Cardiotoxicity Related to Long‐Term Trastuzumab Therapy in Metastatic Breast Cancer: The Potential Role of Treatment Duration and Cardiac Risk Factors

To the Editor: Since its approval, trastuzumab (Herceptin, F. Hoffmann-La Roche Ltd., Basel Switzerland) has dramatically improved outcomes of patients with Human Epidermal growth factor Receptor 2 (HER2+) metastatic breast cancer (MBC) and has ushered in a new era in clinical practice, providing innovative insights on long-term treatment (1–3). Indeed, several studies have shown that long-term HER2 suppression should be maintained in HER2+ MBC both beyond disease response(4,5) and progression (6,7). Therefore, a growing number of patients have been receiving longterm trastuzumab administration, as maintenance monotherapy or in combination with multiple lines of chemotherapy. However, over the last 10 years, trastuzumab cardiotoxicity, ranging from asymptomatic left ventricular dysfunction to congestive heart failure (1,8,9), has emerged as a critical concern. Differently than anthracycline, trastuzumab cardiotoxicity is neither dose-related nor cumulative and appears generally reversible (6). Its pathogenesis seems partly due to antibody-directed cellular cytotoxicity, to HER2 downregulation in cardiomyocites and, as recently demonstrated, to destabilization of mitochondrial membrane with Adenosin Triphosphate depletion and subsequent cardiomyocite contractile dysfunction (4). The large trastuzumab adjuvant trials, including the recent analysis of 2-year arm of HERA trial, showed a low incidence of Cardiac Events (CEs) during adjuvant trastuzumab and demonstrated that the cumulative incidence of CEs tends to plateau after treatment completion, thus suggesting that cardiotoxicity occurs early and mainly while on treatment (5,9). However, these data refer to patients strictly selected on the basis of cardiac risk factors and exposed to trastuzumab for a well-defined time. Conversely, in metastatic setting the cardiac safety of prolonged trastuzumab administration have yet to be clarified, despite an increasing number of patients having received trastuzumab for several years. Data on incidence, onset, and outcome of cardiotoxicity in MBC patients receiving long-term trastuzumb therapy are lacking. Notably, very few studies have weighed benefits and cardiac harms of prolonged trastuzumab therapies in a “real world” MBC population, in which comorbidities, previous treatments and general aging could represent heavy cardiac risk factors (7,10–12). To determine whether duration of trastuzumab and the presence of cardiac risk factors can affect the cardiac safety of trastuzumab in metastatic setting, we conducted a retrospective analysis of 62 HER2+ MBC patients treated with trastuzumab and at least one concomitant chemotherapy regimen at our Institution from December 2003 to June 2012. The median age was 52 years (range 29–76 years); the median cumulative time receiving trastuzumab resulted 29.5 months (range 3–99 months). Forty patients (64.5%) received trastuzumab without interruption from the diagnosis of MBC, for a median time of 29 months (range 3–99 months); in the remaining patients 1 or 2 interruptions were recorded with a median interruption time of 7 months (range 2–30 months). According to previous published data (9,10), we evaluated, in univariate and multivariate Cox regression analysis, the following variables as potential cardiac risk factors: age at start of trastuzumab, body mass index (BMI, <25 versus ≥25 kg/m), antihypertensive therapy, history of cardiac disease, diabetes, smoking, radiotherapy on the left chest wall, prior exposure to anthracyclines, baseline Left Ventricular Ejection Fraction (LVEF), continued/interrupted trastuzumab exposure and duration of concomitant exposure to chemotherapy and trastuzumab. In univariate analysis Address correspondence and reprint requests to: Barbara Pistilli, Oncology Unit, ASUR Marche 3, Macerata Hospital, Via S. Lucia, 1, Macerata 62100, Italy, or e-mail: barbara.pistilli@sanita.marche. it