Расширяя возможности терапии HER2-low метастатического рака молочной железы: опыт применения трастузумаба дерукстекана при агрессивном течении люминального HER2-low рака молочной железы

Полярное деление рака молочной железы на HER2-позитивный и HER2-негативный подтипы длительное время оставалось клинически обоснованным. Однако до 60% HER2-негативных опухолей имеют экспрессию рецептора HER2, определяемую при иммуногистохимическом исследовании на 1+ или 2+. В отсутствие амплификации гена такие опухоли относят к HER2-low. Попытки применения классических анти-HER2-агентов не улучшали результатов лечения для этих опухолей. Разработка конъюгата «антитело – цитостатик» нового поколения трастузумаба дерукстекана, нацеленного на рецептор HER2, меняет диагностические подходы и клиническую практику лечения метастатического HER2-low рака молочной железы. Настоящей революцией стали результаты исследования III фазы DESTINY-Breast04 по изучению трастузумаба дерукстекана у больных метастатическим раком молочной железы с низкой экспрессией HER2. Медиана выживаемости без прогрессирования в когорте пациентов, получавших трастузумаб дерукстекан, составила 9,9 мес. против 5,1 мес. в группе пациентов, получавших стандартную химиотерапию по выбору врача (ОР 0,50; 95% ДИ 0,40–0,63, P < 0,001), медиана общей выживаемости – 23,4 мес. против 16,8 мес. соответственно (ОР 0,64; 95% ДИ 0,48–0,86, P = 0,003). Объективный ответ на фоне терапии трастузумабом дерукстеканом зафиксирован в 52,3% случаев против 16,3% в группе стандартного лечения. Терапия новым препаратом продемонстрировала благоприятный профиль безопасности и не снижала качество жизни пациентов. В данной публикации мы представляем собственный опыт лечения трастузумабом дерукстеканом пациентки с метастатическим люминальным HER2-low раком молочной железы. Несмотря на агрессивное течение, количество предшествующих линий терапии и массивное поражение печени, применение трастузумаба дерукстекана позволило в течение 2 лет контролировать болезнь при сохранении высокого качества жизни пациентки. Трастузумаб дерукстекан – это новая эффективная опция для лечения HER2-low метастатического рака молочной железы.

1. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–119. https://doi.org/10.1056/nejmoa1113216.

2. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–734. https://doi.org/10.1056/NEJMoa1413513.

3. Nicolò E, Zagami P, Curigliano G. Antibody-drug conjugates in breast cancer: the chemotherapy of the future? Curr Opin Oncol. 2020;32(5):494–502. https://doi.org/10.1097/CCO.0000000000000656.

4. Chen Z, Jia H, Zhang H, Chen L, Zhao P, Zhao J et al. Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients. Breast Cancer Res Treat. 2023;202(2):313–323. https://doi.org/10.1007/s10549-023-07079-8.

5. Schettini F, Chic N, Brasó-Maristany F, Paré L, Pascual T, Conte B et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(1):1. https://doi.org/10.1038/s41523-020-00208-2.

6. Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020;38(17):1951–1962. https://doi.org/10.1200/JCO.19.02488.

7. Chen Z, Jia H, Zhang H, Chen L, Zhao P, Zhao J et al. Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients. Breast Cancer Res Treat. 2023;202(2):313–323. https://doi.org/10.1007/s10549-023-07079-8.

8. Franchina M, Pizzimenti C, Fiorentino V, Martini M, Ricciardi GRR, Silvestris N et al. Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes. Int J Mol Sci. 2023;24(16):12795. https://doi.org/10.3390/ijms241612795.

9. Horisawa N, Adachi Y, Takatsuka D, Nozawa K, Endo Y, Ozaki Y et al. The frequency of low HER2 expression in breast cancer and a comparison of prognosis between patients with HER2-low and HER2-negative breast cancer by HR status. Breast Cancer. 2022;29(2):234–241. https://doi.org/10.1007/s12282-021-01303-3.

10. Tarantino P, Jin Q, Tayob N, Jeselsohn RM, Schnitt SJ, Vincuilla J et al. Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer. JAMA Oncol. 2022;8(8):1177–1183. https://doi.org/10.1001/jamaoncol.2022.2286.

11. Xu H, Han Y, Wu Y, Wang Y, Li Q, Zhang P et al. Clinicopathological Characteristics and Prognosis of HER2-Low Early-Stage Breast Cancer: A Single-Institution Experience. Front Oncol. 2022;12:906011. https://doi.org/10.3389/fonc.2022.906011.

12. Won HS, Ahn J, Kim Y, Kim JS, Song JY, Kim HK et al. Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res. 2022;24(1):22. https://doi.org/10.1186/s13058-022-01519-x.

13. Jacot W, Maran-Gonzalez A, Massol O, Sorbs C, Mollevi C, Guiu S et al. Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers. Cancers (Basel). 2021;13(23):6059. https://doi.org/10.3390/cancers13236059.

14. Tan RSYC, Ong WS, Lee KH, Lim AH, Park S, Park YH et al. HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med. 2022;20(1):105. https://doi.org/10.1186/s12916-022-02284-6.

15. Peiffer DS, Zhao F, Chen N, Hahn OM, Nanda R, Olopade OI et al. Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database. JAMA Oncol. 2023;9(4):500–510. https://doi.org/10.1001/jamaoncol.2022.7476.

16. De Calbiac O, Lusque A, Mailliez A, Bachelot T, Uwer L, Mouret-Reynier MA et al. Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France. JAMA Netw Open. 2022;5(9):e2231170. https://doi.org/10.1001/jamanetworkopen.2022.31170.

17. Guven DC, Sahin TK. The association between HER2-low status and survival in patients with metastatic breast cancer treated with Cyclin-dependent kinases 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer Res Treat. 2024;204(3):443–452. https://doi.org/10.1007/s10549-023-07226-1.

18. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–726. https://doi.org/10.1200/JCO.2002.20.3.719.

19. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792. https://doi.org/10.1056/NEJM200103153441101.

20. Mass RD, Press MF, Anderson S, Cobleigh MA, Vogel CL, Dybdal N et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005;6(3):240–246. https://doi.org/10.3816/CBC.2005.n.026.

21. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–1684. https://doi.org/10.1056/NEJMoa052122.

22. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–3752. https://doi.org/10.1200/JCO.2014.55.5730.

23. Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358(13):1409–1411. https://doi.org/10.1056/NEJMc0801440.

24. Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307–4315. https://doi.org/10.1200/JCO.2009.26.2154.

25. Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibodydependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94(2):259–267. https://doi.org/10.1038/sj.bjc.6602930.

26. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–446. https://doi.org/10.1038/74704.

27. Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN et al. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020;38(5):444–453. https://doi.org/10.1200/JCO.19.01455.

28. Лубенникова ЕВ, Артамонова ЕВ. Трастузумаб дерукстекан – новая эпоха терапии метастатического рака молочной железы. Медицинский совет. 2023;(11):26–33. https://doi.org/10.21518/ms2023-192.

29. Mosele MF, Lusque A, Dieras V, Deluche E, Ducoulombier A, Pistilli B et al. LBA1 Unraveling the mechanism of action and resistance to trastuzumab deruxtecan (T-DXd): Biomarker analyses from patients from DAISY trial. Ann Oncol. 2022;33(Suppl. 3):S123. https://doi.org/10.1016/j.annonc.2022.03.277.

30. Diéras V, Deluche E, Lusque A, Pistilli B, Bachelot T, Pierga JY et al. Abstract PD8-02: Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY). Cancer Res. 2022;82(Suppl. 4):PD8-02. https://doi.org/10.1158/1538-7445.SABCS21-PD8-02.

31. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9–20. https://doi.org/10.1056/NEJMoa2203690.

32. Modi S, Jacot W, Iwata H, Park YH, Vidal Losada MJ, Li W et al. 376O Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Updated survival results of the randomized, phase III DESTINY-Breast04 study. Ann Oncol. 2023;34(Suppl. 2):S334–S335. https://doi.org/10.1016/j.annonc.2023.09.553.

33. Andre F, Hamilton EP, Loi S, Im SA, Sohn J, Tseng LM et al. Dose-finding and -expansion studies of trastuzumab deruxtecan in combination with other anti-cancer agents in patients (pts) with advanced/metastatic HER2+ (DESTINY-Breast07 [DB-07]) and HER2-low (DESTINY-Breast08 [DB-08]) breast cancer (BC). J Clin Oncol. 2022;40(16 Suppl.):3025. https://doi.org/10.1200/JCO.2022.40.16_suppl.3025.

34. Hurvitz SA, Wang LS, Chan D, Phan V, Lomis T, McAndrew NP et al. TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early-stage breast cancer. J Clin Oncol. 2022;40(16 Suppl.):TPS623. https://doi.org/10.1200/ JCO.2022.40.16_suppl.TPS623.

35. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12(5):320–327. https://doi.org/10.1016/s0960-9776(03)00106-1.

36. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382(6):514–524. https://doi.org/10.1056/NEJMoa1911149.

37. Cersosimo RJ. Cyclin-dependent kinase 4/6 inhibitors for the management of advanced or metastatic breast cancer in women. Am J Health Syst Pharm. 2019;76(16):1183–1202. https://doi.org/10.1093/ajhp/zxz121.

38. Rugo HS, Cristofanilli M, Loibl S, Harbeck N, DeMichele A, Iwata H et al. Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3. Oncologist. 2021;26(8):e1339–e1346. https://doi.org/10.1002/onco.13833.

39. Yeung C, Hilton J, Clemons M, Mazzarello S, Hutton B, Haggar F et al. Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours – a review. Cancer Metastasis Rev. 2016;35(3):427–437. https://doi.org/10.1007/s10555-016-9631-3.

40. Anderson S, Bartow BB, Siegal GP, Huang X, Wei S. The dynamics of HER2low expression during breast cancer progression. Breast Cancer Res Treat. 2023;201(3):437–446. https://doi.org/10.1007/s10549-023-07020-z.

41. Almstedt K, Krauthauser L, Kappenberg F, Wagner DC, Heimes AS, Battista MJ et al. Discordance of HER2-Low between Primary Tumors and Matched Distant Metastases in Breast Cancer. Cancers (Basel). 2023;15(5):1413. https://doi.org/10.3390/cancers15051413.