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Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

2014; Cell Press; Volume: 6; Issue: 2 Linguagem: Inglês

10.1016/j.celrep.2013.12.035

2639-1856

Filip Janků, David S. Hong, Siqing Fu, Sarina A. Piha‐Paul, Aung Naing, Gerald S. Falchook, Apostolia M. Tsimberidou, Vanda M. Stepanek, Stacy Moulder, J. Jack Lee, Rajyalakshmi Luthra, Ralph Zinner, Russell R. Broaddus, Jennifer J. Wheler, Razelle Kurzrock,

Chronic Lymphocytic Leukemia Research

Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.