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Molecular predictors of response to trastuzumab and lapatinib in breast cancer

Nature Reviews Clinical Oncology volume 7, pages 98–107 (2010)Cite this article

Abstract

Trastuzumab is a monoclonal antibody directed against the human EGFR2 (HER2) protein that has been shown to improve survival in patients with HER2-positive breast cancer. Lapatinib is an oral small-molecule tyrosine kinase inhibitor directed against EGFR and HER2. Lapatinib therapy was shown to prolong the time to progression and increase the rate of response to capecitabine in patients who had received anthracycline-based and taxane-based chemotherapy, and whose tumors had progressed on trastuzumab. HER2 status, either gene copy number or the protein expression level, is the best predictive marker available for assessing response to trastuzumab and lapatinib. Whether the power of this predictive marker is the same in advanced and early-stage cancers is unknown. There is great interest in developing diagnostic tests that predict which patients are more likely to benefit from specific HER2-directed therapies. Novel therapeutics that will overcome resistance to trastuzumab and lapatinib are under intense clinical development. In the future, it will be important to characterize mechanisms of resistance in metastatic tumors to determine which novel targeted therapy will be most appropriate for individual patients.

Key Points

  • The HER2 status of all invasive breast cancers should be assessed by immunohistochemistry (IHC) or in situ hybridization; the former method is most commonly used worldwide

  • Trastuzumab and lapatinib are effective therapies in HER2-positive breast cancer; however, not all HER2-positive patients respond to these therapies, and progression is common in responding patients with metastatic disease

  • Potential molecular predictors of resistance to HER2-directed therapies include loss of PTEN, PI3K/Akt hyperactivation, p95HER2 expression, and IGF-IR overexpression

  • Novel therapeutics are in clinical development to overcome resistance to trastuzumab and lapatinib, and include pertuzumab, trastuzumab-DM1, PI3K inhibitors, HSP90 inhibitors, IGF-IR inhibitors and novel tyrosine kinase inhibitors

  • Randomized clinical trials have shown an improved clinical benefit in patients with HER2-positive metastatic disease who have disease progression and have been treated with drugs that inhibit HER2

  • The molecular mechanism of HER2 blockade beyond disease progression is not known, and represents a new paradigm in breast cancer therapy

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Figure 1: Molecular targets and therapeutic approaches in trastuzumab and lapatinib resistance.

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Acknowledgements

Supported in part by a Breast Cancer SPORE grant (NCI P50 CA116199).

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  1. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, 77030-4009, TX, USA

    Francisco J. Esteva & Gabriel N. Hortobagyi

  2. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, 77030-4009, TX, USA

    Francisco J. Esteva, Dihua Yu & Mien-Chie Hung

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  1. Francisco J. Esteva
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  2. Dihua Yu
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  3. Mien-Chie Hung
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  4. Gabriel N. Hortobagyi
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Correspondence to Francisco J. Esteva.

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Competing interests

Francisco J. Esteva declares he receives research support from Genentech, GlaxoSmithKline, Monogram Biosciences, Myriad Genetics and Novartis. The funds are managed by the University of Texas M. D. Anderson Cancer Center. Gabriel N. Hortobagyi declares he is a consultant for Bristol-Myers Squibb and Novartis and receives research support from Novartis. The other authors declare no competing interests.

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Esteva, F., Yu, D., Hung, MC. et al. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 7, 98–107 (2010). https://doi.org/10.1038/nrclinonc.2009.216

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