Expert Point of View: Marc Lippman, MD and C. Kent Osborne, MD

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An editorial by Marc Lippman, MD, Leonard M. Miller School of Medicine, University of Miami, and C. Kent Osborne, MD, Breast Center, Baylor College of Medicine, Houston,1 accompanied the study by Dawson and colleagues. These authors commented that the study’s key findings—that variation in the level of circulating tumor DNA was reasonably correlated with response to treatment and significantly associated with prognosis—are positive and encouraging. However, they described a number of practical limitations facing clinical application of circulating tumor DNA measurement.

First, mutations or structural variants that could be measured and followed were identified in only about 60% of the original group of 52 patents investigated. Since all patients with breast cancer have mutations in their DNA, development of specific probes for individual patients may require very intensive and costly sequencing strategies or may remain elusive. Although the investigators found that mutations in PIK3CA and TP53 were common (found in 25 of the 52 patients), there is no single locus in these genes that is commonly mutated. “Therefore, very substantial sequencing will be required for probe design; a standard ‘panel’ is unlikely to work for all patients,” Drs. Lippman and Osborne wrote.

Additional Concerns

The commentators also pointed out that the number of patients with an objective response of circulating tumor DNA to treatment was limited, and that the attempt to compare usefulness of this measure with the more standard biomarkers was “more encouraging than definitive.” They continued, “And of course, many patients have readily measurable lesions that are effectively and cheaply assessed by means of physical examination or imaging. In an era of financial stressors on clinical care, the cost-effectiveness of such new methods will require rigorous study.”

Drs. Lippman and Osborne observed that despite such concerns and limitations, there is considerable potential for assays measuring circulating tumor DNA. Noting that some patients with complete pathologic remissions on adjuvant therapy nevertheless eventually relapse, they posited that “assays of circulating tumor DNA, which has an impressive dynamic range, could more reliably predict patients who might not need further therapy or identify those with localized cancer who would be adequately treated by lumpectomy alone.” Further, the apparent high sensitivity of the assay suggests potential usefulness in screening for recurrence in asymptomatic patients with early-stage disease.

They concluded, “the new study provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden. Demonstration that the method can be used to take better care of patients with metastatic breast or other cancers in a cost-effective manner awaits further studies, which are clearly warranted.” ■

Disclosure: Drs. Lippman and Osborne reported no potential conflicts of interest.


1. Lippman M, Osborne CK: Circulating tumor DNA—ready for prime time? N Engl J Med 368:1249-1250, 2013.

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