PI3K inhibition to overcome endocrine resistance in breast cancer

ABSTRACT

Introduction: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway.

Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker.

Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

KEYWORDS:

• Breast cancer
• endocrine resistance
• PIK3CA
• PI3K inhibitor
• alpelisib
• buparlisib
• pictilisib
• taselisib

Article highlights

• This article reviews the development of selected pan and isoform specific PI3K inhibitors in hormone receptor positive breast cancer.

• It summarises the evidence generated so far on the efficacy and toxicity of these agents alone and in combination from preclinical development to phase III trials.

• It examines in particular at the exploration of the PIK3CA mutation as a potential predictive biomarker for the PI3K inhibitors.

This box summarizes key points contained in the article.

Declaration of Interest

C. R. Flowers receives research grants from Celgene and other research funding from Abbvie, Acerta, Gilead, Janssen, Millenium, Infinity, Pharmacyclics, TG Therapeutics and personal fees from Bayer and Celgene outside of the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

B. T. Hennessy has received research funding from Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.