Abstract
IntroductionPIK3CA is the oncogene showing the highest frequency of gain-of-function mutations in breast cancer, but the prognostic value of PIK3CA mutation status is controversial.MethodsWe investigated the prognostic significance of PIK3CA mutation status in a series of 452 patients with unilateral invasive primary breast cancer and known long-term outcome (median follow-up 10 years).ResultsPIK3CA mutations were identified in 151 tumors (33.4%). The frequency of PIK3CA mutations differed markedly according to hormone receptor (estrogen receptor alpha [ERα] and progesterone receptor [PR]) and ERBB2 status, ranging from 12.5% in the triple-negative subgroup (ER-/PR-/ERBB2-) to 41.1% in the HR+/ERBB2- subgroup. PIK3CA mutation was associated with significantly longer metastasis-free survival in the overall population (P = 0.0056), and especially in the PR-positive and ERBB2-positive subgroups. In Cox multivariate regression analysis, the prognostic significance of PIK3CA mutation status persisted only in the ERBB2-positive subgroup.ConclusionsThis study confirms the high prevalence of PIK3CA mutations in breast cancer. PIK3CA mutation is an emerging tumor marker which might become used in treatment-choosing process. The independent prognostic value of PIK3CA mutation status in ERBB2-positive breast cancer patients should be now confirmed in larger series of patients included in randomized prospective ERBB2-based clinical trials.
Highlights
phosphatidylinositol 3-kinase (PIK3CA) is the oncogene showing the highest frequency of gain-of-function mutations in breast cancer, but the prognostic value of PIK3CA mutation status is controversial
Dysregulation of tyrosine kinase receptor (TKR)-phosphatidylinositol 3-kinase (PI3K) signaling pathways is frequent in human cancers
Sixty-four tumors bore PIK3CA mutations located in exon 9, 86 tumors bore mutations in exon 20, and one tumor bore mutations in both exons 9 and 20 (Table 1)
Summary
PIK3CA is the oncogene showing the highest frequency of gain-of-function mutations in breast cancer, but the prognostic value of PIK3CA mutation status is controversial. Dysregulation of tyrosine kinase receptor (TKR)-phosphatidylinositol 3-kinase (PI3K) signaling pathways is frequent in human cancers. Among the most important molecular events downstream of TKR activation is PI3K activation, which catalyzes the phosphorylation of inositol lipids to phosphatidylinositol-3,4,5-trisphosphate. Phosphatidylinositol-3,4,5-trisphosphate activates the serine/threonine kinase AKT, which in turn regulates several signaling pathways controlling cell survival, apoptosis, proliferation, motility, and adhesion [1]. Gain-of-function mutations in PIK3CA have been found in several cancers, including breast cancer [1,3,4]. PIK3CA is frequently mutated at ‘hotspots’ in exons 9 and 20, corresponding to the helical (E542K and E545K) and kinase (H1047R) domains, respectively. P110a carrying a hotspot mutation shows oncogenic activity: it can transform primary fibroblasts in culture, induce anchorage-independent growth, and cause tumors in animals [5,6]
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