Optimal integration of CDK4/6 inhibitors for treatment of hormone receptor-positive metastatic breast cancer


  • D.Ye. Ryspayeva Hospital of Israeli Oncology “LISOD”, Kyiv, Ukraine, Ukraine




metastatic breast cancer, CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, endocrine therapy, hormone resistance


The paper analyzes the effectiveness of a new class of medications — CDK4/6 cyclin-dependent kinases inhibitors and discover the mechanism of its action. The article describes the general results of studies on palbociclib, ribociclib and abemaciclib* for the first- and subsequent-line of the therapy of HR-positive/HER2-negative metastatic breast cancer. The profile of adverse events of approved CDK4/6 inhibitors are considered. The combination of CDK4/6 inhibitors with endocrine therapy was shown to have benefits in survival, potentiality to reduce hormone resistance and great perspectives to improve clinical results of hormone receptor-positive metastatic breast cancer.


Siegel R.L., Miller K.D., Jemal A. Cancer Statistics, 2017. CA Cancer J. Clin. 2017. 67(1). 7-30.

Федоренко З.П. та ін. Бюлетень Національного канцер-реєстру України «Рак в Україні, 2017–2018». Київ, 2019.

Nadji M. et al. Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers. Am. J. Clin. Pathol. 2005. 123(1). 21-7.

Li C.I., Daling J.R., Malone K.E. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J. Clin. Oncol. 2003. 21(1). 28-34.

Hess K.R. et al. Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res. Treat. 2003. 78(1). 105-18.

Dickson M.A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res. 2014. 20(13). 3379-83.

DeMichele A., Chodosh L.A. “Braking” the Cycle of Resistance in Endocrine Therapy for Breast Cancer. Clin. Cancer Res. 2015. 21(22). 4999-5001.

Finn R.S. 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.

Hortobagyi G.N. et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N. Engl. J. Med. 2016. 375(18). 1738-1748.

Goetz M.P. et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J. Clin. Oncol. 2017. 35(32). 3638-3646.

Baker S.J., Reddy E.P. CDK4: A Key Player in the Cell Cycle, Development, and Cancer. Genes Cancer. 2012. 3(11–12). 658-69.

Infante J.R. et al. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin. Cancer Res. 2016. 22(23). 5696-5705.

Hamilton E., Infante J.R. Targeting CDK4/6 in patients with cancer. Cancer Treat. Rev. 2016. 45. 129-38.

Murphy C.G., Dickler M.N. The Role of CDK4/6 Inhibition in Breast Cancer. Oncologist. 2015. 20(5). 483-90.

Shapiro G.I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 2006. 24(11). 1770-83.

Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res. Treat. 2017. 166(1). 41-54.

Ingham M., Schwartz G.K. Cell-Cycle Therapeutics Come of Age. J. Clin. Oncol. 2017. 35(25). 2949-2959.

DeMichele A. et al. CDK4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin. Cancer Res. 2015. 21(5). 995-1001.

Finn R.S. et al. PD 0332991, 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.

Finn R.S. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2016. 375(20). 1925-1936.

Rugo H.S. et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res. Treat. 2019. 174(3). 719-729.

Hortobagyi G.N. 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.

Johnston S. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019. 5. 5.

Rossi V. et al. Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials. Cancers (Basel). 2019. 11(11).

Cristofanilli M. 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.

Sledge G.W. 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.

Slamon D.J. 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.

Turner N.C. et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2018. 379(20). 1926-1936.

Sledg G.W. 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. 2019.

Slamon D.J. et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2020. 382(6). 514-524.

Di Leo A. et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 2010. 28(30). 4594-600.

Chia S. et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J. Clin. Oncol. 2008. 26(10). 1664-70.

Cardoso F. et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann. Oncol. 2018. 29(8). 1634-1657.

Baselga J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012. 366(6). 520-9.

André F. et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 2019. 380(20). 1929-1940.

Hamilton E.P. et al. A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2(-) Advanced Breast Cancer. Clinical Cancer Research. 2018. 24(15). 3510-3518.

Curigliano G. et al. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER plus), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) with progression on endocrine therapy (ET). Cancer Research. 2019. 79(4). 3.

Dees E.C. et al. Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal wo­men with ER+/HER2-locally advanced or metastatic breast cancer (ABC). Annals of Oncology. 2019. 30. 121.

Giuliano M. et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019. 20(10). 1360-1369.

Verma S. et al. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3). Oncologist. 2016. 21(10). 1165-1175.

Spring L.M. et al. Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations. Oncologist. 2017. 22(9). 1039-1048.

Hu W. et al. Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies. Clin. Cancer Res. 2016. 22(8). 2000-8.

Sammons S.L., Topping D.L., Blackwell K.L. HR+, HER2- Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles. Curr. Cancer Drug. Targets. 2017. 17(7). 637-649.

Rugo H.S. et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J. Clin. Oncol. 2016. 34(25). 3069-103.

ClinicalTrials.gov., Study comparing two different schedules of Palbociclib plus second line endocrine therapy in women with estrogen receptor positive, HER2 negative advanced/metastatic breast cancer. 2016, Available at https://clinicaltrials.gov/ ct2/show/NCT02630693. Accessed April 25, 2016.

Im S.A. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N. Engl. J. Med. 2019. 381(4). 307-316.

Administration, U.F.a.D., FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. 2019.

Barroso-Sousa R., Shapiro G.I., Tolaney S.M. Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Breast Care (Basel). 2016. 11(3). 167-73.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer version 2, 2020.

Gao J.J. et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020. 21(2). 250-260.

Turner N.C. et al. Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases. Ann. Oncol. 2018. 29(3). 669-680.