Targeting the PI3K-AKT-mTOR signaling network in cancer

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.

Operable gastro-oesophageal junctional adenocarcinoma: Where to next?

Oesophageal junctional adenocarcinoma is a challeng-ing and increasingly common disease. Optimisation ofpre-operative staging and consolidation of surgery inlarge volume centres have improved outcomes, howev-er the preferred adjunctive treatment approach remainsa matter of debate. This review examines the benefitsof neoadjuvant, peri-operative, and post-operative che-motherapy and chemoradiotherapy in this setting in anattempt to reach an evidence based conclusion. Recentfindings relating to the molecular characterisation ofoesophagogastric cancer and their impact on therapeu-tics are explored, in addition to the potential benefitsof fluoro-deoxyglucose positron emission tomography(FDG-PET) directed therapy. Finally, efforts to decreasethe incidence of junctional adenocarcinoma using earlyintervention in Barrett's oesophagus are discussed,including the roles of screening, endoscopic mucosalresection, ablative therapies and chemoprevention.

Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer

AIM To investigate the impact of histology on outcome in advanced oesophageal cancer treated with first-line fluoropyrimidine-based chemotherapy.METHODS Individual patient data were pooled from three randomised phase Ⅲ trials of fluoropyrimidine-based chemotherapy ± platinum/anthracycline in patients with advanced, untreated gastroesophageal adenocarcinoma or squamous cell carcinoma(SCC) randomised between 1994 and 2005. The primary endpoint was overall survival of oesophageal cancer patients according to histology. Secondary endpoints were response rates and a toxicity composite endpoint.RESULTS Of the total 1836 randomised patients, 973 patients(53%)were eligible(707 patients with gastric cancer were excluded), 841(86%) had adenocarcinoma and 132(14%) had SCC. There was no significant difference in survival between patients with adenocarcinoma and SCC, with median overall survivals of 9.5 mo vs 7.6 mo(HR = 0.85, 95%CI: 0.70-1.03, P = 0.09) and one-year survivals of 38.8% vs 28.2% respectively. The overall response rate to chemotherapy was 44% for adenocarcinoma vs 33% for SCC(P = 0.01). There was no difference in the frequency of the toxicity composite endpoint between the two groups. CONCLUSION There was no significant difference in survival between adenocarcinoma and SCC in patients with advanced oesophageal cancer treated with fluoropyrimidine-based chemotherapy despite a trend for worse survival and less chemo-sensitivity in SCC. Tolerance to treatment was similar in both groups. This analysis highlights the unmet need for SCC-specific studies in advanced oesophageal cancer and will aid in the design of future trials of targeted agents.