A Genomic Alteration in GATA3 Affects Treatment Responses with a CDK4/6 Inhibitor Collaborating with p18INK4C Expression in Advanced Breast Carcinoma.

Abstract

Cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with endocrine therapy benefits patients with hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2)-negative breast carcinomas. However, most tumors develop resistance to CDK4/6i during the course of therapy. Although preclinical studies have proposed molecular mechanisms for the resistance, predictive markers are yet to be discovered. We investigated the tumor molecular profiling in 42 patients with advanced stage breast carcinoma who received CDK4/6i therapy. The tumors carrying a GATA3 gene mutation, mainly a frameshift variant, showed a better treatment response compared to other tumors. Furthermore, we explored the potential underlining mechanism of this association. To that end, nuclear expression of p18, one of the INK family proteins, was found to be positively associated with the GATA3 mutation, as well as a CDK4/6i treatment response. Therefore, our study suggests that a GATA3 gene mutation, collaborating with p18 protein expression in tumor nuclei, may have a predictive value for CDK4/6i therapy in breast carcinoma.