Imagine being able to detect the beginning stages of cancer up to a year earlier than current methodologies allow. That is exactly what a new study by investigators at the University College London (UCL) have just described in their new study recently published in Genome Medicine, in an article entitled “Methylation Patterns in Serum DNA for Early Identification of Disseminated Breast Cancer.” The UCL team has identified a new marker—a region of DNA called EFC#93—that could be used to diagnose fatal breast cancer up to one year ahead of current methods. Importantly, these patterns are present in blood serum before cancer becomes detectable in the breast.

“For the first time, our study provides evidence that serum DNA methylation markers such as EFC#93 provide a highly specific indicator that could diagnose fatal breast cancers up to one year in advance of current diagnosis,” explained lead study investigator Martin Widschwendter, M.D., professor and head of the department of women’s cancer at UCL. “This may enable individualized treatment, which could even begin in the absence of radiological evidence in the breast.”

The addition of methyl groups to DNA is a cellular mechanism that has evolved to regulate gene expression, and aberrant DNA methylation has been shown to be common in human tumors—specifically during the preliminary stages of breast cancer development. 

For the current study, the research team first analyzed EFC#93 DNA methylation in blood serum samples from 419 breast cancer patients taken at two timepoints: after surgery (before the start of chemotherapy) and after completion of chemotherapy. The UCL scientists demonstrated that aberrant DNA methylation in samples taken before chemotherapy was a marker for poor prognosis, independent of the presence of circulating tumor cells.

To assess whether EFC#93 could diagnose women with a poor prognosis earlier (i.e., before the cancer becomes detectable), the authors further analyzed serum samples of 925 healthy women, 229 of whom went on to develop fatal and 231 of whom went on to develop nonfatal breast cancer, within the first three years of donating serum samples.

“The serum DNA methylation marker EFC#93 correctly identified 43% of women from serum tested six months in advance of their mammography-based breast cancer diagnosis who later died from the disease (sensitivity for fatal breast cancer) and also identified 88% of women who did not go on to develop breast cancer (specificity),” Dr. Widschwendter noted. “Importantly, EFC#93 did not detect nonfatal breast cancers early. In comparison, mammography screening has a specificity of 88% to 92% but leads to very substantial overdiagnosis, which means that tumors are detected that would never have caused any clinical symptoms. Subject to further study, using cell-free DNA as a marker, as we have done here, is a promising way of avoiding this issue. “

The UCL team are optimistic about their findings but stress that obtaining the appropriate serum samples is a key limitation of this kind of study. Blood samples that are not processed immediately after blood is drawn, or are not collected in special tubes, will contain copious amounts of normal background DNA contributed by white blood cells, which makes it difficult to detect tiny amounts of tumor DNA.

“The normal DNA in these samples usually emits a much stronger signal compared with the short fragments of tumor DNA,” Dr. Widschwendter remarked. “Yet despite the massive contamination of our population-based samples with normal DNA, we were able to observe a clear tumor DNA signal.”

According to the authors, clinical trials are now required to assess whether EFC#93-positive women, who do not have cancer that is detectable by mammography, would benefit from antihormonal therapy before cancer becomes visible in the breast. Dr. Widschwendter's team is currently preparing a large-scale, population-based, cell-free DNA research program that will also help to address this question.

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