A new study showed that approximately 80% of patients with stage III melanoma who had detectable levels of circulating tumor DNA (ctDNA) before they started treatment to suppress their tumors went on to experience recurrence. Researchers also found that the disease returned more than four times faster in this group than in those with no detectable levels of the biomarker—and the higher their ctDNA levels, the faster their cancer returned. These findings were published by Syeda et al in The Lancet Oncology.
“Our findings suggest that ctDNA tests could help oncologists identify which [patients with] melanoma are most likely to respond well to therapy,” said lead study author Mahrukh Syeda, MS, a research scientist in the Ronald O. Perlman Department of Dermatology at NYU Grossman School of Medicine. “In the future, such assessments may be used routinely in the clinic to help guide treatment decisions.”
The research team also found that nearly all of those with detectable levels of ctDNA at 3, 6, 9, or 12 months into treatment experienced melanoma recurrence. As a result, the authors say, if the gene fragments are not observable prior to therapy but appear later on, this could indicate that the disease might be worsening.
In stage III melanoma, tumor cells have spread from the skin to nearby lymph nodes. After those lymph nodes are surgically removed, explained the authors, recurrence can be hard to spot using common imaging methods like x-rays and computed tomography, which has fueled the search for other ways to detect cancer activity early on. According to Ms. Syeda, swiftly tracking treatment progress and the ability to spot signs of cancer growth could be helpful in a disease as dangerous as melanoma, which is notoriously difficult to treat once it spreads to other body parts. Early feedback from a ctDNA analysis might save lives, she said.
The ctDNA measurement method used in this study works by using droplet digital polymerase chain reaction assays focusing on the most common mutations in the genetic code in melanoma cells—BRAF V600E and BRAF V600K.
In 2021, the authors of the current report found that higher levels of BRAF V600-mutant ctDNA in those with stage IV melanoma were linked to lower chances of survival; they published those earlier findings also in The Lancet Oncology. They also found that changes in ctDNA measurements during treatment could be used to identify patients with better or worse chances of survival.
Their latest investigation is the largest to date to assess ctDNA as a predictor for recurrence in patients with stage III melanoma, said Ms. Syeda. It included 600 men and women who had participated the COMBI-AD trial for stage III melanoma—which was a double-blind, randomized, phase III study of dabrafenib plus trametinib combination therapy vs two matched placebos in patients with resected BRAF V600-mutant disease. The research team used blood samples from patients enrolled in Europe, North America, and Australia, and compared ctDNA measurements to clinical evidence of cancer recurrence. Their statistical analysis accounted for factors other than tumor shedding that could affect recurrence, such as sex, age, and type of therapy.
Among the findings, the results showed that assessing ctDNA levels was as good or better at predicting recurrence than other experimental tests that examine a tumor itself, such as those that measure immune activity within a group of cancer cells.
“Unlike standard, tissue-based analyses of tumor cells, which can only suggest the likelihood of recurrence, ctDNA tests provide a clear, direct measure of the disease itself and can tell us outright that melanoma has returned,” said study senior author and dermatologist David Polsky, MD, PhD, Professor of Dermatologic Oncology in the Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine. He cautioned that in some cases, cancer still recurred, even though the patient had received a negative ctDNA test before starting therapy. To address this, the authors next plan to improve the sensitivity of their test, added Dr. Polsky, also a Professor in the Department of Pathology. They also intend to explore, in a clinical setting, whether using the biomarker to make treatment decisions can indeed improve patients’ chances of survival and quality of life.
Disclosure: Funding support for the study was provided by Novartis. For full disclosures of the study authors, visit thelancet.com.
