Постнеоадъювантное лечение рака молочной железы

Достижение полного патоморфологического регресса в результате неоадъювантного лечения связано с улучшением прогнозов при раке молочной железы (РМЖ). Исследование CREATE-X продемонстрировало значительное улучшение выживаемости при использовании капецитабина у пациентов c трижды негативным РМЖ с резидуальным инвазивным заболеванием после проведенной неоадъювантной химиотерапии, а исследование KATHERINE показало значительную пользу применения трастузумаба эмтанзина (TDM1) у пациентов с экспрессией рецептора эпидермального фактора роста человека 2-го типа (HER2), которые не достигли полного патоморфологического регресса после неоадъювантного лечения. При этом были созданы интересные альтернативные постнеоадъювантные методы терапии для пациентов группы высокого риска. Открытие молекулярных маркеров резистентности к эндокринотерапии (циклинзависимые киназы (CDK 4/6), мутация ER (ESR1), сигнальный путь mTOR, ко-экспресии ER+/HER2+) и ингибиторов к ним расширило возможности эндокринотерапии не только распространенных и метастатических РМЖ, но и резидуальных ER+-опухолей.
Показатели полного патоморфологического регресса (pCR) при гормон-рецептор-позитивном (люминальном) раке молочной железы после проведенной неоадъювантной химиотерапии составляют около 10%, что намного ниже, чем показатели, наблюдаемые при HER2-позитивном и трижды негативном подтипах, поэтому необходимы новые стратегии для улучшения показателей pCR в данной подгруппе, несмотря на то что адъювантная гормонотерапия оказывает значительное влияние на отдаленные результаты у этих пациентов. Циклинзависимые киназы (CDK) представляют собой серин-треонин киназы, которые регулируют переход клеточного цикла от G1 к S-фазе во время митоза. Активность CDKs может быть ненормально повышена или нарушена при раке молочной железы, что приводит к постоянной стимуляции пролиферации и выживанию клеток, что является известным механизмом устойчивости к гормональному лечению. Ингибиторы циклинзависимых киназ (CDKis) воздействуют на CDK и блокируют их активность, восстанавливая тем самым регуляцию клеточного цикла. В исследованиях пациентов с ER-положительным метастатическим раком молочной железы комбинация CDKis с гормонотерапией первой или второй линии показала значительное улучшение в выживаемости без прогрессирования и частоте ответа на лечение. Развивающиеся технологии, такие как секвенирование следующего поколения и профили экспрессии генов, улучшили наше понимание биологии резидуального заболевания и, следовательно, механизмов, влияющих на устойчивость к лечению.

1. Mauri D., Pavlidis N., Ioannidis J.P. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(3):188–194. doi: 10.1093/jnci/dji021.

2. Semiglazov V.F., Topuzov E.E., Bavli J.L., Moiseyenko V.M., Ivanova O.A., Seleznev I.K. et al. Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol. 1994,5(7):591–595. doi: 10.1093/oxfordjournals.annonc.a058929.

3. Cortazar P., Zhang L., Untch M., Mehta K., Costantino J.P., Wolmark N. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–172. doi: 10.1016/S0140-6736(13)62422-8.

4. Masuda N., Lee S.J., Ohtani S., Im Y.H., Lee E.S., Yokota I. et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–2159. doi: 10.1056/NEJMoa1612645.

5. Robson M., Im S.A., Senkus E., Xu B., Domchek S.M., Masuda N. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–533. doi: 10.1056/NEJMoa1706450.

6. Litton J.K., Rugo H.S., Ettl J., Hurvitz S.A., Gonçalves A., Lee K.H. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–763. doi: 10.1056/NEJMoa1802905.

7. Miller K., Tong Y., Jones D.R., Walsh T., Danso M.A., MaPaula Silverman C.X. et al. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: final efficacy results of Hoosier Oncology Group BRE09-146. J Clin Oncol. 2015;33(15):1082. doi: 10.1200/jco.2015.33.15_suppl.1082.

8. Pelekanou V., Carvajal-Hausdorf D.E., Altan M., Wasserman B., CarvajalHausdorf C., Wimberly H. et al. Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance. Breast Cancer Res. 2017;19(1):91. doi: 10.1186/s13058-017-0884-8.

9. Asano Y., Kashiwagi S., Goto W., Takada K., Takahashi K., Hatano T. et al. Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. BMC Cancer. 2017;17(1):888. doi: 10.1186/s12885-017-3927-8.

10. Schachter J., Ribas A., Long G.V., Arance A., Grob J.J., Mortier L. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–1862. doi: 10.1016/S0140-6736(17)31601-X.

11. Wolchok J.D., Chiarion-Sileni V., Gonzalez R., Rutkowski P., Grob J.J., Cowey C.L. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–1356. doi: 10.1056/NEJMoa1709684.

12. Gandara D.R., Paul S.M., Kowanetz M., Schleifman E., Zou W., Li Y. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441–1448. doi: 10.1038/s41591-018-0134-3.

13. Goodman A.M., Kato S., Bazhenova L., Patel S.P., Frampton G.M., Miller V. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598– 2608. doi: 10.1158/1535-7163.MCT-17-0386.

14. Chalmers Z.R., Connelly C.F., Fabrizio D., Gay L., Ali S.M., Ennis R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. doi: 10.1186/s13073-017-0424-2.

15. Gianni L., Pienkowski T., Im Y.H., Roman L., Tseng L.M., Liu M.C. et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32. doi: 10.1016/S1470-2045(11)70336-9.

16. Denduluri N., Somerfield M.R., Eisen A., Holloway J.N., Hurria A., King T.A. et al. Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)-negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology guideline adaptation of the Cancer Care Ontario Clinical Practice guideline. J Clin Oncol. 2016;34(20):2416–2427. doi: 10.1200/JCO.2016.67.0182.

17. Denduluri N., Chavez-MacGregor M., Telli M.L., Eisen A., Graff S.L., Hassett M.J. et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2018;36(23):2433–2443. doi: 10.1200/JCO.2018.78.8604.

18. Diéras V., Miles D., Verma S., Pegram M., Welslau M., Baselga J. et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732–742. doi: 10.1016/S1470-2045(17)30312-1.

19. Harbeck N., Gluz O., Christgen M., Kates R.E., Braun M., Küemmel S. et al. De-Escalation strategies in human epidermal growth factor Receptor 2 (HER2)-positive early Breast Cancer (BC): final analysis of the West German study group adjuvant dynamic marker adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptorpositive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without Endocrine Therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017;35(26):3046–3054. doi: 10.1200/JCO.2016.71.9815.

20. von Minckwitz G., Huang C.S., Mano M.S., Loibl S., Mamounas E.P., Untch M. et al. Trastuzumab emtansine for residual invasive HER2-Positive breast cancer. N Engl J Med. 2019;380(7):617–628. doi: 10.1056/NEJMoa1814017.

21. Semiglazov V.F., Semiglazov V.V., Dashyan G.A., Ziltsova E.K., Ivanov V.G., Bozhok A.A., Berstein L.M. Phaze II randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor positive breast cancer. Cancer. 2007;110(2):244–254. doi: 10.1002/cncr.22789.

22. Семиглазов В.Ф., Криворотько П.В., Семиглазова Т.Ю., Николаев К.С., Комяхов А.В., Дашян Г.А. и др. Рекомендации по лечению рака молочной железы. М.: Мегаполис; 2017. 168 с. Semiglazov V.F., Krivorot’ko P.V., Semiglazova T.Yu., Nikolayev K.S., Komyakhov A.V., Dashyan G.A., et al. Recommendations for the treatment of breast cancer. Moscow: Megapolis; 2017. 168 p. (In Russ.)

23. Семиглазов В.Ф., Семиглазов В.В., Дашян Г.А., Криворотько П.В., Иванов В.Г., Жильцова Е.К. И ДР. Неоадъювантная эндокринотерапия пациентов с эстроген-рецептор положительным раком молочной железы. Сибирский онкологический журнал. 2018;17(3):11–19. doi: 10.21294/1814-4861-2018- 17-3-11-19. Semiglazov V.F., Semiglazov V.V., Dashyan G.A., Krivorotko P.V., Ivanov V.G., Zhiltsova E.K. et al. Neoadjuvant endocrine therapy for patients with estrogen-receptor-positive breast cancer. Sibirskiy onkologicheskiy zhurnal = Siberian journal of oncology. 2018;17(3):11–19. (In Russ.) doi: 10.21294/1814-4861-2018-17-3-11-19.

24. Gunter von Minckwitz P.C., Cortazar P., Zhang L., Untch M., Mehta K., Costantino JP et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–172. doi: 10.1016/S0140-6736(13)62422-8.

25. Malumbres M., Harlow E., Hunt T., Hunter T., Lahti J.M., Manning G. et al. Cyclindependent kinases: a family portrait. Nat Cell Biol. 2009;11(11):1275–1276. doi: 10.1038/ncb1109-1275.

26. Law M.E., Corsino P.E., Narayan S., Law B.K. Cyclin-dependent kinase inhibitors as anticancer therapeutics. Mol Pharmacol. 2015;88(5):846–852. doi: 10.1124/mol.115.099325.

27. Finn R.S., Crown J.P., Lang I., Boer K., Bondarenko I.M., Kulyk S.O. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35. doi: 10.1016/S1470-2045(14)71159-3.

28. Sledge G.W. Jr., Toi M., Neven P., Sohn J., Inoue K., Pivot X. et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–2884. doi: 10.1200/JCO.2017.73.7585.

29. Slamon D.J., Neven P., Chia S., Fasching P.A., De Laurentiis M., Im S.A. et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor Receptor 2–Negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465– 2472. doi: 10.1200/JCO.2018.78.9909.

30. Hortobagyi G.N., Stemmer S.M., Burris H.A., Yap Y.S., Sonke G.S., PaluchShimon S. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541–1547. doi: 10.1093/annonc/mdy155.

31. Jeruss J.S., Mittendorf E.A., Tucker S.L., Gonzalez-Angulo A.M., Buchholz T.A., Sahin A.A. et al. Combined use of clinical and pathologic staging variables to define outcomes for breast cancer patients treated with neoadjuvant therapy. J Clin Oncol. 2008;26(2):246–252. doi: 10.1200/JCO.2007.11.5352.

32. Scholzen T., Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–322. doi: 10.1002/(SICI)109736. Sinn H.P., Schneeweiss A., Keller M., Schlombs K., Laible M., Seitz J. et al. Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer. BMC Cancer. 2017;17(1):124. doi: 10.1186/s12885-017-3111-1.

33. Sobecki M., Mrouj K., Colinge J., Gerbe F., Jay P., Krasinska L. et al. CellCycle regulation accounts for variability in Ki-67 expression levels. Cancer Res. 2017;77(10):2722–2734. doi: 10.1158/0008-5472.CAN-16-0707.

34. Tang L.H., Gonen M., Hedvat C., Modlin I.M., Klimstra D.S. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol. 2012;36(12):1761–1770. doi: 10.1097/PAS.0b013e318263207c.

35. Prihantono P., Hatta M., Binekada C., Sampepajung D., Haryasena H., Nelwan B. et al. Ki-67 Expression by immunohistochemistry and quantitative real-time polymerase chain reaction as predictor of clinical response to neoadjuvant chemotherapy in locally advanced breast cancer. J Oncol. 2017;2017:6209849. doi: 10.1155/2017/6209849.

36. Sinn H.P., Schneeweiss A., Keller M., Schlombs K., Laible M., Seitz J. et al. Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer. BMC Cancer. 2017;17(1):124. doi: 10.1186/s12885-017-3111-1.

37. Lee A.H.S., Pinder S.E., Macmillan R.D., Mitchell M., Ellis I.O., Elston C.W., Blamey R.W. Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma. Eur J Cancer. 2006;42(3):357–362. doi: 10.1016/j.ejca.2005.10.021.

38. Rakha E.A., Martin S., Lee A.H., Morgan D., Pharoah P.D., Hodi Z. et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma: vascular invasion in breast cancer. Cancer. 2012;118(15):3670– 3680. doi: 10.1002/cncr.26711.

39. Hamy A.S., Lam G.T., Laas E., Darrigues L., Balezeau T., Guerin J. et al. Lymphovascular invasion after neoadjuvant chemotherapy is strongly associated with poor prognosis in breast carcinoma. Breast Cancer Res Treat. 2018;169(2):295–304. doi: 10.1007/s10549-017-4610-0.

40. Ellis M.J., Tao Y., Luo J., A’Hern R., Evans D.B., Bhatnagar A.S. et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100(19):1380–1388. doi: 10.1093/jnci/djn309.

41. Symmans W.F., Wei C., Gould R., Yu X., Zhang Y., Liu M. et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049– 1060. doi: 10.1200/JCO.2015.63.1010.

42. Jiang Y.Z., Yu K.D., Bao J., Peng W.T., Shao Z.M. Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. Cancer Res. 2014;74(13):3399–3407. doi: 10.1158/0008-5472.CAN-14-0092.

43. Wang R., Li X., Zhang H., Wang K., He J. Cell-free circulating tumor DNA analysis for breast cancer and its clinical utilization as a biomarker. Oncotarget. 2017;8:75742–75755. doi: 10.18632/oncotarget.20608.

44. Garcia-Murillas I., Schiavon G., Weigelt B., Ng C., Hrebien S., Cutts R.J. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133. doi: 10.1126/scitranslmed.aab0021.

45. Neumann M.H.D., Bender S., Krahn T., Schlange T. ctDNA and CTCs in liquid biopsy – current status and where we need to progress. Comput Struct Biotechnol J. 2018;16:190–195. doi: 10.1016/j.csbj.2018.05.002.

46. Chen Y.H., Hancock B.A., Solzak J.P., Brinza D., Scafe C., Miller K.D., Radovich M. Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. NPJ Breast Cancer. 2017;3:24–24. doi: 10.1038/s41523-017-0028-4.

47. Hwang W.T., Adams S.F., Tahirovic E., Hagemann I.S., Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192–198. doi: 10.1016/j.ygyno.2011.09.039.

48. Mao Y., Qu Q., Zhang Y., Liu J., Chen X., Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One. 2014;9(12):e115103. doi: 10.1371/journal.pone.0115103.

49. Solinas C., Ceppi M., Lambertini M., Scartozzi M., Buisseret L., Garaud S. et al. Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: a meta-analysis of randomized controlled trials. Cancer Treat Rev. 2017;57:8–15. doi: 10.1016/j.ctrv.2017.04.005.

50. Hamy A.S., Pierga J.Y., Sabaila A., Laas E., Bonsang-Kitzis H., Laurent C. et al. Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. Ann Oncol. 2017;28(9):2233–2240. doi: 10.1093/annonc/mdx309.

51. Dieci M.V., Criscitiello C., Goubar A., Viale G., Conte P., Guarneri V. et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol. 2014;25(3):611–618. doi: 10.1093/annonc/mdt556.

52. Bracci L., Schiavoni G., Sistigu A., Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25. doi: 10.1038/cdd.2013.67.

53. Seo A.N., Lee H.J., Kim E.J., Kim H.J., Jang M.H., Lee H.E. et al. Tumourinfiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013;109(10):2705–2713. doi: 10.1038/bjc.2013.634.

54. Kim C.H. FOXP3 and its role in the immune system. Adv Exp Med Biol. 2009;665:17–29. doi: 10.1007/978-1-4419-1599-3_2.

55. Ladoire S., Mignot G., Dabakuyo S., Arnould L., Apetoh L., Rébé C. et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224(3):389–400. doi: 10.1002/path.2866.

56. Liu F., Li Y., Ren M., Zhang X., Guo X., Lang R., Gu F, Fu L. Peritumoral FOXP3+ regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3+ regulatory T cell is prognostic predictor of breast cancer patients. Breast Cancer Res Treat. 2012;135(2):459–467. doi: 10.1007/s10549-012-2132-3.

57. Miyashita M., Sasano H., Tamaki K., Hirakawa H., Takahashi Y., Nakagawa S. et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res BCR. 2015;17(1):124. doi: 10.1186/s13058-015-0632-x.

58. Dieci M.V., Radosevic-Robin N., Fineberg S., van den Eynden G., Ternes N., Penault-Llorca F. et al. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol. 2018;52(2):16–25. doi: 10.1016/j.semcancer.2017.10.003.

59. Lai Y., Wei X., Lin S., Qin L., Cheng L., Li P. Current status and perspectives of patient-derived xenograft models in cancer research. J Hematol Oncol. 2017;10(1):106. doi: 10.1186/s13045-017-0470-7.

60. Pompili L., Porru M., Caruso C., Biroccio A., Leonetti C. Patient-derived xenografts: a relevant preclinical model for drug development. J Exp Clin Cancer Res. 2016;35(1):189. doi: 10.1186/s13046-016-0462-4.

61. Zhang X., Claerhout S., Prat A., Dobrolecki L.E., Petrovic I., Lai Q. et al. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res. 2013;73(15):4885–4897. doi: 10.1158/0008-5472.CAN-12-4081.

62. Yu J., Qin B., Moyer A.M., Sinnwell J.P., Thompson K.J., Copland J.A. 3rd et al. Establishing and characterizing patient-derived xenografts using prechemotherapy percutaneous biopsy and post-chemotherapy surgical samples from a prospective neoadjuvant breast cancer study. Breast Cancer Res. 2017;19(1):130. doi: 10.1186/s13058-017-0920-8.

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