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Thread: Circulating Tumor DNA Detects Metastatic Breast Cancer

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    Distinguished Community Member gpawelski's Avatar
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    Default Circulating Tumor DNA Detects Metastatic Breast Cancer

    Circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) is more effective at monitoring metastatic breast cancer than current biomarkers approved by the US Food and Drug Administration and circulating tumor cells, according to a proof-of-concept study.

    The study, led by Sarah-Jane Dawson, PhD, from the University of Cambridge and the Cancer Research UK Cambridge Institute, in the United Kingdom, was published online today in the New England Journal of Medicine.

    "Metastatic breast cancer is incurable but treatable with serial administration of endocrine, cytotoxic, or biologic therapies," Carlos Caldas, MD, also from the University of Cambridge and one of the study authors, told Medscape Medical News.

    Monitoring treatment response is essential and can be carried out with biomarkers such as cancer antigen (CA) 15-3 and circulating tumor cells, using the CellSearch (Veridex) test, but we are seeking better biomarkers, Dr. Caldas said.

    "Effectively, genomics provides a new type of very specific biomarker for monitoring tumors in response to therapy. In other words, the mutations that each tumor accumulates are an individual genomic 'barcode' that we can then use to monitor tumor burden and response to treatment," he explained.

    The researchers used targeted or whole-genome sequencing to identify somatic genomic alterations, and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. They also measured CA 15-3 levels and numbers of circulating tumor cells at identical time points.

    They found that circulating tumor DNA was superior to the other 2 blood tests. Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) with metastatic breast cancer receiving systemic therapy in whom somatic genomic alterations were identified. In comparison, CA 15-3 was detected in 21 of 27 women (78%) and circulating tumor cells were detected in 26 of 30 women (87%).

    In addition to its superior sensitivity in detecting metastatic breast cancer, circulating tumor DNA had a greater dynamic range, which correlated with changes in tumor burden. The test also provided the earliest measure of treatment response in 10 of the 30 women tested, Dr. Caldas said.

    He added that most laboratories equipped to do molecular testing can do this test using circulating tumor DNA; however, these are usually only located in major tertiary care centers.

    "I think this...will be a landmark report, and circulating tumor DNA is going to be one of the highlights in medicine in 2013. The test will definitely be used in clinical research immediately, although generic use in cancer patients will have wait until diagnostic companies release tests for use," Dr. Caldas said.

    In a press release issued by Cancer Research UK, which funded the study in part, chief clinician Peter Johnson, MD, was quoted as saying: "These results hold the promise of a system that could allow us to modify someone's treatment as their cancer changes, and they suggest an exciting way to quickly get hold of the personal details of a cancer, to target it for the most effective therapy."

    "One of the things that will help our scientists design better cancer treatments is a way of measuring early on which ones are working and which are not. If we can find the molecular footprints of cancers during treatment and see how they change, we hope we will be able to track them down and remove them much more efficiently," he added.

    Approach Has "Remarkable Potential"

    In an accompanying editorial, Marc Lippman, MD, from the Leonard M. Miller School of Medicine, University of Miami, Florida, and C. Kent Osborne, MD, from the Baylor College of Medicine in Houston, Texas, agree that this test has definite possibilities.

    There is remarkable potential for this approach, they write, but they also list some concerns.

    "All patients with breast cancer have mutations in their tumor DNA, but without very intensive sequencing strategies, a specific probe or probes for each patient may remain elusive or very costly," and a standard 'panel' is unlikely to work for all patients," Drs. Lippman and Osborne write.

    Also, the number of patients in whom an objective response to treatment was seen in circulating tumor DNA was limited, so the "laudable effort" to compare the usefulness of circulating tumor DNA with circulating tumor cells and measures of CA 15-3 "was more encouraging than definitive."

    The editorialists conclude that this study provides proof of the concept that circulating tumor DNA is "a sensitive biomarker of tumor burden," and add that studies showing that it can be used to improve the care of patients with metastatic breast or even other cancers "in a cost-effective manner" are needed.

    The study was supported by Cancer Research UK, the Experimental Cancer Medicine Centre, the National Institute for Health Research Cambridge Biomedical Research Centre, and by an Australian National Health and Medical Research Council R.G. Menzies Early Career Fellowship to Dr. Dawson. Dr. Caldas, Dr. Lippman, and Dr. Osborne have disclosed no relevant financial relationships.

    N Engl J Med. Published online March 13, 2013.

    http://www.nejm.org/doi/full/10.1056/NEJMoa1213261
    http://www.nejm.org/doi/full/10.1056/NEJMe1301249

    Citation: Circulating Tumor DNA Detects Metastatic Breast Cancer. Medscape. Mar 13, 2013
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Free-floating DNA from tumor could provide early warning?

    Researchers have been focusing on the development of sensitive assays that allow the specific detection of single tumor cells or small amounts of cell-free tumor DNA in the peripheral blood of cancer patients (Annual Review of Medicine Vol. 63: 199-215). Quantification of circulating DNA by real-time PCR may be a good and simple tool for detection of cancer with a potential to clinical applicability together with other current methods used for monitoring the disease (DNA Cell Biol. 2008 Aug;27(8):415-21).

    Doctors hope to use this to assess how a patient's tumor responds to treatment. Circulating tumor DNA might give doctors an earlier warning that a drug isn't working. The test might allow patients to stop taking a harsh drug that's not working, sparing them months of side effects. Doctors could then prescribe an alternative drug, although there's no evidence yet that switching drugs sooner would help people live longer.

    Is this six of one and a half dozen of the other? The test is "prognostic" and not "predictive."

    The biggest point made by Dr. Eric Winer, director of the breast oncology center at Boston's Dana-Farber Cancer Institute, is that cancer patients shouldn't expect their doctors to test their tumor's circulating DNA anytime soon.

    Genomics provides a new type of very specific biomarker for monitoring tumors in response to therapy. The mutations that each tumor accumulates are an individual genomic 'barcode' that can then be used to monitor tumor burden and response to treatment.

    The researchers use targeted or whole-genome sequencing to identify somatic genomic alterations and design a personalized assay to quantify circulating tumor DNA in serially collected plasma specimens. The also measure CA 15-3 levels and numbers of circulating tumor cells at identical time points.

    Circulating tumor DNA was successfully detected in 29 of 30 women (97%) with metastatic breast cancer receiving systemic therapy in whom somatic genomic alterations were identified. In comparison, CA 15-3 was detected in 21 or 27 women (78%) and circulating tumor cells were detected in 26 of 30 women (87%).

    Circulating tumor DNA has a greater dynamic range, which correlates with changes in tumor burden. The test also can provide the earliest measure of treatment response in 10 of 30 women tested.

    Most laboratories equipped to do molecular testing can do this test using circulating tumor DNA, however, these are usually only located in major tertiary care centers.

    The editorialists pointed out that all patients with breast cancer have mutations in their tumor DNA, but without very intensive sequencing strategies, a specific probe or probes for each patient may remain elusive or very costly, and a standard 'panel' is unlikely to work for all patients.

    The number of patients in whom an objective response to treatment was seen in circulating tumor DNA was limited, so the effort to compare the usefulness of circulating tumor DNA with circulating tumor cells and measures of CA 15-3 is more encouraging than definitive.
    Gregory D. Pawelski

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