Ludwig researchers working in collaboration with colleagues in Australia and the US have shown that fragments of tumor DNA circulating in the blood can be used to gauge the risk of colorectal cancer recurrence and the efficacy of chemotherapy following surgery. The finding, published today in the current issue of the journal Science Translational Medicine, is an important step toward the development of a non-invasive and more effective test for the detection, monitoring and treatment of cancer.
"Prior studies, including ones from our group, have shown that this technique is sensitive enough to detect tumor DNA fragments in patients with advanced cancer," Bert Vogelstein, co-director of the Ludwig Center at Johns Hopkins and one of the study leaders. "But this new study gets us one major step closer to the real goal, because it suggests that it can detect residual disease in early stage patients well before conventional clinical or radiologic criteria can."
The decision of whether a stage II colon cancer patient should be treated with adjuvant, or post-operation, chemotherapy remains one of the most challenging areas in colorectal oncology. Such assessments are currently made by combining a number of clinical and pathologic features--such as the tumor's appearance under the microscope, including how far it has spread through the bowel wall--or looking for the presence of cancer-specific genetic markers that have prognostic significance.
However, current methods are imprecise, and as a result doctors tend to err on the side of caution. Currently, up to 40 percent of stage II patients undergo the rigors and risks of adjuvant chemotherapy even though only a small fraction of them are destined to experience a cancer relapse.
"The routine procedure is to give six months of chemotherapy, but we don't have any way of knowing if the treatment is effective," said Jeanne Tie, a Ludwig investigator at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Victoria, Australia, and lead author of the study.
Cancer cells often shed their DNA into the blood when they die, and recent advances in technology have made it possible to capture and profile these relatively rare fragments of DNA. Mutations in such circulating tumor DNA (ctDNA) can serve as extremely specific cancer biomarkers.
"We have to be able to pick out a single tumor DNA among ten thousand normal DNA fragments," Tie said. "That's the level of sensitivity that we needed to get down to, and that wasn't possible until now."
For the current study, Tie and her colleagues collected tumor samples from 230 patients with stage II colorectal cancer. They analyzed the DNA of the tumor specimens and then designed personalized assays to target each patient's particular genetic mutations.
The assays were applied to blood samples taken from the patients four to 10 weeks after surgery to remove tumors. Twenty of the 230 patients tested positive for ctDNA, and of this group, 80 percent experienced cancer relapse within about two years. Of the 164 patients whose blood tested negative for ctDNA, only 10 percent relapsed.
"A positive ctDNA test is an indicator that cancer cells from the original tumor are hiding somewhere in the body," said Peter Gibbs, a Ludwig investigator at WEHI who co-led the study with Tie and Vogelstein.
The team also looked at whether ctDNA could be used to gauge the impact of chemotherapy treatments. Six of the patients who tested positive for ctDNA following surgery also underwent adjuvant chemotherapy. The scientists continued to collect blood samples from these patients and found that in two patients, ctDNA readings changed from positive after surgery to negative following chemotherapy.
"To an oncologist, that's probably the most exciting aspect of a ctDNA screening test--that it can be used not only to determine the risk of recurrence, but also as a real-time marker of chemotherapy benefits," said Gibbs.
In the current study, the ctDNA assays were custom-tailored to each patient's unique cancer mutations, but the scientists are also developing a ctDNA screening test that covers frequently occurring colorectal cancer mutations.
"When such a generic test is developed, it could still catch more than 90 percent of colorectal cancers, and it would eliminate the need to retrieve and test individual tumor samples, thus saving time, effort and money," Gibbs said.
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