First-Line CDK4/6 Inhibitor Outcomes in HER2-Low Versus HER2-Zero Hormone-Receptor-Positive Metastatic Breast Cancer: A Single-Centre Real-World Cohort Study

Background: A CDK4/6 inhibitor plus endocrine therapy is the standard first-line treatment for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. Post hoc analyses of randomised trials have raised the possibility that HER2-low status influences CDK4/6 inhibitor benefit, whereas real-world data are limited. We compared outcomes between patients with HER2-low and HER2-zero disease treated with first-line CDK4/6-inhibitor-based therapy in a real-world cohort. Methods: In this single-centre retrospective cohort study, we identified 137 patients with HR-positive, HER2-negative metastatic breast cancer who received first-line ribociclib or palbociclib plus endocrine therapy between January 2017 and December 2024. HER2-zero was defined as an immunohistochemistry (IHC) score of 0 and HER2-low as IHC 1+ or 2+ without gene amplification. Objective response, progression-free survival (PFS), overall survival (OS), and neutropenia were compared; Cox models were adjusted for recognised prognostic factors. Results: Of 137 patients, 98 (71.5%) had HER2-zero and 39 (28.5%) HER2-low disease; median follow-up was 29.5 months. Objective response rates were 63.9% versus 56.4% (p = 0.44). Median PFS was 31.4 versus 28.5 months (63 events in 134 evaluable patients; log-rank p = 0.70), and median OS was 69.7 months versus not reached (34 deaths in 127 evaluable patients; p = 0.95). Adjusted hazard ratios for HER2-low versus HER2-zero were 1.01 (95% CI 0.57–1.80) for PFS and 1.04 (95% CI 0.49–2.19) for OS. Any-grade and grade ≥3 neutropenia and dose reductions did not differ. Results were consistent across IHC categories (0, 1+, 2+) and in propensity-score-weighted and misclassification bias analyses, all with wide confidence intervals. Conclusions: In this single-centre real-world cohort, response, survival and tolerability of first-line CDK4/6-inhibitor-based therapy did not differ significantly between HER2-low and HER2-zero disease. However, with only 39 HER2-low patients the study was underpowered: it had 80% power to detect only a PFS hazard ratio of approximately 2.2, so clinically relevant differences cannot be excluded. Because all patients received a CDK4/6 inhibitor, these prognostic data cannot show whether HER2-low status modifies the CDK4/6 inhibitor benefit. The findings are hypothesis-generating and require confirmation in larger, adequately powered studies.