Fifty years ago, oncologists relied upon the clinical exam to follow breast cancer patients with metastatic disease. Patients were treated with chemotherapy, and then the physicians waited for symptoms to return before deciding on the next treatment course. Some patients could go months or even years without symptoms, but during this time they played a waiting game. Technology did not yet exist to allow physicians to detect cancer progression in the absence of overt clinical clues.
Beginning in the 1970s, the development of CT scans allowed physicians to finally look inside the human body to see cancer progression in patients who were otherwise asymptomatic. Novel imaging techniques enabled oncologists to detect relapse at much earlier stages, and decisions about further chemotherapy could now be made when the burden of metastatic disease was much lower.
During the 1990s, novel circulating tumor markers such as Cancer Antigen 15-3 were discovered. It was hoped that serum measurement of CA 15-3 could alert oncologists to the rising burden of metastatic disease before that disease even became radiographically apparent. However, studies of CA 15-3 have shown that this tumor marker has only a sensitivity of 65% for detecting the presence of metastatic disease.
What if instead of looking for circulating tumor surrogates, we actually tried to identify circulating bits of actual tumor? One method to do this is to assay for pieces of circulating tumor DNA.
This week’s NEJM presents a study from England in which 52 women with metastatic breast cancer underwent either targeted or whole genome sequencing to identify tumor specific DNA alterations. The researchers were able to identify breast cancer DNA fingerprints in 30 of these patients, and they designed special assays to detect the “fingerprint DNA” of their tumors. Using these assays the researchers were able to detect the presence of the breast cancer DNA fingerprints in the peripheral blood of 29 of the 30 patients. This novel technique proved to have a higher sensitivity for detecting presence of metastatic disease when compared with assays of CA 15-3 or circulating tumor cells. Furthermore, the researchers found that measurement of levels of circulating tumor DNA corresponds both with treatment response and survival: those who survived longer had lower levels of circulating tumor DNA compared with those who survived a shorter period of time. This observation should fuel prospective trials to test the assay of circulating tumor DNA as a prognostic determinant.
Marc Lippman and Kent Osborne write in an accompanying editorial that this study “provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden.” However, this test is not yet ready for prime time. For one thing, the researchers were only able to identify useful DNA biomarkers in 60% of the women enrolled in the study. More importantly, the process of identifying specific DNA fingerprints for each patient’s breast cancer is a laborious process that is currently too time-intensive and costly for more widespread use.
Further research may help identify better methods of selecting a patient’s individual tumor DNA fingerprint so that this technology can become practical clinically. Looking forward, one can imagine a time in the near future when this novel approach to measuring cancer disease burden becomes a routine part of oncology treatment algorithms.
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