PI3K Pathway Activation in Breast Cancer Is Associated with the Basal-Like Phenotype and Cancer-Specific Mortality.

Abstract

Abstract Background: Current biological therapies for breast cancer are tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may be associated with specific phenotypes and therapeutic resistance. We undertook an integrative study of mutational, copy number and expression analysis of key regulators of the PI3K pathway in a cohort of 292 invasive breast cancer patients with known treatment outcomes.Material and Methods: Mutations in 3 "hotspots" in exons 9 and 20 of the PIK3CA gene were determined by sequencing and PIK3CA gene copy number by qPCR. PTEN loss and Akt activation i.e. pAkt (Ser473) were assessed by immunohistochemistry using tissue microarrays. Cores were scored by 2 independent observers blinded to clinicopathological data and patient outcome and a histoscore calculated by multiplying the percent positive cells and staining intensity in a range 0-3. Standard statistical tests were applied to assess relationship between the measured parameters and patient outcome.Results: Alterations identified included PIK3CA mutations (12/168 i.e. 7%), PIK3CA copy number gain (28/209 i.e. 14%), PTEN loss (73/258 i.e. 28%) and AKT activation (62/258 i.e. 24%). Overall at least one parameter was altered in 72% i.e. 139 of 193 assessable primary breast cancers. PI3K pathway activation was significantly associated with ER negative (P=0.0008) and PR negative (P=0.006) status, high tumor grade (P=0.032) and a "basal-like" phenotype (P=0.01), where 92% (25/27) of tumors had an altered pathway. In univariate analysis PI3K pathway aberrations were associated with death from breast cancer however this relationship was not maintained in multivariate analysis. No association was identified between an activated pathway and outcome in tamoxifen- or chemotherapy-treated patients.Discussion: We conclude that >70% of breast cancers have an alteration in at least one component of the PI3K pathway and this might be exploited to therapeutic advantage especially in "basal-like" cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2123.