Прогностическое и предиктивное значения мутации гена PIK3CA у больных раком молочной железы


DOI: https://dx.doi.org/10.18565/pharmateca.2019.7.10-20

Т.Ю. Семиглазова (1, 2), И.В. Сорокина (3)

1) Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова, Санкт-Петербург, Россия; 2) Северо-Западный государственный медицинский университет им. И.И. Мечникова, Санкт-Петербург, Россия; 3) ООО «Новартис Фарма», Москва, Россия

Принципы лечения HR+-HER2-метастатического рака молочной железы (мРМЖ) в течение длительного периода времени оставались неизменными. Последовательное применение различных вариантов эндокринотерапии обеспечивало значимое увеличение показателей общей и безрецидивной выживаемости при сохранении высокого качества жизни. Однако с течением времени пациенты прогрессируют в связи с развитием резистентности к проводимому лечению. Изучение причин и способов преодоления резистентности к гормонотерапии привело к раскрытию новых мощных возможностей лечения пациентов с HR+-HER2-мРМЖ. В развитии невосприимчивости к эндокринной терапии фундаментальная роль отведена перекрестным взаимодействиям различных сигнальных каскадов в клетке в результате приобретенных мутаций рецепторов эстрогенов. Нарушение функционирования PI3K-опосредованного каскада представляет собой самое частое нарушение при РМЖ и ассоциировано с резистентностью к эндокринной терапии. Фосфатидил-инозитол-3 киназа (PI3K) уже много лет привлекает пристальное внимание ученых как ключевой координатор процессов роста и жизнедеятельности клетки. В текущем обзоре приведены основные положения, характеризующие клиническую значимость мутации гена PIK3CA, кодирующего киназу PI3K: прогностическая и предиктивная роль мутации гена PIK3CA (PIK3CA+) во всех подтипах РМЖ; а также обосновывается выделение особой группы пациентов, нуждающихся в терапии, подавляющей активность PI3K.


Для цитирования: Семиглазова Т.Ю., Сорокина И.В. Прогностическое и предиктивное значения мутации гена PIK3CA у больных раком молочной железы. Фарматека. 2019;26(7):10–20. DOI: https://dx.doi.org/10.18565/pharmateca.2019.7.10-20 


Литература


1. Ciruelos Gil E.M. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev. 2014;40(7):862–71. Doi: 10.1016/j.ctrv.2014.03.004.

2. Mayer I.A., Abramson V.G., Formisano L., et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer. Clin Cancer Res. 2017;23(1):26–34. Doi: 10.1158/1078-0432.CCR-16-0134.

3. Dupont Jensen J., Laenkholm A.V., 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.

4. Dey N., De P., Leyland-Jones B. PI3K-AKT-mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials. Pharmacol Ther. 2017;175:91–106. Doi: 10.1016/j.pharmthera.2017.02.037.

5. Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer Treat Rev. 2017;59:93–101. Doi: 10.1016/j.ctrv.2017.07.005.

6. Courtney K.D., Corcoran R.B., Engelman J.A. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–83. Doi: 10.1200/JCO.2009.25.3641.

7. Miller T.W., Rexer B.N., Garrett J.T., Arteaga C.L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224. Doi: 10.1186/bcr3039.

8. Bosch A., Li Z., Bergamaschi 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. Doi: 10.1126/scitranslmed.aaa4442.

9. Miller T.W., Balko J.M., Fox E.M., et al. ER -Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer. Cancer Discov. 2011;1(4):338–51. Doi: 10.1158/2159-8290.CD-11-0101.

10. Vogt P.K., Hart J.R., Gymnopoulos M., et al. Phosphatidylinositol 3-Kinase: The Oncoprotein. Curr Top Microbiol Immunol. 2010;347:79–104. Doi: 10.1007/82_2010_80.

11. Kaklamani V.G., Richardson A.L., Arteaga C.L. Exploring Biomarkers of Phosphoinositide 3‐Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer. Oncologist. 2019;24(3):305–12. Doi: 10.1634/theoncologist.2018-0314..

12. Samuels Y., Wang Z., Bardelli A., et al. High Frequency of Mutations of the PIK3CA Gene in Human Cancers. Science. 2004;304(5670):554.

13. Samuels Y., Velculescu V.E. Oncogenic Mutations of PIK3CA in Human Cancers. Cell Cycle. 2004;3(10):1221–24.

14. Park B.H., Davidson N.E. PI3 Kinase Activation and Response to Trastuzumab Therapy: What’s neu with Herceptin Resistance? Cancer Cell. 2007;12(4):297–99.

15. Berns K., Horlings H.M., Hennessy B.T., et al. A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer. Cancer Cell. 2007;12(4):395–402.

16. Engelman J.A., Mukohara T., Zejnullahu K., et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116(10):2695–706.

17. Isakoff S.J., Engelman J.A., Irie H.Y., et al. Breast Cancer–Associated PIK3CA Mutations Are Oncogenic in Mammary Epithelial Cells. Cancer Res. 2005;65(23):10992–1000.

18. Zhao J.J., Liu Z., Wang L., et al. The oncogenic properties of mutant p110 and p110 phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA. 2005;102(51):18443–448.

19. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. Doi: 10.1038/nature11412.

20. Herrera-Abreu M.T., Palafox M., Asghar U., et al. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer. Cancer Res. 2016;76(8):2301–13. Doi: 10.1158/0008-5472.CAN-15-0728.

21. Cortés J., Im S.A., Holgado E., et al. The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies, Cancer Treat Rev. 2017;61:53–60. Doi: 10.1016/j.ctrv.2017.09.011.

22. O’Brien N.A., et al. Abstract 4150: Anti-tumor activity of the PI3K/mTOR pathway inhibitors alpelisib (BYL719) and everolimus (RAD001) in xenograft models of acquired resistance to CDK-4/6 targeted therapy. Cancer Res. 2017;13(77):4150–50.

23. Lenihan C., et al. Abstract P3-06-02: Characterization of resistance to the selective CDK4/6 inhibitor palbociclib in ER positive breast cancer. Cancer Res. 2016;4(76):P3-06-02-P3-06–02.

24. Baselga J., Campone M., Piccart M., et al. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2012;6(366):520–29. Doi: 10.1056/NEJMoa1109653

25. Beck J.T., Hortobagyi G.N., Campone M., et al. Everolimus plus exemestane as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2. Breast Cancer Res Treat. 2014;143(3):459–67. Doi: 10.1007/s10549-013-2814-5.

26. Piccart M., Hortobagyi G.N., Campone M., et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25(12):2357–62. Doi: 10.1093/annonc/mdu456.

27. Hortobagyi G.N., et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. J. Clin. Oncol. 2013;18(31):LBA509-LBA509.

28. Chen Z., et al. 345P Everolimus-based therapy versus conventional therapy for refractory breast cancer patients with PI3K/AKT/mTOR mutations. Ann Oncol. 2018;8:29.

29. Juric D., Janku F., Rodón J., et al. Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor–Positive Advanced Breast Cancer. JAMA Oncol. 2018:e184475. Doi: 10.1001/jamaoncol.2018.4475.

30. Neven P., et al. 346P Ribociclib (RIB)+fulvestrant (FUL) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-3 biomarker analyses. Ann Oncol. 2018;29:8

31. O’Leary B., Hrebien S., Morden J.P., et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018;9(1):896. Doi: 10.1038/s41467-018-03215-x.

32. Dogruluk T., Tsang Y.H., Espitia M., et al. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. Cancer Res. 2015;75(24):5341–54. Doi: 10.1158/0008-5472.CAN-15-1654.

33. Kalinsky K., Jacks L.M., Heguy A., et al. PIK3CA Mutation Associates with Improved Outcome in Breast Cancer. Clin Cancer Res. 2009;15(16):5049–59. Doi: 10.1158/1078-0432.CCR-09-0632.

34. Moynahan M.E., 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. Doi: 10.1038/bjc.2017.25.

35. Baselga J., Im S.A., Iwata H., et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904–16. Doi: 10.1016/S1470-2045(17)30376-5.

36. Di Leo A., Johnston S., Lee K.S., 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. Doi: 10.1016/S1470-2045(17)30688-5.

37. Juric D., Ciruelos E.M., et al. Alpelisib (ALP)+fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. Present. San Antonio Breast Cancer Symp. (Abstract GS3–08).

38. Aleskandarany M.A., Soria D., Green A.R., et al. Markers of progression in early-stage invasive breast cancer: a predictive immunohistochemical panel algorithm for distant recurrence risk stratification. Breast Cancer Res Treat. 2015;151(2):325–33. Doi: 10.1007/s10549-015-3406-3.

39. Talmadge J.E., Fidler I.J. AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 2010;70(14):5649–69. Doi: 10.1158/0008-5472.CAN-10-1040.

40. Aleskandarany M.A., Negm O.H., Green A.R., et al. Epithelial mesenchymal transition in early invasive breast cancer: an immunohistochemical and reverse phase protein array study. Breast Cancer Res Treat. 2014;145(2):339–48. Doi: 10.1007/s10549-014-2927-5.

41. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. Doi: 10.1016/j.cell.2011.02.013.

42. Fang X., Cai Y., Liu J., et al. Twist2 contributes to breast cancer progression by promoting an epithelial–mesenchymal transition and cancer stem-like cell self-renewal. Oncogene. 2011;30(47):4707–20. Doi: 10.1038/onc.2011.181.

43. Qiu J., Xue X., Hu C., et al. Comparison of Clinicopathological Features and Prognosis in Triple-Negative and Non-Triple Negative Breast Cancer. J Cancer. 2016;7(2):167–73. Doi: 10.7150/jca.10944.

44. Ramis-Conde I., Chaplain M.A., Anderson A.R., Drasdo D. Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis. Phys Biol. 2009;6(1):016008. Doi: 10.1088/1478-3975/6/1/016008.

45. Filipenko M.L., Os’kina N.A., Oskorbin I.A., et al. Association between the Prevalence of Somatic Mutations in PIK3CA Gene in Tumors and Clinical and Morphological Characteristics of Breast Cancer Patients. Bull Exp Biol Med. 2017;163(2):250–54. Doi: 10.1007/s10517-017-3777-z.

46. Anderson E.J. et al. A systematic literature review of the clinical prognosis of HR+/HER2- advanced or metastatic breast cancer with and without PIK3CA mutation. J Clin Oncol. 2018;15(36):e13037–e13037.

47. Fan H., Li C., Xiang Q., et al. PIK3CA mutations and their response to neoadjuvant treatment in early breast cancer: A systematic review and meta-analysis, Thorac Cancer. 2018;9(5):571–79. Doi: 10.1111/1759-7714.12618.

48. Spring L.M., Fell G., Arfe A., et al. Abstract GS2-03: Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Individual patient-level meta-analyses of over 27,00. Cancer Res. 2018;4(79):GS2–03.


Об авторах / Для корреспонденции


Автор для связи: Т.Ю. Семиглазова, д.м.н., доцент, зав. отделом, ведущий науч. сотр. научного отдела инновационных методов терапевтической онкологии и реабилитации, НМИЦ онкологии им. Н.Н. Петрова, профессор кафедры онкологии СЗГМУ им. И.И. Мечникова, Санкт-Петербург, Россия; e-mail: tsemiglazova@mail.ru, ORCID: https://orcid.org/0000-0002-4305-6691; Адрес: 197758, Россия, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68


Похожие статьи


Бионика Медиа