Review
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World J Clin Oncol. Dec 10, 2014; 5(5): 990-1001
Published online Dec 10, 2014. doi: 10.5306/wjco.v5.i5.990
Overcoming endocrine resistance in metastatic breast cancer: Current evidence and future directions
Andrea Milani, Elena Geuna, Gloria Mittica, Giorgio Valabrega
Andrea Milani, Elena Geuna, Gloria Mittica, Giorgio Valabrega, Institute for Cancer Research and Treatment at Candiolo, University of Torino Medical School, FPO (Fondazione del Piemonte per l’Oncologia), 10060 Candiolo, Italy
Andrea Milani, Elena Geuna, Gloria Mittica, Giorgio Valabrega, Department of Oncology, University of Torino Medical School, 10123 Torino, Italy
Author contributions: Milani A and Geuna E contributed equally to this work; Milani A and Geuna E conceived and wrote the manuscript; Mittica G helped perform the literature search and contributed to writing, revising, and editing the manuscript; Valabrega G supervised the work and contributed to writing, revising, and editing the manuscript.
Correspondence to: Giorgio Valabrega, MD, Institute for Cancer Research and Treatment at Candiolo, University of Torino Medical School, FPO (Fondazione del Piemonte per l’Oncologia), SP 142, Km. 3.95, 10060 Candiolo, Italy. giorgio.valabrega@ircc.it
Telephone: +39-01-19933283 Fax: +39-01-19933299
Received: February 13, 2014
Revised: April 4, 2014
Accepted: July 18, 2014
Published online: December 10, 2014
Processing time: 301 Days and 12.9 Hours
Abstract

About 75% of all breast cancers are estrogen receptor (ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens (such as tamoxifen and fulvestrant) and aromatase inhibitors (such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy (acquired resistance) and a proportion of patients may fail to respond to initial therapy (de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectively overcome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.

Keywords: Everolimus; Mammalian target of rapamycin; PI3K inhibitors; Estrogen receptor; Endocrine resistance

Core tip: Endocrine therapy forms the backbone of treatment for hormone receptor (HR)-positive metastatic breast cancer (MBC) patients. Unfortunately, resistance to endocrine agents develops in the majority of patients. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has boosted the development of strategies designed to overcome resistance to endocrine therapies. In particular, co-targeting of receptor tyrosine kinase and intracellular signaling pathways (such as the PI3K-Akt-mTOR pathway) has emerged as a particularly promising strategy. We predict that the development of new drugs with a strong underlying biological rationale will quickly result in more personalized treatment of patients with HR-positive MBC and further improve outcomes.