: June 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 ( GATA3mut) 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 GATA3mut 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 GATA3mut, patient and tumor characteristics, and prior treatments were assessed using logistic regression. Clinical outcomes were estimated through Cox proportional hazards regression. Results: GATA3mut 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. GATA3mut were the only detectable alteration in 4 patients. The most commonly co-occurring mutations with GATA3mut were ESR1mut in 7/13 (53.8%) and PIK3CAmut in 6/13 (46%) patients. Presence of GATA3mut was associated with prior exposure to chemotherapy (OR = 1.09, 95%CI [1.01 - 1.10], p = 0.03). Patients with GATA3mut tumors had shorter PFS compared to GATA3wild tumors (4.1 vs. 6.7 months, in both univariate and multivariate analysis controlled for presence of ESR1mut: HR = 2.22 95%CI [1.12 – 4.38], p = 0.02). OS was also significantly shorter in patients harboring GATA3mut compared to GATA3wild (14.1 vs. 27.1 months, multivariate analysis: HR = 2.30 95%CI [1.04 – 5.11], p = 0.04). Conclusions: GATA3mut 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 GATA3mut ER+ MBC have worse prognosis compared to those who were GATA3wild. 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.