Summary
Clinicians treating patients with aggressive forms of skin cancer may soon have a simple tool to track treatment efficacy: a blood test. Researchers at the NYU School of Medicine and Perlmutter Cancer Center recently used a test that measures BRAF V600E/K circulating tumor DNA in patients’ plasma—and found it detected the BRAF mutation in nearly 93 percent of study participants. They also noticed the circulating tumor DNA fell below detectable levels in 40 percent of patients, and these patients responded well to treatment. The team presented their findings at the 2019 ASCO Annual Meeting (Abstract 259011).
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Original Article
Blood Test Tracks Melanoma Treatment Response
Oncology Times
By Rebecca Hepp
Clinicians treating patients with aggressive forms of skin cancer may soon have a simple tool to track treatment efficacy: a blood test. Researchers at the NYU School of Medicine and Perlmutter Cancer Center recently used a test that measures BRAF V600E/K circulating tumor DNA in patients’ plasma—and found it detected the BRAF mutation in nearly 93 percent of study participants. They also noticed the circulating tumor DNA fell below detectable levels in 40 percent of patients, and these patients responded well to treatment. The team presented their findings at the 2019 ASCO Annual Meeting (Abstract 259011).
“In other cancers, there are blood tests clinicians can order to see if the treatment is working, but in melanoma the only test we have is the lactate dehydrogenase (LDH), and it’s not sensitive and specific enough for doctors to rely on to change a patient’s treatment,” according to senior study investigator David Polsky, MD, PhD, the Alfred W. Kopf Professor of Dermatologic Oncology at NYU Langone Health.
But that’s all about to change with this new blood test.
Targeted Tracking
As the deadliest form of skin cancer, metastatic melanoma affects more than 200,000 patients each year (Eur J Cancer 2013; doi: 10.1016/j.ejca.2012.11.004). While melanoma is known for its variable genetic mutations, BRAF mutations are implicated in nearly half of all metastatic melanoma diagnoses and are the target of many therapies. Just last year, the FDA approved dabrafenib in combination with trametinib for the adjuvant treatment of melanoma patients with BRAF V600E or BRAF V600K mutations. The approval came in response to positive data from the COMBI-AD trial, which included 870 patients with resected stage III BRAF V600E/K mutation-positive melanoma.
Now, Polsky and his team took a closer look at the COMBI-D trial data, which led to the combination’s approval in 2015 for unrespectable and metastatic disease, this time testing the patient’s blood for trace amounts of circulating tumor DNA at baseline and 4 weeks after initiating therapy. The test capitalizes on the natural cycle of cancer cells, which release their DNA into the bloodstream when they die. Measuring the amount of circulating tumor DNA in the blood before and after treatment could potentially help clinicians both diagnose the condition and gauge treatment response.
To assess the blood test’s utility, the researchers analyzed plasma samples from patients with stage III or IV BRAF mutation-positive melanoma. The patients were not candidates for surgical resection and were being treated with dabrafenib alone or in combination with trametinib. They recorded the circulating tumor DNA levels at baseline and 4 weeks into treatment, and categorized each sample as either positive or negative for circulating tumor DNA based on a validated threshold of 0.25 copies/mL.
At baseline, 92.7 percent of the 345 patients were positive for circulating tumor DNA.
“Our detection rate prior to treatment was 93 percent, which is the highest rate reported for these kinds of tests looking for mutated DNA in the plasma of a melanoma patient,” Polsky noted. “That high sensitivity was very encouraging, and because the test measures the quantity of the mutated DNA precisely and accurately, we found that the more of the mutated DNA we measured in the pre-treatment sample, the worse the patient’s outcome.”
When the team tested the second set of samples at the 4-week treatment mark, they found nearly all patients experienced a substantial drop in circulating tumor DNA levels. Of the 201 patients with 4-week follow-up data, 40 percent had a change of circulating tumor DNA from positive at baseline to negative at follow-up. Those 40 percent experienced longer progression-free survival (PFS) and overall survival (OS) compared with the other 60 percent who remained positive for circulating tumor DNA at 4 weeks (median PFS of 12.9 months vs. 7.1 months; median OS of 28.2 months vs. 14.6 months).
“We call this concept zero-conversion, meaning they got to zero or undetectable levels,” Polsky explained. “Patients who reach zero-conversion have a longer survival than those patients who don’t achieve zero-conversion.”
The data also showed that, even among patients with high LDH at baseline who are expected to do poorly, a negative circulating tumor DNA at 4 weeks indicated they were likely to have prolonged PFS and OS.
Revamping an Old System
Previous methods for tracking treatment efficacy have limited utility in clinical practice, according to Polsky. While measuring LDH is an established prognostic factor, it’s not sensitive and specific enough for doctors to rely on to inform treatment decisions, he explained. Melanoma often causes an elevation in the enzyme, yet any fluctuations in LDH are not reliable predictors of treatment response, he said.
Researchers even know circulating tumor DNA at baseline is associated with poorer outcomes, but little is known about serial testing and survival after therapy. With these new data, Polsky may have finally found the answer.
Not only does the blood test seem to accurately track treatment response, it is more efficient than CT scans, which are the current standard for monitoring disease progression.
“Right now, doctors put the patient through a CT scan every 3 months to see what is going on,” Polsky explained. “Blood tests are much simpler and can be obtained even more frequently, if necessary, at a lower cost.”
Setting Standards
Some commercial labs are already offering the blood test, but clinicians aren’t likely to change their practice model because of it yet, Polsky noted. “It’s all still early in development with a lot of variability in the commercial labs,” he explained. “Our group developed protocols that we are sharing with others. Once we show with additional studies that our protocol works well and has clinical validity, we hope people will adopt the protocol and use it in their commercial labs.”
Polsky and his team are already conducting studies that include additional time points, with the aim of having samples every 4 weeks for several months. “That will allow us to see how the numbers fluctuate with the patient’s treatment and their response to it—and see if it can be used to help the doctors manage the patient,” he said.
In addition to further study with the test for BRAF gene mutations, Polsky already has assays for several other common gene mutations associated with metastatic melanoma, and he is working on similar studies for those blood tests.
Rebecca Hepp is a contributing writer.