A study led by scientists at NYU Langone Health and its Perlmutter Cancer Center has shown that monitoring blood levels of DNA fragments shed by dying tumor cells may accurately predict skin cancer recurrence. The team’s research, involving adult melanoma patients in a Phase III clinical trial (COMBI-AD) found that approximately 80% of stage III melanoma patients who had detectable levels of circulating tumor DNA (ctDNA) before they started treatment to suppress their tumors went on to experience recurrence.
This ctDNA method works by focusing on the most common mutations in the genetic code in melanoma cells. The mutated DNA spills into the surrounding blood as the cells break down. The team’s study results also indicated that the disease returned more than four times faster in this group of individuals than in those with no detectable levels of the biomarker, and that the higher their levels, the faster the cancer returned.
“Our findings suggest that circulating tumor DNA tests could help oncologists identify which melanoma patients are most likely to respond well to therapy,” said Mahrukh Syeda, 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.”
Lead author Syeda and colleagues reported their findings in The Lancet Oncology, in a paper titled: “Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumor DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomized Phase III trial.”
In stage III melanoma, which is among the most aggressive forms of skin cancer, tumor cells have spread from the skin to nearby lymph nodes. After those lymph nodes are surgically removed recurrence can be hard to spot using common imaging methods like X-rays and CT scans, fuelling the search for other ways to detect cancer activity early on.
According to 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 suggested. Cell-free, ctDNA is an established measure of minimal residual disease (MRD) the authors noted, but isn’t utilized in melanoma management. “The discovery of cell-free, circulating tumor DNA (ctDNA) as a direct, albeit imperfect, measurement of tumor burden opens new possibilities for monitoring MRD and tailoring therapies accordingly.”
Previous research has shown that ctDNA tests accurately trace the progression of colorectal and breast cancers, among others. In addition, in 2021, Syeda and colleagues found that higher levels of ctDNA in those with stage IV melanoma, which has spread throughout the body, were linked to lower chances of survival. They also found that changes in ctDNA measurements during treatment could be used to identify patients with better or worse chances of survival.
Their newly reported study is, they suggested, the largest to date to assess ctDNA as a predictor for recurrence in patients with stage III melanoma. The research involved nearly 600 men and women who had participated in an earlier clinical trial for stage III melanoma. Using droplet digital PCR assays to test blood samples the team 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 the resulting data 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. “We showed that detection of post-resection, pretreatment ctDNA, which was present in 13% of patients, identified a group at high risk of early recurrence, and that the risk increased sharply with increasing ctDNA quantities,” they wrote. “In multivariable prognostic models, ctDNA concentrations were a more robust predictor of survival outcome than tumor substage, and tissue-based measures of IFNG gene expression and tumor mutational burden. These tumor-based markers were previously identified as promising candidates to stratify patients into low risk and high risk of recurrence.”
“Unlike standard, tissue-based analyses of tumor cells, which can only suggest the likelihood of recurrence, circulating tumor DNA tests provide a clear, direct measure of the disease itself and can tell us outright that melanoma has returned,” said co-senior study author and dermatologist David Polsky, MD, PhD, who is the Alfred W. Kopf, M.D., Professor of Dermatologic Oncology in the Ronald O. Perelman Department of Dermatology.
Polsky also 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, commented Polsky, a professor at NYU Grossman School of Medicine’s Department of Pathology. The team also intends 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.
“Droplet digital PCR measurements of ctDNA to assess minimal residual disease before adjuvant targeted therapy and during follow-up can identify patients at high risk of early recurrence,” they concluded. They suggested that additional studies using ctDNA measurements to guide therapeutic interventions might lead to improvements in the management of resected stage III melanoma. “Moving forward, newer ctDNA detection approaches using whole-genome sequencing-based analysis are likely to show greater clinical sensitivity than the current technologies to detect MRD in patients with resected melanoma,” they further stated.
In an associated Commentary, Saskia M Wilting, PhD, and Astrid AM van der Veldt, MD, PhD, at the department of medical oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, noted that the study by Syeda and colleagues adds to existing evidence for the independent prognostic value of post-surgical detection of ctDNA. “In our view, these results underline the importance of implementing ctDNA-based prognostic estimates as a stratification factor in future clinical trials,” Wilting and van der Veldt stated. “Although none of the currently available ctDNA tests are perfect, we should remember the quote by Voltaire that sometimes “perfect is the enemy of good.” Otherwise, waiting for the perfect ctDNA test will prevent us from implementing already available, ctDNA-based improvements into the clinical management of today’s patients.”
