Clin Cancer Res
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Activating mutations in the phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway are present in the majority of breast cancers and therefore are a major focus of drug development and clinical trials. Pathway mutations have been proposed as predictive biomarkers for efficacy of PI3K-targeted therapies. However, the precise contribution of distinct PI3K pathway mutations to drug sensitivity is unknown. ⋯ AKT1 E17K is a bona fide oncogene in a human luminal breast cancer context. Distinct PI3K pathway mutations confer differential sensitivity to drugs targeting the pathway at different points and by distinct mechanisms. These findings have implications for the use of tumor genome sequencing to assign patients to targeted therapies.
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The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status. ⋯ MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer.
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Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. ⋯ Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials. Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies. Clin Cancer Res; 19(19); 5300-9. ©2013 AACR.
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In advanced cancer, oncological treatment is influenced by performance status (PS); however, this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (performance status, patient-reported outcomes; PRO) with an inflammation-based score (Glasgow Prognostic Score, mGPS). A new method of prognosis in advanced cancer (combining performance status and mGPS) is tested and then validated. ⋯ A systemic inflammation-based score, mGPS, and performance status predict survival in advanced cancer. The mGPS is similar to performance status in terms of prognostic power. Used together, performance status and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of patients with advanced cancer.