PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data

Dimitrios Zardavas, Wayne A Phillips, Sherene Loi, Dimitrios Zardavas, Wayne A Phillips, Sherene Loi

Abstract

PIK3CA mutations represent one of the most common genetic aberrations in breast cancer. They have been reported to be present in over one-third of cases, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes. Substantial preclinical data on the oncogenic properties of these mutations have been reported. However, whilst the preclinical data have clearly shown an association with robust activation of the pathway and resistance to common therapies used in breast cancer, the clinical data reported up to now do not support that the PIK3CA mutated genotype is associated with high levels of pathway activation or with a poor prognosis. We speculate that this may be due to the minimal use of transgenic mice models thus far. In this review, we discuss both the preclinical and clinical data associated with PIK3CA mutations and their potential implications. Prospective clinical trials stratifying by PIK3CA genotype will be necessary to determine if the mutation also predicts for increased sensitivity to agents targeting the phosphoinositide 3-kinase pathway.

Figures

Figure 1
Figure 1
Schema of phosphoinositide 3-kinase blocking agents currently under clinical development. Dual phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors (for example, BEZ235, XL765, GDC-0980, GSK1059615), pan-PI3K inhibitors (BKM120, GDC-0941, BAY 80–6946, SF1126, PX-866, XL147, CH5132799, GSK1059615), isoform-selective PI3K inhibitors (p110α selective: BYL719, MLN1117; p110β selective: TGX-221, GSK2636771; p110γ selective: AS-252424; p110δ selective: CAL-101), AKT inhibitors (MK-2206, XL418, GDC-0068, AR-67, GSK690693, VQD-002), mTORC1/2 inhibitors (OSI-027, AZD-8055, PP-242, INK-128), and PDK1 inhibitors (AR-12, UCN-01). PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-4,5-trisphosphate; RTK, receptor tyrosine kinase.
Figure 2
Figure 2
Trial design of the ‘NeoPHOEBE’ trial with two identical cohorts and upfront PIK3CA genotyping to ensure adequate power for both mutant and wild-type cohorts. HER2, human epidermal growth factor receptor 2.

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Source: PubMed

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