Objective  To systematically review the efficacy and safety of reduced versus standard doses of CDK4/6 inhibitors in patients with HR+/HER2- advanced breast cancer.

Methods  PubMed, Web of Science, Cochrane Library, Embase, CNKI, WanFang Data, VIP, databases were electronically searched to collect randomized controlled trials (RCTs) on HR+/ HER2- advanced breast cancer patients treated with reduction of CDK4/6 inhibitor dose and standard dose from inception to April 1, 2025. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was performed using RevMan 5.1 software.

Results  A total of 14 RCTs involving 4,958 patients were included. The results of Meta-analysis showed that there was no statistically significant difference in PFS [HR=1.01, 95%CI (0.92, 1.11), P=0.81] and OS [HR=0.78, 95%CI (0.52, 1.18), P=0.25] in the dose-reduced group and the standard dose group, while ORR [RR=0.83, 95%CI (0.71, 0.96), P=0.01] and incidence of grade 3 and above neutropenia [RR=0.42, 95%CI (0.21, 0.85), P=0.02] in the dose-reduced group were significantly better than those in the standard dose group.

Conclusions  Current evidence shows that the dose reduction of CDK4/6 inhibitors can considerably reduce the incidence of grade 3 and above neutropenia without affecting PFS and OS.

1.Corona SP, Generali D. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer[J]. Drug Des Devel Ther, 2018, 12: 321-330. DOI: 10.2147/dddt.s137783.

2.Keskinkilic M, Semiz HS, Yavuzsen T, et al. Is the percentage of hormone receptor positivity in HR+/HER2-metastatic breast cancer patients receiving CDK 4/6 inhibitor with endocrine therapy predictive and prognostic?[J]. Front Oncol, 2024, 14: 1378563. DOI: 10.3389/fonc.2024.1378563.

3.Wu S, Xu J, Ma Y, et al. Advances in the mechanism of CDK4/6 inhibitor resistance in HR+/HER2- breast cancer[J]. Ther Adv Med Oncol, 2024, 16: 17588359241282499. DOI: 10.1177/17588359241282499.

4.Hart LL, Im SA, Tolaney SM, et al. Efficacy, safety, and patient-reported outcomes across young to older age groups of patients with HR+/HER2- advanced breast cancer treated with ribociclib plus endocrine therapy in the randomized monaleesa-2,-3, and -7 trials[J]. Eur J Cancer, 2025, 217: 115225. DOI: 10.1016/j.ejca.2025.115225.

5.马艺文, 徐君南, 孙涛. HR阳性HER2低表达晚期乳腺癌治疗研究进展: 2024 ASCO会议乳腺癌研究热点解读 [J]. 肿瘤防治研究, 2025, 52(2): 98-102. [Ma YW, Xu JN, Sun T. Research progress in treatment of HR-Positive/HER 2-low advanced breast cancer: interpretation of breast cancer research hotspots in 2024 ASCO[J]. Cancer Research on Prevention and Treatment, 2025, 52(2): 98-102.] DOI: 10.3971/j.issn.1000-8578.2025.24.1033.

6.吕文杰, 吴萍. 2024年欧洲肿瘤内科学会乳腺癌年会研究进展[J]. 中国肿瘤临床, 2024, 51(11): 572-579. [Lyu WJ, Wu P. Advancements in breast cancer research: insights from the european society for Med-ical oncology breast cancer congress 2024[J]. Chinese Journal of Clinical Oncology, 2024, 51(11): 572-579.] DOI: 10.12354/j.issn.1000-8179.2024.20240629.

7.郑方超, 杜丰, 刘昊琳, 等. 哌柏西利治疗HR+/HER2-乳腺癌新进展[J]. 肿瘤防治研究, 2022, 49(7): 703-708. [Zheng FC, Du F, Liu HL, et al. New progress of palbociclib in the treatment of HR+/HER2- breast cancer[J]. Cancer Prevention and Treatment Research, 2022, 49(7): 703-708.] DOI: 10.3971/j.issn.1000-8578.2022.22.0220.

8.张佳雯, 李琴, 范国荣, 等. CDK4/6抑制剂联合芳香化酶抑制剂类药物用于HR+/HER2-晚期乳腺癌一线治疗的临床综合评价[J]. 中南药学, 2024, 22(1): 246-252. [Zhang JW, Li Q, Fan GR, et al. Clinical comprehensive evaluation of CDK4/6 inhibitors combined with aromatase inhibitors for first-line treatment of HR+/HER2- advanced breast cancer[J]. Central South Pharmacy , 2024, 22(1): 246-252.] DOI: 10.7539/j.issn.1672-2981.2024.01.039.

9.崔宁, 蔡峰, 曹武杰, 等. 哌柏西利联合芳香化酶抑制剂对HR+/HER2-绝经后晚期乳腺癌的疗效及安全性[J]. 中国药物应用与监测, 2024, 21(6): 792-796. [Cui N, Cai F, Cao WJ, et al. Efficacy and safety of palbociclib combined with aromatase inhibitors in advanced HR+/HER2- postmenopausal breast cancer[J]. Chinese Journal of Drug Application and Monitoring, 2024, 21(6): 792-796.] DOI: 10.3969/j.issn.1672-8157. 2024.06.025.

10.张艳贤, 陆颖, 杨慧, 等. CDK4/6抑制剂联合放疗治疗34例晚期乳腺癌的安全性评估[J]. 肿瘤学杂志, 2023, 29(9): 792-795. [Zhang YX, Lu Y, Yang H, et al. Safety assessment of CDK4/6 inhibitors in combination with radiotherapy for 34 cases with advanced breast cancer[J]. Journal of Chinese Oncology, 2023, 29(9): 792-795.] DOI: 10.11735/j.issn.1671-170X.2023.09.B012.

11.周洁余, 顾俊炜, 傅维达, 等. 哌柏西利联合内分泌治疗激素受体阳性晚期乳腺癌的近期疗效与安全性[J]. 浙江医学, 2022, 44(7): 695-701. [Zhou JY, Gu JW, Fu WD, et al. Short-term efficacy and safety of palbociclib in treatment of hormone-receptor-positive advanced breast cancer[J]. Zhejiang Medical Journal, 2022, 44(7): 695-701.] DOI: 10.12056/j.issn.1006-2785.2022.44.7.2021-2622.

12.Bandiera C, Locatelli I, Courlet P, et al. Adherence to the CDK 4/6 inhibitor palbociclib and omission of dose management supported by pharmacometric modelling as part of the optat study[J]. Cancers (Basel), 2023, 15(1): 316. DOI: 10.3390/cancers15010316.

13.钟冰倩. 哌柏西利联合内分泌治疗在真实世界应用中对HR+/HER2-晚期乳腺癌的疗效及安全性[D]. 重庆: 重庆医科大学, 2022. DOI: 10.27674/d.cnki.gcyku.2022.001214.

14.Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and Meta-analyses: the prisma statement[J]. BMJ, 2009, 339: b2535. DOI: 10.1136/bmj.b2535.

15.曾宪涛, Kwong JSW, 田国祥, 等. Meta分析系列之二: Meta分析的软件[J]. 中国循证心血管医学杂志, 2012, 4(2): 89-91. [Zeng XT, Kwong JSW, Tian GX, et al. Meta-analysis series 2: Meta-analysis software[J]. Chinese Journal of Evidence-Based Cardiovascular Medicine, 2012, 4(2): 89-91.] DOI: 10.3969/j.issn.1674-4055.2012.02.002.

16.Zeng X, Zhang Y, Kwong JS, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and Meta-analysis, and clinical practice guideline: a systematic review[J]. J Evid Based Med, 2015, 8(1): 2-10. DOI: 10.1111/jebm.12141.

17.杨娟, 郑青山. Meta分析的统计学方法[J]. 中国临床药理学与治疗学, 2005, 10(11): 1309-1314. [Yang J, Zheng QS. Statistical methods for Meta-analysis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(11): 1309-1314.] DOI: 10.3969/j.issn.1009-2501.2005.11.023.

18.Cardoso F, Jacot W, Kuemmel S, et al. Abstract PD17-12:  Primary efficacy and safety results from the amalee trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2- advanced breast cancer[J]. Cancer Res, 2023, 83(5): Suppl: PD17-12-PD17-12. DOI: 10.1158/1538-7445.sabcs22-pd17-12.

19.Kim SG, Kim MH, Park S, et al. Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor-positive metastatic breast cancer[J]. Cancer Res Treat, 2023, 55(4): 1198-1209. DOI: 10.4143/crt.2022.1543.

20.Fu F, Kano J, Ma J, et al. The impact of real-world alternative dosing strategies of palbociclib on progression-free survival in patients with metastatic breast cancer[J]. Curr Oncol, 2022, 29(3): 1761-1772. DOI: 10.3390/curroncol29030145.

21.Güren AK, Guliyev M, Alan Ö, et al. Evaluation of dose reduction factors and impact on progression-free survival in patients treated with CDK 4/6 inhibitors[J].J Clin Med, 2025, 14(4): 1071. DOI: 10.3390/jcm14041071.

22.Ismail RK, van Breeschoten J, Wouters MWJM, et al. Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer[J]. Breast, 2021, 60: 263-271. DOI: 10.1016/j.breast.2021.11.013.

23.Ji Y, Darstein C, Yang S, et al. Quantitative assessment of ribociclib exposure-response relationship to justify dose regimen in patients with advanced breast cancer[J]. J Clin Pharmacol, 2023, 63(12): 1359-1370. DOI: 10.1002/jcph.2310.

24.Ji Y, Yartsev V, Quinlan M, et al. Justifying ribociclib dose in patients with advanced breast cancer with renal impairment based on pk, safety, and efficacy data: an innovative approach integrating data from a dedicated renal impairment study and oncology clinical trials[J]. Clin Pharmacokinet, 2023, 62(3): 493-504. DOI: 10.1007/s40262-022-01206-2.

25.Kristensen KB, Thomsen IMN, Berg T, et al. Dose modifications of ribociclib and endocrine therapy for treatment of ER+ HER2- metastatic breast cancer[J]. Breast Cancer Res Treat, 2021, 188(3): 799-809. DOI: 10.1007/s10549-021-06215-6.

26.Kubilay Tolunay P, Kurt Inci B, Usta S, et al. Timing of dose reductions and survival outcomes in metastatic breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors[J]. Current Oncology, 2024, 31: 7426-7436. DOI: 10.3390/curroncol31120548.

27.Moftakhar B, Lekkala M, Strawderman M, et al. Impact of early dose intensity reduction of palbociclib on clinical outcomes in patients with hormone-receptor-positive metastatic breast cancer[J]. Breast Cancer Res Treat, 2020, 183(2): 411-418. DOI: 10.1007/s10549-020-05793-1.

28.Burris HA, Chan A, Bardia A, et al. Safety and impact of dose reductions on efficacy in the randomised monaleesa-2,-3 and-7 trials in hormone receptor-positive, her2-negative advanced breast cancer[J]. Br J Cancer, 2021, 125(5): 679-686. DOI: 10.1038/s41416-021-01415-9.

29.Fernández-Cuerva C, Chinchilla-Alarcón T, Alcaraz-Sánchez JJ. Real-world effectiveness of ribociclib in metastatic breast cancer patients: Does dose affect survival?[J]. J Oncol Pharm Pract, 2023, 29(7): 1619-1627. DOI: 10.1177/10781552221144280.

30.Yildirim HC, Kapar C, Koksal B, 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]. J Chemother, 2025, 37(1): 69-75. DOI: 10.1080/1120009X. 2024.2330835.

31.Elnaghi KAEA, Alghanmi HA, Elsamany SA, et al. Hormonal-receptors-positive and HER2-negative patients with metastatic breast cancer treated with first-line palbociclib and hormonal therapy: Impact of first-cycle neutropenia and dose reduction on therapeutic outcome[J]. Breast J, 2023, 2023: 8994954. DOI: 10.1155/2023/8994954.

32.Zhang J, Liu R, Gao S, et al. A phase i dose-escalation and dose-expansion study of tibremciclib, a novel CDK4/6 inhibitor, monotherapy and in combination with fulvestrant in HR-positive/HER2-negative advanced breast cancer[J]. ESMO Open, 2025, 10(6): 105121. DOI: 10.1016/j.esmoop.2025.105121.

33.王蕾, 杨思原, 张季, 等. CDK4/6抑制剂在HR+晚期乳腺癌治疗中的耐药机制及进展后治疗策略[J]. 中南药学, 2024, 22(4): 1030-1036. [Wang L, Yang SY, Zhang J, et al. Mechanism of resistance to CDK4/6 inhibitors in HR+ advanced breast cancer and subsequent treatment strategies[J]. Central South Pharmacy, 2024, 22(4): 1030-1036.] DOI: 10.7539/j.issn.1672-2981.2024.04.031.

34.Wang J, Zhang Q, Sun T, et al. An open-label, single-arm, multicenter, phase Ⅱ trial of bireociclib as monotherapy for heavily pretreated HR-positive, HER2-negative advanced breast cancer patients: BRIGHT-1 trial[J]. Cancer Commun (Lond), 2025, 45(6): 640-653. DOI: 10.1002/cac2.70009.

35.Jain A, Stebbing J. The relationship between response rate and survival benefits in randomized immunotherapy studies[J]. Cancers (Basel), 2025, 17(3): 495. DOI: 10.3390/cancers17030495.

36.刘娜. CDK4/6抑制剂联合内分泌治疗应用于晚期乳腺癌的有效性及安全性临床研究[D]. 呼和浩特: 内蒙古医科大学, 2023. DOI: 10.27231/d.cnki.gnmyc.2023.000015.

37.王旭东, 汪龙, 黄佩文, 等. 细胞周期蛋白依赖性激酶4/6抑制剂致血栓的研究进展[J]. 中国医院药学杂志, 2025, 45(7): 834-839, 844. [Wang XD, Wang L, Huang PW, et al. Research progress in cyclin-dependent kinase 4/6 inhibitors-related thrombosis[J]. Chinese Journal of Hospital Pharmacy, 2025, 45(7): 834-839, 844.] DOI: 10.13286/j.1001-5213.2025.07.16.