Insights into Effects of Adjuvant CDK4/6 Inhibitors in Breast Cancer

Each of the three available CDK4/6 inhibitors has uniformly improved outcomes in patients with ER-positive metastatic breast cancer. By extension, use of these agents in the setting of high-risk ER-positive, early-stage breast cancer would be predicted to similarly confer benefit in terms of reducing the risk of recurrence. Yet to date, only abemaciclib has been shown to confer such benefit, in the MonarchE trial. Three recent studies provide new findings about the effects of CDK4/6 inhibitors.

Researchers present updated results from the MonarchE trial, including an analysis of the subset of patients with high Ki-67. In the Monarch-E trial, 5637 patients with ER-positive, HER2-negative breast cancer were randomized to endocrine therapy alone for ≥5 years or endocrine therapy plus abemaciclib for 2 years. Two groups of patients were eligible: cohort 1 had ≥4 positive axillary lymph nodes (ALN) or 1 to 3 positive ALN and either grade 3 disease or primary tumor ≥5 cm; cohort 2 had 1 to 3 positive ALN and Ki-67 ≥20%. The primary endpoint was invasive disease-free survival (iDFS) across both cohorts.

During a median follow-up of 27 months, the abemaciclib group had a 5.4% absolute improvement in 3-year iDFS and a 4.2% absolute improvement in distant relapse-free survival (DRFS). In the subset of patients with high Ki-67, the absolute improvement in 3-year iDFS was 6.0% and in DRFS was 4.0%.

In contrast, results from the PALLAS trial of adjuvant palbociclib lead to a different conclusion. A similar population of 5796 high-risk, ER-positive, HER2-negative patients with early-stage breast cancer were randomized to endocrine therapy for ≥5 years or endocrine therapy plus palbociclib for 2 years. During a median follow-up of 31 months, the primary endpoint of iDFS was not statistically different between the two groups. The secondary endpoints of invasive breast cancer–free survival, DRFS, locoregional recurrence-free survival, and overall survival also did not differ between groups.

Recent studies of biomarkers in the neoadjuvant setting may offer some clues as to why particular patients do or do not benefit from the addition of a CDK4/6 inhibitor in any setting. In the PALLET trial, 307 patients with ER-positive/HER2-negative, early-stage breast cancer were randomly assigned to one of four regimens: neoadjuvant letrozole for 14 weeks; letrozole for 2 weeks, then letrozole and palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole and palbociclib to 14 weeks; or letrozole and palbociclib for 14 weeks. Biopsies were performed at baseline, 2 weeks, 14 weeks, and at surgery. The effect of the different treatment regimens was assessed at different time points with respect to Ki-67, ER, PgR, CCNE1 and CCND1 status.

Patients with high CCNE1 levels responded less well to letrozole and palbociclib than those with low CCNE1 levels. CCNE1 is a downstream node in the CDK4/6 signaling pathway and can enhance cell cycling independent of CCND1 and CDK4/6. Additionally, in those samples where Ki-67 was not completely suppressed (complete cell-cycle arrest = Ki-67 <2.7%), recovery was observed 3 to 9 days after discontinuing palbociclib. These findings suggest that the typical palbociclib schedule of 3 weeks on, 1 week off may lead to loss of suppression of tumor cell cycling.