Problems of Radiation Medicine and Radiobiology

S. M. Kozhukhov¹, N. V. Dovganych¹, I. I. Smolanka², O. F. Lygyrda², О. Ye. Bazyka¹,
S. A. Lyalkin², O. M. Ivankova², O. A. Yarinkina¹, N. V. Tkhor¹

¹ National Scientific Center «The M.D. Strazhesko Institute of Cardiology», 5 Narodnoho Opolchennia
Str., Kyiv, 03680, Ukraine
² National Cancer Institute of the Ministry of Health of Ukraine, 33/43 Lomonosova Str., Kyiv, 03022,
Ukraine

CARDIOTOXICITY RISK PREDICTION IN BREAST CANCER PATIENTS

Breast cancer patients receive combined antitumor treatment (surgery, chemotherapy, targeted drugs and radiation), so they are considered to be the patients with potentially high risk of cardiotoxicity (CT). Risk stratification of cardiovascular complications before the beginning and during the cancer treatment is an important issue.
Objective: to develop a CT risk model score taking into account cardiological, oncological and individual risks.
Material and methods. The study included 52 breast cancer patients with retrospective analysis of their medical history, risk factors, and echocardiographic parameters before the onset and in 12 months follow up. Based on the analysis of the data, a CT risk model score was developed and recommended. The patients were divided into groups according to the score: Group 1 – low risk of CT development – score ≤ 4 points, Group 2 – moderate risk – 5–7 points, Group 3 – high risk ≥ 8 points. According to the scale, BC patients with a total of ≥ 8 points are considered to be at high risk for CT complications. Radiation therapy and anthracyclines, as well as associated cardiovascular diseases were the most important risk factors of CT.
Results. Based on the study of retrospective analysis of risk factors, data of heart function monitoring during follow-up, the risk model score of cardiotoxicity has been developed for the BC patients’ stratification. According to the proposed score risk model, BC patients with a total score of ≥ 8 points considered to have high risk of cardiotoxic complications.
Conclusions. Using of the proposed risk model score with calculation of CT risk factors both before the beginning and during cancer therapy is important, because it allows predicting the risk of CT development – to identify highrisk patients, accordingly, to develop an individualized plan for cardiac function monitoring and to start timely cardioprotective therapy.
Key words: breast cancer, cardiotoxicity, heart failure, risk scale, prognosis.

Problems of Radiation Medicine and Radiobiology.
2021;26:498-512. doi: 10.33145/2304-8336-2021-26-498-512

full text

1. Bulletin of the National Cancer Registry of Ukraine. Kyiv; 2019. No. 20. 130 p.
2. Curigliano G, Cardinale D, Dent S, Criscitiello C, Aseyev O, Lenihan D, Cipolla CM. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA Cancer J Clin. 2016;66:309-325. doi: 10.3322/caac.21341.
3. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015;12(9):620-625. doi: 10.1038/nrcardio.2015.65.
4. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768-2801. doi: 10.1093/ eurheartj/ehw211.
5. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31(2):171-190. doi: 10.1016/j.annonc.2019.10.023.
6. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018;29(8):1634-1657. doi: 10.1093/annonc/mdy192.
7. Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol. 2008;26(8):1231-1238. doi: 10.1200/JCO.2007.13.5467.
8. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18(11):1639-1642. doi: 10.1038/nm.2919.
9. Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;(10):337. doi: 10.1186/1471-2407-10-337.
10. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol. 2012;23 Suppl 7:vii155-66. doi: 10.1093/annonc/mds293.
11. Khouri MG, Douglas PS, Mackey JR, Martin M, Scott JM, Scherrer-Crosbie M, Jones LW. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation. 2012;126(23):2749-2763. doi: 10.1161/CIRCULATIONAHA.112.100560.
12. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of anthracyclines. Front Cardiovasc Med. 2020;7:26. doi:10.3389/fcvm.2020.00026.
13. Debiasi M, Polanczyk CA, Ziegelmann P, Barrios C, Cao H, Dignam JJ, et al. Efficacy of anti-HER2 agents in combination with adjuvant or neoadjuvant chemotherapy for early and locally advanced HER2-positive breast cancer patients: a network meta-analysis. Front Oncol. 2018;8:156. doi: 10.3389/fonc.2018.00156.
14. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28(25):3910-3916. doi: 10.1200/JCO.2009.27.3615.
15. Truong J, Yan AT, Cramarossa G, Chan KK. Chemotherapy-induced cardiotoxicity: detection, prevention, and management. Can J Cardiol. 2014;30(8):869-878. doi: 10.1016/j.cjca.2014.04.029.
16. Sawyer DB, Peng X, Chen B, Pentassuglia L, Lim CC. Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis. 2010;53(2):105-113. doi: 10.1016/j.pcad.2010.06.007.
17. Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 ? 2 factorial, randomized, placebo- controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671-1680. doi: 10.1093/eurheartj/ehw022.
18. Darby SC, Ewertz M, McGale P, Bennet AM Blom-Goldman U, Bronnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987-998. doi: 10.1056/NEJMoa1209825.
19. Kozhukhov S, Bazyka O, Dovganych N, Yarinkina O, Tkhor N. Radiation-associated cardiovascular complications: a review. Probl Radiac Med Radiobiol. 2020;25:56-74. doi:10.33145/2304-8336-2020-25-56-74
20. Paiva PF, Soares AA, Pinheiro GS, Paiva CV, Fabri GM, Paiva EG, et al. Heart valve injury induced by mediastinum radiotherapy in cancer treatment. J Pharmacy Pharmacology. 2018;6(6):578-586. doi: 10.17265/2328-2150/2018.06.004.
21. Bouillon K, Haddy N, Delaloge S, Garbay JR, Garsi JP, Brindel P, et al. Long-term cardiovascular mortality after radiotherapy for breast cancer. J Am Coll Cardiol. 2011;57(4):445-452. doi: 10.1016/j.jacc.2010.08.638.
22. Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35:893-911. doi: 10.1200/JCO. 2016.70.5400.
23. Kozhukhov SM, Dovganich NV, Smolanka II, Ligirda OF, Yarynkina OYa, Ivankova OM. Cardiovascular toxicity in brest cancer patient: diagnosis, treatment, prevention. Ukrainian Journal of Cardiology. 2021;28(1):67-80. doi: 10.31928/1608-635X-2021.1.6780.
24. Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. 2013;31(29):3673-3680. doi: 10.1200/JCO.2013.49.3205.
25. Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc. 2014;89(9):1287-1306. doi: 10.1016/j.mayocp.2014.05.013.
26. Lyon AR, Dent S, Stanway S, Earl H, Brezden-Masley C, Cohen-Solal A, 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):1945-1960. doi:10.1002/ejhf.1920.
27. Ezaz G, Long JB, Gross CP, Chen J. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J. Am. Heart Assoc. 2014;3(1):e000472. doi: 10.1161/JAHA.113.000472.
28. Guenancia C, Lefevbvre A, Cardinale D, Yu AF, Ladoire S, Ghiringhelli F, et al. Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis. J Clin Oncol. 2016;34(26):3157-3165. doi: 10.1200/JCO.2016.67.4846.
29. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39.e14. doi: 10.1016/j.echo.2014.10.003.
30. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2014;15:1063-1093. doi: 10.1016/j.echo.2014.07.012.