Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience

Abstract

CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment (p = 0.047), whereas the luminal B subtype was more prevalent (p = 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS (p = 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly (p = 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03–7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression.

Ki67 and progesterone receptor status predicts sensitivity to palbociclib: a real-world study

“…Meanwhile, Ki67 value was not indicated to be a prognostic factor for response to CDK4/6i in a series of prospective trials. Only 1 retrospective study reported that PFS was negatively affected by elevated Ki67 values (22). The key challenge in Ki67 research is the poor interlaboratory assay reproducibility due to the diversity in diagnosis kits and platforms being used.…”

“…Also, retinoblastoma protein (Rb)-negative cases have been shown to have high Ki67 levels (21). In addition, Palleschi et al (22) revealed that the progressionfree survival (PFS) of patients with CDK4/6i and endocrine therapy was inversely related to Ki67 expression, but not to PR. Thus, studies concerning the predictive significance of Ki67 and PR for CDK4/6i are rare and controversial.…”

Evaluating the Response of Palbociclib on Progression-Free Survival in Hormone Receptor-Positive Metastatic Breast Cancer

“…Similarly, in the monarchE trial the authors found that high Ki67 levels (Ki67 ≥20%) showed benefit of abemaciclib and ET in the adjuvant setting for ER-positive, HER2- negative early-stage BC with high-risk features [17]. Although much effort has been exerted in the adjuvant setting, the prognostic benefit of Ki67 and PR expression to predict palbociclib efficacy in the metastatic setting is still not clear despite discussion in the literature [1, 4, 5]. Palleschi et al [1] showed that Ki67 can predict CDK4/6i + ET efficacy in metastatic BC but PR expression failed to show any benefit.…”

“…Palbociclib is the first selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6i) and is widely used for HR+ metastatic BC. Following the success of palbociclib, CDK4/6i in combination with ET has become the standard therapy [1].…”

“…Although no single biomarker currently established is a gold standard, estrogen receptor (ER)/PR receptor status and Ki67 is the most widely used assessment technique because of its convenience and availability. PR expression and Ki67 index have been discussed in multiple studies as prognostic biomarkers for PFS [1,[4][5][6]. Thus, the use of surrogate biomarker to predict clinical outcome provides a greater opportunity in clinical decision-making.…”