CDK4/6i in the Underrepresented Histological Subtypes of HR±/HER2- Metastatic Breast Cancer: A Real-World Cohort Study of Effectiveness and Safety

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Background Metastatic (m) HR-positive/HER2-negative special-type breast cancers (STBC) exhibits distinct biological behaviors compared with no special-type BC (NSTBC), yet their management is largely extrapolated from trials dominated by NSTBC. To improve understanding of real-world (rw) clinical outcomes, this study evaluated the effectiveness of CDK4/6 inhibitors (i) specifically in patients with mSTBC, providing clinical relevant insights into their therapeutic impact. Patients and Methods This retrospective cohort study included patients with mSTBC treated with first- or second-line CDK4/6i plus endocrine therapy (ET). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were estimated using the Kaplan–Meier method, and differences between subgroups were evaluated using log-rank tests. Results From April 2016 to December 2024, 181 patients received CDK4/6i-based therapy. Median rwPFS was 18.2 months (95% CI, 16–22.1) and median rwOS was 58.1 months (95% CI, 49.4–77.4). A statistically significant difference in rwOS was observed between patients treated with aromatase inhibitors + CDK4/6i vs fulvestrant + CDK4/6i (77.4 vs. 42.4 months; unadjusted HR = 2.2; p = 0.002). No other subgroup analyses demonstrated statistically significant differences. Common adverse events included neutropenia, anemia, and diarrhea; 32% of patients required dose reductions, which did not adversely affect survival outcomes. Following CDK4/6i progression, overall rwPFS2 was 29.7 months (95% CI, 25.9–32.2). Chemotherapy was the most frequently used post-CDK4/6i treatment, while ET combined with an mTOR-inhibitor provided the longest rwPFS2. Conclusion CDK4/6i represent a safe and effective therapeutic option for mSTBC. Nevertheless, dedicated studies and tailored treatment strategies are warranted to optimize post-CDK4/6i treatment in these subgroups. Micro Abstract Background: Patients with HR+/HER2- metastatic special type breast cancer (mSTBC) are frequently underrepresented in CDK4/6 inhibitor (CDK4/6i) registration trials. Given that STBC exhibits distinct biological pathways for dissemination compared to no special type (NST) tumors, real-world evidence is required to validate current therapeutic paradigms. This study evaluated the clinical effectiveness and safety of CDK4/6i specifically within the mSTBC population. Patients and Methods: This retrospective, single-center cohort study analyzed patients with mSTBC receiving first- or second-line CDK4/6i plus endocrine therapy (ET) between 2016 and 2024. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (rwOS). Secondary endpoints included the impact of dose reductions and evaluation of subsequent lines of therapy (rwPFS2). Results: Among 181 patients, the median rwPFS was 18.2 months (95% CI, 16.0–22.1) and median rwOS was 58.1 months (95% CI, 49.4–77.4). Notably, patients treated with aromatase inhibitors (AI) + CDK4/6i demonstrated a significantly superior rwOS compared to those receiving fulvestrant + CDK4/6i (77.4 vs. 42.4 months; HR = 2.2; p = 0.002). Dose reductions were required in 32% of the cohort due to adverse events (neutropenia, anemia, diarrhea); however, dose modification did not compromise survival outcomes (p > 0.05). Following progression, the median rwPFS2 was 29.7 months. While chemotherapy was the most common subsequent treatment, ET combined with an mTOR inhibitor yielded the longest rwPFS2. Conclusion: These data provide robust real-world evidence that CDK4/6i are highly effective in mSTBC, with survival outcomes comparable to those seen in NST populations. The finding that dose reductions do not mitigate efficacy supports proactive toxicity management. Furthermore, the superiority of AI-based combinations and the efficacy of post-progression mTOR inhibition suggest specific sequencing strategies for this distinct clinical subgroup.

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