Abstract P5-11-08: Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine

Abstract

Abstract Background: CDK4/6 inhibition combined with endocrine therapy is now a standard of care for advanced estrogen receptor (ER) positive breast cancer. Predictive genetic landscape and mechanisms of resistance to CDK4/6 inhibitors have not been described clearly because of limited evidence from clinical samples. We investigated the genetic landscape and mechanisms of resistance to CDK4/6 inhibitors (palbociclib or abemaciclib). Methods: Using driver mutation targeted sequencing, we conducted longitudinal ctDNA analysis in 39 pairs of baseline of primary tumor and end of treatment or monitoring plasma samples. DNA were extracted and the genomic profiles were analyzed based on NGS. Results: In our cohort, the most frequence mutations were PIK3CA (38.5%), TP53(17.9%), CCND1, ZNF703, FGFR1, MAP2K4, RB1, ARID1A, ATRX, DNMT3A. In five paitents harboring RB1 mutations prior to CDK4/6 inhibitor, only one case occured progressing early with 4mos of PFS, and the others were 5.5+, 6.5+, 13.5+, 21+months, it represented different from pre-clinical results that RB1 mutation was associated with resistance to CDK4/6 inhibitor. Interesting, patients with PIK3CA/PTEN/AKT1 mutations (n=15) were likely sensitivity to CDK4/6 inhibitor than those (n=11) with wild type (median PFS: 17 mos vs. 9.5mos, P=0.046). In another cohort of everolimus, new driver mutations emerged in both FGFR1 and ERBB3 at end of everolimus and significantly disappeared in AKT1 mutation. Three patients used palbociclib after progress disease of everolimus, the prognosis were poor with PFS of 1, 6, 9 mos. Evolution of driver gene mutations was uncommon in patients progressing on CDK4/6 inhibitors treatment, but common in patients progressing on everolimus treatment. Conclusions: De novo PIK3CA/PTEN/AKT1 mutations were likely better prognosis biomarkers with the treatment of CDK4/6 inhibitor. RB1 mutation are common and may not contribute to CDK4/6 inhibitor resistance differ from PALOMA3 ctDNA analysis. Our small sample finding indicate it may be a bad stragegy for CDK4/6 inhibitor after progress disease with mTOR inhibitor everolimus. Citation Format: Xu J, Sun T, Wang X. Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-08.