Circulating Tumor DNA Detects Metastatic Breast Cancer

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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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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