The phosphoinositide-3-kinase (PI3-kinase)-Akt-mTOR pathway is a central signal transduction pathway that regulates many critical aspects of normal and
cancer physiology, including cell proliferation, apoptosis, cell morphology and migration,
protein synthesis, and integration of metabolism. In
breast cancer, somatic mutations that activate the pathway occur in more than 50% of
tumors, underscoring the potentially broad impact of targeting the pathway for
therapy. A vast body of preclinical data demonstrates the efficacy of pathway inhibition on
tumor growth, and evidence also shows that activation of the pathway occurs in models of acquired resistance to hormonal
therapy. This preclinical work led to the investigation of allosteric
mTOR inhibitors,
everolimus and
temsirolimus, in metastatic
hormone receptor-positive
breast cancer. The recent BOLERO-2 trial comparing
everolimus plus
exemestane versus placebo plus
exemestane in women with resistance to nonsteroidal
aromatase inhibitors demonstrated a 6-month improvement in progression-free survival and led to FDA approval of
everolimus for this indication in the United States. This landmark trial is the first demonstration of significant clinical benefit using drugs targeting this pathway in
breast cancer. Many questions remain about the role of
everolimus and other pathway-targeting drugs in clinical development in
breast cancer treatment. This article reviews the role of the PI3-kinase-Akt-mTOR pathway in
breast cancer biology and the clinical trial evidence available to date.