56IN - PI3K/AKT pathways in ovarian and endometrial cancers

Date 01 October 2012
Event ESMO Congress 2012
Session Emerging diagnostic and therapeutic targets in gynecological cancers: From science to clinical practice
Topics Ovarian Cancer
Endometrial Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Cristiana Sessa
Authors C. Sessa
  • IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale Bellinzona e Valli, 6500 - Bellinzona/CH


The PI3K pathway is frequently activated in many human tumors, including ovarian (OC) and endometrial cancer (EC). Mutations of the gene PIK3CA, which codes for the p110α subunit, have been reported in 6% of OC, with a higher incidence in endometrioid and clear cell type; a 24% incidence of amplification has been reported, with no difference among subtypes, with an overall incidence of 30% PIK3CA alterations regardless histotypes, and of 45% in endometrioid and clear cell. In a retrospective study in patients with gynaecologic malignancies receiving combinations with PI3K/AKT/mTOR inhibitors in Phase I studies, the objective response in patients with PIK3CA mutations, including OC, was higher (30%) than in patients with wild type PIK3CA (10%). The presence of many confounding factors (retrospective analysis, treatment with mTOR inhibitors, combinations with cytotoxics) did not allow to determine whether a relationship existed between PIK3CA mutations and sensitivity to PI3K or mTOR inhibitors. Loss of PTEN has been reported in 35%-50% of patients with EC; PIK3CA mutations have been reported in 39% of patients with EC with both PIK3CA and PTEN mutations in 44%. The most recent data in EC in 243 patients samples indicate >80% PI3K pathway alterations including mutations of PIK3R1 and PIK3R2, the genes encoding p85α and p85�. KRAS mutation has been reported in 20% of EC with divergent results on the mutual exclusiveness of PI3K and KRAS mutations. The significance of a crosstalk between the two pathways is unknown and the role of a combinatorial approach is under investigations. The PI3K oncogene is a promising target for the treatment of EC and clinical studies with pan PI3K, isoform specific PI3K or dual PI3K/mTOR inhibitors are ongoing in advanced EC. The general strategy in targeted therapy is to switch from an empirical approach to a more personalized treatment, based on genetic alterations and mechanistic studies. So far, the available data with PI3K inhibitors don't justify the selection of patients according to PI3K mutations. Treatment of patients with both wild type or mutant tumors, together with the availability of representative tumor samples, could lead to the identification, through genetic analysis in responders, of the alteration(s) of the target genes indicative of sensitivity to the agents administered.


All authors have declared no conflicts of interest.