Cardiotoxicity of trastuzumab adjuvant treatment in positive HER2 breast cancer

Abstract

Purpose: Adjuvant Trastuzumab (TRS) improves survival in patients (pts) with HER2-positive Breast Cancer (BC) but at the cost of significant cardiotoxicity. We prospectively assessed TRS-related cardiotoxicity to familiarize with its nature. Methods: Two hundred fifty three women with HER2 positive BC, treated with TRS in adjuvant setting from 01.03.2008 to 01.06 2011 were observed prospectively. Transthoracic echocardiography was performed initially, every three months during TRS treatment and every six months after TRS termination to determine LVEF fluctuations. Cardiotoxicity was defined as each drop of LVEF by >15% points or any drop below 50%. Results: Forty six (18%) women presented with cardiotoxicity. In 1 women LBBB, in 2 RBBB, in 2 negative T-waves in ECG were observed. Out of 46 women 13 (28%) met criteria of cardiotoxicity after 3 months, 22 (48%) after 6 months; 9 (20%) after 9 months and 5 (11%) after 12 months of treatment. TRS was early terminated in 41 pts. Median time to termination was 26,2 weeks (4-52); mean time 25+/-12 weeks (after 8+/-4 dosages). Forty four (96%) pts recovered and in 13 (30%) of them TRS was restarted. In 6 (46%) out of 13 cardiotoxicity occurred again while the others (7) completed full course of trastuzumab. Median recovery time was 9 weeks (4-28), mean 11+/-7 weeks. Twelve months after trastuzumab termination LVEF < 50% was observed in 2 (4%) pts. LVEF decreased from 60,7+/-4,9% initially to 57,6+/-6,6% after 12 months of TRS termination (p<0,001). Twenty two pts received both ACE-I and beta-blocker, 8- beta-blocker, 5- ACE-I, 11- received no HF-treatment. In 28 (60,9%) pts with significant systolic dysfunction local hypokinesis predominantly of interventricular septum (18 pts) was observed in the first echocardiograms. It converted later into universal contractile disturbances. Cardiotoxicity was associated independently with total dose of doxorubicin by multivariable logistic regression [OR 1,01 95% CI; 1,0-1,01; p<0,001). There was no such association for the time from antracyklin termination till trastuzumab initiation, pts age, hypertension, diabetes mellitus, smoking, obesity, overweight, depression, sedentary lifestyle, doses of other cytostatics. Conclusions: TRS-related early cardiotoxicity occurs in every 5-th women treated in adjuvant setting but seems reversible in majority of cases. Systolic function usually recovers after drug discontinuation and/or heart failure medication implementation. Other complications than systolic dysfunction may occur as well. Total dose of antracyklin pts receive before TRS predicts its cardiotoxicity.