Scientists at the Stanford University School of Medicine say they have come up with a technique that monitors levels of tumor DNA circulating in the blood and which can be adapted to the clinic. Their approach, which should be applicable to many types of cancers, is highly sensitive and specific, they point out, adding that they were able to accurately identify about 50% of people in a study with stage-1 lung cancer and all patients whose cancers were more advanced.

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said Maximilian Diehn, M.D., Ph.D., assistant professor of radiation oncology. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it's necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

The researchers describe their findings in a paper (“An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage”) published online in Nature Medicine.

“We're trying to develop a general method to detect and measure disease burden,” added Ash Alizadeh, M.D., Ph.D., a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we're in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

“The vast majority of circulating DNA is from normal, noncancerous cells, even in patients with advanced cancer,” pointed out Scott Bratman, M.D., Ph.D. “We needed a comprehensive strategy for isolating the circulating DNA from blood and detecting the rare, cancer-associated mutations. To boost the sensitivity of the technique, we optimized methods for extracting, processing and analyzing the DNA.

The researchers' technique, which they have dubbed CAPP-Seq, for Cancer Personalized Profiling by deep Sequencing, is sensitive enough to detect just one molecule of tumor DNA in a sea of 10,000 healthy DNA molecules in the blood. Although the researchers focused on patients with non-small-cell lung cancer, the approach should be widely applicable to many different solid tumors throughout the body. It's also possible that it could one day be used not just to track the progress of a previously diagnosed patient, but also to screen healthy or at-risk populations for signs of trouble.

“We detected ctDNA [circulating tumor DNA] in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ~0.02%,” wrote the investigators. “Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.”

According to Dr. Diehn, there are currently no reliable biomarkers available for lung cancer patients, which is the most common cancer and No. 1 cause of cancer deaths. “We are very excited about our findings because a personalized, clinically useful biomarker could revolutionize how we detect and manage this devastating disease,” he said.

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