New Technique to Measure Circulating Tumor DNA May Improve Metastatic Cancer Surveillance

Currently, the primary method for monitoring the progression of metastatic breast cancer relies on medical imaging, supplemented by inexpensive yet non-specific biomarkers such as CA15-3. A more advanced and effective method, known as 'liquid biopsy,' which involves monitoring tumor-specific mutations in circulating DNA (ctDNA), offers superior accuracy. However, interpreting ctDNA concentrations remains a challenge. Now, new research has demonstrated that absolute ctDNA concentration thresholds can be defined to predict or rule out impending cancer progression. The study introduces a dual threshold model, published in The Journal of Molecular Diagnostics, which could enhance cancer surveillance, patient stratification, and personalized treatment by providing more accurate and timely assessments of disease progression.

A research team at AZ Delta General Hospital (Roeselare, Belgium) conducted a two-year-long study with frequent (every five weeks) ctDNA measurements in patients with advanced breast cancer. Their goal was to determine whether ctDNA levels could be used to predict or rule out imminent disease progression. Various techniques, including targeted deep sequencing and digital PCR, were used to measure ctDNA, with both methods showing perfect correlation. The researchers noted that the choice of technique is largely dependent on factors like the pathology laboratory's cost of ownership and logistical considerations, such as turnaround times.

The results of this study confirmed that ctDNA levels were more effective than traditional biomarkers like CA15-3 in detecting tumor progression. Frequent ctDNA measurements led to an earlier (approximately three months) recognition of tumor progression. Most importantly, the researchers developed a simple dual threshold model that provided clear results in 90% of blood draws. If ctDNA levels were below 10 mutant copies/mL (0.25% variant allele frequency or VAF), it suggested that progression was unlikely. Conversely, ctDNA levels exceeding 100 copies/mL (2.5% VAF) indicated a 90% or greater chance of progression. This model, referred to as the ‘0/10/100 copy model,’ holds potential for broader application, though ctDNA concentrations may vary depending on the tumor type and stage.

The researchers advocate for advanced cancer centers to replace conventional protein biomarkers, such as CA15-3, with personalized, mutation-specific digital PCR tests. Regular monitoring of ctDNA could improve advanced cancer surveillance and provide early detection of minimal residual disease. This approach offers several advantages, including more sensitive and specific monitoring, better use of radiology resources, fewer hospital visits, and reduced patient anxiety, ultimately leading to a positive health-economic impact. By measuring ctDNA concentrations with cost-effective PCR tests, doctors can also determine the optimal timing for retesting the tumor or conducting liquid biopsies using Comprehensive Genomic Profiling. Additionally, this research confirmed that the same ctDNA thresholds can be applied for the surveillance of metastatic non–small-cell lung cancer patients.

"In terms of practicality, our concept goes beyond the ‘cohort analyses’ of Kaplan-Meier survival curves,” said lead investigator Geert A. Martens, MD, PhD. “We provide the statistical framework so our work can be critically reproduced and applied retrospectively to ANY data set with registered progression outcomes. We hope this work can inspire other scientists to apply our concept. The actual concentrations of ctDNA hold strong diagnostic potential for cancer progression. We should prepare for ctDNA concentration–guided scheduling of care in advanced cancers."

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