Targeted cancer cell therapies using synthetic proteins produce dramatic results within the first few months of treatment, but cells often become resistant and the cancer returns, according to researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. Scientists studied 28 patients with advanced colon cancer who were treated with the monoclonal antibody panitumumab and found that drugresistant tumor cell mutations appeared in the blood of patients 5 to 7 months later. At the same time, low levels of these mutations were found to exist in nearly all the tumors before the therapy even began, which makes the cancers destined to recur, according to the researchers.1
The resistance mutations occur by chance as cancer cells divide, and the results are likely to apply to any targeted cancer therapy, says Luis Diaz, MD, associate professor of oncology at Johns Hopkins. Adds Bert Vogelstein, MD, professor and co-director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, long-term remissions of advanced cancers are nearly impossible with single-targeted agents.
The 28 patients in the study were enrolled in a clinical trial of panitumumab, which specifically targets the epidermal growth factor receptor. Patients who are most likely to respond to the drug have normal copies of the KRAS gene in their tumors.
The control group of 4 patients had KRAS mutations whereas 24 patients had normal copies of the KRAS gene. Blood samples were taken prior to the initiation of therapy and at 4-week intervals during therapy. The findings indicated that 9 of the 24 patients with normal KRAS genes (38%) exhibited KRAS mutations that were detectable in the blood within 5 to 7 months of starting therapy. KRAS mutations were detected in 3 patients before imaging scans demonstrated metastatic growth.
The investigators then calculated when KRAS mutations likely originated and found that they were present prior to the initiation of treatment. As a result, Dr. Vogelstein notes, the time it takes for cancer to recur is determined simply by the amount of time it takes for cells with mutant genes to multiply.
The best chance for longer remissions is through combination therapies, researchers note. They hope that their work will stimulate the testing of new drugs as combination therapies much earlier in the drug approval process than currently occurs.