Abstract
Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40–29.8; P=0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02–1.31; P=0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.
Highlights
HER2 (ErbB2 or HER-2/neu) belongs to the human epidermal growth factor receptor (HER) family and is significantly correlated with the proliferation, migration, and differentiation of many kinds of cancer cells through its involvement in the activation of the PI3K/Akt and Ras/ Raf/MEK/MAPK pathways
Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in left ventricular ejection fraction (LVEF) was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40–29.8; P=0.257]
We assessed the incidence of cardiac dysfunction in HER2-positive gastric cancer patients who were treated with cytotoxic chemotherapy in combination with trastuzumab
Summary
HER2 (ErbB2 or HER-2/neu) belongs to the human epidermal growth factor receptor (HER) family and is significantly correlated with the proliferation, migration, and differentiation of many kinds of cancer cells through its involvement in the activation of the PI3K/Akt and Ras/ Raf/MEK/MAPK pathways. The monoclonal antibody trastuzumab, which targets HER2, is a well-known HER2directed therapeutic drug [1]. This agent demonstrated www.impactjournals.com/oncotarget improved survival outcomes in cancer patients, especially in cases of breast cancer associated with the amplification of HER2 and/or overexpression of HER2 at the messenger RNA or protein level [2,3,4]. Because preclinical trastuzumab studies suggest that ErbB2 plays an essential role in the developing embryonic heart and is important for maintaining cardiac function in the adult heart [5], there are considerable concerns regarding cardiotoxicity in early clinical trials [2]. Due to the lack of clinical trials and knowledge, the incidence and characteristics of cardiotoxicity related to trastuzumab in gastric cancer patients have not been clearly shown
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