Breast cancer research and treatment · 2025
Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes.
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Medford Arielle J, Velimirovic Marko, Gefen Yifat, Niemierko Andrzej, Gerratana Lorenzo, Davis Andrew A, Clifton Katherine, Keenan Jennifer, Podany Emily, Hensing Whitney L, Reduzzi Carolina, Dai Charles S, Kiedrowski Lesli A, Spring Laura M, Ellisen Leif W, Doebele Robert C, Cristofanilli Massimo, Getz Gad, Bardia Aditya
Аннотация
PURPOSE: GATA3 mutations are among the most common alterations in hormone receptor-positive (HR+) breast cancer (BC), yet these have no targeted therapies. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and pre-clinical data suggests MDM2 inhibition may effectively treat GATA3mut HR+ BC. The GATA3 co-mutational landscape has been described only in primary BC tissue, and the mechanism of MDM2-driven efficacy is incompletely understood.
EXPERIMENTAL DESIGN: Circulating tumor DNA (ctDNA) was assessed for GATA3 mutations via targeted sequencing. Associations with co-alterations and clinical/pathologic factors were estimated using Pearson's chi-squared test, two-sample Wilcoxon rank-sum, and multivariable logistic regression. Impact on survival was analyzed using multivariable Cox regression analysis. Tissue-based data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database was evaluated for expression and phosphorylation of GATA3 and associated proteins.
RESULTS: Among 609 patients with HR + /HER2- MBC, ctDNA detected non-synonymous GATA3 variants ctDNA in 69 (11%) patients, and the genomic landscape was unique from tissue-based primary BC data; GATA3mut were not mutually exclusive from TP53mut (p = 0.30) or PIK3CAmut (p = 0.52) and were associated with poorer survival on endocrine monotherapy. CPTAC analysis showed no difference in GATA3 or breast cancer-associated gene abundance, however there was increased USP48 (LogFC = 0.76, FDR = 1.7 × 10-5), which stabilizes MDM2.
CONCLUSION: The distinct landscape in GATA3mut MBC ctDNA highlights critical information when assessing candidacy for targeted therapies. To our knowledge, this is the first ctDNA-based GATA3mut landscape analysis in MBC. Furthermore, tissue-based proteomic analysis suggests mechanisms for endocrine resistance and sensitivity to MDM2 inhibition in HR+ /HER2- GATA3mut BC.
EXPERIMENTAL DESIGN: Circulating tumor DNA (ctDNA) was assessed for GATA3 mutations via targeted sequencing. Associations with co-alterations and clinical/pathologic factors were estimated using Pearson's chi-squared test, two-sample Wilcoxon rank-sum, and multivariable logistic regression. Impact on survival was analyzed using multivariable Cox regression analysis. Tissue-based data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database was evaluated for expression and phosphorylation of GATA3 and associated proteins.
RESULTS: Among 609 patients with HR + /HER2- MBC, ctDNA detected non-synonymous GATA3 variants ctDNA in 69 (11%) patients, and the genomic landscape was unique from tissue-based primary BC data; GATA3mut were not mutually exclusive from TP53mut (p = 0.30) or PIK3CAmut (p = 0.52) and were associated with poorer survival on endocrine monotherapy. CPTAC analysis showed no difference in GATA3 or breast cancer-associated gene abundance, however there was increased USP48 (LogFC = 0.76, FDR = 1.7 × 10-5), which stabilizes MDM2.
CONCLUSION: The distinct landscape in GATA3mut MBC ctDNA highlights critical information when assessing candidacy for targeted therapies. To our knowledge, this is the first ctDNA-based GATA3mut landscape analysis in MBC. Furthermore, tissue-based proteomic analysis suggests mechanisms for endocrine resistance and sensitivity to MDM2 inhibition in HR+ /HER2- GATA3mut BC.