During the first few months of treatment, targeted cancer cell therapies using man-made proteins significantly shrink many tumors. However, the cancer cells often become resistant, the treatment stops working, and the disease returns. New research, reported online in the journal Nature, may point to why these outcomes frequently occur.
In a study conducted by a Johns Hopkins Kimmel Cancer Center team, advanced colon cancer patients treated with the monoclonal antibody panitumumab had drug-resistance tumor cell mutations in blood samples 5 to 7 months later. Furthermore, scientists report that, before the therapy begins, low levels of these mutations exist in nearly all tumors, making the cancers predestined to recur.
“These resistance mutations develop by chance as cancer cells divide so that tumors always contain thousands of resistance cells,” says Luis Diaz, MD, associate professor of oncology and director of the Swim Across America laboratory at Johns Hopkins. Diaz says the findings likely apply to any targeted cancer therapy.
“The best chance for a cure is when a tumor is very small, but when the cancer is advanced, our research quantifies the probability that we can achieve cures with single-agent targeted therapies,” says Bert Vogelstein, MD, professor and codirector of the Ludwig Center at Johns Hopkins. “Long-term remissions of advanced cancers will be nearly impossible with single targeted agents,” he adds.
The Johns Hopkins scientists analyzed blood samples taken from 28 patients with advanced colorectal cancer. Twenty-four of the 28 patients in the study had normal KRAS gene copies in their tumors, and 4 had mutations in KRAS, serving as a control group. These patients were enrolled in a clinical trial of panitumumab, and they were most likely to respond to the drug due to the presence of the KRAS gene. Blood samples were taken before beginning the therapy and at 4-week intervals during the therapy.
The scientists’ analysis found that 9 of the 24 patients with normal KRAS genes presented detectable KRAS mutations in the blood within 5 to 7 months of beginning therapy. In 3 patients, KRAS mutations were detected before imaging scans showed metastatic tumor growth. Additionally, in cooperation with Martin Nowak, PhD, and his team from Harvard University and with the use of mathematical models, the investigators calculated when KRAS mutations likely originated. Nowak and colleagues determined that KRAS mutations were present prior to the initiation of treatment with panitumumab.
“The probability that the mutations were absent at the beginning of treatment is exceedingly low,” says Vogelstein. The time it takes for cancers to recur is determined simply by how long it takes cancer cells with mutant genes to multiply, he adds.
Results show that combination therapies are the best chance for longer remissions, researchers say. “The good news is that there is a limited number of pathways that go awry in cancer, so it should be possible to develop a small number of agents that can be used in a large number of patients,” says Vogelstein. “However, I hope this research will help stimulate the testing of new drugs as combination therapies much earlier in the drug approval process than the current norm.”
Source: Johns Hopkins.