Breast cancer (BC) may be subdivided into subgroups depending on expression profile of several genes and/or protein.
Her2 over expression in tumours results into a worse prognosis. BC patients having Her2 positive status are preferably not treated with anti oestrogens, but with anti Her2 drugs, such as Trastuzumab (Herceptin).
For the BC patients whose tumours express ER receptor (ER group) but do not over express Her2, the over expression of several genes related to proliferation results into the classification into the luminal B subgroup, with a worse prognosis. These luminal B patients are preferably not treated with anti-oestrogens, but with more aggressive treatments (chemotherapy).
Deregulated phosphatidylinositol 3-kinase (PI3K)-AKT signaling has been implicated in many hallmarks of carcinogenesis as the pathway influences multiple aspects of cell physiology. Many genomic alterations act on this pathway, activating its signaling activity, which contributes to tumor progression, metastases and resistance to treatment.
PI3Ks are heterodimeric lipid kinases for which the p110α catalytic and regulatory p85 subunits are encoded by separate genes. In breast cancer, mutations of the PIK3CA gene, which codes for the p110α catalytic subunit, has been found in 18-40% of human cancers, which makes it one of the most common genetic changes in breast cancer beside p53 mutations and HER2 amplification. Expression of p110α mutants in human mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells and in vivo studies with cells expressing PIK3CA mutants result in a more active PI3K pathway and induction of tumors. The lack of a homogeneous population makes it difficult to investigate the prognostic or predictive effect of PIK3CA mutations in breast cancer. Extensive cross-talk at multiple levels with other pathways both upstream and downstream of PI3K also makes the exact role of PIK3CA mutations in breast cancer difficult to elucidate.
Mutations in the AKT1 pleckstrin homology domain (PHD) reported in breast cancer at a frequency of 8% may result in PI3K-independent membrane recruitment and activation of AKT1 and downstream signaling. The clinical relevance of this mutation is unknown.
Given the complexity of PI3K signaling, it is important to have molecular markers that can predict for prognosis and therapeutic response for incorporation into future breast cancer clinical trials with compounds that act on this pathway.
As the Kaplan-Meier analysis of the PIK3CA mutation versus the wild-type patients did not reveal any statistically significant differences in prognosis, mutation status alone may not be a sensitive marker of significant activation of the PI3K/AKT pathway that would affect tumor progression. Other downstream interactions of an extra oncogenic “hit” may be required.
USPTO Backgrounds
USPTO Backgrounds