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Эверолимус: новые перспективы терапии гормонопозитивного рака молочной железы
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Аннотация
mTOR – ключевой сигнальный белок сигнального пути PI3K/Akt, блокада которого приводит к подавлению пролиферации клеток и повышает чувствительность опухолевой клетки к лекарственному и лучевому воздействию. Доля активирующих мутаций PI3K при раке молочной железы (РМЖ) достигает 40%, что свидетельствует о ее важности в канцерогенезе при данной патологии. Активация mTOR сигнального пути – ключевой адаптивный механизм развития резистентности к эндокринной терапии при РМЖ, а использование ингибиторов mTOR может восстанавливать чувствительность опухоли к эндокринной терапии. Эверолимус – избирательный ингибитор mTOR, нарушающий трансляцию кодируемых мРНК основных протеинов, участвующих в регуляции клеточного цикла, гликолиза и адаптации клеток к гипоксии. Эффективность и безопасность эверолимуса в лечении гормонопозитивного РМЖ изучена в крупных рандомизированных исследованиях. В исследовании TAMRAD показана высокая эффективность и хорошая переносимость комбинации тамоксифена с эверолимусом у пациенток с ER(+)HER2(-) РМЖ, резистентным к терапии ингибиторами ароматазы: клиническая эффективность комбинации значительно превысила таковую при монотерапии тамоксифеном (61% vs 42%), особенно у пациенток с вторичной гормонорезистентностью (74% vs 48%). Использование эверолимуса существенно увеличило время до прогрессирования болезни – 8,6 мес vs 4,5 мес и снизило риск дальнейшего прогрессирования на 46% для всех больных и на 54% – для пациенток с вторичной резистентностью к ингибиторам ароматазы. Исследование BOLERO-2 показало высокую эффективность использования комбинации эверолимуса и экземестана при ER(+)HER2(-) распространенном РМЖ, у пациенток в постменопаузе, предлеченных ингибиторами ароматазы. Показано убедительное увеличение медианы безрецидивной выживаемости (БРВ) при использовании эверолимуса. Важным является факт снижения риска дальнейшего прогрессирования распространенного процесса у пациенток, принимающих эверолимус: с висцеральными метастазами на 53%, без висцеральных метастазов на 59%. Исследование J.Baselga и соавт. показало еще одно перспективное направление использования эверолимуса – неоадъювантную терапию гормонопозитивного РМЖ. Препарат показал высокую клиническую эффективность, подтвержденную данными морфологического исследования опухоли.
Ключевые слова: сигнальный путь PI3K/Akt, резистентность к эндокринной терапии при РМЖ, ингибиторы mTOR, эверолимус, распространенный гормонопозитивный РМЖ.
Ключевые слова: сигнальный путь PI3K/Akt, резистентность к эндокринной терапии при РМЖ, ингибиторы mTOR, эверолимус, распространенный гормонопозитивный РМЖ.
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mTOR is a key signaling protein in the PI3K/Akt signaling pathway whose blockage results in inhibition of cell proliferation and enhances the susceptibility of a tumor cell to drugs and radiation. The proportion of P13K mutations in breast cancer (BC) amounts up to 40%, which is suggestive of its importance in carcinogenesis in this pathology. Activation of the mTOR signaling pathway is a key adaptive mechanism for the development of resistance to endocrine therapy in BC and the use of mTOR inhibitors may restore tumor susceptibility to endocrine therapy. Everolimus is a selective mTOR inhibitor that impairs translation of the mRNAs coding for the major proteins involved in the regulation of a cellular cycle, glycolysis, and hypoxic adaptation. The efficacy and safety of everolimus in the treatment of hormone-positive BC have been investigated in large-scale randomized trials. The TAMRAD trial has shown that a combination of tamoxifen and everolimus is highly effective and well tolerated in patients with ER(+)HER2(-) BC-resistant to therapy with aromatase inhibitors: the clinical efficacy of the combination far exceeds that of tamoxifen monotherapy (61% vs 42%) particularly in patients with secondary hormone resistance (74% vs 48%). The use of everolimus considerably increased time to disease progression (8,6 months vs 4,5 months) and reduced the risk of further progression by 46% for all the patients and by 54% for patients with secondary resistance to aromatase inhibitors. The BOLERO-2 trial has indicated that a combination of everolimus and exemestane is highly effective in disseminated ER(+)HER2(-) BC, in postmenopausal patients pretreated with aromatase inhibitors. The use of everolimus showed a convincing increase in median relapse-free survival. The fact that the risk of further progression of the disseminated process reduces in everolimus-treated patients with and without visceral metastases by 53 and 59%, respectively, is of importance. The investigation conducted by J.Baselga et al demonstrated another promising area for the use of everolimus – neoadjuvant therapy for hormone-positive BC. The drug displayed a high clinical efficacy as evidenced by a tumor morphological study.
Key words: PI3K/Akt signaling pathway, resistance to endocrine therapy in breast cancer, mTOR inhibitors, everolimus, disseminated hormone-positive breast cancer.
Полный текст
Список литературы
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2. Cheng HT, Hung WC. Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells. Oncol Rep 2012; 14.
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7. O’Reilly T, Vaxelaire J, Muller M et al. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res 2002; 43: 71. Abstr. 359.
8. Stoica GE, Franke TF, Wellstein A et al. Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol 2003; 17: 818–30.
9. Ellard S, Gelmon KA, Chia S et al. A randomized phase II study of two different schedules of RAD001C in patients with recurrent/metastatic breast cancer. J Clin Oncol 2007; 25: 141s. Abstr. 3513.
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11. Motzer RJ, Escudier BJ, Ouard S et al. RAD001 plus best supportive care (BSC) vs BSC plus placebo in patients with metastatic renal cell carcinoma (RCC) that has progressed on VEGFr-TKI therapy. Results from a randomized, double-blind, multicenter phase III study. J Clin Oncol 2008; 26: 256s. Abstr. LBA5026.
12. Vogelzang NJ, Bhor M, Liu Z et al. Everolimus vs temsirolimus for advanced renal cell carcinoma: use and use of resources in the US Oncology Network. Clin Genitour Canc 2012; 11 (12): 1558–7673.
13. Dong LX, Sun LL, Zhang X et al. Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells. Acta Pharmacol Sin 2012.
14. Isakoff SJ, Engelman JA, Irie HY et al. Breast cancer associated PI3KCA mutations are oncogenic in mammary epithelial cells. Cancer Res 2006; 65: 10 992–11 000.
15. Kurokawa H, Lenferink AE, Simpson JF et al. Inhibition of HER2/neu (erbB-2) and mitogenactivated protein kinases enhances tamoxifen action against HER-2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000; 60: 5887–94.
16. Kurokawa H, Arteaga CL. ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 2003; 9: 511–5s.
17. Stoica GE, Franke TF, Wellstein A et al. Heregulin-b1 regulates the estrogen receptor-gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene 2003; 22: 2073–87.
18. Perez-Tenorio G, Stal O. Activation of Akt/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002; 86: 540–5.
19. Tokunaga E, Kataoka A, Kimura Y et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006; 42: 629–35.
20 Yue W, Fan P, Wang J et al. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 2007; 106: 102–10.
21 Miller TW, Hennessy BT, Gonzalez-Angulo AM et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010; 120: 2406–13.
22 Santen RJ, Song RX, Zhang Z et al. Adaptive hypersensitivity to estrogen. Mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. J Steroid Biochem Mol Biol 2005; 95: 155–65.
23 Lane HA, Wood JM, McSheehy PM et al. MTOR inhibitor RAD001 (Everolimus) has antiangio-genic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 2009; 15: 1612–22.
24. Bachelot Th, Bourgier C, Cropet C et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors. A GINECO Study. J Clin Oncol 2012; 30 (22): 2718–24.
25. Beck TJ, Rugo HS, Howard A et al. BOLERO-2: health-related quality-of-life in metastatic breast cancer patients treated with everolimus and exemestane vs exemestane. Abstr. ASCO 2012.
26 Piccart M, Baselga J, Noguchi S et al. Poster P6-04-02 final progression-free survival analysis of BOLERO-2. A phase III trial of everolimus for postmenopausal women with advanced breast cancer. San Antonio Breast Cancer Sympos 2012; 4–8.
27. Rugo HS, Pritchard KI, Gnant M et al. Everolimus (EVE) for postmenopausal women with advanced breast cancer (ABC) refractory to Letrozole or Anastrozole: long-term efficacy and safety results of the BOLERO-2 trial. Abstr. 253. 8th European Breast Cancer Conference. Vienna, Austria 2012.
28. Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus Letrozole compared with placebo plus Letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27 (16): 2630–7.
2. Cheng HT, Hung WC. Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells. Oncol Rep 2012; 14.
3. Harquail J, Benzina S, Robichaud GA. MicroRNAs and breast cancer malignancy. An overview of miRNA-regulated cancer processes leading to metastasis. Cancer Biomark 2012; 1.
4. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumor cell growth. Nature 2006; 441: 424–30.
5. Cheng JQ, Lindsley CW, Cheng GZ et al. The Akt/PKB pathway. Molecular target for cancer drug discovery. Oncogene 2005; 24: 7482–92.
6. Tanaka C, O’Reilly T, Kovarik JM et al. Identifying optimal biologic doses of Everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26: 1596–602.
7. O’Reilly T, Vaxelaire J, Muller M et al. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res 2002; 43: 71. Abstr. 359.
8. Stoica GE, Franke TF, Wellstein A et al. Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol 2003; 17: 818–30.
9. Ellard S, Gelmon KA, Chia S et al. A randomized phase II study of two different schedules of RAD001C in patients with recurrent/metastatic breast cancer. J Clin Oncol 2007; 25: 141s. Abstr. 3513.
10. Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrin Metab 2007; 21: 163–72.
11. Motzer RJ, Escudier BJ, Ouard S et al. RAD001 plus best supportive care (BSC) vs BSC plus placebo in patients with metastatic renal cell carcinoma (RCC) that has progressed on VEGFr-TKI therapy. Results from a randomized, double-blind, multicenter phase III study. J Clin Oncol 2008; 26: 256s. Abstr. LBA5026.
12. Vogelzang NJ, Bhor M, Liu Z et al. Everolimus vs temsirolimus for advanced renal cell carcinoma: use and use of resources in the US Oncology Network. Clin Genitour Canc 2012; 11 (12): 1558–7673.
13. Dong LX, Sun LL, Zhang X et al. Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells. Acta Pharmacol Sin 2012.
14. Isakoff SJ, Engelman JA, Irie HY et al. Breast cancer associated PI3KCA mutations are oncogenic in mammary epithelial cells. Cancer Res 2006; 65: 10 992–11 000.
15. Kurokawa H, Lenferink AE, Simpson JF et al. Inhibition of HER2/neu (erbB-2) and mitogenactivated protein kinases enhances tamoxifen action against HER-2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000; 60: 5887–94.
16. Kurokawa H, Arteaga CL. ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 2003; 9: 511–5s.
17. Stoica GE, Franke TF, Wellstein A et al. Heregulin-b1 regulates the estrogen receptor-gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene 2003; 22: 2073–87.
18. Perez-Tenorio G, Stal O. Activation of Akt/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002; 86: 540–5.
19. Tokunaga E, Kataoka A, Kimura Y et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006; 42: 629–35.
20 Yue W, Fan P, Wang J et al. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 2007; 106: 102–10.
21 Miller TW, Hennessy BT, Gonzalez-Angulo AM et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010; 120: 2406–13.
22 Santen RJ, Song RX, Zhang Z et al. Adaptive hypersensitivity to estrogen. Mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. J Steroid Biochem Mol Biol 2005; 95: 155–65.
23 Lane HA, Wood JM, McSheehy PM et al. MTOR inhibitor RAD001 (Everolimus) has antiangio-genic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 2009; 15: 1612–22.
24. Bachelot Th, Bourgier C, Cropet C et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors. A GINECO Study. J Clin Oncol 2012; 30 (22): 2718–24.
25. Beck TJ, Rugo HS, Howard A et al. BOLERO-2: health-related quality-of-life in metastatic breast cancer patients treated with everolimus and exemestane vs exemestane. Abstr. ASCO 2012.
26 Piccart M, Baselga J, Noguchi S et al. Poster P6-04-02 final progression-free survival analysis of BOLERO-2. A phase III trial of everolimus for postmenopausal women with advanced breast cancer. San Antonio Breast Cancer Sympos 2012; 4–8.
27. Rugo HS, Pritchard KI, Gnant M et al. Everolimus (EVE) for postmenopausal women with advanced breast cancer (ABC) refractory to Letrozole or Anastrozole: long-term efficacy and safety results of the BOLERO-2 trial. Abstr. 253. 8th European Breast Cancer Conference. Vienna, Austria 2012.
28. Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus Letrozole compared with placebo plus Letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27 (16): 2630–7.
Авторы
И.В.Колядина, Н.П.Макаренко, И.В.Поддубная
Кафедра онкологии ГБОУ ДПО РМАПО Минздрава РФ, Москва
Кафедра онкологии ГБОУ ДПО РМАПО Минздрава РФ, Москва
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I.V.Kolyadina, N.P.Makarenko, I.V.Poddubnaya
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