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Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine.

Introduction Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate consisting of three components: trastuzumab, a recombinant antiepidermal growth factor receptor 2 (HER2) monoclonal antibody; thioether linker; and mertansine (DM1), a maytansinoid. The trastuzumab moiety of this antibody-drug conjugate binds to HER2 on tumor cell surfaces and on internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics, resulting in cell-cycle arrest and cell death. Pharmacokinetic studies reveal complete proteolysis of the polypeptide backbone of the antibody component to its constituent amino acids, resulting in lysine-linker-DM1 inside the target cell. This major metabolite was reported to have low cytotoxic potency toward hepatocytes because of inability to penetrate the hepatocyte via the charged groups of the lysine residue. Preclinical studies demonstrated generation of lysine-linker-DM1 in liver tissue, mild increase in liver enzymes, and minimal degeneration of hepatocytes in monkeys. Furthermore, the liver was believed to be immune to cytotoxic effects of tubulin-binding antimitotic agents, such as DM1, because the hepatocytes are fully differentiated and nondividing. This drug is currently undergoing evaluation through several phase II and phase III studies in patients with HER2-positive breast cancer. Recently, a large phase III clinical trial (An Open-Label Study of Trastuzumab Emtansine [T-DM1] Versus Capecitabine Lapatinib in Patients With HER2Positive Locally Advanced or Metastatic Breast Cancer [EMILIA]) reported an improvement in progression-free and overall survival with T-DM1 when compared with the combination of lapatinib and capecitabine for patients who had experienced disease progression while receiving previous trastuzumab-based therapy. In this study, the T-DM1 arm had an incidence of AST elevation of 22.4%, ALT elevation of 16.9%, and thrombocytopenia of 28%, resulting in dose reduction or discontinuation. Here we report two heavily pretreated patients with metastatic breast cancer who received T-DM1–based regimens while participating in phase Ib/II clinical trials and developed noncirrhotic portal hypertension (NCPH) as a result of nodular regenerative hyperplasia (NRH).