TARDIS: A ‘game-changer’

Mayo and TGen join hands with Cambridge on test to improve, personalize breast cancer treatment

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CAMBRIDGE, U.K.—Scientists at the Cancer Research UK (CRUK) Cambridge Institute have joined hands with their American cousins at City of Hope affiliate Translational Genomics Research Institute (TGen) and the Mayo Clinic in Arizona to develop a new method for tracking breast cancer that could help future doctors improve and personalize breast cancer treatments and even prevent unnecessary surgeries, chemotherapy and radiation for some patients.
Called TARDIS (TARgeted DIgitial Sequencing), this new technique analyzes circulating tumor DNA (ctDNA)—tiny fragments of DNA from cancer cells in the bloodstream. This highly sensitive blood test is one of the first to successfully monitor breast cancer patients with early-stage disease and could be up to 100 times more sensitive than existing tests, according to a study published in Science Translational Medicine, August 7.
“Until now, blood tests for breast cancer have only been sensitive enough to reliably identify tumor DNA in people with advanced disease,” comments Dr. Muhammed Murtaza, lead author of the study and co-director of TGen’s Center for Noninvasive Diagnostics, where the test was developed. “We’ve shown that TARDIS is able to detect circulating DNA at extremely low concentrations in the blood, opening up the possibility of monitoring patients with early-stage breast cancer to find out how their disease is responding to treatment.”
Breast cancer treatments are already somewhat personalized.
“Women receive different treatments depending on the type (ER+, HER2+, triple negative, etc.) and stage of their cancer,” Murtaza says. “This test has the potential to further personalize treatments by allowing doctors to see whether treatments are working during treatment, i.e. if their chemotherapy is completely effective, they could avoid surgery.”
Or if the cancer doesn’t respond to chemotherapy, these women could receive alternative treatments, he adds. However, TARDIS hasn’t yet been proven to improve outcomes for breast cancer patients, since this first validation study only tested whether the technique worked.
TARDIS was sensitive enough to detect the ctDNA in every patient before starting surgery, and could detect a drop in ctDNA for patients whose treatment was working, Murtaza reports, but the ctDNA thresholds that could inform treatment decisions haven’t yet been established.
Patients enrolled in the study were from both the U.S. and U.K., enrolled at Addenbrookes Hospital in Cambridge, the Mayo Clinic in Arizona and City of Hope in California. Seventeen patients had ER+HER2- cancer, seven had HER2+ cancer and nine had triple-negative breast cancer. Most patients presented with stage II disease (24 of 33 patients) and invasive ductal carcinoma (30 of 33 patients). Researchers analyzed 80 blood samples from 33 women with early-stage and locally advanced breast cancer. Further blood tests were done on the 22 women who received treatment before their surgery, such as chemotherapy, radiotherapy or hormone therapy.
After pre-operative treatment, TARDIS was able to detect circulating tumor DNA in 12 of 13 patients who had breast cancer cells remaining at the point of surgery, and in five of nine patients who had no breast cancer cells remaining, according to the study.
Cambridge researcher Dr. Stephen-John Sammut says that more than 200 women with breast cancer “have already been recruited to a prospective neoadjuvant translational study in Cambridge. The plasma samples required for the study have already been collected and work will soon commence on analyzing the samples.”
If this larger study “shows the test is successful, it is likely to progress to clinical trials, which would probably take several years,” Sammut adds.
Many people with early-stage breast cancer are treated with drugs to shrink the tumor, followed by surgery to remove any remaining cancer, according to researchers. However, for approximately 30 percent of these patients, no breast cancer cells are found when they go under the knife, since the earlier treatments were completely effective, researchers found. Currently, doctors have no way of knowing which women could avoid this unnecessary, invasive procedure.
Prof. Carlos Caldas, director of the Breast Cancer Program at CRUK, believes TARDIS “could be a game-changer. Instead of patients undergoing six to eight cycles of chemotherapy (15 to 21 weeks of treatment), after one or two cycles (3 to 6 weeks), we would use the TARDIS test to look for a significant drop in circulating tumor DNA. If a drop was not detected, the treatment could be stopped or changed.”
TARDIS is more precise than other cancer blood tests as it looks for DNA sequences specific to each patient’s cancer, relying on a traditional biopsy of the tumor being taken first. The tumor DNA is then sequenced, and bioinformatics is used to identify mutations likely to be present in all cancer cells.
“Finding cancer DNA in the blood is like looking for a needle in a haystack,” Caldas says. “But by developing a test that’s unique to each patient, and looking for mutations present across the entire tumor, we’ve made it much harder for the circulating tumor DNA to hide, significantly increasing the chance of identifying cancer relapses earlier.”
Breast cancer is the most common cancer in the UK, with about 55,200 new breast cancer cases in the UK every year. Of those, 81 percent of patients diagnosed with breast cancer have surgery to remove the tumor as part of their primary cancer treatment. CRUK has already seen survival in the UK double in the last 40 years. Today, two in four people survive their cancer for at least 10 years. CRUK’s ambition is to accelerate progress so that by 2034, three in four people will survive their cancer for at least 10 years.

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