Виртуальный форум по вопросам диагностики и лечения метастатического рака молочной железы с мутацией PIK3CA

1. Состояние онкологической помощи населению России в 2019 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2020.
[The state of cancer care for the population of Russia in 2019. Ed. A.D. Kaprin, V.V. Starinsky, A.O. Shahzadova. Moscow: Moscow Scientific Research Institute named after P.A. Herzen – branch of the Federal State Budgetary Institution “National Medical Research Center of Radiology” of the Ministry of Health of Russia, 2020 (in Russian).]
2. Slamon DJ et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382: 514–24.
3. Im S-A et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381: 307–16.
4. Sledge G 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 2A Randomized Clinical Trial. JAMA Oncol 2020; 6 (1): 116–24.
5. Эл. ресурс: http://cr.rosminzdrav.ru/#!/schema/236
[Available from: http://cr.rosminzdrav.ru/#!/schema/236 (in Russian).]
6. Sobhani N et al. The prognostic value of PI3K mutational status in breast cancer: A meta-analysis. J Cell Biochem 2018; 119 (6): 4287–92.
7. Mosele F et al. ESMO Breast Cancer Congress. May 2–4, 2019. Berlin, Germany.
8. Tolaney et al. AACR Annual Meeting. March 29 – April 3, 2019. Atlanta, GA.
9. Di Leo A, Johnston S, Seok Lee K et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018; 19 (1): 87–100.
10. Moynahan ME, Chen D, He W et al. Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2 - advanced breast cancer: results from ­BOLERO-2. Br J Cancer 2017; 116 (6): 726–30. https://www.pik3ca.com/PI3K-PATHWAY/
11. Comprehensive molecular portraits of human breast tumours. The Cancer Genome Atlas Network. Nature 2012; 490 (7418): 61–70. DOI: 10.1038/nature11412. https://www.hcp.novartis.com/products/piqray/metastatic-breast-cancer/pik3ca-mutation/
12. Cardoso F et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020; 321 (12): 1623–49.
13. Vasan N et al. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol 2019. 30 (10). DOI: 10.1093/annonc/mdz281
14. Burke J. PNAS, 2013.
15. Cai L et al. Protective cellular immunity generated by cross-presenting recombinant overlapping peptide proteins. Oncotarget 2017; 8: 76516–24.
16. Mayer IA et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res 2017; 23 (1): 26–34.
17. Loi S et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 2010; 107 (22): 10208–13.
18. Stemke-Hale K et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68 (15): 6084–91.
19. Miller TW et al. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 2011; 29 (33): 4452–61.
20. Bosch A et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med 2015; 7 (283): 283ra51.
21. Miller TW et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010; 120 (7): 2406–13.
22. Crowder RJ et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 2009; 69 (9): 3955–62.
23. Miller TW et al. ERa-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 2011; 1 (4): 338–51.
24. Arthur L et al. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer. Breast Cancer Res Treat 2014; 147: 211–9.
25. Mosele F et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 2020; 31 (3): 377–86.
26. Hortobagyi G et al. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol 2016; 34 (5): 419–26. DOI: 10.1200/JCO.2014.60.1971
27. Neven (Abstract # PD2-05), SABCS’2018
28. Courtney KD et al. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28 (6): 1075–83.
29. Maira SM et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012; 11 (2): 317–28.
30. Dienstmann R et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 2014; 13 (5): 1021–31.
31. Fritsch C et al. Characterization of the novel and specific PI3Ka inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014; 13 (5): 1117–29.
32. Ndubaku CO et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a b-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 2013; 56 (11): 4597–610.
33. Andre F et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380: 1929–40.
34. Andre F et al. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Ann Oncol 2020; 31 (Suppl. 4): S1142–215. DOI: 10.1016/annonc/annonc325
35. Turner S et al. ESMO 2020. Presentation # 309P – E-poster.
36. Эл. ресурс: http://cancergenome.ru/
[Available from: http://cancergenome.ru/ (in Russian).]
37. Эл. ресурс: https://www.nccn.org/professionals/physician_gls/default.aspx
[Available from: https://www.nccn.org/professionals/physician_gls/default.aspx (in Russian).]
38. Świderska E et al. Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake. Blood Glucose Levels 2018.
39. Rugo H et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol 2020; 31 (8): 1001–10. DOI: 10.1016/j.annonc.2020.05.001
40. Piqray [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp, 2019.

________________________________________________

1. The state of cancer care for the population of Russia in 2019. Ed. A.D. Kaprin, V.V. Starinsky, A.O. Shahzadova. Moscow: Moscow Scientific Research Institute named after P.A. Herzen – branch of the Federal State Budgetary Institution “National Medical Research Center of Radiology” of the Ministry of Health of Russia, 2020 (in Russian).
2. Slamon DJ et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382: 514–24.
3. Im S-A et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381: 307–16.
4. Sledge G 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 2A Randomized Clinical Trial. JAMA Oncol 2020; 6 (1): 116–24.
5. Available from: http://cr.rosminzdrav.ru/#!/schema/236 (in Russian).
6. Sobhani N et al. The prognostic value of PI3K mutational status in breast cancer: A meta-analysis. J Cell Biochem 2018; 119 (6): 4287–92.
7. Mosele F et al. ESMO Breast Cancer Congress. May 2–4, 2019. Berlin, Germany.
8. Tolaney et al. AACR Annual Meeting. March 29 – April 3, 2019. Atlanta, GA.
9. Di Leo A, Johnston S, Seok Lee K et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018; 19 (1): 87–100.
10. Moynahan ME, Chen D, He W et al. Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2 - advanced breast cancer: results from ­BOLERO-2. Br J Cancer 2017; 116 (6): 726–30. https://www.pik3ca.com/PI3K-PATHWAY/
11. Comprehensive molecular portraits of human breast tumours. The Cancer Genome Atlas Network. Nature 2012; 490 (7418): 61–70. DOI: 10.1038/nature11412. https://www.hcp.novartis.com/products/piqray/metastatic-breast-cancer/pik3ca-mutation/
12. Cardoso F et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020; 321 (12): 1623–49.
13. Vasan N et al. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol 2019. 30 (10). DOI: 10.1093/annonc/mdz281
14. Burke J. PNAS, 2013.
15. Cai L et al. Protective cellular immunity generated by cross-presenting recombinant overlapping peptide proteins. Oncotarget 2017; 8: 76516–24.
16. Mayer IA et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res 2017; 23 (1): 26–34.
17. Loi S et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 2010; 107 (22): 10208–13.
18. Stemke-Hale K et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68 (15): 6084–91.
19. Miller TW et al. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 2011; 29 (33): 4452–61.
20. Bosch A et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med 2015; 7 (283): 283ra51.
21. Miller TW et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010; 120 (7): 2406–13.
22. Crowder RJ et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 2009; 69 (9): 3955–62.
23. Miller TW et al. ERa-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 2011; 1 (4): 338–51.
24. Arthur L et al. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer. Breast Cancer Res Treat 2014; 147: 211–9.
25. Mosele F et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 2020; 31 (3): 377–86.
26. Hortobagyi G et al. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol 2016; 34 (5): 419–26. DOI: 10.1200/JCO.2014.60.1971
27. Neven (Abstract # PD2-05), SABCS’2018
28. Courtney KD et al. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28 (6): 1075–83.
29. Maira SM et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012; 11 (2): 317–28.
30. Dienstmann R et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 2014; 13 (5): 1021–31.
31. Fritsch C et al. Characterization of the novel and specific PI3Ka inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014; 13 (5): 1117–29.
32. Ndubaku CO et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a b-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 2013; 56 (11): 4597–610.
33. Andre F et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380: 1929–40.
34. Andre F et al. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Ann Oncol 2020; 31 (Suppl. 4): S1142–215. DOI: 10.1016/annonc/annonc325
35. Turner S et al. ESMO 2020. Presentation # 309P – E-poster.
36. Available from: http://cancergenome.ru/ (in Russian).
37. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx (in Russian).
38. Świderska E et al. Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake. Blood Glucose Levels 2018.
39. Rugo H et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol 2020; 31 (8): 1001–10. DOI: 10.1016/j.annonc.2020.05.001
40. Piqray [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp, 2019.

Эксперты
Поддубная Ирина Владимировна – акад. РАН, д-р мед. наук, проф., зав. каф. онкологии и паллиативной медицины 
им. акад. А.И. Савицкого, проректор по лечебной работе и международному сотрудничеству ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, засл. деят. образования РФ, председатель Российского общества онкогематологов, Москва, Россия
Джозеф Глигоров (Joseph Gligorov) – проф. медицинской онкологии в Университете Сорбонны, врач отд-ния медицинской онкологии больницы Тенон (APHP), исполнительный директор Университетского института онкологии (APHP.6), Университет Сорбонны, Париж, Франция
Жукова Людмила Григорьевна – д-р мед. наук, проф., зам. директора по онкологии ГБУЗ «Московский клинический научный центр им. А.С. Логинова» Департамента здравоохранения г. Москвы, Москва, Россия
Коваленко Елена Игоревна – канд. мед. наук, ст. науч. сотр. ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
Фролова Мона Александровна – д-р мед. наук, ст. науч. сотр. отд-ния клинической фармакологии и химиотерапии ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия 

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Experts 
Irina V. Poddubnaya, Joseph Gligorov, Lyudmila G. Zhukova, Elena I. Kovalenko, Mona A. Frolova