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Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review



Human epidermal growth factor receptor 2 (HER2)–targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC).


We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date.


One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)].


Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

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Fig. 1

Source Adapted from Moher et al. [18].aSwain et al. [19] is included in the PRISMA, but the study population is the same as that in Swain et al. [20]; therefore, 153 articles were identified, covering 152 unique populations

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.


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The authors thank Amy Ladner of RTI Health Solutions for critical review of the literature review results and interpretation. Kate Lothman of RTI Health Solutions provided medical writing services, which were funded by Daiichi Sankyo, Inc., during the development of this manuscript.


Financial support for the study was provided by Daiichi Sankyo, Inc. RTI Health Solutions received funding under a research contract with Daiichi Sankyo, Inc. to conduct this study and provide editorial support in the form of manuscript writing, styling, and submission.

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All authors made substantial contributions to the conception or design of the work and/or to the acquisition, analysis, or interpretation of the data. All authors contributed to drafting the article or revising it critically for important intellectual content and approved the final version for publication.

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Correspondence to Edith A. Perez.

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CL and JS are Daiichi Sankyo, Inc. employees. MDH and KW were employees of Daiichi Sankyo, Inc. when this research was conducted. JBL and AG are employees of RTI Health Solutions, an independent nonprofit research organization that performs contracted project work for medical device and pharmaceutical companies. EP, CD, and JC are consultants for Daiichi Sankyo, Inc. but have received no compensation for their contributions to this article.

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Perez, E.A., Dang, C., Lee, C. et al. Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review. Breast Cancer Res Treat 194, 1–11 (2022).

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  • Adverse event
  • Safety
  • Toxicity