Abstract: Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers. There has been much advancement in the treatment of HR+/HER2 negative metastatic breast cancer (MBC), in particular the development of more tailored and targeted therapies. Recently, greater understanding of the role of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer has led to the development of PI3K inhibitors, which have proven to be effective in the treatment of HR+/HER2 negative MBC. In this review, we will discuss the role of the PI3K/AKT/mTOR pathway in breast cancer and therapies that have been developed to inhibit PI3K. We will discuss in detail the development of PI3K inhibitor alpelisib, indications for use in HR+/HER2 negative MBC, safety and tolerability and the future direction of this therapy in the treatment of breast cancer.
Keywords: PI3K, PIK3CA, alpelisib
Breast cancer is the leading cause of cancer and the second leading cause of cancer death in women.1 Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers.1 Recently, there has been a paradigm shift in the treatment of HR+/HER2 negative metastatic breast cancer (MBC) with development of targeted therapies, which have led to patients living longer and with less toxicity. Cyclin dependent kinase 4/6 inhibitors (CDK 4/6i) including palbociclib, ribociclib and abemaciclib, in combination with either aromatase inhibitor (AI) or fulvestrant, have revolutionized the treatment of HR+/HER2 negative MBC and has become the standard first-line treatment in this setting.2–5 Additional treatment options in HR+/HER2 negative MBC include estrogen receptor (ER) antagonist fulvestrant as a single agent and mammalian target of rapamycin (mTOR) inhibitor everolimus, both of which have shown to be an effective treatment in HR+/HER2 negative MBC.6,7 However, resistance to endocrine and targeted therapies ultimately occurs, warranting the need for new therapeutic strategies. In this review, we will discuss the role of the Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer and the development of PI3K inhibitors as a therapeutic option for breast cancer patients. We will also discuss in detail Alpelisib, the first approved PI3K inhibitor for the treatment of HR+/HER2 negative MBC.
The PI3K/AKT/mTOR Pathway and Breast Cancer
The PI3K/AKT/mTOR pathway plays a critical role in regulating cell proliferation, growth and survival. In breast cancer, therapeutic strategies have been developed to target these three important sites in this pathway. BOLERO-2 was a randomized, double-blinded Phase III placebo controlled study that compared the mTOR inhibitor everolimus in combination with exemestane versus exemestane and placebo in HR+/HER2 negative MBC.7 Median progression free survival (PFS) by central assessment was improved from 4.1 month to 10.6 months (HR 0.36, p<0.001).7 The AKT inhibitor capivasertib was studied in the Phase II FAKTION trial.8 This study compared capivasertib plus fulvestrant versus fulvestrant and placebo in HR+/HER2 negative MBC. Median PFS was 10.3 months in the capivasertib group versus 4.8 months in the placebo group (HR 0.58, p= 0.0018).8
PI3Ks are a family of lipid kinases.9 Stimulation of receptor tyrosine kinase activates this pathway, which in turn triggers activation of PI3K (Figure 1).10 Class I PI3K is further divided into subclass IA and IB.11 Class IA PI3Ks are heterodimers consisting of a p110α catalytic subunit and p85 regulatory subunit.11 There are four catalytic isoforms of PI3K including α, β, γ and Δ.11
PIK3CA is an oncogene that encodes the p110α catalytic isoform.11 Three common mutations in PIK3CA include E545K and E542K on exon 9 and H1047R on exon 20.11 Mutation of PIK3CA leads to gain of function activation of the p110α catalytic isoform, which causes a downstream effect that ultimately leads to unregulated cell growth, proliferation and survival.11
PIK3CA has been found to be one of three somatic mutations that occur commonly in breast cancer.12 Approximately 20–50% of all breast cancers harbor a PIK3CA mutation.11 HR positive and HER2 positive breast cancers are the two subtypes that exhibit this mutation most commonly, with incidence 35% and 23%, respectively.11,13 Greater understanding of the role of PIK3CA mutation in cancer cell growth and survival has led to the development of targeted therapeutics aimed at directly inhibiting the PI3K pathway.
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