Efficacy and safety of CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2‒ breast cancer: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

MU Yujing ¹ , FENG Xue ¹ , KONG Jianda ² , ZUO Ximeng ¹ ,  WANG Tangshun ¹ , SHI Xiaoguang ¹

1. Department of General Surgery, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing 100007, P. R. China;
2. College of Sports Science, Qufu Normal University, Jining 273100, P. R. China;

Corresponding author：

WANG Tangshun, Email: wangtangshun2009@163.com

Keywords：

CDK4/6 inhibitors; Endocrine therapy; HR+/HER2-breast cancer; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202303053

Video：

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Objective To systematically review the efficacy and safety of CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2‒ breast cancer. Methods The PubMed, Cochrane Library, Web of Science, WanFang Data, CNKI, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO) and San Antonio Breast Cancer Symposium (SABCS) databases were electronically searched to collect randomized controlled trials on CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2‒ breast cancer from inception to July 5, 2023. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed using RevMan 5.4 software and Stata 14.0 software. Results A total of 8 studies involving 4 580 patients were included. The results of meta-analysis showed that overall survival and progression-free survival were significantly longer in the combination therapy group than those in the endocrine therapy alone group (HR=0.80, 95%CI 0.73 to 0.89, P<0.05; HR=0.54, 95%CI 0.50 to 0.59, P<0.05). The results also showed that patients in the combination therapy group also had significantly higher rates of objective remission and clinical benefit than those in the endocrine therapy group alone (RR=1.47, 95%CI 1.34 to 1.62, P<0.05; RR=1.20, 95%CI 1.11 to 1.30, P<0.05). In addition, the combination treatment group also increased the incidence of haematological toxicity such as neutropenia and leucopenia, but the differences in the incidence of nausea, diarrhoea and headache were not statistically significant between the two groups. Conclusion The combination of CDK4/6 inhibitors with endocrine therapy for HR+/HER2‒ breast cancer patients improve overall survival, progression-free survival, clinical benefit rate and objective remission rate, with significant long-term and near-term efficacy; however, this regimen increased the incidence of several adverse effects, and clinical use should be considered when considering the occurrence of serious adverse effects.

Citation： MU Yujing, FENG Xue, KONG Jianda, ZUO Ximeng, WANG Tangshun, SHI Xiaoguang. Efficacy and safety of CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2‒ breast cancer: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2024, 24(3): 280-287. doi: 10.7507/1672-2531.202303053 Copy

1.	Sung H, Ferlay J, Siegel RL, 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(3): 209-249.
2.	Harb WA. Management of patients with hormone receptor-positive breast cancer with visceral disease: challenges and treatment options. Cancer Manag Res, 2015, 7: 37-46.
3.	Kim ES, Scott LJ. Palbociclib: a review in HR-positive, HER2-negative, advanced or metastatic breast cancer. Target Oncol, 2017, 12(3): 373-383.
4.	Lobbezoo DJ, van Kampen RJ, Voogd AC, et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat, 2013, 141(3): 507-514.
5.	Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol, 2016, 34(25): 3069-3103.
6.	Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol, 2010, 28(16): 2784-2795.
7.	Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med, 2011, 62: 233-247.
8.	Kalliroi V, Aikaterini B, Maria T, et al. Insulin-like growth factor and epidermal growth factor signaling in breast cancer cell growth: focus on endocrine resistant disease. Analytical Cellular Pathology, 2015, 2015: 975495.
9.	Xu Y, Sun Q. Headway in resistance to endocrine therapy in breast cancer. J Thorac Dis, 2010, 2(3): 171-177.
10.	张帆, 毛大华. CDK4/6抑制剂治疗HR阳性和HER2阴性晚期乳腺癌的作用机制研究进展. 医学综述, 2021, 27(12): 2349-2353.
11.	Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene, 2014, 33(15): 1890-1903.
12.	叶敬文, 刘鷖雯, 何怡青, 等. 乳腺癌内分泌治疗耐药的信号通路研究进展. 医学研究杂志, 2022, 51(11): 9-12, 20.
13.	Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
14.	Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021, 372: n71.
15.	Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
16.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
17.	Turner NC, Slamon DJ, Ro J, et al. Overall survival with Palbociclib and Fulvestrant in advanced breast cancer. N Engl J Med, 2018, 379(20): 1926-1936.
18.	Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med, 2015, 373(3): 209-219.
19.	Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med, 2016, 375(20): 1925-1936.
20.	Finn RS, Boer K, Bondarenko I, et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat, 2020, 183(2): 419-428.
21.	Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with Fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol, 2017, 35(25): 2875-2884.
22.	Sledge GW, Toi M, Neven P, 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(1): 116-124.
23.	Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol, 2018, 29(7): 1541-1547.
24.	Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med, 2016, 375(18): 1738-1748.
25.	Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol, 2015, 16(1): 25-35.
26.	Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of Ribociclib and Fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol, 2018, 36(24): 2465-2472.
27.	Slamon DJ, Neven P, Chia S, et al. Overall survival with Ribociclib plus Fulvestrant in advanced breast cancer. N Engl J Med, 2020, 382(6): 514-524.
28.	Im SA, Lu YS, Bardia A, et al. Overall survival with Ribociclib plus Endocrine therapy in breast cancer. N Engl J Med, 2019, 381(4): 307-316.
29.	Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol, 2018, 19(7): 904-915.
30.	Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol, 2017, 35(32): 3638-3646.
31.	Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol, 2016, 17(4): 425-439.
32.	Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer, 2019, 5: 5.
33.	常春, 王静萱. CDK4/6抑制剂治疗乳腺癌的研究进展. 现代肿瘤医学, 2021, 29(17): 3120-3124.
34.	Schettini F, Giudici F, Giuliano M, et al. Overall survival of CDK4/6-inhibitor-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis. J Natl Cancer Inst, 2020, 112(11): 1089-1097.
35.	Deng Y, Ma G, Li W, et al. CDK4/6 Inhibitors in combination with hormone therapy for HR+/HER2-advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Clin Breast Cancer, 2018, 18(5): e943-e953.
36.	秦泽敏, 易凡, 刘满想, 等. CDK4/6抑制剂联合内分泌治疗晚期乳腺癌有效性和安全性的Meta分析. 中国循证医学杂志, 2018, 18(4): 333-339.
37.	Lin M, Chen Y, Jin Y, et al. Comparative overall survival of CDK4/6 inhibitors plus endocrine therapy vs. endocrine therapy alone for hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer, 2020, 11(24): 7127-7136.
38.	Tian Q, Gao H, Zhou Y, et al. Overall survival and progression-free survival with cyclin-dependent kinase 4/6 inhibitors plus endocrine therapy in breast cancer: an updated meta-analysis of randomized controlled trials. Eur Rev Med Pharmacol Sci, 2021, 25(23): 7252-7267.
39.	Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of Abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov, 2016, 6(7): 740-753.
40.	Vidula N, Rugo HS. Cyclin-dependent kinase 4/6 inhibitors for the treatment of breast cancer: a review of preclinical and clinical data. Clin Breast Cancer, 2016, 16(1): 8-17.
41.	Malumbres M, Sotillo R, Santamaría D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases CDK4 and CDK6. Cell, 2004, 118(4): 493-504.

1. Sung H, Ferlay J, Siegel RL, 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(3): 209-249.
2. Harb WA. Management of patients with hormone receptor-positive breast cancer with visceral disease: challenges and treatment options. Cancer Manag Res, 2015, 7: 37-46.
3. Kim ES, Scott LJ. Palbociclib: a review in HR-positive, HER2-negative, advanced or metastatic breast cancer. Target Oncol, 2017, 12(3): 373-383.
4. Lobbezoo DJ, van Kampen RJ, Voogd AC, et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat, 2013, 141(3): 507-514.
5. Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol, 2016, 34(25): 3069-3103.
6. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol, 2010, 28(16): 2784-2795.
7. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med, 2011, 62: 233-247.
8. Kalliroi V, Aikaterini B, Maria T, et al. Insulin-like growth factor and epidermal growth factor signaling in breast cancer cell growth: focus on endocrine resistant disease. Analytical Cellular Pathology, 2015, 2015: 975495.
9. Xu Y, Sun Q. Headway in resistance to endocrine therapy in breast cancer. J Thorac Dis, 2010, 2(3): 171-177.
10. 张帆, 毛大华. CDK4/6抑制剂治疗HR阳性和HER2阴性晚期乳腺癌的作用机制研究进展. 医学综述, 2021, 27(12): 2349-2353.
11. Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene, 2014, 33(15): 1890-1903.
12. 叶敬文, 刘鷖雯, 何怡青, 等. 乳腺癌内分泌治疗耐药的信号通路研究进展. 医学研究杂志, 2022, 51(11): 9-12, 20.
13. Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
14. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021, 372: n71.
15. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
16. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
17. Turner NC, Slamon DJ, Ro J, et al. Overall survival with Palbociclib and Fulvestrant in advanced breast cancer. N Engl J Med, 2018, 379(20): 1926-1936.
18. Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med, 2015, 373(3): 209-219.
19. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med, 2016, 375(20): 1925-1936.
20. Finn RS, Boer K, Bondarenko I, et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat, 2020, 183(2): 419-428.
21. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with Fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol, 2017, 35(25): 2875-2884.
22. Sledge GW, Toi M, Neven P, 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(1): 116-124.
23. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol, 2018, 29(7): 1541-1547.
24. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med, 2016, 375(18): 1738-1748.
25. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol, 2015, 16(1): 25-35.
26. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of Ribociclib and Fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol, 2018, 36(24): 2465-2472.
27. Slamon DJ, Neven P, Chia S, et al. Overall survival with Ribociclib plus Fulvestrant in advanced breast cancer. N Engl J Med, 2020, 382(6): 514-524.
28. Im SA, Lu YS, Bardia A, et al. Overall survival with Ribociclib plus Endocrine therapy in breast cancer. N Engl J Med, 2019, 381(4): 307-316.
29. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol, 2018, 19(7): 904-915.
30. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol, 2017, 35(32): 3638-3646.
31. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol, 2016, 17(4): 425-439.
32. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer, 2019, 5: 5.
33. 常春, 王静萱. CDK4/6抑制剂治疗乳腺癌的研究进展. 现代肿瘤医学, 2021, 29(17): 3120-3124.
34. Schettini F, Giudici F, Giuliano M, et al. Overall survival of CDK4/6-inhibitor-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis. J Natl Cancer Inst, 2020, 112(11): 1089-1097.
35. Deng Y, Ma G, Li W, et al. CDK4/6 Inhibitors in combination with hormone therapy for HR+/HER2-advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Clin Breast Cancer, 2018, 18(5): e943-e953.
36. 秦泽敏, 易凡, 刘满想, 等. CDK4/6抑制剂联合内分泌治疗晚期乳腺癌有效性和安全性的Meta分析. 中国循证医学杂志, 2018, 18(4): 333-339.
37. Lin M, Chen Y, Jin Y, et al. Comparative overall survival of CDK4/6 inhibitors plus endocrine therapy vs. endocrine therapy alone for hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer, 2020, 11(24): 7127-7136.
38. Tian Q, Gao H, Zhou Y, et al. Overall survival and progression-free survival with cyclin-dependent kinase 4/6 inhibitors plus endocrine therapy in breast cancer: an updated meta-analysis of randomized controlled trials. Eur Rev Med Pharmacol Sci, 2021, 25(23): 7252-7267.
39. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of Abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov, 2016, 6(7): 740-753.
40. Vidula N, Rugo HS. Cyclin-dependent kinase 4/6 inhibitors for the treatment of breast cancer: a review of preclinical and clinical data. Clin Breast Cancer, 2016, 16(1): 8-17.
41. Malumbres M, Sotillo R, Santamaría D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases CDK4 and CDK6. Cell, 2004, 118(4): 493-504.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2‒ breast cancer: a meta-analysis

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