Эффективность и переносимость абемациклиба у пожилых больных

Пожилые онкологические пациенты представляют собой гетерогенную популяцию не только по хронологическому возрасту, но и по функциональному статусу, сопутствующим заболеваниям и терапии, гериатрическим синдромам и, как следствие, по переносимости онкологического лечения. Выбор лечения метастатического рака молочной железы (мРМЖ) у этой категории пациентов зачастую является сложной задачей для онкологов. Появление нового класса препаратов – ингибиторов циклинзависимых киназ 4/6 (CDK4/6) – изменило парадигму лечения пациентов с люминальным HER2-негативным мРМЖ (ЭР+ HER2мРМЖ), однако данные по эффективности и переносимости этих препаратов у пожилых больных ограниченны. Как показали объединенные подгрупповые анализы исследований с CDK4/6, пожилые пациентки с ЭР+ HER2РМЖ имеют несомненный выигрыш в ВБП от добавления таргетных препаратов к гормонотерапии. Нежелательные явления наблюдаются чаще на комбинированной терапии с увеличением возраста, что требует модификации доз и соответствующей терапии. В этом плане весьма привлекателен препарат абемациклиб, характеризующийся более низкой по сравнению с другими CDK4/6ингибиторами частотой нейтропении, но более высокой диареей, которая может контролироваться приемом соответствующих препаратов и не является поводом для полной отмены лечения. Безусловно, при принятии решения о назначении любой терапии пожилым онкологическим пациентам необходим их тщательный отбор. Только комплексный мультидисциплинарный подход позволит максимально индивидуализировать лечение этой непростой категории пациентов и минимизировать вероятность получения ими избыточного или недостаточного онкологического лечения.

1. Smith B.D., Smith G.L., Hurria A., Hortobagyi G.N., Buchholz T.A. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758–2765. doi: 10.1200/JCO.2008.20.8983.

2. Bastiaannet E., Liefers G.J., de Craen A.J., Kuppen P.J., van de Water W., Portielje J.E. et al. Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast Cancer Res Treat. 2010;124(3):801–807. doi: 10.1007/s10549-010-0898-8.

3. van de Water W., Markopoulos C., van de Velde C.J., Seynaeve C., Hasenburg A., Rea D. et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA. 2012;307(6):590–597. doi: 10.1001/jama.2012.84.

4. Bastiaannet E., Portielje J.E., van de Velde C.J., de Craen A.J., van der Velde S., Kuppen P.J. et al. Lack of survival gain for elderly women with breast cancer. Oncologist. 2011;16(4):415–423. doi: 10.1634/theoncologist.2010-0234.

5. Bouchardy C., Rapiti E., Blagojevic S., Vlastos A.T., Vlastos G. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol. 2007;25(14):1858–1869. doi: 10.1200/JCO.2006.10.4208.

6. Schonberg M.A., Marcantonio E.R., Ngo L., Li D., Silliman R.A., McCarthy E.P. Causes of death and relative survival of older women after a breast cancer diagnosis. J Clin Oncol. 2011;29(12):1570–1577. doi: 10.1200/JCO.2010.33.0472.

7. Yancik R., Wesley M.N., Ries L.A. Havlik R.J., Edwards B.K., Yates J.W. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA. 2001;285(7):885–892. doi: 10.1001/jama.285.7.885.

8. Allemani C., Storm H., Voogd A.C., Holli K., Izarzugaza I., Torrella-Ramos A. et al. Variation in ‘standard care’ for breast cancer across Europe: a EUROCARE-3 high resolution study. Eur J Cancer. 2010;46(9):1528–1536. doi: 10.1016/j.ejca.2010.02.016.

9. Lavelle K., Moran A., Howell A., Bundred N., Campbell M., Todd C. Older women with operable breast cancer are less likely to have surgery. Br J Surg. 2007;94(10):1209–1215. doi: 10.1002/bjs.5834.

10. Giordano S.H., Hortobagyi G.N., Kau S.W., Theriault R.L., Bondy M.L. Breast cancer treatment guidelines in older women. J Clin Oncol. 2005;23(4):783–791. doi: 10.1200/JCO.2005.04.175.

11. Markopoulos C., van de Water W., Putter H., Seynaeve C., Hasenburg A., Rea D. et al. 5015 ORAL Age Specific Competing Mortality in Breast Cancer Patients -a TEAM Study Analysis. Eur J Cancer. 2011;47(1 Suppl.):S334. doi: 10.1016/S0959-8049(11)71457-5.

12. Zulman D.M., Sussman J.B., Chen X., Cigolle C.T., Blaum C.S., Hayward R.A. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med. 2011;26(7):783–790. doi: 10.1007/s11606-010-1629-x.

13. Lewis J.H., Kilgore M.L., Goldman D.P., Trimble E.L., Kaplan R., Montello M.J. et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21(7):1383–1389. doi: 10.1200/JCO.2003.08.010.

14. Singh H., Kanapuru B., Smith C., Fashoyin-Aje L., Myers A., Kim G., Pazdur R. FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: a 10-year experience by the U.S. Food and Drug Administration. J Clin Oncol. 2017;35(15):10009–10009. doi: 10.1200/ JCO.2017.35.15_suppl.10009.

15. Markopoulos C., van de Water W. Older patients with breast cancer: is there bias in the treatment they receive? Ther Adv Med Oncol. 2012;4(6):321–327. doi: 10.1177/1758834012455684.

16. Fusco D., Allocca E., Villani R., Franza L., Laudisio A., Colloca G. An update in breast cancer management for elderly patients. Translational Cancer Research. 2018;7(3):319–328. doi: 10.21037/tcr.2018.03.21.

17. Girre V., Falcou M., Gisselbrecht M., Gridel G., Mosseri V., Bouleuc C. et al. Does a geriatric oncology consultation modify the cancer treatment plan for elderly patients? J Gerontol A Biol Sci Med Sci. 2008;63(7):724–730. doi: 10.1093/gerona/63.7.724.

18. Onitilo A.A., Engel J.M., Greenlee R.T., Mukesh B.N. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7(1–2):4–13. doi: 10.3121/ cmr.2009.825.

19. Hirama T., Koeffler Н.Р. Role of the Cyclin-Dependent Kinase Inhibitors in the Development of Cancer. Blood. 1995;86(3):841–854. Available at: https://pubmed.ncbi.nlm.nih.gov/7620180.

20. Fry D., Harvey P.J., Keller P.R., Elliott W.L., Meade M., Trachet E. et al. Specific Inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–1437. Available at: https://pubmed.ncbi.nlm.nih.gov/15542782.

21. Choi Y.J., Anders L. Signaling through cyclin D-dependent kinases. Oncogene. 2014;33:1890–1903. doi: 10.1038/onc.2013.137.

22. MLA style: The Nobel Prize in Physiology or Medicine 2001. NobelPrize.org. Nobel Media AB 2020. Available at: http://www.nobelprize.org/nobel_priz- es/medicine/laureates/2001/?google_referrer=mail.ru.

23. Finn R.S., Dering J., Conklin D., Kalous O., Cohen D.J., Desai A.J. 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. doi: 10.1186/bcr2419.

24. Lamb R., Lehn S., Rogerson L., Clarke R.B., Landberg G. Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity. Cell Cycle. 2013;12(15):2384–2394. doi: 10.4161/cc.25403.

25. Im S.A., Lu Y.S., Bardia A., Harbeck N., Colleoni M., Franke F. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019;381(4):307–316. doi: 10.1056/NEJMoa1903765.

26. Slamon D.J., Neven P., Chia S., Fasching P.A., De Laurentiis M., Im S.A. et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382(6):514–524. doi: 10.1056/NEJMoa1911149.

27. Slamon D.J., Neven P., Chia S., Fasching P.A., De Laurentiis M., Im S.A. 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. doi: 10.1200/JCO.2018.78.9909.

28. Sledge G.W.Jr., Toi M., Neven P., Sohn J., Inoue K., Pivot X. et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone ReceptorPositive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019;6(1):116–124. doi: 10.1001/jamaoncol.2019.4782.

29. Sledge G.W. Jr., Toi M., Neven P., Sohn J., Inoue K., Pivot X. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35(25):2875–2884. doi: 10.1200/JCO.2017.73.7585.

30. Tripathy D., Im S.A., Colleoni M., Franke F., Bardia A., Harbeck N. 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. doi: 10.1016/ S1470-2045(18)30292-4.

31. Finn R.S., Martin M., Rugo H.S., Jones S., Im S.A., Gelmon K. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925–1936. doi: 10.1056/NEJMoa1607303.

32. Rugo H.S., Finn R.S., Diéras V., Ettl J., Lipatov O., Joy A.A. 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. doi: 10.1007/s10549-018-05125-4.

33. Johnston S., Martin M., Di Leo A., Im S.A., Awada A., Forrester T. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi: 10.1038/ s41523-018-0097-z.

34. Cristofanilli M., Turner N.C., Bondarenko I., Ro J., Im S.A., Masuda N. 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. doi: 10.1016/S1470-2045(15)00613-0.

35. Cardoso F., Paluch-Shimon S., Senkus E., Curigliano G., Aapro M.S., André F. et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020. doi: 10.1016/j.annonc.2020.09.010.

36. Knudsen E.S., Witkiewicz A.K. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3(1):39–55. doi: 10.1016/j.trecan.2016.11.006.

37. Battisti N.M.L., De Glas N., Sedrak M.S., Loh K.P., Liposits G., Soto-Perezde-Celis E. et al. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. Ther Adv Med Oncol. 2018;10:1758835918809610. doi: 10.1177/1758835918809610.

38. Howie L.J., Singh H., Bloomquist E., Wedam S., Amiri-Kordestani L., Tang S. et al. Outcomes of Older Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis. J Clin Oncol. 2019;37(36):3475–3483. doi: 10.1200/ JCO.18.02217.

39. Tolaney S., Lam A., Mukundan S., Nanda S., Cox J., Barriga S. Abstract P6-15-01: Analysis of renal function in MONARCH 1: A phase 2 study of abemaciclib, a CDK4 & 6 inhibitor, as monotherapy, in patients with HR+/HER2breast cancer, after chemotherapy for metastatic breast cancer (MBC). Cancer Res. 2017;77(4 Suppl.):P6-15-01-P6-15-01. doi: 10.1158/1538-7445. SABCS16-P6-15-01.

40. Beauchamp R.D., Sheng H.M., Shao J.Y., Thompson E.A., Ko T.C. Intestinal cell cycle regulations. Interactions of cyclin D1, Cdk4, and p21Cip1. Ann Surg. 1996;223(5):620–627. doi: 10.1097/00000658-199605000-00018.

41. Goetz M.P., Okera M., Wildiers H., Campone M., Grischke E., Manso L. et al. Abstract P1-19-10: Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials. Cancer Res. 2020;80(4 Suppl.). doi: 10.1158/1538-7445.