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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Trastuzumab and Ado-Trastuzumab Emtansine

Last Update: April 18, 2020.

OVERVIEW

Introduction

Trastuzumab is a humanized monoclonal antibody to the HER2 receptor which is used in combination with other antineoplastic agents in the therapy of breast and gastric cancer. Trastuzumab has been implicated in causing instances of transient, marked serum enzyme elevations, but has only rarely been linked to instances of clinically apparent liver injury with jaundice. In contrast, the recently developed conjugate of trastuzumab with the microtubule inhibitor emtansine, which is used as an antineoplastic agent for advanced resistant breast cancer, has been linked to frequent serum enzyme elevations during therapy, to occasional instance of acute clinically apparent liver injury and, when given chronically, to nodular regenerative hyperplasia.

Background

Trastuzumab (tras tooz’ ue mab) is a humanized monoclonal antibody to HER2 which is a human growth factor receptor that is overexpressed in 20% to 25% of breast cancers. The interaction of epidermal growth factor (EGF) with HER2 results in rapid cell growth and proliferation via intracellular pathways that include MAP and PI3 kinase. Binding of trastuzumab to the HER2 receptor blocks this cell signaling pathway and causes growth arrest. Trastuzumab was shown to decrease recurrences and prolong survival in women with breast cancer that were HER2 positive. Trastuzumab was approved for use in the United States in 1998 and current indications include breast and gastric cancers that express HER2. Trastuzumab is available in multiple use vials generically under the brand name Herceptin. The typical dose is 2 to 8 mg/kg intravenously every week, the dose and duration of therapy varying with different indications. Common side effects include fatigue, nausea and vomiting, diarrhea, infusion reactions, rash, headache, neutropenia, infections and anemia. Rare, but serious side effects include infusion reactions (usually with the initial dose), cardiomyopathy (especially when combined with an anthracycline), pneumonitis, tumor lysis syndrome and fetal toxicity.

Ado-trastuzumab emtansine (em tan’ seen), also known as trastuzumab emtansine, is a conjugate of trastuzumab with emtansine (DM1), a microtubule inhibitor derived from maytansine that is taken up with trastuzumab into HER2 expressing cancer cells and degraded in lysosomes resulting in release of DM1, which binds to tubulin and disrupts microtubular networks resulting in cell cycle arrest and cell death. This conjugate, when combined with other antineoplastic agents, has shown increased efficacy in advanced, metastatic breast cancer. Ado-trastuzumab emtansine was approved for use in previously treated, advanced breast cancer in the United States in 2013. The antibody conjugate is available in single use vials under the brand name Kadcyla. The recommended dose is 3.6 mg/kg intravenously every 3 weeks until disease progression or intolerability. The antibody conjugate has a higher rate of adverse side effects than trastuzumab alone; the more common adverse events include fatigue, nausea, myalgias, headache, constipation, serum enzyme elevations and thrombocytopenia. Less common but potential severe adverse events include hepatotoxicity, anaphylaxis, heart failure and embryo-fetal toxicity.

Hepatotoxicity

In large registration trials of trastuzumab for breast and other cancers, rates of serum enzyme elevations were low and there were no instances of clinically apparent liver injury. Since its approval and wide scale use, there have been several isolated reports of serum ALT elevations occurring after 1 to 8 cycles of trastuzumab therapy. The abnormalities have been elevations of ALT and AST with no or minimal increase in alkaline phosphatase levels and no symptoms or bilirubin elevations. The abnormalities were invariably self-limited and, in at least one instance, did not recur with use of lower doses of trastuzumab. There have been a few published reports of clinically apparent, acute liver injury with jaundice attributed to trastuzumab but typically when given in combination with other potentially hepatotoxic agents.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

In contrast, in large registration trials, ado-trastuzumab emtansine was linked to serum enzyme elevation or bilirubin elevations in up to 20% to 80% of patients and levels rose to above 5 times the upper limit of normal (ULN) in at least 5%. Furthermore, instances of acute liver injury including deaths from hepatic failure were reported, although details of the timing and pattern of injury were not always provided. Some of these cases may represent acute sinusoidal obstruction syndrome and in other cases acute, direct hepatotoxic injury.

More recently, cases of noncirrhotic portal hypertension have been described in patients on long term trastuzumab emtansine. The typical presentation is with signs and symptoms of portal hypertension after years of therapy and usually with only modest increases in serum aminotransferase elevations and bilirubin. Strikingly, in patients who undergo liver biopsy, cirrhosis is not present, although mild-to-moderate fibrosis is present in some. This phenotype of injury is classified as noncirrhotic portal hypertension, but the underlying liver condition is usually nodular regenerative hyperplasia with elements of sinusoidal obstruction. Hepatic imaging shows a nodular and somewhat shrunken liver and prominent splenomegaly and varices. Typically, patients improve clinically once trastuzumab emtansine is discontinued, although without chemotherapy the malignancy may return and progress. Another syndrome with somewhat similar clinical features associated with long term trastuzumab emtansine therapy is a disordered, nodular liver cause by shrinkage of necrotic hepatic metastases, sometimes referred to as “pseudocirrhosis.” These patients are generally asymptomatic and the diagnosis is made by hepatic imaging often done as a part of routine follow up of the metastatic liver disease.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the serum enzyme elevations during trastuzumab therapy is not known, but appears to be dose related and may be a mild direct toxicity of the infusions. The mechanism of the hepatotoxicity of ado-trastuzumab emtansine has not been fully defined, but may be due to injury to endothelial cells and vasculature, possibly by the microtubule inhibitor conjugate. Several instances of liver injury in patients taking trastuzumab emtansine have been attributed to sinusoidal obstruction syndrome and mild forms of it may explain the frequent serum enzyme and bilirubin elevations during ado-trastuzuemab emtansine therapy. In other instances the underlying condition appears to be nodular regenerative hyperplasia, which is likely the result of acute or chronic vascular injury or both.

Outcome and Management

The liver injury attributed to trastuzumab has invariably been self-limited and not associated with symptoms or jaundice. There is no information on possible cross sensitivity to the injury among different monoclonal antibodies or therapies directed at epidermal growth factor receptors. In some instances, trastuzumab has been tolerated at lower doses after recovery with minimal ALT elevations. In contrast, the liver injury attributed to ado-trastuzumab emtansine is often severe and can be fatal. The chronic liver injury from the monoclonal-cytotoxic conjugate is generally persistent although signs and symptoms usually regress with drug discontinuation. Patients who develop evidence of portal hypertension or nodular regeneration during ado-trastuzumab emtansine therapy should have the drug discontinued.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Trastuzumab – Herceptin®

Trastuzumab Emtansine – Kadcyla®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING (Trastuzumab)

COMPLETE LABELING (Ado-Trastuzumab Emtansine)

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Trastuzumab180288-69-1Monoclonal AntibodyNot Available
Trastuzumab
Emtansine
1018448-65-1Monoclonal Antibody with
Microtubular Inhibitor
image 135353969 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 27 April 2020

Abbreviations: TNF, tumor necrosis factor; HER-2, human epidermal growth factor receptor 2; CT, computerized tomography; MR, magnetic resonance; NRH, nodular regenerative hyperplasia.

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    (Among 991 women with HER2 expressing breast cancer who had failed previous therapy who received either trastuzumab emtansine or lapatinib with capecitabine, overall survival was improved with the antibody conjugate, but ALT levels were elevated in 17%, AST in 22%, and platelets decreased in 28% of patients; 3 patients stopped therapy early because of aminotransferase elevations, but no patient had both bilirubin and marked ALT elevations and there were no liver related deaths).
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    (60 year old Japanese woman with breast cancer developed liver test abnormalities after a second cycle of trastuzumab [bilirubin normal, ALT 246 U/L, Alk P 553 U/L] which recurred one year later after readministration of a single infusion [bilirubin normal, ALT 102 U/L, Alk P 377 U/L], resolving within 2 months of stopping).
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    (Among 835 patients with breast cancer receiving targeted therapy, rates of ALT elevations were slightly higher in the 52 with HBsAg [35%] and the 21 with anti-HCV [43%] than controls [28%] as were rates of chemotherapy disruption for liver test abnormalities [9.6% and 9.5% vs 5%] but no patient developed viral reactivation, although the proportion of those with HBsAg who were receiving antiviral prophylaxis was not provided).
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    (Among 835 patients with breast cancer receiving target therapy, rates of “hepatitis” were slightly higher in the 21 with anti-HCV in serum [23%] than in controls [14%] as were rates of chemotherapy disruption for liver test abnormalities [9.5% vs 5%], but no patient develop viral reactivation as define by a 1 log increase in HCV RNA levels).
  • Hidalgo-Blanco A, Aguirresarobe-Gil de San Vicente M, Aresti S, de Miguel E, Cabriada-Nuno JL. Pseudocirrhosis in metastatic breast cancer. Gastroenterol Hepatol. 2018;41:111–3. [PubMed: 28187872]
    (39 year old woman with HER2 positive breast cancer received a 1 year course of trastuzumab at the end of which she had normal ALT levels and CT appearance of the liver, but 18 months later she presented with abnormalities of both suggestive of pseudocirrhosis).
  • Lepelley M, Allouchery M, Long J, Boucherle D, Ranchoup Y, Le Marc'Hadour F, Villier C, Sturm N. Nodular regenerative hyperplasia induced by trastuzumab emtansine: role of emtansine? Ann Hepatol. 2018;17:1067–71. [PubMed: 30600283]
    (48 year old woman with HER2-negative breast cancer in 2008 had recurrence in 2012 that was HER2-positive and after 12 months of trastuzumab emtansine therapy presented with mild ALT and AST elevations and MRI showing splenomegaly and dystrophic liver a biopsy of which showed NRH, liver abnormalities improving but cancer progressing when chemotherapy was stopped).
  • Talima S, Kassem H, Kassem N. Chemotherapy and targeted therapy for breast cancer patients with hepatitis C virus infection. Breast Cancer. 2019;26:154–63. [PubMed: 30191397]
    (Two of 58 Egyptian women with advanced breast cancer and chronic hepatitis C developed viral reactivation during targeted chemotherapy, one on lapatinib and one trastuzumab).
  • Fujii Y, Doi M, Tsukiyama N, Hattori Y, Ohya K, Shiroma N, Morio K, et al. Sinusoidal obstruction syndrome post-treatment with trastuzumab emtansine (T-DM1) in advanced breast cancer. Int Cancer Conf J. 2019;9:18–23. [PMC free article: PMC6942611] [PubMed: 31950012]
    (Two women with metastatic HER2 positive breast cancer developed noncirrhotic portal hypertension 2.5 and 4.5 years of trastuzumab emtansine therapy, in both of whom liver biopsy showed sinusoidal obstruction syndrome and disordered hepatic plates).
  • Milam P, Berger M, Ramaswamy B, Reinbolt R, Wesolowski R, Kaffenberger BH. Spider telangiectases and palmar erythema as harbingers of structural liver changes in three breast cancer patients on ado-trastuzumab emtansine. J Clin Aesthet Dermatol. 2019;12:23–6. [PMC free article: PMC6715332] [PubMed: 31531159]
    (Three women [ages 53, 60 and 63 years] with advanced breast cancer developed cutaneous stigmata of cirrhosis after 17 to 34 cycles of trastuzumab emtansine with spider angiomata and palmar erythema, minimal ALT and AST elevations, decreased platelet counts [43,000-123,000/µL], and usually with splenomegaly and nodular liver on CT or MR imaging).
  • Duret-Aupy N, Lagarce L, Blouet A, Kettani S, Conte C, Bourneau-Martin D, Drablier G, et al. Liver sinusoidal obstruction syndrome associated with trastuzumab emtansine treatment for breast cancer. Therapie. 2019;74:675–7. [PubMed: 31023619]
    (87 year old woman on trastuzumab emtansine for two years developed variceal hemorrhage, ascites and edema, with normal ALT, and CT showing no evidence of cirrhosis, but liver biopsy showing sinusoidal obstruction syndrome).

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