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This Week in NEJM: Feb 24, 2011


In NEJM this week, two researchers from the Memorial Sloan-Kettering Cancer Center discuss the clinical relevance of a model that elucidates the reasons behind resistance to BRAF inhibition in melanoma. About half of all melanomas contain a mutation in the gene that encodes the RAF family member BRAF, the authors write, and the mutation — which usually substitutes glutamic acid for valine at position 600 of the protein — activates and deregulates the kinase activity of BRAF. Selective RAF inhibitors do a good job helping patients with the V600E mutation, but the response is "often profound but temporary," the researchers say. Two recent studies shed light on the reasons why and validate a clinical model of how these inhibitors work, showing that the inhibitors' strength is also a weakness as a new mutation often develops in response to the drug, making the patient resistant to it. The studies suggest new treatment strategies, the authors conclude, but more work is needed to determine the relative prevalence of each event that could lead to drug resistance.

Also in NEJM this week, two teams of researchers respond to a study that was published in the journal last October, which concluded that the inhibition of anaplastic lymphoma kinase in patients with non-small cell lung cancer through treatment with crizotinib results in tumor shrinkage or disease stabilization in most patients. A team of clinicians from Italy writes that while ALK-positive lymphomas respond to cytotoxic drugs, "relapses occur and require salvage therapy." The team says they treated two such relapsed patients with crizotinib and found that their symptoms and lesions subsided with treatment. So while the crizotinib worked to treat relapsed patients, the two cases indicate that ALK inhibition in advanced ALK-positive lymphomas leads to relapse of the disease at first, rather than stabilization.

Another team of researchers from Japan also writes to respond to the crizotinib article. The researchers suggest that a "substantial" number of patients in the original study who were identified as having ALK rearrangements by means of FISH analysis were actually false positives, and that the diagnostic method should include other techniques like immunohistochemical staining for further studies of ALK inhibitors. In response, the authors of the original study, Kwak et al., say that the success of the crizotinib trial clearly shows that FISH is clinically valid for diagnosis and that the causes of different response rates between patients are "under investigation."

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.