AACR 2025: ctDNA Testing Identifies Recurrence Risk Within Weeks of Surgery in Colorectal Cancer

Circulating tumor DNA (ctDNA) is a strong predictor of recurrence in patients with colorectal cancer; however, it often goes undetected due to low levels in the blood. In the VICTORI study, a novel circulating ctDNA-based liquid biopsy assay (NeXT Personal^®) detected identified recurrence indicators before imaging and offered prognostic value for individuals with colorectal cancer (CRC) within a month following surgery. The interim results were presented at the American Association for Cancer Research Annual Meeting 2025.

3D rendering of circulating tumor cells | Image Credit: © Nasr - stock.adobe.com

CRC is the fourth most common cancer in the US and is estimated to impact 152,810 individuals in 2024, of whom 53,010 will die from the disease, according to the Colorectal Cancer Alliance. Despite significant treatment advancements, recurrence remains an obstacle for many patients, especially those with advanced disease. ctDNA are small pieces of DNA that are released into the bloodstream by tumor cells when they die and are used to determine disease recurrence. Through a blood sample, health care providers can identify mutations, diagnose some types of cancers, and determine treatment responses.^1,2

“After surgery, ctDNA-based liquid biopsies may help identify patients who would benefit most from additional treatment,” said Jonathan Loree, MD, MS, a medical oncologist at BC Cancer and the senior investigator of the study. “Alternatively, this may help patients with good prognoses avoid toxicities from unnecessary chemotherapy. By monitoring patients for recurrences, liquid biopsies can continue to support clinical care and allow more patients to undergo second curative intent surgeries to remove early recurrences.”³

In a prospective study of patients with CRC, Loree and their team explored the use of an ultra-sensitive minimal residual disease (MRD) assay to identify the best timepoint after surgery to identify MRD. They collected and performed whole genome sequencing on 474 tissue samples to create a customized panel of up to 1800 somatic variations for MRD detection, which allows for the detection of ctDNA down to about 1 part per million (PPM). The blood samples were drawn prior to surgery with the MRD landmark window at weeks 2, 4, 6, and 8, and upon follow-up every 3 months for 3 years.³

In the report, the research team presents preliminary results of samples from the first 68 patients, of which 59% had rectal cancer and 41% had colon cancer (stage 1 to 3: 75%; stage 4: 25%). Clinical outcomes were evaluable for 67 patients, of whom 23 experienced disease recurrence. All evaluable patients with recurrence were ctDNA-positive prior to relapse (100%; 2 patients were excluded due to missing plasma samples prior to recurrence). Among treatment-naïve patients, presurgery ctDNA positivity was 93.8% (2 negative cases were both stage 1). In patients who received neoadjuvant therapy, ctDNA positivity was 72.4%.³

The majority of recurrences (86%) were detected during the MRD landmark window. In these cases, the median ctDNA level in the first MRD-positive sample postsurgery was about 54.9 PPM (range: 2.45–111,120 PPM). Notably, higher ctDNA levels at initial detection were associated with shorter disease-free survival (Spearman r = -0.47, P = 0.05).³

Detection of MRD at each individual time point within the landmark window was consistently associated with reduced disease-free survival. MRD positivity at week 2 was associated with a hazard ratio (HR) of 4.75 (95% CI: 1.63–13.84, P = 0.0043). At week 4, the HR increased to 11.72 (95% CI: 3.87–35.47, P = 1.33×10^-5), while MRD detection at week 6 yielded an HR of 7.73 (95% CI: 2.79–21.41, P = 8.4×10^-5). The strongest association was observed at week 8, with an HR of 16.70 (95% CI: 4.85–57.49, P = 8.08×10^-6).³

“The results from our study help to clarify the ideal time point for ctDNA testing following a surgical procedure, showing that we can detect residual cancer as early as two weeks following surgery,” said Emma Titmuss, MSc, a bioinformatician at BC Cancer in Vancouver and the study presenter. “However, with ctDNA assessments this close to surgery, there is the potential for normal cell-free DNA to dilute ctDNA, and 4 weeks appears to be a better time point clinically to sample for ctDNA to inform clinical decision-making.”³

The initial findings show great promise for the liquid biopsy-based assay; however, continued trials are needed to determine the most effective use of the tool in clinical practice. The authors are enrolling more patients into the study to help improve the precision of these preliminary results, helping to drive forward this promising MRD detection tool.

REFERENCES

1. Encorafenib with cetuximab and mFOLFOX6 receives accelerated approval for patients with metastatic colorectal cancer. Pharmacy Times. December 20, 2024. Accessed April 23, 2025. https://www.pharmacytimes.com/view/encorafenib-with-cetuximab-and-mfolfox6-receives-accelerated-approval-for-patients-with-metastatic-colorectal-cancer

2. ctDNA. National Cancer Institute. Accessed April 23, 2025. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ctdna

3. Titmuss E, Vasconcelos J, Navarro F, et al. A liquid biopsy-based assay could detect recurrence prior to imaging in patients with resectable colorectal cancer. American Association for Cancer Research Annual Meeting 2025. April 25, 2025 to April 30, 2025. Chicago, IL.