Circulating Tumor DNA Early Indicator of Cancer

Ron Zimmerman

March 13, 2014

SAN DIEGO — A blood test that identifies cancer and helps track progression is showing promise as an early warning sign, say researchers. The so-called liquid biopsy works by detecting circulating tumor DNA.

"The most significant advance is that it can give us an indication that cancer is there up to 5 months before it even shows up on a tissue biopsy," said Sarah-Jane Dawson, MD, from the Molecular Biomarkers and Translational Genomics Laboratory at the Peter MacCallum Cancer Centre in Melbourne, Australia.

She spoke to a rapt audience here at Future of Genomic Medicine VII about how this diagnostic and monitoring tool can best be used in clinical practice.

"I'm a clinician and my research focus is trying to find novel molecular biomarkers that we can use to improve the way we diagnose patients," Dr. Dawson told Medscape Medical News. Liquid biopsy "is one of the most exciting developments in the past few years."

"The practical, simple, noninvasive test can be performed in real time at very little inconvenience to the patient, who is often having blood tests anyway," she explained. "In contrast, tissue biopsies are invasive and sometimes impossible to perform, depending on the site of the disease; it's not feasible to biopsy multiple tissue sites for someone who may have metastatic disease. There's also the problem of tumor heterogeneity. A tissue biopsy samples just one very small area of a patient's tumor; with circulating tumor DNA, we're capturing a complete picture of the underlying disease."

It can give us an indication that cancer is there up to 5 months before it even shows up on a tissue biopsy.

Dr. Dawson's own center developed a tagged-amplicon deep-sequencing strategy called TAm-Seq. "It's a compromise between sensitivity and specificity, and allows us a high-throughput of a large number of clinical samples," she noted. Her team conducted an analysis of circulating tumor DNA in women with metastatic breast cancer (N Engl J Med. 2013;368:1199-209).

Their first significant finding was that DNA levels accurately reflect changes in tumor burden in a patient.

The researchers were able to quantify the levels in serial liquid biopsies collected from individual patients using TAm-Seq. "In 1 patient, we found 6 different mutations," she reported. "The level of DNA in the plasma followed the tumor burden very closely in that individual. The levels were high before treatment with her first drug, they then fell as the disease stabilized. Unfortunately, they rose again just before she started on the next drug."

Their second finding was that rising circulating tumor DNA levels often predate the appearance of progressive disease on imaging.

The fact that DNA changes occurred an average of 5 months before changes were visible on CT imaging "has important clinical implications," Dr. Dawson said. "Five months is not an insignificant amount of time for someone to remain on a therapy if it's ineffective."

Their third finding was that increasing circulating tumor DNA levels are associated with inferior overall survival.

"Patients with lower levels of circulating tumor DNA did much better than those with the highest levels, who unfortunately had the worst prognosis," she noted.

Some physicians at the meeting voiced frustration that liquid biopsies are not more widely available.

Limited Availability

"I think many patients would immediately benefit from this," said Carol Westbrook, MD, from the Geisinger Health System in Wilkes Barre, Pennsylvania. However, "there's currently no place in our practices to get this testing, and there's no reimbursement."

"I see 16 to 20 patients a day," Dr. Westbrook pointed out. "What's defined as our practice is what our bosses allow us to do, and that doesn't include genetic testing. Even if we were allowed to order the test, there would be hours of interpretation and then hours more for counseling — none of which is reimbursable. It takes time we don't have. That's simply the standard of care in oncology practice today."

I remember one patient who would have benefited. At a minimum, it would have at least prolonged his life.

Heidi Rehm, PhD, the chief laboratory director for molecular medicine at Partners HealthCare and associate professor at Harvard Medical School in Boston, added that "I absolutely think this where we want to head — the very early diagnosis long before the clinical manifestation of disease."

"Change will come from 2 directions," said Dr. Rehm. "Physicians are learning about these new tools, but their patients are also savvy. They're on the Internet and, in the same way that patients see a drug on TV and then ask their doctors about it, they're going to be asking about sequencing. There will be continuous pressure to adopt these methods," she said. "It will be the same thing for reimbursement."

Many meeting attendees expressed a desire to have liquid biopsy testing available now, not in 5 years. "I'm frustrated," said Dr. Westbrook. "I remember one patient who would have benefited. At a minimum, it would have at least prolonged his life. Unfortunately, before we could find a way to order tests, the patient died. In cancer, time is always a factor."

Dr. Dawson, Dr. Westbrook, and Dr. Rehm have disclosed no relevant financial relationships.

Future of Genomic Medicine (FoGM) VII. Presented March 6, 2014.


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