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.
Josh Lauring, Ben Ho Park, and Antonio C. Wolff
Alexander S. Baras, Jarushka Naidoo, Christine L. Hann, Peter B. Illei, Charles W. Reninger III, and Josh Lauring
Tumor DNA sequencing can identify rare driver genomic alterations that suggest targets for cancer therapy, even when these drivers cannot be suspected on clinical grounds. In some cases, genomic alterations identified in the tumor can lead to a change in diagnosis with implications for prognosis and therapy. This report describes a case in which evaluation of tumor sequencing results by a molecular tumor board (MTB) led to rediagnosis of a non–small cell lung cancer as highly aggressive NUT midline carcinoma, with implications for targeted therapy using an investigational bromodomain and extraterminal (BET) inhibitor. We discuss the molecular biology and diagnosis of this rare tumor, and suggest how improved annotation of tumor sequencing reports and multidisciplinary expertise of MTBs can facilitate timely diagnosis of rare tumors and application of potential targeted therapies.
Justin Lee, Jennifer Axilbund, W. Brian Dalton, Daniel Laheru, Stanley Watkins, David Chu, Karen Cravero, Berry Button, Kelly Kyker-Snowman, Ian Waters, Christopher D. Gocke, Josh Lauring, and Ben Ho Park
Next-generation sequencing (NGS) is increasingly being used in cancer care to identify both somatic tumor driver mutations that can be targeted for therapy, and heritable mutations in the germline associated with increased cancer risk. This report presents a case of a JAK2 V617F mutation falsely identified as a duodenal cancer mutation via NGS. The patient was found to have a history of polycythemia vera, a disorder with a high incidence of JAK2 somatic mutations. Buccal cell DNA showed heterozygosity for the mutation, suggesting that it was potentially germline. However, subsequent resequencing of tumor, adjacent normal tissue, and fingernail DNA confirmed the mutation was somatic, and its presence in tumor and buccal cells resulted from contaminating blood cells. This report highlights important nuances of NGS that can lead to misinterpretation of results with potential clinical implications.