The PI3K pathway is the most frequently altered pathway in cancer, and its activation has been shown to confer resistance to endocrine and HER2-targeted therapies preclinically. Conflicting data have been published regarding the prognostic significance, hormone receptor association, and treatment implications of PIK3CA mutations. Given the high frequency of these mutations and their prognostic implications in breast cancers, an increasing focus has been placed on the development of inhibitors of the PI3K pathway. Emerging clinical data in ER+ and HER2-amplified breast cancers suggest preliminary clinical activity from PI3K inhibitors in combination with endocrine therapy and HER2-targeted therapy, respectively. This manuscript will review the rationale for exploring PI3K inhibitors in ER+ and HER2-amplified breast cancers.
The phosphoinositide-3 kinase (PI3K)/AKT signaling network is the most frequently mutated pathway in breast cancer. Of the somatic alterations in the PI3K/AKT pathway, the mutation of the genes encoding the PI3K catalytic subunits p110α (PIK3CA) are the most common genetic alteration of this pathway, where ≥80% occur within the helical (E542K, E545K) and kinase (H1047R) domains of p110α.1
PIK3CA mutations induce a transformed phenotype in vitro and in vivo, including enhanced cell proliferation and survival, growth factor independence, protection from apoptosis, and drug resistance. 2-5
Data surrounding the association of PIK3CA mutations with estrogen/progesterone receptor expression (ER/PR+) or human epidermal growth factor receptor-2 gene (HER2) amplification have been variable. Given the high frequency of these mutations and their prognostic implications, an increasing focus has been placed on the development of inhibitors of the PI3K pathway. In this manuscript, we will review the rationale for exploring PI3K inhibitors in breast cancer.
Numerous PI3K inhibitors (ATP-mimetics that bind competitively and reversibly to the ATP-binding pocket of p110α subunit) have been developed and are in varying stages of clinical testing (Table 1
). These include pan-PI3K inhibitors, isoform specific inhibitors (that allow higher doses of anti-p110a and anti-p110b drugs to be delivered without incurring side effects caused by pan-PI3K inhibitors), and combined PI3K/mTOR inhibitors (which aim to overcome the loss of feedback inhibition of PI3K activation seen with the analogues of rapamycin). Janku et al showed a favorable response to PI3K/AKT/mTOR inhibitors in patients with PIK3CA mutant tumors who had failed conventional therapy.6
Table 1. Select PI3K Inhibitors in Clinical Development
Overall, toxic effects from PI3K inhibitors have been primarily mild to moderate, and manageable with supportive medication. Several of the toxic effects seen are “off-target” effects, but others seem to be directly related to PI3K target engagement and mechanisms of action, such as hyperglycemia, which is more commonly seen upon more sustained inhibition of p110α.7
Dose-limiting toxic effects reported with multiple agents include hyperglycemia, maculo-papular rash, gastrointestinal intolerance (anorexia, nausea, vomiting, dyspepsia, diarrhea), and stomatitis. Of note, the only pan-PI3K inhibitor that can cross the blood-brain barrier (buparlisib [BKM120], Novartis, data on file) potentially inhibits PI3K in the central nervous system,8,9
and was commonly associated with mood alteration (anxiety, irritability, or depression) in phase I clinical trials.7,10
The mood alteration is mild overall, and responsive to dose reductions/interruptions (suggesting dose dependency), as well as treatment with selective serotonin reuptake inhibitors and anxiolytics.
ER+ Breast Cancer
ER+ Breast Cancer and PI3K Pathway
The ER signaling pathway and PI3K pathway have significant cross-talk. PI3K has been shown to interact with ER directly and indirectly, resulting in ER phosphorylation and an increase in ER transcription.11,12
Conversely, ER also upregulates the PI3K pathway by promoting transcription of genes involved in the PI3K pathway, including receptor ligands, RTKs, and signaling adaptors.13
Interestingly, estrogen deprivation has been shown to downregulate PI3K and phosho-mTOR,14
suggesting that part of the antitumoral activity seen with endocrine therapies may stem from abrogation of cell survival, via downregulation of the PI3K/ AKT/mTOR pathway.