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

Abstract

Purpose

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).

Methods

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.

Results

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)].

Conclusion

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.

References

  1. Goddard KA, Weinmann S, Richert-Boe K, Chen C, Bulkley J, Wax C (2012) HER2 evaluation and its impact on breast cancer treatment decisions. Public Health Genomics 15(1):1–10

    CAS  Article  Google Scholar 

  2. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA et al (2014) US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. https://doi.org/10.1093/jnci/dju055

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jerusalem G, Lancellotti P, Kim SB (2019) HER2+ breast cancer treatment and cardiotoxicity: monitoring and management. Breast Cancer Res Treat 177(2):237–250

    Article  Google Scholar 

  4. Asif HM, Sultana S, Ahmed S, Akhtar N, Tariq M (2016) HER-2 positive breast cancer—a mini-review. Asian Pac J Cancer Prev 17(4):1609–1615

    Article  Google Scholar 

  5. Hackshaw MD, Danysh HE, Singh J, Ritchey ME, Ladner A, Taitt C et al (2020) Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Breast Cancer Res Treat 183(1):23–39

    CAS  Article  Google Scholar 

  6. Andre F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G et al (2014) Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15(6):580–591

    CAS  Article  Google Scholar 

  7. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP et al (2015) Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16(7):816–829

    CAS  Article  Google Scholar 

  8. Kashiwaba M, Ito Y, Takao S, Doihara H, Rai Y, Kanatani K et al (2016) A multicenter Phase II study evaluating the efficacy, safety and pharmacokinetics of trastuzumab emtansine in Japanese patients with heavily pretreated HER2-positive locally recurrent or metastatic breast cancer. Jpn J Clin Oncol 46(5):407–414

    Article  Google Scholar 

  9. Pyrotinib Maleate Tablets Full Prescribing Information. Beijing, China: National Medical Products Administration Center for Drug Evaluation 2018. http://202.96.26.102/index/detail/id/508. Accessed: 5 Aug 2020.

  10. ENHERTU(R) (fam-trastuzumab deruxtecan-nxki) full prescribing information. Daiichi Sannkyo, Inc.; December 2019 2019. https://dsi.com/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true. Accessed: 5 Aug 2020.

  11. TUKYSATM (tucatinib) full prescribing information. Seattle Genetics; April 2020. https://seagendocs.com/TUKYSA_Full_Ltr_Master.pdf. Accessed: 5 Aug 2020.

  12. NERLYNX® (neratinib) full prescribing information. Puma Biotechnology, Inc.; July 2020 2017. https://nerlynx.com/pdf/full-prescribing-information.pdf. Accessed: 5 Aug 2020.

  13. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K et al (2020) Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382(7):610–621

    CAS  Article  Google Scholar 

  14. Herceptin (trastuzumab) prescribing information. South San Francisco, CA: Genentech, Inc.; November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103792s5345lbl.pdf. Accessed: 26 Sept 2019.

  15. KADCYLA® (ado-trastuzumab emtansine) full prescribing information. Genentech, Inc; May 2019. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf. Accessed: 5 Aug 2020.

  16. Perjeta (pertuzumab) prescribing information. South San Francisco, CA: Genentech, Inc; December 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125409s123lbl.pdf. Accessed: 27 Sept 2019.

  17. Tykerb (lapatinib) full prescribing information. East Hanover, NJ: 2018. https://www.novartis.us/sites/www.novartis.us/files/tykerb.pdf. Accessed: 12 May 2020.

  18. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  Google Scholar 

  19. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724–734

    CAS  Article  Google Scholar 

  20. Swain SM, Ewer MS, Cortes J, Amadori D, Miles D, Knott A et al (2013) Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study. Oncologist 18(3):257–264

    CAS  Article  Google Scholar 

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Acknowledgements

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.

Funding

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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Conflict of interest

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). https://doi.org/10.1007/s10549-021-06469-0

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Keywords

  • Adverse event
  • Safety
  • Toxicity