Trastuzumab is a humanized monoclonal antibody to the human epidermal growth factor receptor 2 (HER2) 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 serum enzyme elevations, but has only rarely been linked to instances of clinically apparent liver injury with jaundice. In contrast, the recently developed conjugates of trastuzumab with the microtubule inhibitor emtansine or the topoisomerase inhibitor deruxtecan, which are used as an antineoplastic agents for advanced resistant breast cancer, has been linked to frequent serum enzyme elevations during therapy. Trastuzumab emtansine has been linked to instances of acute clinically apparent liver injury that can be severe and even fatal and, when given chronically, to non-cirrhotic portal hypertension.


Trastuzumab (tras tooz’ ue mab) is a humanized monoclonal antibody to HER2 which is a human epidermal growth factor receptor that is overexpressed in 20% to 25% of breast cancers and a smaller proportion of other cancers such as gastric, lung, ovarian and pancreatic. The interaction of epidermal growth factor (EGF) with HER2 results in rapid cell growth and proliferation via intracellular pathways. Binding of trastuzumab to HER2 blocks this cell signaling pathway and causes growth arrest. Trastuzumab was shown to decrease recurrences and prolong survival in patients 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 single use vials of 150 mg lyophilized powder generically under the brand name Herceptin. The typical dose is 2 to 8 mg/kg intravenously weekly or every three weeks, the dose and duration of therapy varying with different indications. Common side effects include fatigue, nausea and vomiting, diarrhea, infusion reactions, rash, headache, fever, cough, dyspnea, neutropenia, infections, thrombocytopenia, and anemia. Rare, but serious side effects include severe infusion reactions (usually with the initial dose), cardiomyopathy (especially when combined with an anthracycline), pneumonitis, tumor lysis syndrome and fetal toxicity. Trastuzumab should be prescribed and administered only by health care workers with expertise and experience in cancer chemotherapy and management of its adverse events.

Trastuzumab emtansine (em tan’ seen) and transtuzumab deruxtecan (de rux” tee can) are conjugates of trastuzumab with toxic molecules, which are released after binding and uptake by HER2 expressing cells and are used in the therapy of metastatic breast, gastric, or lung cancers that express HER2. The two conjugates have separate toxicities and their likelihood of causing hepatotoxicity varies, perhaps due to the different toxin conjugates rather than the monoclonal antibody. These monoclonal antibody conjugates are discussed separately in different chapters in LiverTox.


In large registration trials of trastuzumab for advanced or metastatic breast and other cancers, rates of serum enzyme elevations and instances of clinically apparent liver injury are rarely mentioned. In one large study, ALT elevations arose in 3% of patients treated but there were no instances of clinically apparent liver disease. The package insert for trastuzumab does not provide information of the rate of serum ALT or AST elevations or report cases of liver injury. Since its approval and widescale use, there have been at least 4 published case reports of serum ALT elevations occurring after 1 to 8 cycles of trastuzumab therapy. One case was symptomatic but none were accompanied by jaundice or hyperbilirubinemia. Immune allergic features and autoantibodies were not present. The abnormalities improved on stopping therapy and in one case recurred in a similar pattern on re-exposure. Abnormalities of liver enzymes during trastuzumab therapy are often attributed to progressive disease or hepatic effects of other medications being given with the monoclonal antibody. Thus, trastuzumab can probably cause clinically significant liver injury but it is uncommon, mild and usually self-limited in course, resolving with discontinuation.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the serum enzyme elevations during trastuzumab therapy is not known, but may be due to the direct effect of inhibiting human epidermal growth factor signaling in liver. While the liver injury may be dose related and may be a mild direct toxicity of the infusions, other possibilities are that it is caused by the antineoplastic agents that are used with trastuzumab such as doxorubicin, cyclophosphamide, paclitaxel, docetaxel, carboplatin, or 5-fluorouracil.

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.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies



Trastuzumab – Herceptin®


Antineoplastic Agents

Trastuzumab Conjugates: Trastuzumab Emtansine, Trastuzumab Deruxtecan


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 30 January 2024

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

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    (31 year old woman with breast cancer developed marked ALT elevations [1403 U/L] after first infusion of trastuzumab [8 mg/kg], which resolved within 4 weeks and did not recur with subsequent lower dose regimens, although minor ALT continued to occur thereafter).
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  • Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, et al.; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-91. [PMC free article: PMC5125250] [PubMed: 23020162]
    (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).
  • Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, Guardino E, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30: 3234-41. [PubMed: 22649126]
    (Among 110 patients with advanced, resistant breast cancer treated with trastuzumab emtansine for an average of 17 months, ALT elevations occurred in 14% and one patient died from "abnormal hepatic function").
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    (Among 160 women with breast cancer treated with trastuzumab [for a median of 5.3 years], long term adverse events included cardiac failure and cardiomyopathy; no mention of ALT elevations or hepatotoxicity).
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    (Among 884 patients with HER2 positive breast cancer treated with trastuzumab emtansine in 6 controlled trials, common adverse events were fatigue [46%], nausea [43%], thrombocytopenia [32%], headache [29%], constipation [27%] and ALT elevations [16%], typically during the first few months, rising to above 5 times ULN in 3.1%, resulting in drug discontinuation in 0.5% and death in 2 patients).
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    (35 year old woman with HER2 positive breast cancer developed evidence of metastatic replacement of the liver [bilirubin 5.0 mg/dL, ALT 236 U/L, GGT 449 U/L] and improvement with combination chemotherapy including trastuzumab, liver tests returning to normal but then died with progressive disease 9 months later, indicating that this symptom is not as grim as previously reported using more modern chemotherapy regimens).
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    (59 year old woman with HER2 positive breast cancer, refractory after multiple chemotherapy regimens, developed jaundice associated with a 7 cm liver mass [bilirubin ~8.2 mg/dL, ALT ~1000 U/L, Alk P ~650 U/L], which responded to therapy with trastuzumab emtansine with resolution of jaundice, improvement in liver enzymes, and shrinkage of the mass).
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, only four cases were attributed to a monoclonal antibody [3 to infliximab and 1 to adalimumab]; no cases were attributed to trastuzumab).
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    (Review of literature on hepatotoxicity of newly approved agents mentions that trastuzumab can cause ALT elevations in 7-12% of patients and rarely acute hepatitis but has not been linked to reactivation of HBV, while trastuzumab emtansine causes ALT elevations in 17-22% of patients and has been linked to cases of hepatitis, acute liver failure, portal hypertension and nodular regenerative hyperplasia [NRH], but not to reactivation of HBV).
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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).
  • Liu Y, Li ZY, Wang JN, Li X, Huang QA, Huang Y. Effects of hepatitis C virus infection on the safety of chemotherapy for breast cancer patients. Breast Cancer Res Treat 2017; 164: 379-83. [PubMed: 28447238]
    (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).
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    (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 angiomas 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).
  • Nodehi RS, Kalantari B, Raafat J, Ansarinejad N, Moazed V, Mortazavizadeh SMR, Hosseinzadeh M, et al. A randomized, double-blind, phase III, non-inferiority clinical trial comparing the efficacy and safety of TA4415V (a proposed Trastuzumab biosimilar) and Herceptin (Trastuzumab reference product) in HER2-positive early-stage breast Cancer patients. BMC Pharmacol Toxicol. 2022;23:57. [PMC free article: PMC9336069] [PubMed: 35902898]
    (Among 92 patients with early stage HER2 positive breast cancer treated with conventional chemotherapy followed by adjuvant trastuzumab or a biological equivalent, the objective response rate was 83% and 89% and adverse event rates were similar; no mention of hepatotoxicity or ALT elevations).
  • Sun C, Yang X, Tang L, Chen J. A pharmacovigilance study on drug-induced liver injury associated with antibody-drug conjugates (ADCs) based on the food and drug administration adverse event reporting system. Expert Opin Drug Saf. 2023:1-12. [PubMed: 37898875]
    (Analysis of the FDA reporting system [FAERS] for cases of drug induced liver injury submitted between 2004 and 2022, found 17,784 reports, 504 [3%] attributed to antibody-drug conjugates, 202 from the US, the implicated agents being gemtuzumab ozogamicin [n=98], brentuximab vedotin [n=37], trastuzumab emtansine [n=25], enfortumab vedotin [n=16], inotuzumab ozogamicin [n=15], transtuzumab deruxtecan [n=8], and polatuzumab vedotin [3]).