Расширение возможностей цитотоксического лечения метастатического рака молочной железы с тройным негативным фенотипом

Карабина Е.В., Жукова Л.Г. Расширение возможностей цитотоксического лечения метастатического рака молочной железы с тройным негативным фенотипом. Современная Онкология. 2016; 18 (2): 34–38.

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Karabina E.V., Zhukova L.G. Development of cytotoxic chemotherapy in metastatic breast cancer with a triple-negative phenotype. Journal of Modern Oncology. 2016; 18 (2): 34–38.

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Аннотация

Лечение больных с метастатическими формами тройного негативного фенотипа рака молочной железы (РМЖ) представляет собой наиболее сложную задачу для клиницистов. Оптимальные режимы лекарственной терапии тройного негативного РМЖ (ТН РМЖ) длительное время не были определены. Однако в более поздние периоды были найдены молекулярные точки приложения (6 подтипов ТН РМЖ) для конкретного терапевтического агента и проведено немалое количество исследований и подгрупповых анализов, тестировавших соответствующие препараты при ТН РМЖ. Клеточные линии этих подтипов проявляли разную чувствительность к противоопухолевым препаратам. Результаты дальнейших исследований таргетных препаратов в чистом виде и комбинации с химиопрепаратами при ТН РМЖ, несмотря на молекулярно-генетическую обоснованность их применения, не оправдали ожиданий, хотя продемонстрировали некоторое увеличение показателей выживаемости без прогрессирования и общей выживаемости. Появление в 2010 г. препарата эрибулин (нетаксанового ингибитора активности микротрубочек) значительно расширило возможности терапии у больных метастатическим и местно-распространенным РМЖ. Согласно результатам объединенного анализа рандомизированных исследований III фазы EMBRACE и исследования 301, в который вошли данные о 1864 больных, было продемонстрировано, что эрибулин достоверно увеличивает общую выживаемость по сравнению с другими препаратами в монотерапии в общей популяции и среди пациентов с ТН РМЖ (в подгруппе ТН РМЖ получены наиболее выраженные различия общей выживаемости больных, получавших эрибулин, по сравнению с контрольной группой: 12,9 и 8,2 мес соответственно (относительный риск 0,74, 95% доверительный интервал 0,60–0,92; р=0,006). В данной статье представлен собственный опыт успешного и длительного применения эрибулина у молодой пациентки с ТН фенотипом метастатического РМЖ.

Ключевые слова: тройной негативный фенотип рака молочной железы, метастатический тройной негативный рак молочной железы, эрибулин, таксаны, антрациклины, продолжительность жизни, общая выживаемость.

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Treatment of patients with metastatic breast cancer (BC) with a triple-negative phenotype represents the most difficult challenge for clinicians. The optimal chemotherapy regimens for triple-negative BC (TNBC) have not been determined for a long time. However, in the later periods were found molecular agents of application (6 subtypes of TNBC) for the specific therapeutic agent and were performed many studies and subunit analysis, examined appropriate drugs for TNBC. Cell lines of these subtypes have different anticancer drug sensitivity. The results of further studies of targeted drugs using as monotherapy or in combination with chemotherapy in patients with TNBC, in spite of molecular genetic evidence for their application, have fallen short of expectations, although have shown increase in progression-free survival and overall survival. The development of eribulin (nontaxane microtubule dynamics inhibitor) in 2010 significantly increased the possibility of therapy in patients with locally advanced and metastatic BC who had already received chronic treatment. According to the joint analysis of the randomized phase III EMBRACE trial and Study 301, which included data about 1864 patients, it was demonstrated that eribulin statistically significant improve overall survival compared with other drugs using as monotherapy in the general population and among patients with TNBC [statistically significant differences in overall survival was associated with the subgroup of TNBC in patients who had been treated with eribulin, in comparison with the control arm: 12.9 and 8.2 months, respectively (relative risk 0.74; 95% confidence interval, 0.60 to 0.92, p=0.006)]. This article deals with the own experience of successful and long-term eribulin application in young woman with TN metastatic BC who have had already received chronic treatment.

Key words: breast cancers with a triple-negative phenotype, triple-negative metastatic breast cancer, eribulin, taxanes, anthracyclines, life expectancy, overall survival.

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1. Sorlie T, Perou CM, Tibshirani R et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10869–74.
2. Rakha EA, El-Sayed ME, Green AR et al. Prognostic markers in triple-negative breast cancer. Cancer 2007; 109: 25–32.
3. Haffty BG, Yang Q, Reiss M et al. Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer. J Clin Oncol 2006; 24 (36): 5652–7.
4. Baser O, Wei W, Xie L et al. Retrospective study of patients with metastatic triple- negative breast cancer: survival, health care utilization, and cost. Commun Oncol 2012; 9: 8–14.
5. Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology 2008; 52: 108–18.
6. Lehmann BD, Bauer JA, Chen X et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011; 121: 2750–67.
7. Zhukova L.G., Okruzhnova M.A., Chasovnikova E.O. Eribulin v lechenii metastaticheskogo raka molochnoi zhelezy s troinym negativnym fenotipom. Farmateka. 2014; 17: 1–8. [in Russian]
8. Fan Y, Xu BN, Yuan P et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol 2013; 24 (5): 1219–25.
9. Bhattacharyya GS, Basu S, Agarwal V et al. Single institute phase II study of weekly cisplatinum and metronomic dosing of cyclophosphamide and methotrexate in second line metastatic breast cancer triple-negative. Eur J Cancer 2009.
10. Gluz O, Nitz UA, Harbeck N et al. Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: Results of WSG AM-01 trial. Ann Oncol 2008; 19: 861–70.
11. Frasci G, Comella P, Rinaldo M et al. Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer. Ann. Oncol 2009; 20: 1185–92.
12. Pivot XB, Li RK, Thomas ES et al. Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor 2-negative metastatic breast cancer. Eur J Cancer 2009; 45 (17): 2940–6.
13. Baselga J, Zambetti M, Llombart-Cussac A et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol 2009; 27 (4): 526–34.
14. Mufazalov F.F., Sharipova N.S. Troinoi negativnyi rak molochnoi zhelezy: sovremennoe sostoianie problemy i ne sovsem obychnyi sluchai lecheniia. Zlokachestvennye opukholi. 2014; 1: 19–31. [in Russian]
15. Perou CM. Molecular stratification of triple-negative breast cancer. Oncologist 2011; 16 (Suppl. 1): 61–70.
16. Prat A, Parker JS, Karginova O et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010; 12: R68.
17. Rouzier R, Perou CV, Symmans WF et al. Breast Cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2008; 11: 5678–85.
18. Сarey LA. Directed therapy of subtypes of triple-negative breast cancer. Oncologist 2011; 16 (Suppl 1): 71–8.
19. Cortes J, O‘Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician,s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet 2011; 377: 914–23. doi: 10.1016/S0140-6736 (11)60070-6.
20. Kaufman PA, Cortes J, Awada A et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and taxan. J Clin Oncol 2015; 33 (6): 594–601. doi: 10.1200/JCO. 2013.52.4892.
21. Chris Twelves, Ahmad Awada, Javier Cortes et al. Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate Versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer: Breast Cancer: Basic and Clinical Research 2016: 10; 77–84.
22. Borisov O.V., V'iushkov D.M., Voitsitskii V.E. i soavt. Rol' eribulina v uvelichenii obshchei vyzhivaemosti bol'nykh rakom molochnoi zhelezy: rezoliutsiia po itogam zasedaniia ekspertnogo soveta ekspertov-onkologov Sibirskogo federal'nogo okruga “Odna predshestvuiushchaia liniia khimioterapii: registratsiia Khalavena vo vtoroi linii MRMZh. Klinicheskie dokazatel'stva i preimushchestvo v obshchei vyzhivaemosti” (29 marta 2015 g., Irkutsk). Sib. onkol. zhurn. 2015; 4: 93–9. [in Russian]
23. Twelves C, Cortes J, Vahdat L et al. Efficacy of eribulin in patients with metastatic breast cancer: a pooled analysis by HER2 and ER status. ASCO. 2014; post. 95.
24. Instruktsiia po meditsinskomu primeneniiu preparata Khalaven (RU LP-001782 ot 24.07.2012 (s izmeneniiami ot 25.11.2014)). [in Russian]
25. Yoshida T, Ozava Y, Kimura T et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer 2014; 110: 1497–505. doi:10.1038/bjc.2014.80.

Авторы

Е.В.Карабина*1, Л.Г.Жукова2

1 ГУЗ Тульский областной онкологический диспансер. 300040, Россия, Тула, ул. Плеханова, д. 201а;
2 ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*kev-251@yandex.ru

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E.V.Karabina*1, L.G.Zhukova2

1 Tula Region Oncology Center. 300040, Russian Federation, Tula, ul. Plekhanova, d. 201a;
2 N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*kev-251@yandex.ru

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