Real-World Predictors of Survival in CDK4/6 Inhibitor-Treated Metastatic Breast Cancer: The Significance of ER Expression Level and Treatment Naivety

Objective: CDK4/6 inhibitors are the standard first-line treatment for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, treatment response shows heterogeneity among patients. The objective of this multicentre, retrospective study is to investigate real-world parameters affecting overall survival (OS) in patients receiving CDK4/6 inhibitor therapy, particularly the effect of high oestrogen receptor (ER) expression (≥90%). Methods: A total of 603 HR-positive/HER2-negative MMK patients treated with a CDK4/6 inhibitor (ribociclib or palbociclib) from five centres were retrospectively reviewed. Age, menopausal status, metastatic status, metastatic sites, pathological subtype, HER2 status (low/negative), ER expression level (< 90% vs ≥90%), progesterone receptor (PR) status, and prior endocrine therapy (ET) or chemotherapy (CT) before CDK4/6 inhibitor were evaluated for their impact on OS using univariate and multivariate Cox regression analyses. Results: In the univariate analysis, OS was significantly longer in patients who did not receive ET prior to CDK4/6 inhibitor treatment (median OS: 51.0 months vs. 33.3 months; p< 0.01). OS was also better in patients without liver metastases (50.0 months vs. 34.0 months; p=0.019), those with bone metastases only (57.7 months vs. 40.5 months; p=0.022), and PR-positive patients (50.0 months vs. 36.0 months; p=0.037) also had better OS. OS was numerically longer in patients with ER expression ≥90% compared to those with < 90% (49.0 months vs. 41.0 months; p=0.072). In multivariate analysis, not having received ET prior to CDK4/6 inhibitor therapy (p=0.045) and high ER expression (≥90%) (p=0.031) were independently associated with better OS. Conclusion: Our study demonstrates that HR-positive/HER2-negative MBC patients who are naive to endocrine therapy prior to CDK4/6 inhibitor treatment and have high ER expression (≥90%) in their tumours derive greater OS benefit from this treatment. The ER expression level threshold of ≥90% may be proposed as a potential biomarker for predicting response to CDK4/6 inhibitor therapy. These findings necessitate further prospective studies to improve patient selection.