Abstract
The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting.
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References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science. 2002;298:1912–34.
Roskoski R. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res. 2016;107:249–75.
Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenom Pers Med. 2014;7:203–15.
https://clinicaltrials.gov. Accessed Oct 2017.
Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat. 2017;166:41–54. https://doi.org/10.1007/s10549-017-4385-3 (Epub 24 Jul 2017).
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;16:25–35.
Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.
Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor–positive advanced breast cancer. N Engl J Med. 2015;373:209–19.
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;17:425–39.
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48.
Tripathy D, Sohn J, Im S-A, et al. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. 2017 San Antonio Breast Cancer Symposium (abstract GS2-05). http://www.ascopost.com/News/58328. Accessed 22 Dec 2017.
Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875–84. https://doi.org/10.1200/JCO.2017.73.7585 (Epub 3 Jun 2017).
Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017. https://doi.org/10.1200/JCO.2017.75.6155.
Walker AJ, Wedam S, Amiri-Kordestani L, et al. FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016;22:4968–72.
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm578081.htm. Accessed 29 Oct 2017.
Gerdes J, Lemke H, Baisch H, et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.
Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.
Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11:951s–958s.
Ellis MJ, Coop A, Singh B, et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res. 2003;63:6523–31.
Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastozole for clinical stage 2 or 3 estrogen receptor positive breast cancer. Clin Cancer Res. 2017;23:4055–65.
Curigliano G, Gómes Pardo P, Meric-Bernstam F, et al. Ribociclib plus letrozole in early breast cancer: a presurgical, window-of-opportunity study. Breast. 2016;28:191–8.
Hurvitz S, Abad MF, Rostorfer R, et al. Interim results from neoMONARCH: a neoadjuvant phase II study of abemaciclib in postmenopausal women with HR+/HER2-breast cancer (BC). Abstract LBA13. Ann Oncol. 2016;27(6):1–36. https://doi.org/10.1093/annonc/mdw435.
Hurvitz S, Martin M, Abad MF, et al. Biological effects of abemaciclib in a phase 2 neoadjuvant study for premenopausal patients with HR+, HER2- breast cancer. In: 2016 San Antonio Breast Cancer Symposium, San Antonio, 6–10 Dec, abstract S4-06.
Arnedos M, Cheaib B, Bayar MA, et al. Anti-proliferative response and predictive biomarkers to palbociclib in early breast cancer: the preoperative palbociclib (POP) randomized trial (abstract). In: Proceedings of the 107th annual meeting of the American Association for Cancer Research, New Orleans, 16–20 Apr 2016. AACR, Philadelphia; Cancer Res 2016;76(14 Suppl):Abstract nr CT041.
Dowsett M, Bundred NJ, Decensi A, et al. Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer Epidemiol Biomark Prev. 2001;10:961–6.
Guix M, Granja Nde M, Meszoely I, et al. Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. J Clin Oncol. 2008;26:897–906.
Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res. 2001;61:6739–46.
Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100:1380–8.
Ellis MJ, Suman VJ, Goncalves, et al. Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: results from the American College of Surgeons Oncology Group Z1031 trial (alliance). J Clin Oncol. 2017;35:1061–9.
Bagegni N, Thomas S, Liu N, et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res. 2017;19:123. https://doi.org/10.1186/s13058-017-0913-7.
Chow LWC, Lam C-K, Loo WTY. OOTR-N007: a phase II neoadjuvant study of letrozole plus palbociclib in postmenopausal patients with ER positive, HER2 negative breast cancer (abstract). In: Proceedings of the thirty-seventh annual CTRC-AACR San Antonio breast cancer symposium, San Antonio, 9–13 Dec 2014; AACR, Philadelphia. Cancer Res 2015; 75(9 Suppl):abstract nr P6-11-04.
Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018. https://doi.org/10.1016/S1470-2045(18)30001-9.
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Kwapisz, D. Cyclin-dependent kinase 4/6 inhibitors in hormone receptor-positive early breast cancer: preliminary results and ongoing studies. Breast Cancer 25, 506–516 (2018). https://doi.org/10.1007/s12282-018-0864-6
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DOI: https://doi.org/10.1007/s12282-018-0864-6