Editorial
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Dec 20, 2018; 9(8): 172-179
Published online Dec 20, 2018. doi: 10.5306/wjco.v9.i8.172
Current status of PI3K-mTOR inhibition in hormone-receptor positive, HER2-negative breast cancer
Navid Sobhani, Daniele Generali, Fabrizio Zanconati, Marina Bortul, Bruna Scaggiante
Navid Sobhani, Daniele Generali, Fabrizio Zanconati, Marina Bortul, Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Academic Hospital, Trieste 34149, Italy
Bruna Scaggiante, Department of Life Sciences, University of Trieste, Trieste 34127, Italy
Author contributions: Sobhani N proposed and planned the topic of the editorial and wrote the first draft that has been revised and implemented by Generali D and Scaggiante B; Zanconati F and Bortul M further edited the manuscript.
Supported by Ricerca Sanitaria LILT 2015; and Beneficentia Foundation Stiftung, No. BEN2016/16 grants.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author to: Bruna Scaggiante, PhD, Professor, Department of Life Sciences, University of Trieste, Via Giorgeri, 1, Trieste 34127, Italy. bscaggiante@units.it
Telephone: +39-34-59700000
Received: July 13, 2018
Peer-review started: July 13, 2018
First decision: October 8, 2018
Revised: October 16, 2018
Accepted: November 26, 2018
Article in press: November 26, 2018
Published online: December 20, 2018
Abstract

Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments. The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.

Keywords: Hormone receptor positive/Her2-negative breast cancer, PI3K, mTOR, TORC1/2, Akt, Everolimus

Core tip: The phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway sustains cancer progression and drug resistance. The first Food and Drug Administration approved molecule against this pathway was everolimus, an mTOR inhibitor, to be used in combination with exemestane in hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancers progressing to non-steroidal aromatase inhibitors. Drugs targeting other effectors such as PI3K, PI3Kα, Akt and mTORC1/2 have gained clinical interest. Nevertheless, everolimus remains the best option due to the relevant toxicity of the other drugs targeting the PI3K-mTOR pathway. Future directions point towards the development of biomarkers that would identify those patients who would benefit from the PI3K-mTOR inhibitors for improving overall survival.