PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients

Abstract

PI3K/AKT signalling pathway controls important cellular processes such as the cell proliferation and apoptosis. PIK3CA gene encoding a catalytic subunit of the PI3K is mutated and/or amplified in various neoplasms, including ovarian cancer. We aimed to evaluate PIK3CA alterations and their clinical importance in ovarian cancer patients. Molecular analysis was performed on 117 ovarian carcinomas with the use of qPCR, SSCP and sequencing. In a group of 98 patients with complete clinical data, 62 patients were treated with standard taxane-platinum regimens and 36 patients with platinum-cyclophosphamide regimens. A multivariate analysis was performed by the Cox's and logistic regression models. PIK3CA mutations occurred in 5/117 (4.3%) carcinomas, exclusively in the endometrioid and clear cell types (p = 0.0002); they were also associated with low FIGO stage (p = 0.0003), low tumor grade (p = 0.045) and early patient's age at diagnosis (p = 0.0005). The PIK3CA amplification (predominantly a low-level) was found in 28/117 (24%) ovarian carcinomas. It was more frequent in TP53 mutant tumors (p = 0.012) and tended to associate with high pAKT expression (p = 0.061). The PIK3CA amplification strongly diminished odds of complete remission (OR = 0.25, p = 0.033) and platinum sensitive response (PS, OR = 0.12, p = 0.004) in the taxane-platinum treated patients. The odds of PS were also much lower in all patients with the PIK3CA amplification evaluated together, regardless of the treatment applied (OR = 0.18, p = 0.001). Our results suggest that PIK3CA amplification may be a marker predicting ovarian cancer response to chemotherapy.

The Role of the PTEN/PI3K/Akt Pathway on Prognosis in Epithelial Ovarian Cancer: A Meta-Analysis

“…Other methods used included immunocytochemistry and real-time quantitative polymerase chain reaction. There was only 1 prospective study [11], and the rest were all retrospective studies [10,12,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36].…”

“…There was no heterogeneity between studies. However, there was only one study that reported an association between PI3K expression and PFS with multivariate analysis [34].…”

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

“…These tumors commonly exhibit activation of the PI3K/Akt pathway via PIK3CA mutation (6), loss of PTEN, PTEN mutation (7), or increased expression of mir-214 targeting PTEN (8). Current therapeutic strategies for ovarian cancer involve platinum-or taxane-based chemotherapeutics, which are typically effective initially, but often fail because of acquired resistance attributed to diverse molecular causes, one of which is increased activity of the PI3K pathway (9)(10)(11). These findings indicate that ovarian cancer patients are likely to benefit from the development of PI3K pathway inhibitors.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…Pathway activation through PIK3CA can occur through either amplification or activating mutation of the catalytic subunit. Mutations of PIK3CA are typically associated with endometrioid and clear cell subtypes and are associated with lower tumor stage and grade (Campbell et al 2004, Kolasa et al 2009, Willner et al 2007. Amplifications, on the other hand, have been detected in all histological subtypes, though there was an association with poorer differentiation.…”

“…Amplifications, on the other hand, have been detected in all histological subtypes, though there was an association with poorer differentiation. PIK3CA amplification has been reported in 13-24% of ovarian carcinomas and is associated with increased expression of phosphorylated AKT indicating that amplification results in increased activation of the pathway (Campbell et al 2004, Kolasa et al 2009, Nakayama et al 2006b, Willner et al 2007, Woenckhaus et al 2007. Clinical data is lacking in the majority of these studies and the prognostic role of AKT and mTOR in ovarian cancer is unclear.…”