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Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Cancers Manuscript
Authors Jin Sun Lee, Susan E. Yost, Sierra Min Li, Yujie Cui, Paul H. Frankel, Yate-Ching Yuan, Daniel Schmolze, Colt A. Egelston, Weihua Guo, Mireya Murga, Helen Chang, Linda Bosserman, and Yuan Yuan

The mechanisms of intrinsic and acquired resistance to CDK4/6 inhibitors are poorly understood. Patients with HR+ MBC treated with CDK4/6i and antiestrogen therapy were grouped into early (<6 months), intermediate (6–24 months for 0–1 lines; 6–9 months for ≥2 lines), or late progressors (>24 months for 0–1 lines; >9 months PFS for ≥2 lines). Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed association with PFS (p-value < 0.15 and HR ≥ 1.5 or HR < 0.5). RNAseq was analyzed for 24/109 (22%) patients with 0–1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). Genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.