The Time Is Now
Personalized Treatment Designed For Cancer Patients
Genes and Their Locations
Breast Cancer Panel
Classically, treatment decisions have been based upon histology of the tumor and on the status of three main biomarkers: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Despite significant improvements in the treatment of breast cancer, novel therapies and treatment strategies are needed.
Molecular alterations involving the PI3K/AKT pathway occur in over 30% of invasive breast tumors. Alterations in breast cancer resulting in hyperactivity of the PI3K pathway include gain-of-function mutations in PIK3CA (the gene encoding the PI3K catalytic subunit p110α), mutations in AKT1, amplification of AKT2, and loss of the phosphatase PTEN (Engelman, Luo, and Cantley 2006). Expression of these mutant p110α isoforms confers growth factor-independent proliferation and protection from anoikis (a form of cell death) and chemotherapy.
Both genetic and biochemical data suggest that activation of the PI3K/AKT survival pathway contributes to breast cancer development and tumorigenesis. PIK3CA mutations in primary breast tumors have been associated with lymph node metastases, presence of ER and PR, and HER2 overexpression (Saal et al. 2005; Stemke-Hale et al. 2008). PI3K hyperactivity has been associated with resistance to anti-HER2 and anti-estrogen therapies. For example, presence of activating PIK3CA mutations and loss of PTEN in HER2-overexpressing cancers correlates with a lower response to trastuzumab and lapatinib (Berns et al. 2007; Nagata et al. 2004; Serra et al. 2008). Prospective studies to confirm these findings are in progress. These data also suggest that inhibitors of the PI3K pathway currently in clinical development (Brachmann et al. 2009; Engelman 2009) can be used to reverse acquired and de novo drug resistance.
Currently, there are many kinds of PI3K/AKT pathway inhibitors in clinical development. Preclinical studies suggest the main activity of these drugs will be limited to tumors with PIK3CA mutations (Brachmann et al. 2009; O'Brien et al. 2010; She et al. 2008). Agents include PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. Although these small molecules block different elements within the same cellular signaling pathway, their differential selectivity may have distinct therapeutic impact in patients with breast cancer.