Prognostic significance of PI3K mRNA expression in patients with operable high-risk breast cancer

Abstract

577 Background: The aim of the study was to examine the prognostic and predictive significance of PI3K, AKT-1, mTOR, and PTEN mRNA expression and PIK3CA mutations in patients with operable high-risk breast cancer. Methods: Formalin-fixed paraffin-embedded tumor tissue blocks were available from 279 out of 595 operable high-risk breast cancer patients enrolled in a phase III clinical trial of E-T-CMF vs E-CMF. Updated clinical data were retrospectively used in the present translational research study. RNA was isolated followed by kinetic one-step quantitative RT-PCR for assessment of the expression of PI3K, AKT-1, mTOR, and PTEN. Mutations (E542K, E545K and H1047R) in the helical (exon 9) and the kinase (exon 20) domains of the PIK3CA gene encoding the catalytic p110 subunit of PI3K were investigated with custom Taqman SNP genotyping assays in 223 tumor DNA samples from the patient population enrolled in this study. Results: The two groups were well balanced concerning their basic characteristics except for grade (p = 0.015). The vast majority of hormone receptor positive patients (92%) received tamoxifen for 5 years, with LHRH analogs for premenopausal patients. The distribution of AKT-1 values was bimodal and therefore the 25th percentile was a natural cut-off. The median was used as a cut-off for all other genes. Mutations of the PIK3CA gene were detected in 51 patients (23%) (E542K in 8, E545K in 17 and H1047R in 26 patients). After a median follow-up time of 97 months, 93 patients (33%) had relapsed and 65 (23%) had died. High PI3K mRNA expression was associated with significantly shorter DFS (p = 0.044), irrespectively of the treatment arm. Multivariate analysis showed that high PI3K mRNA expression was an adverse prognostic factor for OS (HR = 2.14, 95% CI = 1.16–3.94, p = 0.015) and DFS (HR = 1.71, 95% CI = 1.09–2.68, p = 0.02), while PIK3CA mutations negatively affected OS (HR = 2.05, 95% CI = 1.07–3.95, p = 0.031). None of the other genes assessed was found to be of prognostic significance. Conclusions: High PI3K mRNA expression and PIK3CA mutations appear to be of adverse prognostic significance in patients with high-risk operable breast cancer. No significant financial relationships to disclose.