Hepatotoxicity associated with lapatinib in an experimental rat model

Breast cancer is the second most common cancer after lung cancer, and the leading cause of cancer death in women. The epidermal growth factor receptors (HER), also called type I tyrosine kinases receptors, have been acted a role for increased cell proliferation, cell survival and apoptosis. In breast cancer, overexpression and activation of HER1 and HER2 have been associated with the resistance of hormonal treatment and cytotoxic chemotherapy, enhanced risk of recurrence after primary treatment, consequently worsening of clinical progress. HER2 targeted therapies are cornerstone for the treatment of breast cancer. Lapatinib ditosylate is the first oral, dual-targeted inhibitor of HER1 and HER2. Lapatinib is approved for the use in combination with capecitabine in patients with HER2-positive metastatic breast cancer whom progressed after prior treatment with taxanes, anthracyclines, and trastuzumab.Lapatinib associated toxicity is generally asymptomatic, may develop days to several months after initiation of treatment and liver function abnormalities returned to normal when lapatinib is stopped. Lapatinib was followed because of serious hepatic toxic events and its prescription information was changed to follow up for liver function tests.Current study is the first study that evaluates the biochemical and histopathologic features of hepatic toxiciy of lapatinib. In our study, the subjects of group 1 and group 2 had significant higher levels of ALT, albumin, triglyceride and VLDL when compared with control group. Although normal histology was achieved in control group, none of the subjects in study group did not show normal histology. There were parenchymal asinar transformation zones, sinusoidal dilatation, hydropic degeneration in hepatocyte, vacuolization of hepatocyte around the portal areas, and mild inflammation with dominance of mononuclear cells besides neutrophil and eosinophil leukocytes in portal areas marked in especially group 2 in study groups. However fibrosis was not detected in any subjects.This study showed lapatinib triggers hepatic toxicity mainly as sinuzoidal injury with elevation in transaminase levels, especially ALT.