Проблема оценки эффективности неоадъювантной эндокринотерапии рака молочной железы и ее возможные решения: обзор литературы

Гормон-рецептор-позитивный рак молочной железы является наиболее распространенным подтипом заболевания и характеризуется значительной гетерогенностью клинического течения и ответа на терапию. Адъювантная эндокринотерапия с использованием ингибиторов ароматазы представляет собой высокоэффективную альтернативу химиотерапии у пациенток в постменопаузе, демонстрируя сопоставимые показатели клинического ответа с меньшей токсичностью. Несмотря на доказанную эффективность НЭТ в снижении объема опухоли и повышении частоты органосохраняющих операций, частота полного патоморфологического ответа при HR+/HER2– раке молочной железы остается низкой (10–20%). Прогнозирование того, какие пациенты с раком молочной железы отреагируют на лечение, остается сложной задачей. Отсутствие прогностической способности часто приводит к использованию нескольких линий терапии в поисках варианта, который обеспечит терапевтический ответ. В этой связи особое значение приобретают биомаркеры эффективности терапии, включая динамику индекса Ki67, прогностический индекс PEPI и мультигенные панели. В последние годы активно изучаются молекулярные механизмы эндокринорезистентности, включая мутации гена ESR1, активацию сигнальных путей PI3K/AKT/mTOR и изменения в регуляции клеточного цикла. Существенную роль в данных процессах играет посттранскрипционная регуляция экспрессии генов с участием микроРНК. Отдельные микроРНК (в частности, miR‑221/222, miR‑21, miR‑342) продемонстрировали ассоциацию с чувствительностью или резистентностью кэндокринной терапии ирассматриваются как потенциальные предиктивные биомаркеры. Особый интерес представляет анализ циркулирующих микроРНК, которые могут быть использованы в качестве минимально инвазивных маркеров для динамического мониторинга ответа налечение ираннего выявления эндокринорезистентности. Таким образом, интеграция клинических, морфологических и молекулярных параметров, включая профиль микроРНК, представляет собой перспективное направление для персонализации неоадъювантной эндокринотерапии и оптимизации лечебной стратегии у пациенток с HR+ раком молочной железы.

1. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S, Senkus E; ESMO Guidelines Committee. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019 Aug 1; 30 (8): 1194–1220. DOI: 10.1093/annonc/mdz173. PMID: 31161190

2. Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15; 110 (2): 244–54. DOI: 10.1002/cncr.22789. PMID: 17538978

3. Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, Moy B, Bardia A. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2016 Nov 1; 2 (11): 1477–1486. DOI: 10.1001/jamaoncol.2016.1897. PMID: 27367583; PMCID: PMC5738656

4. Cain H, Macpherson IR, Beresford M, Pinder SE, Pong J, Dixon JM. Neoadjuvant Therapy in Early Breast Cancer: Treatment Considerations and Common Debates in Practice. Clin Oncol (R Coll Radiol). 2017 Oct; 29 (10): 642–652. DOI: 10.1016/j.clon.2017.06.003. Epub 2017 Jun 29. PMID: 28669449

5. Morgan J, Wyld L, Collins KA, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev. 2014 May 19; 5 (5): CD004272. DOI: 10.1002/14651858.CD004272.pub3. PMID: 35658165; PMCID: PMC9645779

6. Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, Dube P, de Oliveira CT. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative «Arimidex» Compared to Tamoxifen (PROACT) trial. Cancer. 2006 May 15; 106 (10): 2095–103. DOI: 10.1002/cncr.21872. PMID: 16598749

7. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001 Nov; 12 (11): 1527–32. DOI: 10.1023/a:1013128213451. PMID: 11822750

8. Matthew J. Ellis, Andrew Coop, Baljit Singh, Louis Mauriac, Antonio Llombert-Cussac, Fritz Jänicke, William R. Miller, Dean B. Evans, MargaretDugan, Carolyn Brady, Erhard Quebe-Fehling, and Mieke Borgs. Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial. J Clin Oncol 19, 3808–3816 (2001). Volume 19, Number 18. DOI: 10.1200/JCO.2001.19.18.3808

9. Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, Nishimura R, Iwase H, Kamigaki S, Takei H, Noguchi S. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012 Apr; 13 (4): 345–52. DOI: 10.1016/S1470-2045 (11) 70373-4. Epub 2012 Jan 20. PMID: 22265697

10. Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G; IMPACT Trialists Group. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005 Aug 1; 23 (22): 5108–16. DOI: 10.1200/JCO.2005.04.005. Epub 2005 Jul 5. PMID: 15998903

11. Hurvitz SA, Martin M, Press MF, Chan D, Fernandez-Abad M, Petru E, Rostorfer R, Guarneri V, Huang CS, Barriga S, Wijayawardana S, Brahmachary M, Ebert PJ, Hossain A, Liu J, Abel A, Aggarwal A, Jansen VM, Slamon DJ. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer. Clin Cancer Res. 2020 Feb 1; 26 (3): 566–580. DOI: 10.1158/1078-0432.CCR-19-1425. Epub 2019 Oct 15. PMID: 31615937; PMCID: PMC7498177

12. Prat A, Saura C, Pascual T, Hernando C, Muñoz M, Paré L, González Farré B, Fernández PL, Galván P, Chic N, González Farré X, Oliveira M, Gil-Gil M, Arumi M, Ferrer N, Montaño A, Izarzugaza Y, Llombart-Cussac A, Bratos R, González Santiago S, Martínez E, Hoyos S, Rojas B, Virizuela JA, Ortega V, López R, Céliz P, Ciruelos E, Villagrasa P, Gavilá J. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020 Jan; 21 (1): 33–43. DOI: 10.1016/S1470-2045 (19) 30786-7. Epub 2019 Dec 11. PMID: 31838010.

13. Johnston S, Puhalla S, Wheatley D, Ring A, Barry P, Holcombe C, Boileau JF, Provencher L, Robidoux A, Rimawi M, McIntosh SA, Shalaby I, Stein RC, Thirlwell M, Dolling D, Morden J, Snowdon C, Perry S, Cornman C, Batten LM, Jeffs LK, Dodson A, Martins V, Modi A, Osborne CK, Pogue-Geile KL, Cheang MCU, Wolmark N, Julian TB, Fisher K, MacKenzie M, Wilcox M, Huang Bartlett C, Koehler M, Dowsett M, Bliss JM, Jacobs SA. Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. J Clin Oncol. 2019 Jan 20; 37 (3): 178–189. DOI: 10.1200/JCO.18.01624. Epub 2018 Dec 6. PMID: 30523750.

14. Cottu P, D’Hondt V, Dureau S, Lerebours F, Desmoulins I, Heudel PE, Duhoux FP, Levy C, Mouret-Reynier MA, Dalenc F, Frenel JS, Jouannaud C, Venat-Bouvet L, Nguyen S, Ferrero JM, Canon JL, Grenier J, Callens C, Gentien D, Lemonnier J, Vincent-Salomon A, Delaloge S. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018 Dec 1; 29 (12): 2334–2340. DOI: 10.1093/annonc/mdy448. PMID: 30307466.

15. Yao LT, Wang MZ, Wang MS, Yu XT, Guo JY, Sun T, Li XY, Xu YY. Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer. World J Clin Cases. 2019 Aug 6; 7 (15): 1937–1953. DOI: 10.12998/wjcc.v7.i15.1937. PMID: 31423426; PMCID: PMC6695538.

16. https://conferences.medicom-publishers.com/specialisation/oncology/esmo-2025-spotlight-on-breast-cancer/how-to-avoid-adjuvant-chemo-in-high-risk-er-her2-early-bc/

17. Khan JQ, O’Dea A, Bardia A, Kalinsky K, Wisinski KB, O’Regan R, Yuan Y. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). J Clin Oncol 38, 505(2020) Volume 38, Number 15_suppl DOI: 10.1200/JCO.2020.38.15_suppl.505

18. Burstein HJ, Curigliano G, Thürlimann B, Weber WP, Poortmans P, Regan MM, Senn HJ, Winer EP, Gnant M; Panelists of the St Gallen Consensus Conference. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021 Oct; 32 (10): 1216–1235. DOI: 10.1016/j.annonc.2021.06.023. Epub 2021 Jul 6. PMID: 34242744; PMCID: PMC9906308.

19. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC; American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010 Jul; 134 (7): e48–72. DOI: 10.5858/134.7.e48. PMID: 20586616.

20. Ellis MJ, Suman VJ, Hoog J, Goncalves R, Sanati S, Creighton CJ, DeSchryver K, Crouch E, Brink A, Watson M, Luo J, Tao Y, Barnes M, Dowsett M, Budd GT, Winer E, Silverman P, Esserman L, Carey L, Ma CX, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther JM, Dayao Z, Ota D, Leitch M, Olson JA Jr, Allred DC, Hunt K. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017 Apr 1; 35 (10): 1061–1069. DOI: 10.1200/JCO.2016.69.4406. Epub 2017 Jan 3. PMID: 28045625; PMCID: PMC5455353.

21. Suman VJ, Ellis MJ, Ma CX. The ALTERNATE trial: assessing a biomarker driven strategy for the treatment of post-menopausal women with ER+/Her2- invasive breast cancer. Chin Clin Oncol. 2015 Sep; 4 (3): 34. DOI: 10.3978/j.issn.2304-3865.2015.09.01. PMID: 26408301; PMCID: PMC4734643.

22. Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Morden J, Sidhu K, Dodson A, Bliss JM, Dowsett M. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443–1454. DOI: 10.1016/S1470–2045 (20) 30458-7. Erratum in: Lancet Oncol. 2020 Dec; 21 (12): e553. DOI: 10.1016/S1470-2045(20)30677-X. PMID: 33152284; PMCID: PMC7606901.

23. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018 Jul 12; 379 (2): 111–121. DOI: 10.1056/NEJMoa1804710. Epub 2018 Jun 3. PMID: 29860917; PMCID: PMC6172658.

24. Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, Pierga JY, Brain E, Causeret S, DeLorenzi M, Glas AM, Golfinopoulos V, Goulioti T, Knox S, Matos E, Meulemans B, Neijenhuis PA, Nitz U, Passalacqua R, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Sotiriou C, Stork L, Straehle C, Thomas G, Thompson AM, van der Hoeven JM, Vuylsteke P, Bernards R, Tryfonidis K, Rutgers E, Piccart M; MINDACT Investigators. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016 Aug 25; 375 (8): 717–29. DOI: 10.1056/NEJMoa1602253. PMID: 27557300.

25. Sestak I, Martín M, Dubsky P, Kronenwett R, Rojo F, Cuzick J, Filipits M, Ruiz A, Gradishar W, Soliman H, Schwartzberg L, Buus R, Hlauschek D, Rodríguez-Lescure A, Gnant M. Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone. Breast Cancer Res Treat. 2019 Jul; 176 (2): 377–386. DOI: 10.1007/s10549-019-05226-8. Epub 2019 Apr 30. PMID: 31041683; PMCID: PMC6555778.

26. Bear HD, Wan W, Robidoux A, Rubin P, Limentani S, White RL Jr, Granfortuna J, Hopkins JO, Oldham D, Rodriguez A, Sing AP. Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial. J Surg Oncol. 2017 Jun;115(8):917–923. DOI: 10.1002/jso.24610. Epub 2017 Apr 13. Erratum in: J Surg Oncol. 2018 Sep;118(4):722. DOI: 10.1002/jso.24798. Erratum in: J Surg Oncol. 2021 Oct; 124 (5): 914. DOI: 10.1002/jso.26625. PMID: 28407247; PMCID: PMC5481477.

27. Grazia Arpino et al. Circulating tumor DNA (ctDNA) and serum thymidine kinase 1 activity (TKa) matched dynamics in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2-) advanced breast cancer (ABC) treated in first-line (1L) with ribociclib (RIB) and letrozole (LET) in the BioItaLEE trial.. J Clin Oncol 40, 1012–1012 (2022). DOI:10.1200/JCO.2022.40.16_suppl.1012

28. Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic – implementation issues and future challenges. Nat Rev Clin Oncol. 2021 May; 18 (5): 297–312. DOI: 10.1038/s41571-020-00457-x. Epub 2021 Jan 20. PMID: 33473219.

29. Papakonstantinou A, Gonzalez NS, Pimentel I, Suñol A, Zamora E, Ortiz C, Espinosa-Bravo M, Peg V, Vivancos A, Saura C, Villacampa G, Oliveira M. Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: A systematic review and meta-analysis. Cancer Treat Rev. 2022 Mar; 104: 102362. DOI: 10.1016/j.ctrv.2022.102362. Epub 2022 Feb 18. PMID: 35219090.

30. Magbanua MJM, Swigart LB, Wu HT, Hirst GL, Yau C, Wolf DM, Tin A, Salari R, Shchegrova S, Pawar H, Delson AL, DeMichele A, Liu MC, Chien AJ, Tripathy D, Asare S, Lin CJ, Billings P, Aleshin A, Sethi H, Louie M, Zimmermann B, Esserman LJ, van ‘t Veer LJ. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann Oncol. 2021 Feb; 32 (2): 229–239. DOI: 10.1016/j.annonc.2020.11.007. Epub 2020 Nov 21. PMID: 33232761; PMCID: PMC9348585.

31. Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I, Garrido JA, Dowsett M, Reis-Filho JS, Smith IE, Turner NC. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015 Aug 26; 7 (302): 302ra133. DOI: 10.1126/scitranslmed.aab0021. PMID: 26311728.

32. McDonald BR, Contente-Cuomo T, Sammut SJ, Odenheimer-Bergman A, Ernst B, Perdigones N, Chin SF, Farooq M, Mejia R, Cronin PA, Anderson KS, Kosiorek HE, Northfelt DW, McCullough AE, Patel BK, Weitzel JN, Slavin TP, Caldas C, Pockaj BA, Murtaza M. Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. Sci Transl Med. 2019 Aug 7; 11 (504): eaax7392. DOI: 10.1126/scitranslmed.aax7392. PMID: 31391323; PMCID: PMC7236617.

33. Cailleux F, Agostinetto E, Lambertini M, Rothé F, Wu HT, Balcioglu M, Kalashnikova E, Vincent D, Viglietti G, Gombos A, Papagiannis A, Veys I, Awada A, Sethi H, Aleshin A, Larsimont D, Sotiriou C, Venet D, Ignatiadis M. Circulating Tumor DNA After Neoadjuvant Chemotherapy in Breast Cancer Is Associated With Disease Relapse. JCO Precis Oncol. 2022 Sep; 6: e2200148. DOI: 10.1200/PO.22.00148. PMID: 36170624.

34. Iorio, M.V., Croce, C.M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 4, 143–159 (2012). https://doi.org/10.1002/emmm.201100209

35. He, L., Hannon, G. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522–531 (2004). https://doi.org/10.1038/nrg1379

36. Reddy, K.B. MicroRNA (miRNA) in cancer. Cancer Cell Int 15, 38 (2015). https://doi.org/10.1186/s12935-015-0185-1

37. Takahashi R, Miyazaki H and Ochiya T (2014) The role of microRNAs in the regulation of cancer stem cells. Front. Genet. 4:295. DOI: 10.3389/fgene.2013.00295

38. Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019 Jan; 20 (1): 21–37. DOI: 10.1038/s41580-018-0045-7. PMID: 30108335; PMCID: PMC6546304.

39. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006 Nov; 6 (11): 857–66. DOI: 10.1038/nrc1997. PMID: 17060945.

40. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010 Sep; 11 (9): 597–610. DOI: 10.1038/nrg2843. Epub 2010 Jul 27. PMID: 20661255.

41. Lou W, Liu J, Gao Y, Zhong G, Ding B, Xu L, Fan W. MicroRNA regulation of liver cancer stem cells. Am J Cancer Res. 2018 Jul 1; 8 (7): 1126–1141. PMID: 30094089; PMCID: PMC6079154.

42. Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, Onuchic JN and Levine H (2015) Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front. Oncol. 5: 155. DOI: 10.3389/fonc.2015.00155

43. Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008 May 30; 283 (22): 14910–4. DOI: 10.1074/jbc.C800074200. Epub 2008 Apr 14. PMID: 18411277; PMCID: PMC3258899.

44. Ma, L., Young, J., Prabhala, H. et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12, 247–256 (2010). https://doi.org/10.1038/ncb2024

45. Liang, YK., Lin, HY., Dou, XW. et al. MiR-221/222 promote epithelial-mesenchymal transition by targeting Notch3 in breast cancer cell lines. npj Breast Cancer 4, 20 (2018). https://doi.org/10.1038/s41523-018-0073-7

46. Campos, A.; Sharma, S.; Obermair, A.; Salomon, C. Extracellular Vesicle-Associated miRNAs and Chemoresistance: A Systematic Review. Cancers 2021, 13, 4608. https://doi.org/10.3390/cancers13184608

47. Rodríguez-Martínez A, de Miguel-Pérez D, Ortega FG, García-Puche JL, Robles-Fernández I, Exposito J, Martorell-Marugan J, Carmona-Sáez P, Garrido-Navas MDC, Rolfo C, Ilyine H, Lorente JA, Legueren M, Serrano MJ. Exosomal miRNA profile as complementary tool in the diagnostic and prediction of treatment response in localized breast cancer under neoadjuvant chemotherapy. Breast Cancer Res. 2019 Feb 6; 21 (1): 21. DOI: 10.1186/s13058-019-1109-0. PMID: 30728048; PMCID: PMC6366103.

48. Patellongi I, Amiruddin A, Massi MN, Islam AA, Pratama MY, Sutandyo N, Latar NHM, Faruk M. Circulating miR-221/222 expression as microRNA biomarker predicting tamoxifen treatment outcome: a case-control study. Ann Med Surg (Lond). 2023 Jul 10; 85 (8): 3806–3815. DOI: 10.1097/MS9.0000000000001061. PMID: 37554919; PMCID: PMC10406100.

49. Al Hashami ZS, van der Vegt B, Mourits MJE, Kluiver J, van den Berg A. miRNA-dependent resistance mechanisms to anti-hormonal therapies in estrogen receptor-positive breast cancer patients. Mol Ther Oncol. 2025 Jan 28; 33 (1): 200941. DOI: 10.1016/j.omton.2025.200941. PMID: 40190354; PMCID: PMC11969448.

50. Shang C, Chen Q, Zu F, Ren W. Integrated analysis identified prognostic microRNAs in breast cancer. BMC Cancer. 2022 Nov 12; 22 (1): 1170. DOI: 10.1186/s12885-022-10242-x. PMID: 36371182; PMCID: PMC9652801.

51. Ouyang YX, Feng J, Wang Z, Zhang GJ, Chen M. miR-221/222 sponge abrogates tamoxifen resistance in ER-positive breast cancer cells through restoring the expression of ERα. Mol Biomed. 2021 Jun 30; 2 (1): 20. DOI: 10.1186/s43556-021-00045-0. PMID: 35006452; PMCID: PMC8607419.

52. Davey MG, Abbas R, Kerin EP, Casey MC, McGuire A, Waldron RM, Heneghan HM, Newell J, McDermott AM, Keane MM, Lowery AJ, Miller N, Kerin MJ. Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer. Breast Cancer Res Treat. 2023 Nov; 202 (1): 73–81. DOI: 10.1007/s10549-023-07033-8. Epub 2023 Aug 4. PMID: 37540289; PMCID: PMC10504160.

53. Treeck, O.; Haerteis, S.; Ortmann, O. Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer. Cancers 2023, 15, 1632. https://doi.org/10.3390/cancers15061632

54. Lettlova S, Brynychova V, Blecha J, Vrana D, Vondrusova M, Soucek P, Truksa J. MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERα Positive Breast Cancer. Cell Physiol Biochem. 2018; 46 (6): 2601–2615. DOI: 10.1159/000489687. Epub 2018 May 7. PMID: 29763890.

55. Kim, T., Croce, C.M. MicroRNA: trends in clinical trials of cancer diagnosis and therapy strategies. Exp Mol Med 55, 1314–1321 (2023). https://doi.org/10.1038/s12276-023-01050-9

56. Ryspayeva, D., Halytskiy, V., Kobyliak, N. et al. Response to neoadjuvant chemotherapy in breast cancer: do microRNAs matter?. Discov Onc 13, 43 (2022). https://doi.org/10.1007/s12672-022-00507-z

57. Pridko O, Borikun T, Rossylna O, Rusyn AV. Association of miRNA expression pattern with outcome of letrozole therapy in breast cancer patients. Exp Oncol. 2023 Oct 11; 45 (2): 180–186. DOI: 10.15407/exp-oncology.2023.02.180. PMID: 37824774.

58. Howard, E.W., Yang, X. microRNA Regulation in Estrogen Receptor-Positive Breast Cancer and Endocrine Therapy. Biol Proced Online 20, 17 (2018). https://doi.org/10.1186/s12575-018-0082-9

59. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, Kulke MH, Baird RD, Prabhu JS, Carbone D, Pecoraro C, Teh DBL, Sethi G, Cavalieri V, Lin KH, Javidi-Sharifi NR, Toska E, Davids MS, Brown JR, Diana P, Stebbing J, Fruman DA, Kumar AP. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023 Aug 18; 22 (1): 138. DOI: 10.1186/s12943-023-01827-6. PMID: 37596643; PMCID: PMC10436543.

60. Di Martino MT, Tagliaferri P, Tassone P. MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications. J Exp Clin Cancer Res. 2025 Apr 21; 44 (1): 126. DOI: 10.1186/s13046-025-03391-x. PMID: 40259326; PMCID: PMC12010629.