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Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

  • Systemic Therapy (J O’Shaughnessy, Section Editor)
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Abstract

About 70% of breast cancers are hormone receptor (HR) positive, meaning an estrogen receptor (ER) and/or a progesterone receptor (PgR) are present in the tumor. Compounds that modulate ER or PgR signaling, by either competing for estrogen binding to estrogen receptors (synthetic estrogen receptor modulators [eg, tamoxifen]) or opposing the production of estrogen in the body (aromatase inhibitors in postmenopausal women), are dominant among those used to treat HR-positive breast cancer. Although HR-positive tumors are associated with a better prognosis, in the case of advanced disease, most will develop resistance to hormonal treatments over time. Multiple mechanisms of endocrine resistance have been proposed, including ER receptor loss and cross-talk between the ER and HER2/neu (human epidermal growth factor receptor 2; also known as ErbB-2) receptor signaling pathways. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway may result from genetic alterations in critical components in this pathway. Therapeutic targeting of alternate pathways of growth signaling in ER-positive tumors has the potential to translate into practice-changing therapeutic strategies. This article discusses the concept of primary and secondary endocrine resistance, outlines the proposed mechanisms, and reviews the emerging evidence for interventions designed to overcome resistance and restore ER sensitivity. The recently reported result of the BOLERO-2 study using an mTOR inhibitor (everolimus or RAD001) in combination with an aromatase inhibitor (exemestane) is discussed in some detail.

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Disclosure

M. Khasraw is a consultant for Hoffman LaRoche and has received a research grant (paid to his institution) from Merck Serone. S.Harvey: none. R. Bell is a consultant for Novartis and has received a research grant (paid to his institution) from AstraZeneca.

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  1. Andrew Love Cancer Centre, 70 Swanston Street, Geelong, VIC, 3220, Australia

    Mustafa Khasraw & Richard Bell

  2. Peter MacCallum Cancer Centre, Melbourne, Australia

    Sandra L. Harvey

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  1. Mustafa Khasraw
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  2. Sandra L. Harvey
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Correspondence to Mustafa Khasraw.

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Khasraw, M., Harvey, S.L. & Bell, R. Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies. Curr Breast Cancer Rep 4, 66–74 (2012). https://doi.org/10.1007/s12609-011-0065-1

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