PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer

Abstract

The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Fifty-micron paraffin sections were used for DNA extraction and 3-micron slides for immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH). ER, PR and HER2 IHC were repeated in a central laboratory for both primary and metastasis. PTEN levels were assessed by IHC and PI3K pathway mutations detected by a mass spectroscopy-based approach. Median age was 48 years (range, 30 to 83 years). Tumor subtype included 72% hormone receptor-positive/HER2-negative, 20% HER2-positive, and less than 7.8% triple receptor negative. Tissues were available for PTEN IHC in 46 primary tumors and 52 metastases. PTEN was lost in 14 (30%) primary tumors and 13 (25%) metastases. There were 5 cases of PTEN loss and eight cases of PTEN gain from primary to metastasis (26% discordance). Adequate DNA was obtained on 46 primary tumors and on 50 metastases for PIK3CA analysis. PIK3CA mutations were detected in 19 (40%) of primary tumors and 21 (42%) of metastases. There were five cases of PIK3CA mutation loss, and four cases of mutation gain (18% discordance). There was an increase of the level of PIK3CA mutations in four cases, and decrease in one from primary to metastasis. There is a high level of discordance in PTEN level, PIK3CA mutations, and receptor status between primary and metastatic disease that may influence patient selection and response to PI3K-targeted therapies.

IKBKE Protein Activates Akt Independent of Phosphatidylinositol 3-Kinase/PDK1/mTORC2 and the Pleckstrin Homology Domain to Sustain Malignant Transformation

“…Hyperactivation of Akt is observed in more than 50% human cancers, which has been shown to be resulted from activated mutation of upstream molecules such as PIK3CA and PTEN (46,47). We demonstrated in this study a close correlation between overexpression of IKBKE and elevated pAkt in breast cancer, indicating that aberrant expression of IKBKE is a causal factor of Akt activation in human cancer.…”

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

“…12,27,28 One important finding in the current study is the significant association of KRAS and PIK3CA mutations in primary tumors (P ¼ 0.008), which seems to be driven by the helical (exon 9) mutations (P ¼ 0.039) as kinase domain (exon 20) mutations alone do not associate with KRAS mutations (P ¼ 0.312). Conversely, a similar association could not be observed in metastases, despite the existence of a statistical trend (P ¼ 0.092); this is in line with the observed discrepancy of PIK3CA mutation status in the paired specimens and could possibly have an impact in determining the optimal algorithm for mutation screening in metastatic colorectal cancer.…”

The regulatory roles of phosphatases in cancer

“…Loss of functional PTEN has been described in primary and metastatic breast tumours (231,232) resulting in hyperactivation of the PI3K pathway and an increase in cell proliferation (233). Down-regulation of PTEN activity and activation of the PI3K signaling pathway is associated with resistance to anti-estrogen therapy (234).…”