Efficacy and safety of trastuzumab emtansine treatment in patients with metastatic HER-2 positive breast cancer: a single center study
Eficacia y seguridad del tratamiento con trastuzumab emtansina en pacientes con cáncer de mama metastásico HER-2 positivo: estudio de un solo centro
Eyyup Cavdar, Kubilay Karaboyun, Yakup Iriagac, Okan Avci, Erdoğan Selcuk Seber
Abstract
Introduction: Trastuzumab emtansine (T-DM1) is one of the effective treatment options in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. In this study, we aimed to find the effect of T-DM1 on survival, its tolerability and prognostic factors of T-DM1 treatment.
Material and methods: The study was designed as a single-center, retrospective study that included patients treated in the oncology department of a university hospital in Turkey. HER2-positive patients with metastatic breast cancer who had a progression response to trastuzumab and taxane treatment and received T-DM1 treatment for at least 2 months between 2016-2022 were included in the study. Adverse events were defined according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Kaplan-Meier methodology and Cox proportional hazard modelling were used for survival analyses.
Results: The median progression-free survival (mPFS) for T-DM1 was 10.4 months and the median overall survival (mOS) was 22 months. In the created univariate cox regression model, liver metastasis, ECOG performance status, and pre-treatment serum CA 15-3 were found to be factors associated with PFS. Liver metastasis (HR=2.54, p=0.019), ECOG performance status (HR=4.66, p=0.002), and serum CA 15-3 (HR= 2.55, p=0.041) maintained their statistical significance for PFS in the established multivariate analysis. In the regression analysis for OS, only ECOG performance status (HR= 2.61, p=0.023) was found to be prognostic. While toxicity occurred in 46 (82.1%) of the patients, grade 3-4 toxicity developed in 10 (17.9%) patients. The most common side effects were anemia, thrombocytopenia, fatigue and nausea.
Conclusions: T-DM1 is a safe and tolerable agent that prolongs survival. Liver metastasis, ECOG performance status, and pre-treatment serum CA 15-3 levels are independent prognostic factors for patients using T-DM1.
Keywords
Resumen
Introducción: Trastuzumab emtansina (T-DM1) es una de las opciones de tratamiento eficaces en pacientes con cáncer de mama positivo para el receptor 2 del factor de crecimiento epidérmico humano (HER2). En este estudio, nuestro objetivo fue encontrar el efecto de T-DM1 en la supervivencia, su tolerabilidad y los factores pronósticos del tratamiento con T-DM1.
Material y métodos: El estudio se diseñó como un estudio retrospectivo unicéntrico que incluyó pacientes tratados en el departamento de oncología de un hospital universitario en Turquía. Se incluyeron en el estudio pacientes HER2 positivas con cáncer de mama metastásico que tuvieron una respuesta progresiva al tratamiento con trastuzumab y taxanos y recibieron tratamiento con T-DM1 durante al menos 2 meses entre 2016 y 2022. Los eventos adversos se definieron de acuerdo con los Criterios de Terminología Común para Eventos Adversos v5.0 (CTCAE). Se utilizaron la metodología de Kaplan-Meier y el modelo de riesgos proporcionales de Cox para los análisis de supervivencia.
Resultados: La mediana de supervivencia libre de progresión (mPFS) para T-DM1 fue de 10,4 meses y la mediana de supervivencia general (mOS) fue de 22 meses. En el modelo de regresión de cox univariable creado, se encontró que la metástasis hepática, el estado funcional ECOG y el CA 15-3 sérico previo al tratamiento son factores asociados con la SLP. La metástasis hepática (HR = 2,54, p = 0,019), el estado funcional ECOG (HR = 4,66, p = 0,002) y el suero CA 15-3 (HR = 2,55, p = 0,041) mantuvieron su significación estadística para la SLP en el estudio multivariable establecido. análisis. En el análisis de regresión para OS, solo se encontró que el estado funcional ECOG (HR= 2.61, p=0.023) era pronóstico. Si bien se produjo toxicidad en 46 (82,1 %) de los pacientes, se desarrolló toxicidad de grado 3-4 en 10 (17,9 %) pacientes. Los efectos secundarios más comunes fueron anemia, trombocitopenia, fatiga y náuseas.
Conclusiones: T-DM1 es un agente seguro y tolerable que prolonga la supervivencia. La metástasis hepática, el estado funcional ECOG y los niveles séricos de CA 15-3 previos al tratamiento son factores pronósticos independientes para los pacientes que usan T-DM1.
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References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660.
2. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30(8):1194-220. doi: 10.1093/annonc/mdz173.
3. Hsu JY, Chang CJ, Cheng JS. Survival, treatment regimens and medical costs of women newly diagnosed with metastatic triple-negative breast cancer. Sci Rep. 2022;12(1):729. doi: 10.1038/s41598-021-04316-2.
4. Nader-Marta G, Martins-Branco D, de Azambuja E. How we treat patients with metastatic HER2-positive breast cancer. ESMO Open. 2022;7(1):100343. doi: 10.1016/j.esmoop.2021.100343.
5. Bartsch R, Bergen E. ASCO 2018: highlights in HER2-positive metastatic breast cancer. Memo. 2018;11(4):280-3. doi: 10.1007/s12254-018-0441-x.
6. Yin W, Jiang Y, Shen Z, Shao Z, Lu J. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One. 2011;6(6):e21030. doi: 10.1371/journal.pone.0021030.
7. Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-54. doi: 10.1016/S1470-2045(17)30313-3.
8. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128(2):347-56. doi: 10.1007/s10549-010-1090-x.
9. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776.
10. Kowalczyk L, Bartsch R, Singer CF, Farr A. Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients. Breast Care (Basel). 2017;12(6):401-8. doi: 10.1159/000480492.
11. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. 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;134(7):e48-72. doi: 10.5858/134.7.e48.
12. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91. doi: 10.1056/NEJMoa1209124.
13. Bahçeci A, Paydaş S, Ak N, Ferhatoğlu F, Saip PM, Seydaoğlu G, et al. Efficacy and Safety of Trastuzumab Emtansine in Her2 Positive Metastatic Breast Cancer: Real-World Experience. Cancer Invest. 2021;39(6-7):473-81. doi: 10.1080/07357907.2021.1933011.
14. Fabi A, De Laurentiis M, Caruso M, Valle E, Moscetti L, Santini D, et al. Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study. Oncotarget. 2017;8(38):64481-9. doi: 10.18632/oncotarget.16373.
15. Kacan T, Yucel B, Bahar S, Celasun G, Seker MM, Babacan N, et al. The prognostic value of high pretreatment plasma d-dimer levels in non-metastatic breast cancer patients with absence of venous thromboembolism. UHOD. 2016;26(3):136-44. doi: 10.4999/uhod.161266.
16. Griguolo G, Pouderoux S, Dieci MV, Jacot W, Bourgier C, Miglietta F, et al. Clinicopathological and Treatment-Associated Prognostic Factors in Patients with Breast Cancer Leptomeningeal Metastases in Relation to Tumor Biology. Oncologist. 2018;23(11):1289-99. doi: 10.1634/theoncologist.2018-0200.
17. Tataroglu Ozyukseler D, Basak M, Ay S, Koseoglu A, Arıcı S, Oyman A, et al. Prognostic factors of ado-trastuzumab emtansine treatment in patients with metastatic HER-2 positive breast cancer. J Oncol Pharm Pract. 2021;27(3):547-54. doi: 10.1177/1078155220924088.
18. Vici P, Pizzuti L, Michelotti A, Sperduti I, Natoli C, Mentuccia L, et al. A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience. Oncotarget. 2017;8(34):56921-31. doi: 10.18632/oncotarget.18176.
19. Jacot W, Pons E, Frenel JS, Guiu S, Levy C, Heudel PE, et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat. 2016;157(2):307-18. doi: 10.1007/s10549-016-3828-6.
20. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134-50. doi: 10.1200/JCO.2015.65.2289.
21. Shering SG, Sherry F, McDermott EW, O'Higgins NJ, Duffy MJ. Preoperative CA 15-3 concentrations predict outcome of patients with breast carcinoma. Cancer. 1998;83(12):2521-7.
22. Shao Y, Sun X, He Y, Liu C, Liu H. Elevated Levels of Serum Tumor Markers CEA and CA15-3 Are Prognostic Parameters for Different Molecular
Subtypes of Breast Cancer. PLoS One. 2015;10(7):e0133830. doi: 10.1371/journal.pone.0133830.
23. Albuquerque KV, Price MR, Badley RA, Jonrup I, Pearson D, Blamey RW, et al Pre-treatment serum levels of tumour markers in metastatic breast cancer: a prospective assessment of their role in predicting response to therapy and survival. Eur J Surg Oncol. 1995;21(5):504-9. doi: 10.1016/s0748-7983(95)96935-7.
24. Zhao HY, Gong Y, Ye FG, Ling H, Hu X. Incidence and prognostic factors of patients with synchronous liver metastases upon initial diagnosis of breast cancer: a population-based study. Cancer Manag Res. 2018;10:5937-50. doi: 10.2147/CMAR.S178395.
25. Rashid NS, Grible JM, Clevenger CV, Harrell JC. Breast cancer liver metastasis: current and future treatment approaches. Clin Exp Metastasis. 2021;38(3):263-77. doi: 10.1007/s10585-021-10080-4.
26. Llombart-Cussac A, Pivot X, Biganzoli L, Cortes-Funes H, Pritchard KI, Pierga JY, et al. A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial. Breast. 2014;23(5):656-62. doi: 10.1016/j.breast.2014.06.017.
27. Adam R, Aloia T, Krissat J, Bralet MP, Paule B, Giacchetti S, et al. Is liver resection justified for patients with hepatic metastases from breast cancer? Ann Surg. 2006;244(6):897-907; discussion 907-8. doi: 10.1097/01.sla.0000246847.02058.1b.
28. Noda-Narita S, Shimomura A, Kawachi A, Sumiyoshi-Okuma H, Sudo K, Shimoi T, et al. Comparison of the efficacy of trastuzumab emtansine between patients with metastatic human epidermal growth factor receptor 2-positive breast cancers previously treated with combination trastuzumab and pertuzumab and with trastuzumab only in Japanese population. Breast Cancer. 2019;26(4):492-8. doi: 10.1007/s12282-019-00949-4.
29. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380(7):617-28. doi: 10.1056/NEJMoa1814017.
30. Montemurro F, Ellis P, Anton A, Wuerstlein R, Delaloge S, Bonneterre J, et al. Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1. Eur J Cancer. 2019;109:92-102. doi: 10.1016/j.ejca.2018.12.022.
31. Cavdar E, Iriagac Y, Karaboyun K, Avci O, Seber ES. Prospective comparison of the value of CARG, G8, and VES-13 toxicity tools in predicting chemotherapy-related toxicity in older Turkish patients with cancer. J Geriatr Oncol. 2022;13(6):821-7. doi: 10.1016/j.jgo.2022.03.004.
32. Shen K, Ma X, Zhu C, Wu X, Jia H. Safety and Efficacy of Trastuzumab Emtansine in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: a Meta-analysis. Sci Rep. 2016;6:23262. doi: 10.1038/srep23262.
Submitted date:
07/23/2022
Reviewed date:
08/15/2022
Accepted date:
08/23/2022
Publication date:
08/23/2022
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