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Purpose <p><i>GATA3</i> 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 <i>GATA3</i><sup>mut</sup> HR+ BC. The <i>GATA3</i> co-mutational landscape has been described only in primary BC tissue, and the mechanism of MDM2-driven efficacy is incompletely understood.</p> Experimental design <p>Circulating tumor DNA (ctDNA) was assessed for <i>GATA3</i> 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.</p> Results <p>Among 609 patients with HR + /HER2− MBC, ctDNA&#xa0;detected non-synonymous <i>GATA3</i> variants ctDNA in 69 (11%) patients, and the genomic landscape was unique from tissue-based primary BC data; <i>GATA3</i><sup>mut</sup> were not mutually exclusive from <i>TP53</i><sup>mut</sup> (<i>p</i> = 0.30) or <i>PIK3CA</i><sup>mut</sup> (<i>p</i> = 0.52) and were associated with poorer survival on endocrine monotherapy. CPTAC analysis showed no difference in <i>GATA3</i> or breast cancer-associated gene abundance, however there was increased USP48 (LogFC = 0.76, FDR = 1.7 × 10<sup>–5</sup>), which stabilizes MDM2.</p> Conclusion <p>The distinct landscape in <i>GATA3</i><sup>mut</sup> MBC ctDNA highlights critical information when assessing candidacy for targeted therapies. To our knowledge, this is the first ctDNA-based <i>GATA3</i><sup>mut</sup> landscape analysis in MBC. Furthermore, tissue-based proteomic analysis suggests mechanisms for endocrine resistance and sensitivity to MDM2 inhibition in HR+ /HER2− <i>GATA3</i><sup>mut</sup> BC.</p>

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Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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  • Arielle J. Medford,
  • Marko Velimirovic,
  • Yifat Gefen,
  • Andrzej Niemierko,
  • Lorenzo Gerratana,
  • Andrew A. Davis,
  • Katherine Clifton,
  • Jennifer Keenan,
  • Emily Podany,
  • Whitney L. Hensing,
  • Carolina Reduzzi,
  • Charles S. Dai,
  • Lesli A. Kiedrowski,
  • Laura M. Spring,
  • Leif W. Ellisen,
  • Robert C. Doebele,
  • Massimo Cristofanilli,
  • Gad Getz,
  • Aditya Bardia

摘要

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.