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Old 03-14-2013, 12:08 AM   #1
gdpawel
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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
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Old 03-14-2013, 12:09 AM   #2
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Free-floating DNA from tumor could provide early warning?

I think the most difficult markers to validate are panels in which a SNP (single nucleotide polymorphism) array or microarray of tumor DNA or RNA are assessed and the goal is to come up with a multifactor signature to predict responsiveness.

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.
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Old 05-25-2013, 04:27 PM   #3
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Blood Test Tracks Response To Cancer Treatment

A blood test that tracks fragments of DNA shed by dying tumor cells could one day be used to monitor how well patients are responding to cancer treatment, according to a small study in women with advanced breast cancer. Such a test could provide a non-invasive alternative to biopsies, and help adapt treatment to individual patients and the progress of disease.

Researchers at the Cancer Research UK Cambridge Institute at the University of Cambridge in the UK write about their findings in the 13 March online issue of the New England Journal of Medicine.

Co-lead author, Professor Carlos Caldas, senior group leader at the Cancer Research UK Cambridge Institute, says in a statement: "This study offers a practical application of cancer genomics and highlights the potential of personalised cancer medicine. By understanding the point at which a cancer changes we can select the most effective treatments and minimise side effects for patients."

"We can use blood samples to track how breast cancer is progressing as fragments of DNA are shed by cancer cells when they die, meaning they can be detected in blood samples using sensitive new sequencing techniques. The levels of tumor DNA are telling us how the cancer is responding to treatment," he adds.

Using DNA Biomarkers to Assess Tumor Progress

To manage the treatment of cancer, doctors have to assess whether the tumor is growing and spreading. Currently the way to do this is to take biopsies, invasive procedures that remove small samples of tissue and send them to the lab for analysis.

Researchers are studying non-invasive alternatives to biopsies, such as looking for biomarkers in the form of cells or traces of cells that shed from the tumor and enter the bloodstream.

Most studies looking for blood biomarkers tend to focus on cancer antigen 15-3 (CA 15-3) and circulating tumor cells, but advances in genome sequencing technology means searching for fragments of DNA shed from tumor cells, could also be a viable option. Indeed some studies have shown there is potential here in a limited number of various solid cancers. But few cases of breast cancer have been analyzed, explain the researchers.

The Study

For their study Caldas and colleagues compared using circulating tumor DNA against the two other well-researched biomarkers, cancer antigen 15-3 (CA 15-3), and circulating tumor cells, to assess disease progress in 30 women being treated for advanced breast cancer that was spreading (metastic).

The 30 women were part of a larger group of 52 women who were originally sampled for the study, but after DNA analysis and full genome sequencing, only 30 of them had tumor DNA changes that could be tracked, including two hallmark mutations in genes TP53 and PIK3CA.

The researchers compared the three sets of biomarker results with CT scans to see if changes in the biomarkers matched up with changes in the cancer.

Results Show Tumor DNA Gives Most Accurate Assessment of Changes

Caldas and colleagues found that, out of the three biomarkers, the circulating tumor DNA gave the most accurate "real time" picture of changes taking place in the body.

They successfully detected tumor DNA in 29 of the 30 women (97%), while circulating tumor cells were detected in 26 of the 30 (87%) and CA 15-3 was detected in 21 of 27 (78%).

"Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells," note the researchers.

And, of the the three biomarkers, they found circulating tumor DNA also gave the earliest measure of treatment response in 10 of 19 women (53%).

The authors conclude: "This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer."

Implications and Next Step

The results now need to be replicated in a larger, randomized trial before the method can be considered for clinical use, but the researchers are optimistic that their approach offers a viable, quick and easy way to monitor a patient's response to treatment.

Co-leader of the study, Nitzan Rosenfeld, group leader at the Cancer Research UK Cambridge Institute, says: "This work marks an important step in establishing circulating tumour DNA as a key biomarker for monitoring advanced breast cancer patients."

"By rigorous comparison to markers such as circulating tumour cells and CT imaging, we have shown that personalized genomic tests provide a sensitive and non-invasive measure of cancer spread and response to treatment. We also showed that these can be measured effectively by a variety of practical methods," says Rosenfeld.

Peter Johnson, professor and chief clinician at Cancer Research UK, says the study promises to allow patients' treatment to change as their cancer progresses, because such a test enables doctors quickly to get hold of the personal details of a cancer, and then 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 explains.

Cancer Research UK, the Experimental Cancer Medicine Centre and National Institute for Health Research Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust helped to support the study.

In 2012, researchers in Germany reported how they used a Google algorithm to find cancer biomarkers that can help physicians evaluate how aggressive a patient's cancer is and whether or not they should receive chemotherapy.

Reference: "Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer"; Sarah-Jane Dawson, Dana W.Y. Tsui, Muhammed Murtaza, Heather Biggs, Oscar M. Rueda, Suet-Feung Chin, Mark J. Dunning, Davina Gale, Tim Forshew, Betania Mahler-Araujo, and others; NEJM, published online 13 March 2013; DOI:10.1056/NEJMoa1213261

Citation: Catharine Paddock PhD. "Blood Test Tracks Response To Cancer Treatment." Medical News Today. MediLexicon, Intl., 18 Mar. 2013
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Old 05-25-2013, 04:28 PM   #4
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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer
Dawson SJ, Tsui DW, Murtaza M, et al

N Engl J Med. 2013;368:1199-1209

Summary

In an effort to determine whether it might be possible to improve upon current methods to monitor the course of metastatic breast cancer in patients treated with antineoplastic therapy, investigators developed personalized assays that could measure circulating cell-free tumor DNA using somatic mutations specific to each individual patient. Within the overall cohort of 30 patients, investigators were successfully able to identify and assess individualized tumor DNA biomarkers in 97% of patients (29 of 30), along with CA 15-3 tumor antigen in 78% of patients and circulating tumor cells in 87% of patients. Changes in the level of cell-free tumor DNA were found to be an earlier indicator of response to antineoplastic therapy and showed a superior correlation with the overall tumor burden vs the other 2 parameters evaluated.

Viewpoint

Although this is only a preliminary report of a small group of patients and requires confirmation by others, this study provides a provocative view of the future of cancer monitoring.

For several reasons, there has been considerable interest among both researchers and clinical oncologists in a potential role for some form of a circulating tumor DNA marker. First, as suggested in this small series in the management of metastatic breast cancer, it has been hoped that such testing would be more sensitive as a marker of overall tumor burden rather than simply indicating the presence of the cancer.

Second, there is a desire to establish indication of an earlier response to treatment compared with currently employed methodology, such as radiographic imaging demonstrating a decrease in the size of a measurable mass, or a decrease in the level of a nonspecific tumor marker such as CA 15-3. This type of information would be quite useful in the decision to continue a particular antineoplastic strategy despite the development of side effects and could help to justify the costs associated with a regimen.

Third, in the absence of a response (or evidence of progression), alternative strategies could be implemented earlier, avoiding both the toxicities and costs associated with continuing an ineffective program.

Finally, and perhaps most important, a particularly attractive feature of circulating tumor DNA would be the opportunity to examine changes in the somatic genomic profile of the tumor itself, which might provide vitally important molecular information related to the mechanism of tumor resistance within that individual cancer.

With our increasing understanding of the mechanisms of resistance, the genetic events that underlie the success of tumors to escape the inhibitory effects of targeted drugs, and the availability of novel agents designed to effectively affect particular molecular targets, knowledge of the unique mechanism in an individual tumor type is essential to the development of the most rational strategy to overcome developing resistance. Rebiopsying a solid tumor is often difficult (if not impossible in many settings), potentially quite risky, and certainly expensive, particularly if it is to be done on several occasions. However, an ability to find unique patterns of circulating tumor-specific DNA related to specific mutations may provide critical assistance in future disease management.

The current report offers a potential window into this issue, which will hopefully be a focus of future research.

Citation: A Window Into the Future of Cancer Monitoring. Medscape. Apr 24, 2013.

http://www.medscape.com/medline/abstract/23484797
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Old 05-25-2013, 04:30 PM   #5
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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Silvana Martino, M.D.
Director of Breast Cancer Research and Education
The Angeles Clinic Foundation

The management of metastatic breast cancer requires the ability to judge whether a therapy is working. The primary method by which this is done is to evaluate the amount of tumor present at the start of a therapy, to re-evaluate again at a later time point and to compare the two measurements. The goal, of course is to see that the tumor has decreased in size. These measurements are traditionally done using X-ray or scan measurements.

There are additional tools that can be used often in conjunction with X-ray or scans. These are blood tests known as tumor markers (CA 27-29 or CA 15-3) or another blood test known as a circulating tumor cell count. I find these to be helpful when their value is elevated at start of therapy. They are particularly useful in clinical situations where scans and x-rays are not very helpful, such as when one is dealing with only metastases to bones since in that setting the pictures can be confusing or show minimal change.

A recent report by Sarah-Jane Dawson and colleagues from the Department of Oncology, University of Cambridge and Cancer Research, UK Cambridge Institute, recently published in the New England Journal of Medicine, describes another blood test that may prove to be even more accurate. Using certain laboratory techniques, these investigators measured circulating cell-free or circulating tumor DNA.

The basic principle of this test is that as tumor cells circulating in blood become damaged or die, they will release the DNA that they contain. This DNA can be found floating in blood. It is then available for identification, separation from other sources of free-floating DNA and can be quantified at different time points. Their work is based on 30 women with metastatic breast cancer who were receiving systemic therapy.

They compared radiographic images of their tumors with measurements of circulating tumor DNA, CA 15-3 blood level measurements and number of circulating tumor cells. They found that circulating tumor DNA provided a more accurate correlation to x-ray measurements than the other two blood tests. Further, in about half of the women, it also provided the earliest measure of treatment response.

They are not the first to try to measure free floating (tumor) DNA. The concept has been around for a while and is quite logical. There are considerable issues with this idea. Is one really measuring free floating DNA from the tumor? Could it be from some other cells in the body? Do the levels vary from day to day? Is finding free floating tumor DNA always a bad thing? How well does it correlate with the volume of tumor in the body? When should it be measured? How much of a difference should one see to predict that a therapy is going to work or not?

These are but a few issues to resolve. Nevertheless, it is an interesting idea. We are all looking for a simple and reliable blood test to guide us in determining treatment response. It could provide a way to avoid repeat scans and X-rays. Perhaps, we could also use this DNA to help us identity which drugs might be most effective against the tumor and avoid the need for tissue biopsy. Though this line of work is still preliminary, I believe it holds considerable promise.

Reference: Dawson SJ, Tsui DWY, Murtaza M, Biggs H, et al. Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer, The New England Journal of Medicine 368;13, March 28,2013, pg. 1199-1208
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Old 05-27-2013, 01:29 PM   #6
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Re: Circulating Tumor DNA Detects Metastatic Breast Cancer

would it be useful in those of us who are in"remission"To monitor this cell debris/
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Old 05-27-2013, 02:26 PM   #7
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Re: Circulating Tumor DNA Detects Metastatic Breast Cancer

It would be important to develop a method of in vivo labelling of tumor cells in the circulation and to monitor their trafficking and homing to other sites. If these cells are viable and therefore able to disseminate, I think the most robust test to this end is to document their ability to metastasize. It's perhaps useful as an adjunct to traditional methods for following tumor response, such as x-rays, blood tests, CTs, MRIs, history, physical exam, etc.
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