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ASCO Educational Book; 2009
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Role of the mTOR Pathway in Endocrine-resistant Breast Cancer — Opportunities for Novel Combination Strategies

Stephen R.D. Johnston, MA, PhD, FRCP

From the Department of Medicine, The Royal Marsden Hospital, London, England

Author's disclosure of potential conflicts of interest are found at the end of this article.

Address reprint requests to Stephen R. D. Johnston, MA, PhD, FRCP, Consultant Medical Oncologist, Department of Medicine, The Royal Marsden Hospital, 197 Fulham Road, Chelsea, London SW3 6JJ, UK; e-mail: stephen.johnston{at}rmh.nhs.uk

Overview: For estrogen receptor (ER)-positive breast cancer, the antiestrogen tamoxifen and aromatase inhibitors for postmenopausal women have both demonstrated substantial efficacy in advanced/metastatic disease, as adjuvant therapy, in the neoadjuvant setting, and as chemopreventive agents. However their effectiveness is ultimately limited by the development of resistance, either de novo in a significant proportion of ER-positive breast carcinomas or as acquired resistance in those ER-positive tumors with initial hormone sensitivity that develop resistance over time.1,2 Although the mechanisms for endocrine resistance are varied and have been extensively studied, an increasing role has been shown for various peptide growth factor receptors that interact with ER and modulate endocrine responsiveness.3 Several studies have now demonstrated that estrogen independent growth in ER-positive breast cancer cells may be mediated in part by the serine/threonine protein kinase B or Akt,4 and that, in particular, this pathway (which can be activated by growth factor signaling and is integrally involved in cell survival) may indeed protect breast cancer cells from tamoxifen-induced apoptosis.4,5 This article describes the molecular biology of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, discusses the potential role of this intracellular signaling in causing endocrine resistance in ER-positive breast cancer, and reviews the recent preclinical and clinical data that have examined whether mTOR inhibition can be combined with aromatase inhibition in an attempt to enhance endocrine efficacy in breast cancer.