Абемациклиб – новые возможности терапии гормонопозитивного метастатического рака молочной железы ингибиторами CDК4/6


DOI: https://dx.doi.org/10.18565/pharmateca.2020.7.96-103

Т.Ю. Семиглазова (1, 2), О.А. Волынщикова (1), В.В. Семиглазов (1, 3), В.В. Клименко (1), Н.А. Бриш (1), Ю.В. Алексеева (1), В.А. Клюге (1), А.А. Крутов (1), Р.М. Палтуев (1), Б.С. Каспаров (1), П.В. Криворотько (1, 2), В.Ф. Семиглазов (1, 2)

1) Научный медицинский исследовательский центр онкологии им. Н.Н. Петрова, Санкт-Петербург, Россия; 2) Северо-Западный государственный медицинский университет им. И.И. Мечникова, Санкт-Петербург, Россия; 3) Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Санкт-Петербург, Россия
В обзоре особое внимание уделено абемациклибу – избирательному ингибитору CDK4/6 непрерывного перорального применения с активностью в отношении CDK4 в 14 раз выше, чем в отношении CDK6. Выделена группа больных ЭР+ HER2- метастатическим раком молочной железы (мРМЖ), для которых назначение абемациклиба оптимально. Абемациклиб зарегистрирован в комбинации с эндокринотерапией в качестве первой линии лечения ЭР+ HER2- мРМЖ и после прогрессирования на фоне гормонотерапии. Применение абемациклиба в режиме монотерапии пациенток с ЭР+ HER2- мРМЖ с неблагоприятным прогнозом, получавших интенсивное предшествовавшее лечение, показало обнадеживающую эффективность и удовлетворительную переносимость.
Ключевые слова: HR+ HER2-рак молочной железы, эндокринотерапия, абемациклиб

Литература


1. Gradishar W.J., Anderson B.O., Balassanian R., et al. National Comprehensive Cancer Network. Invasive Breast Cancer Version 1.2016 NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14:324–54. Doi: 10.6004/jnccn.2016.0037.


2. Rugo H.S., Rumble R.B., Barton D.L., et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American society of clinical oncology guideline. J Clin Oncol. 2016;34:3069–103. Doi: 10.1200/JCO.2016.67.1487.


3. Milani A., Geuna E., Mittica G., et al. Overcoming endocrine resistance in metastatic breast cancer: current evidence and future directions. World J Clin. Oncol. 2014;5:990–1001. Doi: 10.5306/wjco.v5.i5.990.


4. Семиглазов В.В., Криворотько П.В., Семиглазов В.Ф.и др. Международные рекомендации по лечению рака молочной железы: руководство для врачей. Под ред. В.Ф. Семиглазова. М.: МК, 2020. 232 с.


5. Sledge G.W. 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: 2875–84. Doi: 10.1200/JCO.2017.73.7585.


6. Goetz M.P., Toi M., Campone M., Sohn J., et al. MONARCH 3: Abemaciclib as Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017;35:3638–46. Doi: 10.1200/JCO.2017.75.6155.


7. Sledge G.W., Toi M., 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;6:116–24. Doi: 10.1001/jamaoncol.2019.4782.


8. Finn R.S., Martin M., Rugo H.S., et al. Palbociclib and letrozole in advanced breast cancer N Engl J Med. 2016;375:1925–36. Doi: 10.1056/NEJMoa1607303.


9. Hortobagyi G.N., Stemmer S.M., Burris H.A., et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48. Doi: 10.1056/NEJMoa1609709.


10. Turner N.C., Ro J., et al. Palbociclib in hormone-receptor-positive advanced breast cancer N Engl J Med. 2015;373:209–19. Doi: 10.1056/NEJMoa1505270.


11. Turner N.C., Slamon D.J., et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926–36. Doi: 10.1056/NEJMoa1810527.


12. Slamon D.J., 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;36:2465–72. Doi: 10.1200/JCO.2018.78.9909.


13. Slamon D.J., Neven P., Chia S., et al.Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2019. Published online Dec 11. Doi: 10.1056/NEJMoa1911149.


14. Tripathy D., Im S.A., 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;19:904–15. Doi: 10.1016/S1470-2045(18)30292-4.


15. Patnaik A., Rosen L.S., Tolaney S.M., 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;6:740–53. Doi: 10.1158/2159-8290.CD-16-0095.


16. Gelbert L.M., Cai S., Lin X., et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32:825–37. Doi: 10.1007/s10637-014-0120-7.


17. Torres-Guzman R., Calsina B., Hermoso A., et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017;8(41):69493–69507. Published online 2017 May 10. Doi: 10.18632/oncotarget.17778.


18. Lukas J., Bartkova J., Bartek J. Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinasepRb-controlled G1 checkpoint. Mol Cell Biol. 1996;16:6917–25. Doi: 10.1128/mcb.16.12.6917.


19. Altucci L., Addeo R., Cicatiello L., et al. 17betaEstradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)- arrested human breast cancer cells. Oncogene. 1996;12:2315–24.


20. Bartkova J., Lukas J., Muller H., et al. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994;57:353–61. Doi: 10.1002/ijc.2910570311.


21. Стенина М.Б. и др. Практические рекомендации по лекарственному лечению инвазивного рака молочной железы. Злокачественные опухоли: Практические рекомендации RUSSCO#3s2. 2019;9:128–63.


22. Butt A.J., Musgrove E.A., Sutherland R.L., et al. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer. 2005;12(suppl 1):S47–S59. DOI: org/10.1677/erc.1.00993.


23. Musgrove E.A., Lee C.S., Buckley M.F., et al. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle Proc Natl Acad Sci USA. 1994;91:8022–26. DOI: 10.1073/pnas.91.17.8022.


24. Nair B.C., Vadlamudi R.K. Regulation of hormonal therapy resistance by cell cycle machinery Gene Ther Mol Biol. 2008;12:395.


25. Thangavel С., Dean J.L., Ertel A., et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer Endocr Relat Cancer. 2011;18:333–45. Doi: 10.1530/ERC-10-0262.


26. Altucci L., Addeo R., Cicatiello L., et al. Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinology. 1997;138:978–84.


27. Geum D., Sun W., Paik S.K., et al. Estrogen-induced cyclin D1 and D3 gene expressions during mouse uterine cell proliferation in vivo: differential induction mechanism of cyclin D1 and D3 Mol Reprod Dev. 1997;46:450–58. Doi: 10.1210/endo.138.3.5002.


28. Roberts P.J., Bisi J.E., Strum J.C., et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012;104:476–87. Doi: 10.1093/jnci/djs002.


29. Malumbres M., Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. Doi: 10.1038/nrc2602.


30. Musgrove E.A., Caldon C.E., Barraclough J., et al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11:558–72. Doi: 10.1038/nrc3090.


31. Lallena M.J., Boehnke K., Torres R., et al. In-vitro characterization of abemaciclib pharmacology in ER+ breast cancer cell lines. Cancer Res. 2015;75(15 suppl; abstract nr 3101). Doi: 10.1158/1538-7445.AM2015-3101.


32. Dickler M.N., Tolaney S.M., Rugo H.S., et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Published September 2017 CCR-17-0754. Doi: 10.1158/1078-0432.CCR-17-0754.


33. Goel S., DeCristo M.J. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548:471–75. Doi: 10.1038/nature23465.


34. Patnaik A., Rosen L.S., Tolaney S.M., et al. LY2835219, a novel cell cycle inhibitor selective for CDK 4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer. J Clin Oncol. 2014;32(suppl):abstr 534.


35. Raub T.J., Wishart G.N., Kulanthaivel P., et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos. 2015;43:1360–71. Doi: 10.1124/dmd.114.062745.


36. Tate S.C., Sykes A.K., Kulanthaivel P., et al. A population pharmacokinentic and pharmacodynamic analysis of abemaciclib in a phase I clinical trial in cancer patients. Clin Pharmacokinet. 2018;57:335–44.


37. Di Leo A., O’Shaughnessy J., Sledge G.W. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. Reprinted from an article originally published online in NPJ Breast Cancer on December 18, 2018. URL: www.nature.com/npjbcancer.


38. van Dam P.A., et al. Neoadjuvant endocrine treatment in early breast cancer: an overlooked alternative? Eur J Surg Oncol. 2016;42:333–42. Doi: 4010.1016/j.ejso.2015.10.015.


39. 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. https://doi.org/10.1038/s41523-018-0097-z.


Об авторах / Для корреспонденции


Автор для связи: Т.Ю. Семиглазова, д.м.н., доцент, зав. отделом – ведущий науч. сотр. научного отдела инновационных методов терапевтической онкологии и реабилитации, НМИЦ онкологии им. Н.Н. Петрова; профессор кафедры онкологии, СЗГМУ им. И.И. Мечникова Санкт-Петербург, Россия; e-mail: tsemiglazova@mail.ru, https://orcid.org/0000-0002-4305-6691 
Адрес: 197758, Россия, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68


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