Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, accounting for 23% (1.38 million) of the total new cancer cases and 14% (458,400) of the total cancer deaths in 2008 (Jemal et al. 2011; Jemal, Siegel, and Ward 2010). In the U.S., 234,580 new cases and 40,030 deaths are estimated for 2013 (ACS 2013). 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 (Figure 1) 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). Mutations in PIK3CA cluster in two major 'hot spots' located in the helical (E542K and E545K in exon 9) and catalytic (H1047R in exon 20) domains (Bachman et al. 2004; Saal et al. 2005). 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). The impact of these mutations and of PTEN loss on the virulence of breast cancer and patient outcome is not completely clear yet. However, 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.
|Table 1. Frequency of Somatic Gene Mutations in the HER2 and PI3K/AKT Pathway in Breast Cancer Subtypes.|
|Gene Mutation||Invasive Breast Cancer||Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer||HER2 positive Invasive Breast Cancer||Triple-negative Invasive Breast Cancer|
|AKT1||4% (O'Brien et al. 2010)||3.2% (Stemke-Hale et al. 2008)||<1% (Stemke-Hale et al. 2008)a||<1% (Stemke-Hale et al. 2008)a|
|HER2||1.6–2.0% (25 cases reported in Bose et al. 2013; COSMIC)||8 cases reported (Bose et al. 2013)||One case reported (Bose et al. 2013)||No cases reported (Bose et al. 2013)|
(O'Brien et al. 2010; Saal, et al. 2005; Stemke-Hale et al. 2008)
||34.5% (Saal et al. 2005; Stemke-Hale et al. 2008)||22–31% (Saal et al. 2005; Stemke-Hale et al. 2008)||8.3% (Stemke-Hale et al. 2008)|
|PTEN||7% (O'Brien et al. 2010)||3.4% (Stemke-Hale et al. 2008)a||5% (Stemke-Hale et al. 2008)a||<1% (Stemke-Hale et al. 2008)a|
NOTE: ER = estrogen receptor; PR = progesterone receptor.
a small sample size <100 patients
Figure 1. Schematic of the PI3K/AKT signaling pathway. Growth factor binding to receptor tyrosine kinases results in activation of the PI3K signaling pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: April 12, 2013
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