Частота и спектр мутаций PIK3CA при гормонозависимом HER2-отрицательном распространенном раке молочной железы у российских пациенток

Соколова Т.Н., Алексахина С.Н., Янус Г.А., Султанбаев А.В., Меньшиков К.В., Лысенко А.Н., Зуков Р.А., Зюзюкина А.В., Мурунова Ю.Н., Россоха Е.И., Бахарев С.Ю., Басова Е.А., Касмынина Т.А., Шумская И.С., Бакшун Я.И., Мусаева Х.С., Хасанова А.И., Дмитриев В.Н., Болиева М.Б., Гадзаова К.Х., Петренко О.Л., Максимов Д.А., Владимиров В.И., Гольдберг В.Е., Попова Н.О., Кибишева М.В., Хамгоков З.М., Васильев А.Е., Иевлева А.Г., Имянитов Е.Н. Частота и спектр мутаций PIK3CA при гормонозависимом HER2-отрицательном распространенном раке молочной железы у российских пациенток. Современная Онкология. 2021; 23 (1): 61–67. DOI: 10.26442/18151434.2021.1.200744

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Sokolova TN, Aleksakhina SN, Yanus GA, Sultanbaev AV, Menshikov KV, Lysenko AN, Zukov RA, Zyuzyukina AV, Murunova YuN, Rossokha EI, Bakharev SY, Basova EA, Kasmynina TA, Shumskaya IS, Bakshun YaI, Musaeva KS, Khasanova AI, Dmitriev VN, Bolieva MB, Gadzaova CH, Petrenko OL, Maksimov DA, Vladimirov VI, Goldberg VE, Popova NO, Kibisheva MV, Khamgokov ZM, Vasilyev AE, Iyevleva AG, Imyanitov EN. The frequency and spectrum of PIK3CA mutations in patients with estrogen receptor-positive HER2-negative advanced breast cancer residing in various regions of Russia. Journal of Modern Oncology. 2021; 23 (1): 61–67.
DOI: 10.26442/18151434.2021.1.200744

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Аннотация

Актуальность. Мутации в гене PIK3CA относятся к наиболее частым генетическим повреждениям при эстроген-рецептор-(ER)-позитивном раке молочной железы (РМЖ). Детекция мутаций PIK3CA приобрела особую значимость после недавнего внедрения в практику ингибитора PI3K алпелисиба. Частота и спектр обнаруживаемых соматических дефектов PIK3CA зависят от особенностей включенных в анализ случаев, в том числе распределения гистологических и экспрессионных вариантов опухолей, возрастного и даже этнического состава изучаемой группы.
Цель. Характеристика частоты и спектра мутаций PIK3CA у российских пациенток с РМЖ.
Материалы и методы. Присутствие мутаций в 7, 9 и 20-м экзонах гена PIK3CA определено в выборке из 206 случаев распространенного ER+/HER2- РМЖ. Для поиска мутаций использовалась комбинация плавления ПЦР-продуктов с высоким разрешением, аллель-специфической полимеразной цепной реакции (ПЦР) и цифровой капельной ПЦР.
Результаты. Мутации в гене PIK3CA детектированы в 62/206 (30%) случаев. Примечательно, что абсолютное большинство выявленных повреждений (59/62, 95%) представлено всего тремя частыми разновидностями миссенс-замен: p.E542K, p.E545K и p.H1047R. При анализе клинико-морфологических характеристик обнаружены тенденции к ассоциации мутаций PIK3CA со старшим возрастом и более частым метастатическим поражением легких.
Заключение. Информация о частоте и спектре соматических аберраций PIK3CA может быть применена при организации молекулярно-генетического тестирования больных РМЖ и использовании ингибиторов PI3K в нашей популяции.

Ключевые слова: рак молочной железы, мутации, PIK3CA, алпелисиб

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Background. PIK3CA belongs to the top three most frequently mutated genes in breast cancer (BC), especially in estrogen receptor (ER) positive, HER2 negative BC subtype. With an approval of selective PI3K-alpha inhibitor, alpelisib, this alteration has become actionable in ER+HER2- tumors. The frequency and spectrum of PIK3CA alterations in various cohorts is affected by a number of factors, including the distribution of BC expression subtypes, histological types, patient age, and even ethnicity.
Aim. Aim of the current study was to characterize the frequency and spectrum of PIK3CA alterations in Russian BC patients.
Materials and methods. The analysis of PIK3CA exon 7, 9 and 20 mutations was performed in a cohort of Russian ER+HER2- BC patients by a combination of high-resolution melting analysis, allele-specific PCR, and digital droplet PCR.
Results. PIK3CA lesions were identified in 62/206 (30%) patients. Noteworthy, 59/62 (95%) of the identified variants were represented by the three most common p.E542K, p.E545K, and p.H1047R substitutions. The analysis of clinical and morphological characteristics revealed the trends towards association of PIK3CA mutations with older age and more frequent metastatic lung involvement.
Conclusion. The obtained data on the frequency and spectrum of PIK3CA somatic aberrations can be helpful when organizing molecular genetic testing of breast cancer patients and using PI3K inhibitors in Russian population.

Keywords: breast cancer, mutations, PIK3CA, alpelisib

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Список литературы

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5. Lehmann BD, Bauer JA, Schafer JM, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 2014; 16 (4): 406. DOI: 10.1186/s13058-014-0406-x
6. Pascual J, Lim JSJ, Macpherson IR, et al. Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers. Cancer Discov 2020. doi: 10.1158/2159-8290.CD-20-0553
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8. Khoury K, Tan AR, Elliott A, et al. Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. Front Oncol 2020; 10: 1475. DOI: 10.3389/fonc.2020.01475
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10. Moon WK, Chen HH, Shin SU, et al. Evaluation of TP53/PIK3CA mutations using texture and morphology analysis on breast MRI. Magn Reson Imaging 2019; 63: 60–9. DOI: 10.1016/j.mri.2019.08.026
11. Sobral-Leite M, Salomon I, Opdam M, et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res 2019; 21 (1): 90. DOI: 10.1186/s13058-019-1176-2
12. Magometschnigg H, Pinker K, Helbich T, et al. PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2- Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT. Mol Imaging Biol 2019; 21 (5): 991–1002. DOI: 10.1007/s11307-018-01308-z
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23. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 2020; 31 (3): 377–86. DOI: 10.1016/j.annonc.2019.11.006
24. Perez EA, de Haas SL, Eiermann W, et al. Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. BMC Cancer 2019; 19 (1): 517. DOI: 10.1186/s12885-019-5687-0
25. Guarneri V, Dieci MV, Bisagni G, et al. PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype. Clin Cancer Res 2020; 26 (22): 5843–51. DOI: 10.1158/1078-0432.CCR-20-1731
26. Barbareschi M, Buttitta F, Felicioni L, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 2007; 13 (20): 6064–9. DOI: 10.1158/1078-0432.CCR-07-0266
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28. Papaxoinis G, Kotoula V, Alexopoulou Z, et al. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study. PLoS One 2015; 10 (10): e0140293. DOI: 10.1371/journal.pone.0140293
29. Spangle JM, Von T, Pavlick DC, et al. PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition. Proc Natl Acad Sci U S A. 2020 Sep 29; 117 (39): 24427–33. DOI: 10.1073/pnas.2000060117
30. Dupont Jensen J, Laenkholm AV, Knoop A, et al. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 2011; 17 (4): 667–77. DOI: 10.1158/1078-0432.CCR-10-1133
31. Ang DC, Warrick AL, Shilling A, et al. Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions. Mod Pathol 2014; 27 (5): 740–50. DOI: 10.1038/modpathol.2013.197
32. O'Leary B, Cutts RJ, Liu Y, et al. The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov 2018; 8 (11): 1390–403. DOI: 10.1158/2159-8290.CD-18-0264
33. Yanus GA, Belyaeva AV, Ivantsov AO, et al. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. Medical Oncology 2013; 30 (3): 686.
34. Клинические рекомендации. Рак молочной железы. 2021. Режим доступа: http://cr.rosminzdrav.ru/schema/379. Ссылка активна на 16.02.2021 [Klinicheskie rekomendatsii. Rak molochnoi zhelezy. 2021. Available at: http://cr.rosminzdrav.ru/schema/379. Accessed: 16.02.2021 (in Russian).]
35. Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020; 31 (12): 1623–49. DOI: 10.1016/j.annonc.2020.09.010

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1. Available at: https://gco.iarc.fr/today/ Accessed: 19.02.2021.
2. Sung H, Ferlay J, Siegel RL, et al. Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 2021; 0: 1–41. DOI: 10.3322/caac.21660
3. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA 2019; 321 (3): 288–300. DOI: 10.1001/jama.2018.19323
4. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol 2021; 32 (2): 208–17. DOI: 10.1016/j.annonc.2020.11.011
5. Lehmann BD, Bauer JA, Schafer JM, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 2014; 16 (4): 406. DOI: 10.1186/s13058-014-0406-x
6. Pascual J, Lim JSJ, Macpherson IR, et al. Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers. Cancer Discov 2020. doi: 10.1158/2159-8290.CD-20-0553
7. Anderson EJ, Mollon LE, Dean JL, et al. Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer. Int J Breast Cancer 2020; 2020: 3759179. DOI: 10.1155/2020/3759179
8. Khoury K, Tan AR, Elliott A, et al. Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. Front Oncol 2020; 10: 1475. DOI: 10.3389/fonc.2020.01475
9. Willis O, Choucair K, Alloghbi A, et al. PIK3CA gene aberrancy and role in targeted therapy of solid malignancies. Cancer Gene Ther 2020; 27 (9): 634–44. DOI: 10.1038/s41417-020-0164-0
10. Moon WK, Chen HH, Shin SU, et al. Evaluation of TP53/PIK3CA mutations using texture and morphology analysis on breast MRI. Magn Reson Imaging 2019; 63: 60–9. DOI: 10.1016/j.mri.2019.08.026
11. Sobral-Leite M, Salomon I, Opdam M, et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res 2019; 21 (1): 90. DOI: 10.1186/s13058-019-1176-2
12. Magometschnigg H, Pinker K, Helbich T, et al. PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2- Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT. Mol Imaging Biol 2019; 21 (5): 991–1002. DOI: 10.1007/s11307-018-01308-z
13. Koundouros N, Karali E, Tripp A, et al. Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids. Cell 2020; 181 (7): 1596–1611.e27. DOI: 10.1016/j.cell.2020.05.053
14. Gerratana L, Davis AA, Polano M, et al. Understanding the organ tropism of metastatic breast cancer through the combination of liquid biopsy tools. Eur J Cancer 2020; 143: 147–57. DOI: 10.1016/j.ejca.2020.11.005
15. Muller KE, Marotti JD. Genotype-phenotype associations in breast pathology: Achievements of the past quarter century. Breast J 2020; 26 (6): 1123–31. DOI: 10.1111/tbj.13861
16. Tray N, Taff J, Singh B, et al. Metaplastic breast cancers: Genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast 2019; 44: 29–32. DOI: 10.1016/j.breast.2018.12.010
17. Martínez-Sáez O, Chic N, Pascual T, Adamo B, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res 2020; 22 (1): 45. DOI: 10.1186/s13058-020-01284-9
18. Clifton K, Luo J, Tao Y, et al. Mutation profile differences in younger and older patients with advanced breast cancer using circulating tumor DNA (ctDNA). Breast Cancer Res Treat 2020. DOI: 10.1007/s10549-020-06019-0
19. Omilian AR, Wei L, Hong CC, et al. Somatic mutations of triple-negative breast cancer: a comparison between Black and White women. Breast Cancer Res Treat 2020; 182 (2): 503–9. DOI: 10.1007/s10549-020-05693-4
20. Tao Z, Li T, Feng Z, et al. Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients. Front Oncol 2020; 10: 1023. DOI: 10.3389/fonc.2020.01023
21. Loibl S, Treue D, Budczies J, et al. Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial. Clin Cancer Res 2019; 25 (13): 3986–95. DOI: 10.1158/1078-0432.CCR-18-3258
22. Zardavas D, Te Marvelde L, Milne RL, et al. Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data. J Clin Oncol 2018; 36 (10): 981–90. DOI: 10.1200/JCO.2017.74.8301
23. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 2020; 31 (3): 377–86. DOI: 10.1016/j.annonc.2019.11.006
24. Perez EA, de Haas SL, Eiermann W, et al. Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. BMC Cancer 2019; 19 (1): 517. DOI: 10.1186/s12885-019-5687-0
25. Guarneri V, Dieci MV, Bisagni G, et al. PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype. Clin Cancer Res 2020; 26 (22): 5843–51. DOI: 10.1158/1078-0432.CCR-20-1731
26. Barbareschi M, Buttitta F, Felicioni L, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 2007; 13 (20): 6064–9. DOI: 10.1158/1078-0432.CCR-07-0266
27. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490 (7418): 61–70. DOI: 10.1038/nature11412
28. Papaxoinis G, Kotoula V, Alexopoulou Z, et al. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study. PLoS One 2015; 10 (10): e0140293. DOI: 10.1371/journal.pone.0140293
29. Spangle JM, Von T, Pavlick DC, et al. PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition. Proc Natl Acad Sci U S A. 2020 Sep 29; 117 (39): 24427–33. DOI: 10.1073/pnas.2000060117
30. Dupont Jensen J, Laenkholm AV, Knoop A, et al. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 2011; 17 (4): 667–77. DOI: 10.1158/1078-0432.CCR-10-1133
31. Ang DC, Warrick AL, Shilling A, et al. Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions. Mod Pathol 2014; 27 (5): 740–50. DOI: 10.1038/modpathol.2013.197
32. O'Leary B, Cutts RJ, Liu Y, et al. The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov 2018; 8 (11): 1390–403. DOI: 10.1158/2159-8290.CD-18-0264
33. Yanus GA, Belyaeva AV, Ivantsov AO, et al. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. Medical Oncology 2013; 30 (3): 686.
34. Klinicheskie rekomendatsii. Rak molochnoi zhelezy. 2021. Available at: http://cr.rosminzdrav.ru/schema/379. Accessed: 16.02.2021 (in Russian).
35. Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020; 31 (12): 1623–49. DOI: 10.1016/j.annonc.2020.09.010

Авторы

Т.Н. Соколова*1, С.Н. Алексахина1, Г.А. Янус1,2, А.В. Султанбаев3, К.В. Меньшиков3, А.Н. Лысенко4, Р.А. Зуков5, А.В. Зюзюкина5, Ю.Н. Мурунова6, Е.И. Россоха7, С.Ю. Бахарев7, Е.А. Басова8, Т.А. Касмынина8, И.С. Шумская9, Я.И. Бакшун10, Х.С. Мусаева11, А.И. Хасанова12,13, В.Н. Дмитриев14, М.Б. Болиева15, К.Х. Гадзаова15, О.Л. Петренко16, Д.А. Максимов17, В.И. Владимиров18, В.Е. Гольдберг19, Н.О. Попова19, М.В. Кибишева20, З.М. Хамгоков20, А.Е. Васильев21, А.Г. Иевлева1,2, Е.Н. Имянитов1,2

1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова» Минздрава России, Санкт-Петербург, Россия;
2 ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России, Санкт-Петербург, Россия;
3 ГАУЗ «Республиканский клинический онкологический диспансер» Минздрава Республики Башкортостан, Уфа, Россия;
4 ГБУЗ СК «Ставропольский краевой клинический онкологический диспансер», Ставрополь, Россия;
5 ФГБОУ ВО «Красноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого» Минздрава России, Красноярск, Россия;
6 БУ «Сургутская окружная клиническая больница», Сургут, Россия;
7 КГБУЗ «Алтайский краевой онкологический диспансер», Барнаул, Россия;
8 ОГБУЗ «Онкологический диспансер», Биробиджан, Россия;
9 ГБУЗ НО «Нижегородский областной клинический онкологический диспансер», Нижний Новгород, Россия;
10 ОГБУЗ «Костромской онкологический диспансер», Кострома, Россия;
11 ГБУ «Республиканский онкологический диспансер», Грозный, Россия;
12 ГАУЗ «Республиканский клинический онкологический диспансер Минздрава Республики Татарстан им. проф. М.З. Сигала», Казань, Россия;
13 ФГАОУ ВО «Казанский (Приволжский) федеральный университет», Казань, Россия;
14 ОГБУЗ «Белгородский онкологический диспансер», Белгород, Россия;
15 ГБУЗ «Республиканский онкологический диспансер» Минздрава Республики Северная Осетия – Алания, Владикавказ, Россия;
16 ГБУЗ КО «Центральная городская клиническая больница», Калининград, Россия;
17 ГБУЗ «Тверской областной клинический онкологический диспансер», Тверь, Россия;
18 ГБУЗ СК «Пятигорский межрайонный онкологический диспансер», Пятигорск, Россия;
19 ФГБНУ «Томский национальный исследовательский медицинский центр» РАН, Томск, Россия;
20 ГБУЗ «Онкологический диспансер» Минздрава Кабардино-Балкарской Республики, Нальчик, Россия;
21 ГБУЗ «Оренбургский областной клинический онкологический диспансер», Оренбург, Россия
*stretanya@yandex.ru

________________________________________________

Tatiana N. Sokolova*1, Svetlana N. Aleksakhina1, Grigoriy A. Yanus1,2, Aleksandr V. Sultanbaev3, Konstantin V. Menshikov3, Anna N. Lysenko4, Ruslan A. Zukov5, Alena V. Zyuzyukina5, Yulia N. Murunova6, Elena I. Rossokha7, Sergey Y. Bakharev7, Elena A. Basova8, Tatiana A. Kasmynina8, Irina S. Shumskaya9, Yana I. Bakshun10, Khedi S. Musaeva11, Alfia I. Khasanova12,13, Vadim N. Dmitriev14, Marina B. Bolieva15, Christina H. Gadzaova15, Oleg L. Petrenko16, Dmitriy A. Maksimov17, Vladimir I. Vladimirov18, Viktor E. Goldberg19, Nataliya O. Popova19, Marianna V. Kibisheva20, Zaur M. Khamgokov20, Alexey E. Vasilyev21, Aglaya G. Iyevleva1,2, Evgeny N. Imyanitov1,2

1 Petrov Institute of Oncology, Saint Petersburg, Russia;
2 Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia;
3 Republican Clinical Oncological Dispensary, Ufa, Russia;
4 Regional Oncology Dispensary, Stavropol, Russia;
5 Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, Russia;
6 Surgut Regional Hospital, Surgut, Russia;
7 Altai Regional Oncological Dispensary, Barnaul, Russia;
8 Oncology Dispensary, Birobidzhan, Russia;
9 Nizhny Novgorod Regional Clinical Oncological Dispensary, Nizhny Novgorod, Russia;
10 Сancer Hospital, Kostroma, Russia;
11 Republican Oncology Dispensary, Grozniy, Russia;
12 Sigal Republic Clinical Oncology Dispensary, Kazan, Russia;
13 Scientific and Clinical Center for Precision and Regenerative Medicine, Kazan Federal University, Kazan, Russia;
14 Belgorod Oncology Dispensary, Belgorod, Russia;
15 Republican Oncology Dispensary, Vladikavkaz, Russia;
16 Kaliningrad Regional Clinical Hospital, Kaliningrad, Russia;
17 Tver Regional Clinical Oncology Dispensary, Tver, Russia;
18 Pyatigorsk Oncology Dispensary, Pyatigorsk, Russia;
19 Tomsk National Research Medical Center, Tomsk, Russia;
20 Oncology Dispensary, Nalchik, Russia;
21 Orenburg Regional Clinical Oncological Dispensary, Orenburg, Russia
*stretanya@yandex.ru

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