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Liquid Biopsy to Predict Colon Cancer Recurrence Moves Closer to Clinic

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NEW YORK (GenomeWeb) – Results of a prospective trial published this week have provided strong evidence that circulating tumor DNA can be used to identify stage II colorectal cancer patients who are highly likely to recur after a surgical tumor resection, helping to better distinguish which patients may need adjuvant chemotherapy treatment and which may avoid it.

Expanding on results shared earlier this year at the annual meeting of the American Society of Clinical Oncology, the study, published Wednesday in Science Translational Medicine, also provides evidence that ctDNA can be used to assess the efficacy of adjuvant treatment.

Led by Jeanne Tie of the University of Melbourne, along with researchers from Johns Hopkins, the University of Melbourne, and several other Australian medical centers and clinics, the study prospectively analyzed blood samples from 230 stage II colon cancer patients who had undergone purportedly curative surgery.

Almost all of the patients in the study who tested positive for ctDNA after their surgery eventually relapsed when not treated with adjuvant chemotherapy. In contrast, more than 90 percent of patients who had no detectable ctDNA remained recurrence-free.

According to Nickolas Papadopoulos, one of the study authors and a researcher at Johns Hopkins, the results provide clear evidence of the clinical value that ctDNA measurement could add in the setting of stage II colorectal cancer.

The decision of whether and how to treat patients with these tumors has been a difficult one for physicians, because while 80 percent of these patients are cured by surgery alone, the other 20 percent relapse and often develop fatal metastatic disease.

Clinicians have to this point had limited ability to predict whether an individual patient falls into one of these two segments. As a result, up to 40 percent of stage II patients undergo adjuvant chemotherapy, which carries risks of potentially serious adverse events for a modest reduction in absolute risk.

This clear unmet clinical need coupled with the persuasive data collected by the study investigators suggests that it shouldn't be long before this type of testing is made available clinically either through academic hospital labs or by commercial companies, Papadopoulos told GenomeWeb.

In the study, the researchers used a detection method called the Safe-Sequencing System (Safe-SeqS), developed by researchers at Johns Hopkins, which relies on a barcoding strategy to distinguish amplification or sequencing errors from real variants.

The strategy for the investigation was to initially test patients' tumor tissue using Safe-SeqS with a narrow focus on 15 genes commonly mutated in colon cancer. Based on the results of this initial tumor sequencing, the group then chose a mutation for each of the 230 patients that had at least one variant — whichever had the greatest prevalence — to then measure in circulation using personalized Safe-SeqS assays.

About a quarter of the patients in the study were treated with adjuvant chemotherapy at the discretion of their physicians, who were blinded to the ctDNA results. All the subjects were then followed with standard surveillance measures, and 15 percent (34 individuals) eventually had a recurrence.

When the group assessed the prognostic significance of the presence of ctDNA after surgery in patients not treated with adjuvant chemo, they found that after a median follow-up of 27 months, 11 of the 14 patients with positive post-op ctDNA — almost 80 percent — had recurred, compared to less than 10 percent of the ctDNA-negative group.

This difference in risk between those with or without detectable ctDNA remained significant even when the researchers divided the cohort into clinical low-risk and clinical high-risk subgroups.

In a discussion of some of the study data last month at the ASCO annual meeting, Tie said that she and her colleagues estimated that if a patient's postoperative ctDNA is positive, their probability of having residual disease and subsequent recurrence at three years is 100 percent, while patients with negative ctDNA have a 90 percent chance of being recurrence-free at three years.

According to the researchers, the risk of recurrence for patients with postsurgical ctDNA who are not treated with chemotherapy actually appears to be greater than that of patients with stage III colorectal cancer, based on the study results.

Conversely, patients with negative ctDNA postoperatively with their 90 percent chance of avoiding recurrence appear to have similar results to those with stage I colorectal cancer.

In addition to showing that ctDNA after surgery was strongly associated with later recurrence, while a lack of ctDNA marked the opposite, the study also found that in a small subset of patients treated with both surgery and adjuvant drugs persistent ctDNA was also a clear indicator that a patient would have a poor response to adjuvant chemotherapy treatment.

Tie said at the ASCO annual meeting that this observation suggests that the use of ctDNA could improve clinical trials of adjuvant regimens by offering an earlier readout of either treatment benefit or treatment failure.

Based on the results for the study, she and her colleagues have recently initiated a randomized, ctDNA-driven clinical trial in stage II colon cancer, called DYNAMIC.

While Papadopoulos said that it isn't yet clear exactly when or which hospital labs or commercial companies may make ctDNA testing available clinically to predict recurrence in stage II colon cancer patients, he does not expect it to take long given the strength of the study results and the clinical need in this setting.

Several of the study authors from Johns Hopkins also hold roles at commercial spinout Personal Genome Diagnostics, which has licensed IP covering Safe-SeqS.

Other companies with alternative ctDNA sequencing or other molecular analysis methods could also potentially develop tests with similar indications, although Papadopoulos argued that his and his colleagues' results with Safe-SeqS offer the most robust and compelling evidence so far published for this type of clinical utility, and that the method has advantages in flexibility and cost compared to other sequencing strategies.

In the meantime, Papadopoulos said he and his colleagues will continue to use the method in a research setting, collecting data from additional subjects to further support its clinical utility. They are also hoping to conduct studies of whether ctDNA detection in stage III colorectal cancer patients can also help predict recurrence risk and guide therapeutic decision-making.

At ASCO, Tie noted that she and her colleagues have also tested the method in patients with resectable colorectal cancer liver metastases and saw the same patterns of ctDNA negativity linked to a high likelihood of recurrence-free survival.

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