CONICET | Buscador de Institutos y Recursos Humanos

INTRODUCTION:Trastuzumab emtansine (T-E) is the combination of humanized monoclonal antibody against ERBB-2 RECEPTOR (HER2) and a cytotoxic agent. T-E is a standard of care for second or higher-line treatment of HER2-positive advanced breast cancer, improving both progression-free and overall survival with a safety profile.2 There is 3566 adverse drug reactions reported to the International Drug Monitoring Program (thought VigiAccess), including 560 gastrointestinal disorders among which, only 8 are pancreatitis. Despite the importance of this reaction, only one case have been published [1]. Main Section: We report two cases of acute pancreatitis sent to Argentine Pharmacovigilance System. OBJECTIVE:To describe 2 cases of Trastuzumab emtansine (T-E) induced pancreatitis, its characteristics and review the predisposing clinical risk factors reported in the recent bibliography.METHODS:The clinical cases were registered in one Clinical Pharmacology center in Buenos Aires (Argentina). For the literature review, standard search strategies were used in Medline through https://www.ncbi.nlm.nih.gov/pubmed/ site. The strategies were based on the use of MESH terms (("Trastuzumab") AND "Pancreatitis"[Majr]).RESULTS:First Case: A 66-year-old woman with breast cancer (Strogen receptor Negative, Her2 Positive) was treated with radical mastectomy and 6 cycles of Doxorubicin + Cyclophosphamide in 2010. Later, she receives Docetaxel + carboplatin for 6 cycles with trastuzumab for 1 year. In 2013 hepatic, pleural and bone progression was detected and he started Docetaxel, Trastuzumab, Pertuzumab with a favorable response until 2014 when she stopped due to toxicity. In 2015, hepatic relapse was confirmed and T-E was initiated. One year later, pancreatitis was attributed to the T-E, with positive de challenge and negative re challenge. Second-Case: A woman with breast cancer at 39 years (1998) was treated with quadrantectomy and adjuvant therapy with cyclophosphamide + Methotrexate + Fluoruracil + radiotherapy. In 1999, an infiltrating ductal carcinoma was detected in the contralateral breast and a bilateral mastectomy was performed, followed by paclitaxel and 6 tamoxifen cycles (2003). For recurrence in the site of mastectomy plus positive axillary nodes occurred (2008) started capacitabine + lapatinib. She presented sternal progression (2012) and started paclitaxel followed by trastuzumab (Her +++). In 2015, new sternal recurrence was detected sternal and she started radiotherapy plus trastuzumab emtansine that continues until presenting pancreatitis in 2017 with positive de challenge and negative re challenge.DISCUSSION:Ado-trastuzumab emtansine is a Antibody?drug conjugate (ADC) that optimizes delivery of chemotherapy with an anti-HER-2 monoclonal antibody thus significantly minimizing the systemic side effects of cytotoxic agent. It was approved for metastatic breast HER-2 positive breast cancer in second-line setting after phase III trial EMILIA reported improvement in both PFS and OS.Post marketing pharmacovigilance can be of significant importance in recognizing and treating adverse event. We report two cases of acute pancreatitis after patient received trastuzumab emtansine. The causal relationship between trastuzumab and acute pancreatitis in this case is probable as per Naranjo algorithm.The cytotoxic component of emtansine belongs to maytansinoid family and interacts with tubulin and microtubules thus inhibiting tubulin assembly into microtubules. It has been reported to share its binding site with Vinca alkaloids on tubulin and is more potent than Vinca alkaloids. Antineoplastic agent?induced pancreatitis is rare. Vinca alkaloids have been reported to cause autophagy and degeneration in pancreatic acinar cell, and there are multiple reports of acute pancreatitis associated with these drugs. Emtansine can be the implicating factor causing pancreatic injury in this case, but this adverse event does not seem to be a common occurrence. The most common adverse events reported in clinical trials with trastuzumab emtansine have been hepatotoxicity, thrombocytopenia, and cardiac, among other side effects.Other maytansine analogs, such as monomethyl auristatin E is part of brentuximab vedotin used in lymphomas and has been associated with pancreatitis, in some cases fatal.Phase III trials are ongoing to establish role of trastuzumab in early stage HER-2-positive breast cancer along with first-line setting for metastatic breast cancer, thus making it pertinent to report any new side effect with possible association. Extensive review of literature result in only one reported cases of acute pancreatitis associated with trastuzumab. In the context of temporal relationship after drug administration along with no other evident cause of acute pancreatitis, there is probable association between the drug and adverse event reported. Post marketing surveillance is essential to determine the true risk profile of a drug. Recognizing and reporting potentially new side effects will improve safety and patient care.Trastuzumab pancreatitis appears to be a more frequent reaction than has been described in the literature. The characteristics of the pictures seem to imply reversible reactions that do not contraindicate the restart of the treatment. It is necessary to monitor and control pancreatic function in patients under this treatment.