Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

QIN Zemin ¹ , YI Fan ¹ , LIU Manxiang ² ,  GUAN Quanlin ² , YUAN Wenzhen ²

1. The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, P.R.China;
2. Department of Oncological Surgery, the First Hospital of Lanzhou University, Lanzhou, 730000, P.R.China;

Corresponding?author：

GUAN Quanlin, Email: guanquanlin@163.com

Keywords：

Advanced breast cancer; CDK4/6 inhibitor; Endocrine therapy; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.201710030

Video：

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ObjectiveTo systematically review the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer.MethodsPubMed, EMBase, The Cochrane Library, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer from inception to October 13^th, 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 4 RCTs involving 2 524 patients were included. The results of meta-analysis showed that: compared with placebo combined with endocrine therapy, CDK4/6 inhibitors combined with endocrine therapy could improve the median progression free survival rate (RR=0.53, 95%CI 0.47 to 0.60, P<0.000 01) and the objective response rate (RR=1.67, 95%CI 1.47 to 1.91,P<0.000 01). While there was no statistical difference in clinical benefit rate (RR=0.59, 95%CI 0.75 to 1.19,P=0.64). In terms of adverse reactions, CDK4/6 inhibitors combined with endocrine therapy had higher rates of neutropenia (RR=49.76, 95%CI 26.85 to 90.21, P<0.000 01), leukopenia (RR=48.69, 95%CI 18.74 to 133.61,P<0.000 01), fatigue (RR=3.11, 95%CI 1.37 to 7.08,P=0.007) and anemia (RR=2.96, 95%CI 1.61 to 5.42, P=0.000 3). There were no significant differences between two groups in nausea, diarrhea and decreased appetite.ConclusionCDK4/6 inhibitors combined with endocrine therapy for the patients with advanced breast cancer can improve median progression free survival and objective response rate, while increase the incidence of adverse events such as neutropenia, leukopenia, fatigue and anemia. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify above conclusion.

Citation： QIN Zemin, YI Fan, LIU Manxiang, GUAN Quanlin, YUAN Wenzhen. Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2018, 18(4): 333-339. doi: 10.7507/1672-2531.201710030 Copy

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2.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
3.	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.
4.	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.
5.	Chlebowski RT. Changing concepts of hormone receptor-positive advanced breast cancer therapy. Clin Breast Cancer, 2013, 13(3): 159-166.
6.	Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer, 2011, 18(3): 333-345.
7.	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.
8.	Ekholm SV, Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol, 2000, 12(6): 676-684.
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11.	Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med, 2015, 373(3): 209-219.
12.	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.
13.	Sledge GW Jr, 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.
14.	Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
15.	Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
16.	王浩, 田超. CDK4/6 抑制劑在乳腺癌治療中的研究進展. 藥品評價, 2017, 14(12): 12-19.
17.	姜秀, 趙文輝. CDK4/6 抑制劑在乳腺癌中的研究進展. 中國腫瘤, 2017, 26(2): 125-129.
18.	Finn RS, Dering J, Conklin D, et al. PD0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res, 2009, 11(5): R77.
19.	O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol, 2016, 13(7): 417-430.
20.	Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res, 2016, 18(1): 17.
21.	Mullard A. FDA approves Novartis’s CDK4/6 inhibitor. Nat Rev Drug Discov, 2017, 16(4): 229.
22.	Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
23.	Prat A, Fan C, Fernández A, et al. Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med, 2015, 13: 303.
24.	Costa R, Costa RB, Talamantes SM, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: palbociclib and ribociclib. Breast, 2017, 35: 1-7.
25.	Hu W, Sung T, Jessen BA, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res, 2016, 22(8): 2000-2008.

1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
3. 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.
4. 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.
5. Chlebowski RT. Changing concepts of hormone receptor-positive advanced breast cancer therapy. Clin Breast Cancer, 2013, 13(3): 159-166.
6. Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer, 2011, 18(3): 333-345.
7. 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.
8. Ekholm SV, Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol, 2000, 12(6): 676-684.
9. Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
10. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med, 2016, 375(20): 1925-1936.
11. Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med, 2015, 373(3): 209-219.
12. 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.
13. Sledge GW Jr, 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.
14. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
15. Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
16. 王浩, 田超. CDK4/6 抑制劑在乳腺癌治療中的研究進展. 藥品評價, 2017, 14(12): 12-19.
17. 姜秀, 趙文輝. CDK4/6 抑制劑在乳腺癌中的研究進展. 中國腫瘤, 2017, 26(2): 125-129.
18. Finn RS, Dering J, Conklin D, et al. PD0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res, 2009, 11(5): R77.
19. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol, 2016, 13(7): 417-430.
20. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res, 2016, 18(1): 17.
21. Mullard A. FDA approves Novartis’s CDK4/6 inhibitor. Nat Rev Drug Discov, 2017, 16(4): 229.
22. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
23. Prat A, Fan C, Fernández A, et al. Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med, 2015, 13: 303.
24. Costa R, Costa RB, Talamantes SM, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: palbociclib and ribociclib. Breast, 2017, 35: 1-7.
25. Hu W, Sung T, Jessen BA, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res, 2016, 22(8): 2000-2008.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer: a meta-analysis

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