Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer

Abstract

Breast cancer (BCa) is the most common cancer and the second cause of death among women. Phosphoinositide 3-kinase (PI3K) signaling pathway has a crucial role in the cellular processes such as cell survival, growth, division, and motility. Moreover, oncogenic mutations in the PI3K pathway generally involve the activation phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutation which has been identified in numerous BCa subtypes. In this review, correlations between PIK3CA mutations and their clinicopathological parameters on BCa will be described. It is reported that PIK3CA mutations which have been localized mostly on exon 9 and 20 hot spots are detected 25-40 % in BCa. This relatively high frequency can offer an advantage for choosing the best treatment options for BCa. PIK3CA mutations may be used as biomarkers and have been major focus of drug development in cancer with the first clinical trials of PI3K pathway inhibitors currently in progress. Screening of PIK3CA gene mutations might be useful genetic tests for targeted therapeutics or diagnosis. Increasing data about PIK3CA mutations and its clinical correlations with BCa will help to introduce new clinical applications in the near future.

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

“…Due to the difference in the clinical effect of PIK3CA mutations in the helical versus kinase domains, the prognostic effect may not be consistent. This finding suggests that the presence of Ex9 mutations predicted a more favorable outcome, whereas the presence of the Ex20 mutations predicted a relatively poor prognosis [2]. In this study, we could not evaluate the difference in the prognosis for each PIK3CA mutation, since PIK3CA Ex20 mutations were observed in 90.9% (10/11) of patients with PIK3CA mutations, and PIK3CA Ex9 and Ex20 mutations were observed in 10.1% (1/11) of patients with PIK3CA mutations (Additional file 1: Table S2).…”

“…1a, b and Additional file 1: Tables S4, S5). In general, among the ER+ PBC patients, the PIK3CA mutations had varying clinical outcomes, but they were associated with a favorable prognosis [2]. Due to the difference in the clinical effect of PIK3CA mutations in the helical versus kinase domains, the prognostic effect may not be consistent.…”

“…Importantly, somatic activating mutations of PIK3CA and AKT1 affect the magnitude of PI3K/AKT activation [1]. Meta-analysis of the BC literature shows that the PIK3CA mutation is present in 20%-40% of all BCs, making this gene the second most frequently mutated in BC, with most mutations being expressed in 'hotspots' in the helical domain (exon (Ex) 9) or the catalytic domain (Ex20) [2]. A somatic mutation in the plekstrin homology domain of AKT1:p.Glu17Lys is found in approximately 4% of breast tumors [3].…”

Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design

“…6–10 As many as 80% of these mutations occur in three hotspot positions within the catalytic subunit, p110α (encoded by the PIK3CA gene) of the heterodimeric enzyme (Fig. 1b).…”

Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer

“…The phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) signaling pathway has been identified as one of the most important and most frequently mutated pathways involved in these processes. In BC, PI3KCA mutations are frequently detected, most commonly in exon 10 (E454K and E424K) and exon 21 (H1047R), which encode the helical and kinase domain (4,5). Whereas mutations in the helical domain remove the interaction between p85 and p110, leading to constitutive PI3KCA activity, mutations in the kinase domain directly affect the catalytic subunit of PI3KCA by allosteric changes, allowing easier access of the substrate to the catalytic site (6,7).…”