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.

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.

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.

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.”

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.

Written by Catharine Paddock PhD