Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer

Abstract

To evaluate the interest in assessing left ventricular diastolic function at baseline for prediction of trastuzumab-mediated cardiotoxicity (TMC) in the setting of adjuvant treatment for breast cancer. The study included 118 women presenting with HER2-positive early-stage invasive breast cancer. Patients received trastuzumab therapy over 1 year, concurrent with six cycles of docetaxel (n = 53), or following anthracycline-based chemotherapy with a cumulative dose of 300 mg/m(2) (n = 45) or 600 mg/m(2) (n = 20) of epirubicine. RNA was performed before anthracycline-based chemotherapy, before trastuzumab treatment (baseline), and every 3 months during treatment. Left ventricular ejection fraction (LVEF) and peak ejection rate (PER) were calculated to evaluate LV systolic function; peak filling rate (PFR), and time to peak filling rate (TPFR) were also calculated to evaluate LV diastolic function. Eighteen patients (15%) developed grade 1 or 2 TMC during follow-up. No significant difference was observed for age, cardiovascular risk factors, fasting blood glucose level, heart rate, systolic blood pressure, baseline LVEF, PER, and PFR between patients with and without TMC. In contrast, patients with TMC showed a longer TPFR at baseline (median [Q1-Q3]: 165 ms [149-190] vs. 142 ms [130-162]; P < 0.001). Furthermore, by logistic regression analysis, baseline TPFR >180 ms and the cumulative dose of epirubicin remained independent predictors of TMC. Patients receiving 600 mg/m(2) of epirubicin before trastuzumab showed a higher incidence of TMC (35%) than did both patients who previously received 300 mg/m(2) of epirubicin (13%) and those who received only docetaxel associated with trastuzumab (9%). Impaired left ventricular diastolic function before treatment is an independent predictor of trastuzumab-mediated cardiotoxicity. The evaluation of diastolic function could allow optimal risk stratification before the introduction of trastuzumab.

Early Diastolic Dysfunction after Cancer Chemotherapy: Primary Endpoint Results of a Multicenter Cardio-Oncology Study

“…These results support the hypothesis that DD is the earliest manifestation of cardiotoxicity from cancer drugs. Postchemotherapy injuries, such as left thorax irradiation or administration of the anti-Erbb2 monoclonal antibody, trastuzumab, might cause DD to progress toward systolic dysfunction [27]. Developing comorbidities, which tend to accumulate in cancer survivors, might also build on DD to precipitate late cardiac events [4].…”

Diastolic Dysfunction Occurs Early in HER2-Positive Breast Cancer Patients Treated Concurrently With Radiation Therapy and Trastuzumab

“…In this study, we found a higher prevalence of LVDD in patients receiving concurrent treatment than RT alone, although the difference was not statistically significant (35.2% versus 19.7%, p 5 .061). The major mechanism proposed for trastuzumab-associated cardiac toxicity is that blocking HER2 has a negative impact on the response of the heart to stress and myocardial damage [28,29]. Lack of resistance to stresses within the HER2-blocked myocardium may lead to amplified signs of injury, especially when cardiotoxic agents, such as anthracycline and irradiation, are administered in combination with trastuzumab [28,30].…”

An update on cardio-oncology

“…In particular, a previous cumulative dose >240 mg/m(2) of doxorubicin or >500 mg/m(2) of epirubicin increases the risk 3-fold compared with lower doses. (62) (63) Diastolic function assessment after completion of the anthracycline-containing elements of current treatment protocols might be an integrative index of the risk for trastuzumab-induced cardiotoxicity based on prior chemotherapy and cardiovascular risk factors. (63) The value of baseline strain imaging has not been studied so far.…”