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Colorectal Cancer Relapse Can Be Predicted by ctDNA Clearance, Study Shows

DNA fragments

NEW YORK – A study of colorectal cancer patients with localized disease has shown that circulating tumor DNA, or ctDNA, testing after surgery can identify those at risk for cancer recurrence earlier than standard screening methods and may be useful for managing patients' adjuvant treatment strategies.

The study, published in the Journal of Hematology and Oncology on Monday, analyzed clinical and ctDNA data from 240 patients with stage II or stage III colorectal cancer who were recruited at three Chinese academic hospitals from 2017 to 2020. The researchers collected peripheral blood leukocytes, primary tumor, and plasma samples from these patients for ctDNA analysis using Geneseeq's 425-gene next-generation sequencing panel.

Tumor samples were collected at surgery, and blood samples were obtained seven days before surgery, within a week after surgery, six months after surgery, and every three months for the two years until patients passed away or withdrew study participation. Researchers deemed patients ctDNA-positive if the number of tumor variants in their plasma was more than 5 percent of the number of total tracking variants in each patient.

In the first blood sample collected shortly after surgery, the researchers found that 8.3 percent of patients were ctDNA positive, while 91.7 percent were ctDNA negative. Over the two-year follow-up, these ctDNA-negative patients were less likely than ctDNA-positive patients to have cancer recurrence, with a two-year recurrence-free survival rate of 89.4 percent versus 39.3 percent, respectively.

Among the 20 ctDNA-positive patients, 60 percent, or 12 patients, experienced radiological relapse. Seven patients in this subset received adjuvant chemotherapy and became ctDNA negative, and one patient was lost to follow-up.

In the post-operative ctDNA analysis, researchers also identified three mutated genes in the tumor that were associated with decreased recurrence-free survival: SMAD4, PTEN, and PKHD1.

The study further broke down data by patients who received adjuvant chemo. In the study, 174 patients received adjuvant chemo, yet those who were ctDNA positive after surgery still had a higher risk of recurrence than those who were ctDNA negative. The authors wrote that this suggests "the association between ctDNA status and [recurrence-free survival] was independent of [adjuvant chemo]."

However, among the 17 ctDNA-positive patients who received adjuvant chemo, seven were recurrence-free at the two-year follow-up, while 10 still experienced recurrence. These findings suggested to the authors that some patients who have remaining ctDNA can benefit from adjuvant chemo. Patients who were still ctDNA positive after adjuvant treatment had a 25 percent two-year recurrence-free survival rate compared to 87.7 percent for patients who were ctDNA negative after adjuvant chemo. The patients who had remaining ctDNA after surgery and adjuvant chemo were 12 times more likely to experience recurrence than patients who reached ctDNA-negative status.

The authors wrote that their analysis suggests that ctDNA testing could help guide the use of adjuvant chemo or determine if patients need to undergo a second surgery. "As the ctDNA measuring technology continues to evolve and manifest its significance, the real-time detection of minimal residual disease using ctDNA may help guide the precise administration of [adjuvant chemo], evaluation of [adjuvant chemo] efficacy, and monitoring of disease recurrence," they concluded.

While this study is not practice changing, the authors noted that there are several ongoing randomized clinical trials that could be informative in this regard, including randomized controlled trials such as the DYNAMIC/DYNAMIC-III trials in Australia, the CIRCULATE trial in France, and the US COBRA trial. "As more than half of the stage III colorectal cancer patients could be cured by surgery alone, this ctDNA-guided strategy may benefit patients by sparing them from unnecessary drug toxicity, economic burden, and even radiological exposure," the authors wrote.

The researchers also said some ctDNA NGS assays may not have a fast enough turnaround time to help clinicians decide whether a patient needs adjuvant chemo, which needs to begin no later than eight weeks after surgery.

When compared to standard methods of recurrence monitoring, ctDNA testing outperformed other screening methods like serum carcinoembryonic antigen, or CEA. In preoperative samples, CEA was elevated in only 39 percent of patients. By comparison, ctDNA was detected in 64 percent of preoperative plasma samples. The researchers were also able to detect recurrence about five months earlier by ctDNA than by imaging, while screening via CEA showed no significant lead time in recurrence detection.