Just one mutation can make a world of a difference to a patient, researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hosptial and Richard J. Solove Research Institute (OSUCCC-James) and collaborators from the University of Texas Southwestern Medical Center, recently discovered. Reported in the Journal of Clinical Investigation, the team’s study detailed the treatment of an advanced-stage lung cancer patient with the drug sorafenib during a clinical trial. The patient responded within two months of beginning treatment and has remained progression-free and asymptomic for five years while continuing oral sorafenib therapy—she had the most positive response by far among the other 305 trial participants.
Whole-genome sequencing of cancerous tissue samples and RNA sequencing of cancerous and healthy tissues taken from the patient before treatment with sorafenib were able to identify a possible reason for the patient’s positive response: a mutation in ARAF S214C. It is common for cancerous cells to contain more than a hundred alterations in DNA relative to normal cells, but this specific mutation was both expressed at a high level and a possible target for sorafenib. When the researchers introduced this mutation into normal lung cells, tumors formed, and the tumors were inhibited by sorafenib.
Genome sequencing is often used to identify genetic mutations in a patient’s cancer cells that may indicate which drugs would be of most benefit to the patient. “Knowing which mutations are present in lung tumors can help us tailor a patient’s treatment to the unique genetic features present in his or her cancer cells,” said David Carbone, MD, from The OSUCCC-James Thoracic Oncology Program. “Our study suggests that we can discover important new gene mutations that drive cancer development and progression by analyzing genes in cancer cells from patients who fare far better or far worse than others in a particular clinical trial.”
In the case at hand, the patient might be considered lucky. “If recurrent but rare mutations underlie cancer growth and responsiveness, they are not likely to be statistically called out as a potential driver of cancer through a genome scan of several hundred or even thousands of cases because they are so rare. But for the patients who do have these specific genetic mutations, having this information is critical,” said Dr. Carbone.
This work was funded by NCI U01CA114771, Uniting Against Lung Cancer, the Lung Cancer Research Foundation, Novartis, Department of Defense Congressionally Directed Medical Research Programs Lung Cancer Research Program W81XWH-12-1-0269, and the American Lung Association.