The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer

Abstract

The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.

Figure 1.. Downstream signaling of phosphatidylinositol-3 kinase (PI3K) in cancer.

After activation and phosphorylation of growth factor receptors by a ligand, PI3K is recruited to the membrane through the p85 adaptor subunit, resulting in the activation of the p110 catalytic subunit and production of phosphatidylinositol-3,4,5 trisphosphate (PIP₃). This second messenger forms a docking site for cytoplasmic proteins that carry pleckstrin homology (PH) domains to the membrane, including the serine threonine kinase AKT. Once activated, AKT mediates the activity of several target proteins, which results in cell survival, proliferation, and protein synthesis. In this schematic representation, lines indicate either phosphorylation leading to activation (arrow) or inhibition (blunt end) of downstream targets. The star represents gain-of-function mutations in the p110 subunit.

Figure 2.. PI3K proteins and functional domains.

The Subclass IA PI3Ks are heterodimers that consist of a p85 regulatory subunit and a p110 catalytic subunit. Key functional domains are identified. The three most common mutations in the PIK3CA gene are depicted with stars.