Prospective evaluation of the cardiotoxicity profile of modern anthracycline-free therapy regimens for HER2-positive breast cancer

Aim. To evaluate the incidence, profile, and predictors of cardiotoxicity associa­ted with anti-HER2 therapy in patients with newly diagnosed HER2-positive breast cancer receiving modern anthracycline-free regimens.

Material and methods. The prospective study included 133 patients primarily receiving the TCHP regimen (taxanes, carboplatin, trastuzumab, pertuzumab). The pre-treatment examination protocol and then every 3 months during antitumor therapy included echocardiography with assessment of global left ventricular longitudinal strain, determination of natriuretic peptide and high-sensitivity troponin I, and risk stratification using the HFA-ICOS score.

Results. Complications developed in 11 patients (8%). The most common complications were hypertension (HTN) destabilization, hydropericardium, and subclinical myocardial injury. The HFA-ICOS score demonstrated low sensitivity (27%). In multivariate analysis, left ventricular mass index (LVMI) was the only independent predictor of cardiotoxicity (odds ratio=1,037 per 1 g/m²; 95% confidence interval: 1,010-1,064; p=0,007). A LVMI cutoff value of ≥83,5 g/m² had a sensitivity of 64% and a specificity of 74%. HTN control was the key modifiable risk factor as follows: achieving target blood pressure before treatment was associated with a more than fivefold reduction in the risk of complications (odds ratio=0,20; 95% confidence interval: 0,03-1,15; p=0,087).

Conclusion. With anthracycline-free therapy, the profile of complications is dominated by HTN destabilization, hydropericardium, and subclinical myocardial injury. The HFA-ICOS score has limited prognostic value. These results suggest that LVMI should be considered as a parameter in the initial cardio-oncology evaluation to improve risk stratification.

1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. doi:10.1126/science.3798106.

2. Slamon DJ, Leyland-Jones B, Shak S, 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):783-92. doi:10.1056/NEJM200103153441101.

3. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215-21. doi:10.1200/JCO.2002.20.5.1215.

4. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195-205. doi:10.1016/S0140-6736(16)32616-2.

5. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020;7:26. doi:10.3389/fcvm.2020.00026.

6. Yu AF, Mukku RB, Verma S, et al. Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer. Breast Cancer Res Treat. 2017;166(1):241-7. doi:10.1007/s10549-017-4362-x.

7. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377(2):122-31. doi:10.1056/NEJMoa1703643.

8. Mamedov MN, Karimov AK, Saribekyan EK, et al. Risk factors and prevention of cardiovascular complications in breast cancer. Cardiovascular Therapy and Prevention. 2024;23(12):4194. (In Russ.) doi:10.15829/1728-8800-2024-4194.

9. Herrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022;43(4):280-99. doi:10.1093/eurheartj/ehab674.

10. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020;22(11):1945-60. doi:10.1002/ejhf.1920.

11. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229-361. doi:10.1093/eurheartj/ehac244.

12. Di Lisi D, Madaudo C, Faro DC, et al. The added value of the HFA/ICOS score in the prediction of chemotherapy-related cardiac dysfunction in breast cancer. J Cardiovasc Med (Hagerstown). 2024;25(3):218-24. doi:10.2459/JCM.0000000000001589.

13. Cronin M, Crowley A, Davey MG, et al. Heart Failure Association-International Cardio-Oncology Society Risk Score Validation in HER2-Positive Breast Cancer. J Clin Med. 2023;12(4):1278. doi:10.3390/jcm12041278.

14. Nguyen HH, Giang NM, Vo DT, et al. Decoding anthracycline- and trastuzumab-related cardiac dysfunction prediction: HFA-ICOS scores versus strain imaging. ESC Heart Fail. 2025;12(5):3667-77. doi:10.1002/ehf2.15399.

15. Brodskaya TA, Geltser BI, Satalkina TS, et al. Hypertension and breast cancer in women: mechanisms of comorbidity and drug iatrogenism. "Arterial’naya Gipertenziya" ("Arte­rial Hypertension"). 2022;28(2):147-56. (In Russ.) doi:10.18705/1607-419X-2022-28-2-147-156.

16. Gynnild MN, Vinje-Jakobsen V, Holtrop J, et al. Prognostic Performance of a Modified HFA-ICOS Tool for Prediction of Cardiovascular Complications in Cancer Patients. JACC Adv. 2025;4(12 Pt 2):102344. doi:10.1016/j.jacadv.2025.102344.

17. Semb KA, Aamdal S, Oian P. Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. Journal of Clinical Oncology. 1998;16(10):3426-32. doi:10.1200/jco.1998.16.10.3426.

18. Dogan SE, Mizrak D, Alkan A, Demirkazik A. Docetaxel-induced pericardial effusion. J Oncol Pharm Pract. 2017;23(5):389-91. doi:10.1177/1078155216643859.

19. Vincenzi B, Santini D, Frezza AM, et al. Docetaxel induced pericardial effusion. J Exp Clin Cancer Res. 2007;26(3):417-20.