HR Pozitif/HER2 Negatif Metastatik Meme Kanserinde CDK4/6 İnhibitörlerinin Gerçek Yaşam Sonuçları: Türkiye’den Tek Merkezli Bir Kohort

Öz

Amaç: Hormon reseptör pozitif/human epidermal growth factor reseptör 2 negatif (HR+/HER2-) metastatik meme kanserinde (MMK) endokrin tedavi (ET) ile kombinasyon halinde siklin bağımlı kinaz 4/6 inhibitörleri (CDK4/6i) birinci basamak standart tedavidir; ancak Türkiye’den gerçek yaşam verileri sınırlıdır. Bu çalışmada CDK4/6i-ET’nin farklı tedavi basamaklarındaki etkinlik ve güvenlilik sonuçları ile birinci basamakta palbosiklib-letrozol ve ribosiklib-letrozol rejimlerinin sonuçları araştırıldı. Gereç ve Yöntemler: Bu tek merkezli, retrospektif kohort çalışmasına, rutin pratikte palbosiklib veya ribosiklib ile ET (letrozol veya fulvestrant) kombine edilerek tedavi edilen ardışık HR+/HER2– MMK’li erişkin hastalar dahil edildi. Birincil sonlanım noktası progresyonsuz sağkalım (PFS) idi. İkincil sonlanım noktaları genel sağkalım (OS), objektif yanıt oranı (OYO), klinik yarar oranı (KYO; KR+KY+SD ≥24 hafta) ve güvenlilikti. Sağkalım Kaplan–Meier yöntemi ile hesaplandı, log-rank testi ve tek değişkenli Cox modelleri ile karşılaştırıldı. Keşifsel analizlerde tedavi basamağına (1., 2., ≥3. basamak) göre sonuçlar ve birinci basamakta palbosiklib-letrozol ile ribosiklib-letrozol karşılaştırıldı. Bulgular: Toplam 124 hasta dahil edildi; CDK4/6i-ET birinci, ikinci ve ≥üçüncü basamakta sırasıyla %65,3, %19,4 ve %15,3 oranında kullanıldı. Toplam 51 hastada (%41,1) progresyon ve 19 hastada (%15,3) ölüm izlendi. Birinci, ikinci ve ≥üçüncü basamakta 12 aylık PFS oranları sırasıyla %82,7, %69,9 ve %42,1 idi; birinci basamağa kıyasla progresyon veya ölüm riski ikinci basamakta daha yüksek bulundu (HR 2,20; %95 GA 1,09–4,46) ve ≥üçüncü basamakta daha da belirgindi (HR 4,71; %95 GA 2,45–9,05). 12 aylık OS oranları sırasıyla %93,4, %86,5 ve %83,6 olup, ≥üçüncü basamakta ölüm riski anlamlı derecede artmıştı (HR 3,88; %95 GA 1,41–10,71). OYO %37,9, KYO %87,9 idi. Birinci basamak aromataz inhibitörü alt grubunda, palbosiklib-letrozol ile ribosiklib-letrozol arasında PFS (HR 0,77; %95 GA 0,43–1,39; p=0,392) ve OS (HR 0,83; %95 GA 0,20–3,47; p=0,797) açısından istatistiksel olarak anlamlı fark saptanmadı. En az bir advers olay hastaların %85,4’ünde görüldü; derece ≥3 nötropeni oranı %42,7 iken toksisiteye bağlı kalıcı tedavi kesilmesi nadirdi (%2,4). Sonuç: Bu gerçek yaşam kohortunda CDK4/6i-ET, faz III çalışmalara uyumlu bir güvenlilik profili ile klinik olarak anlamlı hastalık kontrolü sağlamıştır. CDK4/6 inhibitörlerinin daha erken basamakta kullanılması daha uzun PFS ve OS ile ilişkili bulunurken, birinci basamaktaki rejim-düzeyindeki karşılaştırmalar palbosiklib-letrozol ile ribosiklib-letrozol arasında anlamlı fark göstermemiş ve keşifsel olarak yorumlanmalıdır. Bulgularımız, HR+/HER2– MMK’de CDK4/6i-ET’nin erken dönemde tedaviye entegre edilmesini ve rejim seçiminin komorbiditeler, izlem gereksinimleri ve hasta tercihine göre bireyselleştirilmesini desteklemektedir.

Anahtar Kelimeler

• Metastatik meme kanseri
• Hormon reseptör pozitif/HER2 negatif
• CDK4/6 inhibitörü
• Palbosiklib
• Ribosiklib
• Gerçek yaşam verisi
• Progressyonsuz sağkalım; Genel sağkalım.

Real-world outcomes of CDK4/6 inhibitors in HR-positive/HER2- negative metastatic breast cancer: a single-center cohort from Turkey

Öz

Aim: Endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard first-line treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC); however, real-world data from routine practice in Türkiye remain limited. We evaluated the effectiveness and safety of CDK4/6i-ET across treatment lines and explored first-line outcomes with palbociclib–letrozole versus ribociclib–letrozole. Material and Methods: This single-center, retrospective cohort study included consecutive adults with HR+/HER2–MBC treated with palbociclib or ribociclib plus ET (letrozole or fulvestrant) in routine practice. The primary endpoint was progression-free survival (PFS), the and secondary endpoints were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR: CR+PR+SD ≥24 weeks), and safety. Survival was estimated using Kaplan–Meier methods and compared with log-rank tests and univariable Cox models. Exploratory analyses examined outcomes by treatment line (first, second, and ≥third) and compared first-line palbociclib–letrozole with ribociclib–letrozole. Results: A total of 124 patients were included; CDK4/6i-ET was administered as first-, second-, and ≥ third-line therapyin 65.3%, 19.4%, and 15.3% of patients, respectively. Overall, 51 patients (41.1%) experienced disease progression, and 19 (15.3%) died. Twelve-month PFS rates were 82.7%, 69.9%, and 42.1% in the first-, second-, and ≥third-line groups, respectively; the risk of progression or death was higher in the second line (HR 2.20, 95% CI 1.09–4.46) and ≥third line (HR 4.71, 95% CI 2.45–9.05) than in the first line. Twelve-month OS rates were 93.4%, 86.5%, and 83.6%, with a significantly higher hazard of death in the ≥third line (HR 3.88, 95% CI 1.41–10.71) compared with the first line. The ORR was 37.9%, and the CBR was 87.9%. In the first-line aromatase inhibitor subset, no statistically significant differences were observed between palbociclib–letrozole and ribociclib–letrozole for PFS (HR 0.77, 95% CI 0.43–1.39; p=0.392) or OS (HR 0.83, 95% CI 0.20–3.47; p=0.797). At least one adverse event occurred in 85.4% of patients; grade ≥3 neutropenia occurred in 42.7% of patients, while permanent discontinuation due to toxicity was infrequent (2.4%). Conclusion: In this real-world cohort, CDK4/6i-ET achieved clinically meaningful disease control with a safety profile consistent with pivotal trials. The earlier introduction of CDK4/6 inhibition was associated with longer PFS and OS, whereas exploratory first-line comparisons did not demonstrate a significant difference between palbociclib and letrozole and ribociclib–letrozole. These findings support the early incorporation of CDK4/6i-ET in HR+/HER2– MBC and the individualized choice of regimen based on comorbidities, monitoring requirements, and patient preference.

Anahtar Kelimeler

• metastatic breast cancer
• HR-positive/HER2-negative
• CDK4/6 inhibitor
• palbociclib
• ribociclib
• real-world data
• progression-free survival
• overall survival

Etik Beyan

Approved by the Memorial Antalya Hospital Clinical Research Ethics Committee (Approval No. 848/2025, Date: 20.10.2025).

Kaynakça

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
2. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022;386:942–50.
3. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382:514–24.
4. Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, et al. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022;28:851–9.
5. Slamon DJ, Diéras V, Rugo HS, Harbeck N, Im SA, Gelmon KA, et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol. 2024;42:994–1000.
6. Sledge GW Jr., Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2020;6:116–24.
7. Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32:1475–95.
8. Burstein HJ, Somerfield MR, Barton DL, Dorris A, Fallowfield LJ, Jain D, et al. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021;39:3959–77.

9. Harbeck N, Brufsky A, Rose CG, Korytowsky B, Chen C, Tantakoun K, et al. Real-world effectiveness of CDK4/6i in first-line treatment of HR+/HER2- advanced/metastatic breast cancer: updated systematic review. Front Oncol. 2025;15:1530391.
10. Gehrchen ML, Berg T, Garly R, Jensen MB, Eßer-Naumann S, Rønlev JD, et al. Real-world effectiveness of CDK 4/6 inhibitors in estrogen-positive metastatic breast cancer. BJC Rep. 2024;2:44.
11. Rugo HS, Layman RM, Lynce F, Liu X, Li B, McRoy L, et al. Comparative overall survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR+/HER2- metastatic breast cancer in the US real-world setting. ESMO Open. 2025;10:104103.
12. Stanciu IM, Parosanu AI, Nitipir C. An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials. Biomolecules. 2023;13:1422.
13. Murad B, Reis PCA, Deberaldini Marinho A, Marin Comini AC, Pinheiro Xavier D, Mella Soares Pessoa B, et al. QTc prolongation across CDK4/6 inhibitors: a systematic review and meta-analysis of randomized controlled trials. JNCI Cancer Spectr. 2024;8:pkae078.
14. Kim JH. Profiling the Cardiovascular Toxicities of CDK4/6 Inhibitors: A Real-World Pharmacovigilance Study. Cancers (Basel). 2024;16:2869.
15. Lin W, Zeng Y, Weng L, Yang J, Zhuang W. Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA's adverse event reporting system: a case control pharmacovigilance study. BMC Pharmacol Toxicol. 2024;25:47.
16. Demir A, Mandel NM, Paydas S, Demir G, Er Ö, Turhal NS, et al. Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive/HER2-negative Advanced Breast Cancer: Retrospective Multicenter Trial. Balkan Med J. 2020;37:104–7.
17. Yildirim HC, Kapar C, Koksal B, Seyyar M, Sanci PC, Guliyev M, et al. Efficacy of first-line CDK 4-6 inhibitors in premenopausal patients with metastatic breast cancer and the effect of dose reduction due to treatment-related neutropenia on efficacy: a Turkish Oncology Group (TOG) study. J Chemother. 2025;37:69–75.
18. Beypınar İ, Demir H, Yaslıkaya Ş, Köşeci T, Demir B, Çolak G, et al. Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study. Breast Cancer Res Treat. 2024;208:597–604.