Endocrine Therapy versus Chemotherapy After CDK4/6 Inhibitor Progression in HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Study from Turkey

Can Cangür,1 Büşra Bülbül,1 Irem Turgut Yeğen,1 Bekir Ucun,1 Orhan önder Eren,1 Hamit Başaran,2 Atike Pınar Erdoğan,3 Ece Şahin Hafızoğlu,3 Erhan Gökmen,4 Oğuzcan Özkan,4 Murat Araz,5 Ahmet Oruç,5 Cengiz Yilmaz,6 Gürkan Gül,6 Serkan Yildirim1 1Department of Medical Oncology, Selcuk University, Konya, Turkey; 2Department of Radiation Oncology, Selcuk University, Konya, Turkey; 3Department of Medical Oncology, Celal Bayar University, Manisa, Turkey; 4Department of Medical Oncology, Ege University, İzmir, Turkey; 5Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey; 6Department of Medical Oncology, Izmir City Hospital, İzmir, TurkeyCorrespondence: Can Cangür, Department of Medical Oncology, Selcuk University, Konya, Turkey, Tel +90 535 3469301, Email [email protected]: HR (hormone receptor)-positive, HER2 (Human Epidermal Growth Factor Receptor 2)-negative metastatic breast cancer represents the majority of advanced breast cancer cases. Although CDK4/6 (cyclin-dependent kinase) inhibitors combined with endocrine therapy have become the standard first-line approach, the optimal treatment strategy after disease progression remains unclear.Methods: We conducted a multicenter retrospective study of 218 patients treated across five tertiary oncology centers in Turkey who progressed on CDK4/6 inhibitors and subsequently received either endocrine therapy (ET) or chemotherapy (CT).Results: Endocrine therapy, administered in 65 patients—most commonly with everolimus-based combinations—was associated with a significantly longer overall survival (OS) compared with CT (18.0 vs 10.0 months, p = 0.011). While progression-free survival (PFS) showed a numerical advantage for ET (6.0 vs 4.9 months), the difference did not reach statistical significance. Multivariate analysis confirmed both treatment type and de novo metastatic presentation as independent predictors of survival.Conclusion: These findings demonstrate that, in real-world clinical practice, continued endocrine therapy beyond CDK4/6 inhibitors progression yields superior survival compared to chemotherapy, particularly in patients with de novo metastatic disease. Our results support the prioritization of endocrine-based approaches over chemotherapy in this setting and underscore the urgent need for prospective trials to refine treatment sequencing strategies for this large patient population.Plain Language Summary: Hormone receptor-positive, HER2-negative metastatic breast cancer is the most common subtype of advanced breast cancer, yet the best treatment strategy after progression on CDK4/6 inhibitors remains uncertain. Many patients are switched directly to chemotherapy, which is often associated with limited benefit and significant toxicity. In this large multicenter study from Turkey, we compared endocrine therapy with chemotherapy in women whose disease progressed after CDK4/6 inhibitors. We found that patients who continued endocrine therapy, particularly with mTOR-based combinations, lived significantly longer than those who received chemotherapy. Importantly, patients who presented with de novo metastatic disease also had better survival. These findings highlight that chemotherapy may not always be the best option after CDK4/6 inhibitor failure and support the continued use of endocrine-based strategies. Our results provide real-world evidence that could influence clinical decision-making and guide the design of future prospective trials.Keywords: metastatic breast cancer, CDK4/6 inhibitor, endocrine therapy, chemotherapy, overall survival