viernes, 7 de septiembre de 2012

Sequencing "Outlier" Genome Suggests Some Patients May Benefit from Cancer Drug || NCI Cancer Bulletin for September 4, 2012 - National Cancer Institute

NCI Cancer Bulletin for September 4, 2012 - National Cancer Institute

Sequencing "Outlier" Genome Suggests Some Patients May Benefit from Cancer Drug

Clinical trials that fail to identify drugs that benefit most patients may still yield valuable information by identifying subsets of patients who would benefit from the drugs. That is the conclusion of a study in which researchers used whole-genome sequencing to salvage a potentially beneficial drug that might have been discarded.
In a report published August 23 in Science, researchers at Memorial Sloan-Kettering Cancer Center describe how they sequenced the tumor genome of a 73-year-old woman with advanced bladder cancer who had a complete response to the drug everolimus (Afinitor) that has lasted for more than 2.5 years. The patient was part of a 45-patient, early-phase clinical trial in which treatment with everolimus failed to improve progression-free survival, the trial’s primary endpoint, among the patient population enrolled in the trial as a whole.
“The patient was a dramatic outlier in terms of her clinical response,” said the study’s senior author, Dr. David Solit.
After targeted sequencing of a few specific genes in the woman’s tumor “didn’t turn up anything revealing,” Dr. Solit continued, the researchers decided to sequence the woman’s entire tumor genome to see if they could discover a molecular basis for her strong response.
Among the many genomic alterations the researchers identified, inactivating mutations in two genes, TSC1 and NF2, stood out. Evidence from laboratory studies had suggested that loss-of-function mutations in TSC1 and NF2 might increase sensitivity to everolimus.
The researchers then analyzed the tumor DNA from 13 other patients enrolled in the trial and found TSC1-inactivating mutations in the tumors of three more patients, two of whom had measurable tumor shrinkage and lived longer without their cancer progressing than patients whose tumors lacked a TSC1 mutation. None of the 13 patients’ tumors had an NF2 mutation.
Sequencing the TSC1 and NF2 genes in tumor samples from 96 other patients with advanced bladder cancer revealed five more patients with TSC1 mutations, but no NF2 mutations.
Dr. Solit and his colleagues hope to launch a small clinical trial testing everolimus in patients with bladder cancer tumors that have mutations in TSC1 or a related gene, TSC2.
“We often see cases where just a few patients in an otherwise negative trial have significant benefit,” Dr. Solit said. “With the in-depth analysis provided by novel technologies like whole-genome sequencing, we can possibly salvage potentially beneficial drugs that were otherwise going to fail.”

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