Evaluation of overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) according to phosphathidylinositol-3-kinase (PI3K) pathway status.

Abstract

e21130 Background: In breast cancer (BC), PI3K pathway activation is frequently identified and is a potential target for therapies currently in development. Nowadays, the role of PIK3CA mutation as a prognostic marker is controversial. The aim of this study is to determine the prognostic implications of PI3K pathway in MBC and to correlate it with BC subtypes. Methods: We analyzed 148 MBC pts. DNA was extracted from paraffin-embedded tumor tissue with EZ1 DNA Tissue Kit and was analyzed with DxS PI3K Mutation Test Kit or Sequenom MALDI-TOF MassARRAY technology. PTEN status was determined by immunohistochemistry and PTEN loss was defined as H-score ≤50. All pts signed informed consent. SPSS v.15 software was used for statistical analysis. Results: PIK3CA status was tested in 119 pts and mutations were found in 44 (37%): 26 (59%) in exon 20 [H1047R] and 18 in exon 9 [11 E545K, 5 Q546K and 2 E542K]. PIK3CA mutations were present in 35% of hormonal receptor positive BC group (HR+), 21% of HER2 positive (HER2+) and 25% of triple negative BC (TNBC). In HR+, the frequency of mutations in exon 9 was higher (52%) than in HER2+ (14%) and TNBC (25%) (p=0.057). PTEN H-score was determined in 142 pts; loss of function was present in 40 pts (28%): 23 (57%) of HR+ tumors, 10 (25%) of TNBC and 7 (18%) of HER2 +. There is no significant difference in PTEN expression between BC subtypes. PIK3CA mutation and PTEN loss of function were not mutually exclusive as 9 pts had both alterations assessed. In pts with PIK3CA mutation and/or PTEN loss OS was shorter compared to wild-type cases (p=0.009). Among those with a PI3K pathway alteration, TNBC was associated with shorter OS, but not HR+ and/or HER2+ (p=0.015). No differences were found in disease free survival among different BC subtypes. Overall, 17 pts were enrolled in a PI3K-pathway inhibitor phase 1 clinical trial. Conclusions: In our BC population, the prevalence of the different PIK3CA mutations and PTEN loss rates correlates with previous published data. A higher frequency of exon 9 mutations was found in HR+ compared with HER2+ and TNBC. In our database, PI3K pathway alteration is associated with lower OS, especially among TNBC pts.