The prognostic value of PI3K mutational status in breast cancer: A meta‐analysis

Abstract

Breast cancer (BC) is the second most common cause of cancer-related deaths in women worldwide. The availability of reliable biomarkers of response/resistance to cancer treatments would benefit patients and clinicians allowing for a better selection of BC patients most likely to respond to a specific treatment. Phosphatidylinositol 3-kinase (PI3K) enzymes are involved in numerous cellular- functions and processes. The gene encoding for PI3K catalytic subunit p110α is mutated in 20-40% of BC. We performed a meta-analysis of the current literature on randomized clinical trials, investigating the role of PIK3CA mutational status as prognostic factor and predictor of response to anti-cancer treatments. Overall 1929 cases were included. The pooled analysis confirmed that the presence of a PIK3CA mutation represents an independent negative prognostic factor (HR = 1.67, 95% CI: 1.15-2.43; p = 0.007) in BC, as previously reported. Since PI3K signalling is also a result of other pathways’ hyperactivation, further investigation of potential biomarkers able to predict likelihood of response to anti-PI3K/mTOR, anti-HER2 and other TKRs is warranted in future randomized clinical trials. This article is protected by copyright. All rights reserved

PIK3CA mutation enrichment and quantitation from blood and tissue

“…Ten samples were identified to correctly having a high VAF (> 15%) for one of the four mutations of interest and were not included in further enrichment experiments, with the exception of sample 17, which showed a high VAF for E545K mutation and a very low VAF for H1047R mutation. Three samples were detected to have a very low mutant allele fraction (VAF < 2%) for E542K (sample 4) and H1047R (samples 15,17). In case of sample 4, this might have been a false positive result, which is prevalent in FFPE samples due to fixation derived error 37 .…”

“…Such trials have recently resulted in the FDA approval of Alpelisib/BYL719, a PI3K p110α selective inhibitor for advanced breast cancers which are hormone receptor positive, HER2 negative and PIK3CA mutant 7 . This and other clinical circumstances [8][9][10][11][12][13][14][15] identify PIK3CA status as an important biomarker with both predictive and prognostic value, and motivate the development of reliable, facile, economic tests for these mutations.…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…The PI3K signaling pathway has a key role in the regulation of cell proliferation, differentiation, migration and trafficking (77). The PI3K/Akt cell survival pathway has been revealed to be upregulated by EP2 and EP4 activation (78,79), thereby upregulating the level of matrix metalloproteinases, which has been observed in several types of human cancer and regulates the efficacy of various therapies (5).…”

Testing considerations for phosphatidylinositol‐3‐kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer

“…In breast cancer, PIK3CA mutations are the most frequent alterations in the PI3K pathway, with at least 80% occurring within the helical (E542K and E545K) and kinase (H1047R) domains of p110α 11 . Mutations in PIK3CA have been reported in 20%‐40% of breast cancer cases, and their incidence also varies across different breast cancer molecular subtypes 11‐13 . The incidence of PIK3CA mutations has been estimated at 36%‐45% of HR+, HER2‐negative breast cancers; up to 40% of HER2‐positive breast cancers; and 9%‐14% of triple‐negative breast cancers 12,14,15 …”

“…Regarding PIK3CA mutation as a prognostic factor, there are conflicting results on the association of PIK3CA mutations and breast cancer outcome 16 . A pooled analysis showed that the presence of PIK3CA mutations is a negative prognostic factor (pooled overall survival [OS], disease‐free survival [DFS], and progression‐free survival [PFS]) in breast cancer 13 . It has been suggested that PIK3CA may offer a differing prognostic role in early versus advanced or metastatic BC.…”