Does Trastuzumab cause permanent severe mitral regurgitation?

Abstract

A 49-year-old postmenopausal woman without any known systemic and chronic diseases was admitted to our hospital because of a mass in the left breast. Following detection of BIRADS 5 mass on mammography, the patient underwent breast-conserving surgery and axillary lymph node dissection. Pathological evaluation of the mass was consistent with stage 3a infiltrating lobular carcinoma. In immunohistochemical evaluation, the tumor was estrogen receptor-positive, progesterone receptor negative and HER-2 receptor positive (+++). Adjuvant chemotherapy was planned and transthoracic echocardiography (TTE) was performed priorly. Left ventricular systolic and diastolic functions were normal and no evidence of mitral regurgitation was observed [LVEF 65%, left ventricular end diastolic diameter (LVEDD): 4.9 cm and left ventricular end systolic diameter (LVESD): 2.9 cm]. The patient was given 4 cures of Adriamycin (A), 60 mg/m2/day, 360 mg cumulative dose and Cyclophosphamide (C) 600 mg/m2/day, 4000 mg total dose once in every 21 days. After 4 cures of AC, weekly Herceptin 2 mg/kg, initial dose of 360 mg, maintenance dose of 180 mg and once in three weeks Docetaxel 100 mg/m2/day were started and planned to continue for 12 weeks. In the sixth week of Trastuzumab therapy (at the end of 6th cure) the patient admitted to the cardiology clinic because of dyspnea. The patient had no history of organic valvular disease (rheumatic heart disease, mitral valve prolapse, etc.). There was also no history of smoking, dyslipidemia, diabetes mellitus and coronary artery disease (CAD). On physical examination, apical 2/6 systolic murmur and bilateral crepitant rales in the lung bases were detected. TTE was repeated and left ventricular ejection fraction (LVEF) was found to be 45% (calculated by Simpson's method) with global hypokinesia. Severe central mitral regurgitation (effective regurgitant orifice area 0.42 cm2, proximal isovelocity surface area radius 1.0 cm, vena contracta 0.7 cm, regurgitant jet area/left atrium area, 65%) was also detected. An increase was observed in both left ventricular end diastolic and end systolic diameters (5.7 cm and 3.9 cm respectively in parasternal long axis M-mode imaging). Adjuvant Trastuzumab therapy was discontinued and the patient was hospitalized. Diuretic (furosemide 20 mg/iv/day), ACE inhibitor (ramipril 5 mg/po/day) and metoprolol (50 mg/po/day) were started. The symptoms regressed and the patient was discharged on the 7th day of hospitalization with furosemide 40 mg/po/d, ramipril 5 mg/po/d and metoprolol 50 mg/po/d.

Monoclonal antibodies targeting the Human Epidermal Growth Factor-2 (HER-2) proteins have been frequently used to treat breast cancer in the last decade. HER-2 receptor is a member of the transmembrane receptor tyrosine kinase family which mediates cell growth, differentiation and survival [1]. Trastuzumab is a monoclonal antibody developed against the extracellular domain of HER-2. It was shown to be effective when administered alone [2], [3] or in combination [4], [5] in patients with HER-2 (+) metastatic breast cancer. Although well tolerated, it can cause serious cardiotoxicity which is quite rare and is the most important side effect. When used as a single agent, incidence of cardiotoxicity ranges from 2% to 8% and this rate rises up to 27% when used in combination with Anthracyclines [6]. Although strong evidence is present about Trastuzumab associated cardiotoxicity, the exact pathogenesis is still unknown.

The patient was called for control visits in the 1st and 3rd months considering that cardiotoxicity would recover in 1–3 months following discontinuation of Trastuzumab therapy [7], [8], [9]. It was observed that LV systolic function was slightly improved in the 1st and 3rd months (1st month LVEF 47%, 3rd month LVEF 49%), but severe mitral regurgitation was still prominent. In the 6th and the 12th month controls, LV systolic function was observed to recover completely but severe mitral regurgitation persisted (LVEF: 62%, LVEDD: 49 mm, LVSDD: 2.9). Because of asymptomatic maintenance of the patient with medical therapy and improvement in LV diameters, we continue to monitor the patient medically.