Hormone receptor expression and ribociclib activity in hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer

Abstract

In the randomized, placebo-controlled, phase 3 MONALESSA-2 trial, in patients with hormone receptor positive (HR+) [the estrogen receptor (ER) and/or progesterone receptor (PR)] and human epidermal growth factor 2 receptor negative (HER2-) advanced breast cancer (BC), progression-free survival (PFS) was significantly longer among those receiving ribociclib [cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor] plus letrozole compared to patients receiving placebo plus letrozole. Additionally, ER+/PR+ cohort demonstrated higher hazard ratio for PFS than ER+/PR- cohort (0.62 vs. 0.36). Evidence from cell-line models suggests that PR signaling is tightly linked to cell-cycle regulation in terms of inhibition of CDK 4/6 activity when exposed to progestin. A possible explanation of this finding may be that high PR expression could interfere with ribociclib activity on the cyclin-kinase level. Furthermore, it is questionable whether PR level determines the efficacy of ribociclib administration with higher levels of this receptor being predictive of ribociclib inefficacy. Considering the safety profile of ribociclib, it’s necessary to perform analysis of PFS among ER+/PR+ patients receiving ribociclib, to potentially assess the cut-off value of PR expression (or ER/PR ratio) as a predictive marker of CDK4/6 efficacy.