Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

the Cancer Therapy Advisor take:

Targeting the overexpression of HER2 in patients with breast cancer has been shown to make improvements in the survival outcomes of some patients.

Resistance to these HER2-targeted therapies, however, is common and thus there is a need for the development of strategies to overcome treatment resistance.

In patients with metastatic breast cancer, almost 70% show fundamental resistance to treatment and almost 100% of those who initially respond to targeted therapy eventually become treatment resistant. Added to this, even with HER2-targeted treatment, the development of central nervous system progression is common within this group of patients who have limited therapeutic options.

Development of novel treatment approaches for HER2-positive breast cancer is clinically significant, particularly in the context of strategies to overcome resistance to HER2-targeted therapy. Through the identification of the mechanisms that cause resistance, researchers have been able to develop novel therapeutic strategies to overcome treatment resistance.

Strategies like novel HER2-targeted therapies, therapies that target downstream pathways, and the use of VEGF inhibitors, telomerase, and Hsp90 have been developed. It is now hoped that clinical trials, including phase 3 data for the mTOR inhibitor everolimus, will uncover additional strategies to help aid in the successful treatment of patients with HER2-resistant breast cancer.

Vaccines

HER2 is a tumor-specific antigen and an ideal immunotherapeutic target, and vaccines based on HER2-derived peptides, including E75, GP2, and AE37, are being developed.⁷⁹ A phase 1 study assessed HER2 immunotherapy in combination with lapatinib in 12 patients with metastatic breast cancer resistant to trastuzumab. However, the effect of lapatinib on the immune responses induced by vaccination was inconclusive, with vaccination triggering variable levels of anti-HER2 antibodies in all patients and an HER2-specific T-cell response in one patient.¹⁰²

Clinical investigation of vaccines in patients who have undergone or are currently receiving trastuzumab therapy is underway (ClinicalTrials.gov identifiers NCT01632332, NCT00343109). A phase 2 study of a vaccine in trastuzumab-resistant disease has been terminated because of a change in the development plan (ClinicalTrials.gov identifier NCT00522457).

Conclusions

HER2 overexpression is associated with poor prognosis in patients with breast cancer. Targeting HER2 with therapies has markedly improved outcomes in patients with HER2⁺ breast cancer.

However, because resistance to HER2-targeted therapies is common, the development of strategies to overcome resistance is important, because it might lead to improved outcomes for patients with HER2⁺ breast cancer.

Identifying the underlying mechanisms contributing to resistance has facilitated the development of novel therapeutic strategies to overcome resistance. These strategies include novel HER2-targeted therapies; therapies targeting downstream pathways; and use of Hsp90, telomerase, and VEGF inhibitors. It is hoped that ongoing and completed clinical trials, including phase 3 data for the mTOR inhibitor everolimus, will lead to additional treatment strategies to manage patients with HER2-resistant disease.

Acknowledgments

Writing and editorial support in the preparation of this manuscript was provided by Tricia Newell, PhD, and Matthew Grzywacz, PhD (ApotheCom, Yardley, PA).

Footnotes

Author Contributions

AB conceived the concept, analyzed the data, was involved in writing the first draft and contributed to the writing of the manuscript, agreed with manuscript results and conclusions, developed the structure and arguments for the paper, made critical revisions and approved the final manuscript. Under the direct supervision of AB, Tricia Newell, PhD, and Matthew Grzywacz, PhD of ApotheCom assisted in the writing of the first draft of the manuscript and provided additional editorial support during the manuscript’s development.

ACADEMIC EDITOR: Goberdhan Dimri, Editor in Chief

FUNDING: Editorial support was funded by Novartis Pharmaceuticals Corporation.

COMPETING INTERESTS: Dr. Brufsky is a paid consultant for Novartis.

This paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. All editorial decisions were made by the independent academic editor. All authors have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants. Provenance: the author was invited to submit this paper.

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