Genetic analysis of the tumors from patients with advanced melanoma can clue researchers in to how well patients will respond to a therapy that targets the growth-promoting protein called BRAF, a researcher from the Perelman School of Medicine at the University of Pennsylvania will report on Monday, June 6 at the annual meeting of the American Society of Clinical Oncology. Looking outside of the BRAF gene, the researchers found loss of the tumor suppressor gene PTEN also appears to be associated with patient response to GSK436, which could help guide researchers to even more personalized approaches to melanoma therapy.
The phase I clinical trial data highlight the role that genetic changes other than that in BRAF may play in a patient's resistance to BRAF inhibitors, a targeted therapy that has shown unprecedented efficacy among patients with metastatic disease.
"These findings are important because they suggest that performing genetic characterization of melanomas for genetic changes outside of BRAF could help predict the patients that may have worse responses to BRAF inhibitors," says Katherine Nathanson, MD, an associate professor of Medical Genetics in Penn's Abramson Cancer Center, who led the study. Armed with such information, a physician could prescribe a different drug or combination of drugs to target these advanced cancers. Guiding such decisions early can save time in the race to control metastatic melanomas, which commonly kill patients within a year after they're identified.
An estimated 40 to 60 percent of all melanomas carry a mutated BRAF gene. Although patients with advanced melanoma are often resistant to chemotherapy, drugs that go after the overactive BRAF protein - which acts as a foot on a gas pedal promoting tumor growth -- have demonstrated promising results in Phase I and II trials. Research shows that as many as 80 percent of patients who take these drugs experience a clinical benefit. However, despite signs of initial success, months into receiving the therapy, the tumors of many patients receiving the BRAF inhibitor return and begin growing again.
"There has been a lot of focus on what happens with tumors as they develop resistance to BRAF inhibitors," Nathanson says. "We asked a different question: Are there mutations that help predict response to inhibitors before the patients begin drug treatment?"