Highlights of This Issue

Abstract

The concept of clinically meaningful outcome is very broad. This article makes that concept more specific. It focuses on OS as the primary indicator of patient benefit and develops a model based upon the four types of treatment effect identifiable in OS curves (hazard ratio, gains in median OS, proportional and absolute increases at long-term OS). Threshold levels for these four parameters were postulated and compared with the results of the pivotal phase III trials on new drugs with mature OS data. If the bar for the clinically meaningful outcome is raised too much, positive trials are exceptional.Activating mutations in BRAF are frequent in differentiated thyroid cancer and contribute to resistance to radioactive iodine. To explore the potential for BRAF inhibition to restore radioiodine uptake, Rothenberg and colleagues treated ten patients with iodine-refractory, BRAF-mutant thyroid cancer with dabrafenib. Just three weeks of treatment led to new radioactive iodine uptake in 6/10 patients, sufficient to warrant administering a treatment dose of radioactive iodine. This change in therapy led to dramatic tumor responses. These data suggest that radioiodine resensitization with dabrafenib can have substantial therapeutic efficacy and minimal toxicity.Great strides have been made in appropriately selecting patients to receive anti-EGFR therapies. Although KRAS status currently guides the use of these agents in metastatic colorectal cancer (mCRC), additional biomarkers are needed urgently. In this article, gene expression of EGFR signaling pathway members from patients treated on CALGB80203, a randomized phase II trial of cetuximab versus chemotherapy in mCRC, demonstrated that gene expression of HER3 and CD73 were predictive of benefit in patients treated with cetuximab. These data implicate both HER3 signaling and immune modulation in cetuximab sensitivity and resistance.The development of new technologies for mutant allele detection and quantification allows reaching unprecedented precision and sensitivity. Nevertheless, the implication of minor mutant allele in clinical decision is poorly understood. In this article, Laurent-Puig and colleagues investigated the role of a low fraction of mutant KRAS alleles for response to anti-EGFR therapy in advanced colon cancer by picoliter digital droplet PCR. Their results showed that patients with a low fraction of KRAS mutant allele do benefit from anti-EGFR treatment and thus highlight the need for the definition of a clinically relevant threshold for treatment decisions.