New Blood-based Biomarker May Predict Recurrence of Breast Cancer and Treatment Response
PHILADELPHIA — A newly developed, noninvasive blood-based assay, cMethDNA, is highly sensitive and specific in detecting breast cancer recurrence early, and shows promise as a viable tool in predicting treatment outcome, according to data published in Cancer Research, a journal of the American Association for Cancer Research.
The cMethDNA assay is a blood-based test built on a panel of 10 breast cancer-specific genes. Blood collected from breast cancer patients is processed to isolate circulating tumor DNA, and the assay detects if any of the 10 genes are hypermethylated, a process by which the activity of some genes that keep the cancers in check are “silenced.” Detection of hypermethylation in any of these genes in blood indicates that the patient may have a disease recurrence.
“Currently, the parameters used to find out whether a patient has had a recurrence after being treated successfully is mostly self-reported complaints, followed by imaging studies,” said Saraswati Sukumar, Ph.D., professor of oncology and pathology at the Johns Hopkins University School of Medicine in Baltimore, Md. “Our goal was to develop a noninvasive assay that can potentially detect recurrence in breast cancer patients before traditional methods, and administer this test during their scheduled visits.
“Using cMethDNA, we were able to detect a drop in methylation levels as early as two weeks, and weeks before traditional imaging methods can detect a recurrence,” added Sukumar. “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.”
Development of this assay required two critical strategies: sensitivity, to ensure that the methylated genes floating 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 any other normal tissue.
To this end, Sukumar and colleagues did a large-scale, genomewide search for genes specifically found to be methylated in the blood and tumor tissues of cancer patients. Then, they selected a panel of genes that best differentiated between cancer and normal samples.
Next, this carefully selected panel was tested in independent samples from patients who participated in prospective clinical trials. Using this approach, they confirmed that the blood test detected the presence of cancer DNA in the serum with a sensitivity and specificity that were higher than 90 percent.
The researchers then analyzed blood samples from patients with metastatic breast cancer, collected before and at different times during treatment. Using the cMethDNA assay, they 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.
Using data from The Cancer Genome Atlas, the researchers also determined that this assay may be efficient in detecting recurrent lung, colon, and rectal tumors. cMethDNA, however, requires further validation, according to Sukumar.
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. Sukumar is a co-inventor of and U.S. patent holder on the cMethDNA assay.