Novel Blood-Based Biomarkers May Predict Breast Cancer Recurrence and Treatment Response
Researchers have developed a quantitative multiplexed methylation-specific polymerase chain reaction assay called cMethDNA for a panel of 10 breast cancer–specific genes. The blood-based assay was found to be highly sensitive in detecting advanced breast cancer and monitoring tumor burden and treatment response in women with metastatic breast cancer. The study by Fackler et al is published in Cancer Research.
For the study, the researchers prospectively collected whole blood and tissue from women with stage IV metastatic breast cancer following disease recurrence after prior therapy, as well as from healthy controls. Using the cMethDNA assay, the investigators found a significant decrease in serum DNA methylation levels in patients who responded to the treatment, while no such decrease was observed in patients who showed no response or in those whose disease progressed.
The 10 genes in the panel include seven novel markers (AKR1B1, COL6A2, GPX7, HIST1H3C, HOXB4, RASGRF2, and TM6SF1) and three previously described markers, (ARHGEF7, TMEFF2, and RASSF1).
Development of the Assay
Development of cMethDNA required two strategies: sensitivity, to ensure that the methylated genes circulating in the serum are highly indicative of the tumor, and specificity, to ensure that these genes are not hypermethylated in white blood cells or in other normal tissue. To accomplish this goal, the researchers conducted a large-scale, genome-wide search for genes specifically found to be methylated in the blood and tumor tissues of patients with cancer. They then selected a panel of genes that best differentiated between cancer and normal samples.
Next, the selected panel was tested in independent samples from patients who participated in prospective clinical trials. The researchers were then able to confirm that the blood test detected the presence of cancer DNA in the serum with sensitivity and specificity that were higher than 90%. Finally, the researchers analyzed blood samples from patients with metastatic breast cancer collected before and at different times during treatment.
Promising Results
“Using cMethDNA, we were able to detect a drop in methylation levels as early as 2 weeks, and weeks before traditional imaging methods can detect a recurrence,” Saraswati Sukumar, PhD, Professor of Oncology and Pathology at the Johns Hopkins University School of Medicine in Baltimore, and the corresponding author for the study, said in a statement. “Detecting early on whether or not the treatment is working for a patient can greatly help prevent unnecessary exposure to highly toxic agents, save time, and help initiate other treatments more likely to be beneficial.”
Although the assay requires further validation, using data from The Cancer Genome Atlas, the researchers also determined that cMethDNA may also be useful in detecting recurrent lung, colon, and rectal tumors.
“The cMethDNA assay is a promising new liquid biopsy tool for detecting tumor-specific cell-free circulating DNA in a noninvasive manner. With further refinement, it could serve to monitor response to therapy, potentially prognosticate disease outcome, and serve as an early indicator of tumor recurrence,” wrote the researchers.
This study was funded by the Avon Foundation, the Rubenstein family, the John A. Sellon Charitable Trust, the Department of Defense Center of Excellence on Targeting Metastatic Breast Cancer Grant, Susan G. Komen, and the Breast Cancer Research Foundation.
Dr. Sukumar, Mary Jo Fackler, PhD, Zoila Lopez Bujanda, and Wei Wen Teo have ownership interest (including patents) in a patent application for the cMethDNA method (no financial interests). Dr. Sukumar is a consultant/advisory board member of California Breast Cancer Research Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
