Abstract P5-02-07: Cell-free DNA detection of GATA3 mutations in metastatic hormone receptor positive breast cancer: a retrospective, observational multi-institutional analysis
Authors: Medford Arielle J. , Velimirovic Marko , Niemierko Andrzej , Hensing Whitney L. , Davis Andrew A. , Clifton Katherine K. , Keenan Jennifer C. , Dai Charles S. , Kiedrowski Lesli A. , Shah Ami N. , Gerratana Lorenzo , Spring Laura M. , Ellisen Leif , Doebele Robert C. , Cristofanilli Massimo , Bardia Aditya 
Published: March 2023

Abstract
Background GATA3 mutations (GATA3mut) have been reported in 10-20% of hormone receptor positive (HR+) breast cancers. It has been shown that targeting GATA3mut HR+ breast cancer with MDM2 inhibitors invokes synthetic lethality. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and research suggests that restoring p53 by blocking MDM2 may be effective in treating GATA3mut HR+ breast cancer. One potential mechanism of this efficacy has been shown to be through the PI3K-AKT pathway. We thus sought to characterize the GATA3mut landscape in a multi-institutional cell-free DNA (cfDNA) analysis and to determine the association between GATA3mut and TP53 mutations, as well as alterations in the PI3K-AKT pathway and the impact of GATA3 on survival. Methods We analyzed cfDNA data collected at the Massachusetts General Hospital and at Washington University in St Louis via Guardant360, a next generation sequencing assay that analyzed up to 74 genes during the study period. The association of GATA3mut and co-mutations as well as number of prior therapies was estimated using Pearson’s chi-squared test for categorical variables, two-sample Wilcoxon rank-sum test for continues variables, and multivariable logistic regression. The impact of GATA3mut and GATA3 wildtype (WT) on progression-free survival (PFS) and overall survival (OS) was analyzed using multivariable Cox regression analysis, adjusting for age, number of prior therapies, visceral metastases, and de novo metastases. PFS and OS were evaluated in the overall study population, as well as in subgroups of patients that received endocrine monotherapy and chemotherapy. Results Out of 647 patients with HR+ MBC, 10% (n = 68) had non-synonymous GATA3 mutations. Among these 68 GATA3mut patients, 37% (n = 25) were mutations in exon 5, all but two of which were in the second zinc finger, and 62% (n = 42) were in exon 6. 62% (n = 42) were frameshift mutations, 20% (n = 14) were indels, and 18% (n = 12) were point mutations. Median mutant allele fraction (MAF) of GATAmut was 0.95% (range 0.03 – 30.5%). There was no statistically significant association of GATA3mut with the number of prior therapies, PR status, or the presence of ESR1, TP53, or PI3K-AKT pathway mutations. In the GATA3mut population, TP53 co-mutations (n = 21) were found with a median MAF of 0.6%. PI3K-AKT pathway alterations occurred in 47% (n=32) of GATA3mut patients (PIK3CA n = 27; AKT n = 2; PTEN n = 3). In the combined cohort, there was no significant difference in PFS or OS after adjusting for visceral metastases, de novo disease, number of prior therapies, and age. In a cohort of 80 patients that received endocrine monotherapy (GATA3 WT n = 74, GATA3mut n = 6), GATA3mut were associated with borderline worse PFS (HR 2.6; p = 0.061) and worse OS (HR 4.5; p = 0.009). There was no statistically significant difference in PFS or OS in a subgroup that received chemotherapy. Conclusions GATA3 mutations can be identified via cfDNA in patients with HR+ MBC. Co-mutations in TP53 occurred at overall low MAF. Further research is needed to characterize the functional impact of these low level TP53 co-mutations and develop therapeutic strategies to target GATA3 mutant MBC.
Citation Format: Arielle J. Medford, Marko Velimirovic, Andrzej Niemierko, Whitney L. Hensing, Andrew A. Davis, Katherine K. Clifton, Jennifer C. Keenan, Charles S. Dai, Lesli A. Kiedrowski, Ami N. Shah, Lorenzo Gerratana, Laura M. Spring, Leif Ellisen, Robert C. Doebele, Massimo Cristofanilli, Aditya Bardia. Cell-free DNA detection of GATA3 mutations in metastatic hormone receptor positive breast cancer: a retrospective, observational multi-institutional analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-07.