NEW YORK (Reuters Health) – Methylation patterns in serum DNA might allow for the early identification of disseminated breast cancer and ovarian cancer, according to two new reports from the U.K.
“We are of the opinion that the most important conclusion to materialize from our breast and ovarian cancer papers is that for the first time we have shown that analysis of cell-free DNA (we analyzed DNA methylation in our studies) shed from the tumor into the bloodstream is capable of identifying women with cancer up to 2 years in advance of current diagnosis,” Dr. Martin Widschwendter from University College London, who worked on both studies, told Reuters Health by email.
DNA methylation is a hallmark of cancer and occurs very early in cancer involvement. Centered around specific regions (CpG islands), DNA methylation is observed more frequently than somatic mutations, Dr. Widschwendter and colleagues note.
They identified 18 breast-cancer-specific DNA methylation patterns and then evaluated the best candidate, EFC#93, for clinical use.
EFC#93 occurred with significantly higher frequency in women with metastatic breast cancer than in healthy women or women with benign lesions or primary breast cancer. Its overall accuracy (as determined by the area under the curve (AUC) of a receiver operating characteristics (ROC) curve) was 85.0% for discriminating healthy/benign lesions from metastatic breast cancer and 84.5% for discriminating primary breast cancer from metastatic breast cancer.
In a separate cohort, EFC#93 positivity before chemotherapy was a strong marker of poor prognosis for both relapse-free and overall survival, independent of the prognostic capability of circulating tumor cells (CTCs).
Neither serum marker EFC#93 nor CTCs were predictive of outcome in samples collected after chemotherapy, the researchers report in Genome Medicine, online December 22.
In the group of women with low serum DNA amounts, there was a significantly higher frequency of the EFC#93 DNA methylation pattern in those who developed breast cancer within one year after sample donation and subsequently died; but there were no significant findings in women with high levels of background DNA in their serum.
In the low-DNA group, EFC#93 DNA methylation identified 43% of women three to six months and 25% of women six to 12 months before the diagnosis of breast cancer that eventually led to death, with a specificity of 88%. This pattern was more sensitive for detecting fatal breast cancer (33.9%) than nonfatal breast cancer (9.3%) up to one year in advance of diagnosis.
In their second study, Dr. Widschwendter and colleagues developed a panel of three DNA-methylation serum markers that discriminated high-grade serous ovarian cancer patients from healthy women and women with a benign pelvic mass with 41.4% sensitivity and 90.7% specificity.
The same panel correctly identified 78% of responders and 86% of nonresponders prior to chemotherapy, including 78% of responders and 100% of nonresponders among women who were left without residual disease after debulking surgery.
As with the DNA-methylation pattern for breast cancer, the ovarian-cancer panel was better able to identify cases in samples with lower DNA concentrations.
In these lower-DNA samples, the ovarian cancer DNA methylation panel was more sensitive but less specific than CA125 for the early detection of ovarian cancer.
“This is extremely encouraging, especially in light of the fact that we received these data despite the fact that the serum samples were not of ideal quality,” Dr. Widschwendter said. “The serum samples which we used were collected from 202,000 healthy women who were subsequently followed up for several years after sample donation in order to assess who developed a cancer and who died; these archived blood samples were only centrifuged 24-48 hours after blood collection, which led to very substantial leakage of normal high-quality white blood cell DNA into the serum, making it even more of a challenge to detect the small DNA fragments shed from the tumor into the serum.”
“The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses,” he said.
“Based on our data we are now initiating a large clinical trial to prospectively evaluate our findings and to assess whether cell-free DNA-based screening is capable of reducing the proportion of late-stage ovarian cancer presentation,” Dr. Widschwendter said. “Prospective clinical trials are now also planned to assess the merits of cell-free DNA-methylation-based individualization of cancer treatment.”
One of the authors of these two reports is employed by Genedata AG, and another has stock ownership in and research funding from Abcodia Pvt Ltd, which has an interest in cancer biomarkers.
SOURCE: http://bit.ly/2BTGyg8 and http://bit.ly/2Clp5OF
Genom Med 2017.
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