By Nana O 
A groundbreaking study led by researchers at NYU Langone Health and its Perlmutter Cancer Center has revealed that monitoring blood levels of tiny DNA fragments shed by dying tumor cells, known as circulating tumor DNA (ctDNA), can accurately predict the recurrence of skin cancer, specifically melanoma. This innovative approach offers a less invasive and potentially more precise method for oncologists to identify patients at high risk of their disease returning, thereby enabling more personalized and timely treatment strategies.
Early Detection: A Crucial Advance in Melanoma Management
Melanoma, particularly in its advanced stages, presents a significant challenge in cancer treatment. Stage III melanoma, characterized by the spread of tumor cells from the skin to nearby lymph nodes, often requires aggressive treatment, including surgical removal of affected lymph nodes. However, after surgery, detecting microscopic residual disease or early signs of recurrence can be difficult with conventional imaging techniques like X-rays and CT scans, which may not pick up very small tumors. This diagnostic gap has long fueled the search for more sensitive and accurate methods to monitor patients post-treatment.
The new study, published online on April 15th in the prestigious journal The Lancet Oncology, represents the largest investigation to date assessing ctDNA as a predictor for recurrence in patients with stage III melanoma. The research involved nearly 600 men and women who had previously participated in a clinical trial for stage III melanoma. Blood samples were collected from participants across Europe, North America, and Australia, and ctDNA measurements were rigorously compared against clinical evidence of cancer recurrence.
ctDNA: A Window into Tumor Activity
The ctDNA method leverages the fact that as tumor cells break down, they release fragments of their DNA into the bloodstream. These fragments carry the unique genetic mutations characteristic of the cancer. By analyzing these mutated DNA sequences in a patient’s blood, scientists can gain insights into the presence, extent, and behavior of the tumor, even when it’s not readily visible on scans.
The findings from this extensive study are compelling. Approximately 80% of stage III melanoma patients who had detectable levels of ctDNA before commencing treatment aimed at suppressing their tumors ultimately experienced a recurrence. This indicates a strong correlation between the presence of ctDNA and the likelihood of the cancer returning.
Furthermore, the study revealed a stark difference in the speed of recurrence between patients with and without detectable ctDNA. Those with detectable levels of this biomarker experienced a return of their disease more than four times faster than those with undetectable levels. Crucially, the higher the ctDNA levels detected before treatment, the faster the cancer tended to return. This suggests a dose-dependent relationship, where higher tumor burden or more aggressive tumor biology is reflected in higher ctDNA concentrations.
Implications for Treatment Guidance
The implications of these findings for clinical practice are profound. "Our findings suggest that circulating tumor DNA tests could help oncologists identify which melanoma patients are most likely to respond well to therapy," stated study lead 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 observed a critical pattern during treatment. Nearly all patients who had detectable ctDNA at three, six, nine, or twelve months into their therapy experienced melanoma recurrence. This highlights the potential of ctDNA not only for pre-treatment risk stratification but also for real-time monitoring of treatment effectiveness. If ctDNA fragments are not observable prior to therapy but appear later on, this could serve as an early warning sign that the disease is not being controlled and may be worsening, prompting clinicians to consider alternative or intensified treatment regimens.
Beyond Stage III: A Growing Body of Evidence
This study builds upon a growing body of evidence supporting the utility of ctDNA in various cancers. Previous research has demonstrated the accuracy of ctDNA tests in tracing the progression of colorectal and breast cancers, among others. In 2021, the same research team published findings indicating that higher ctDNA levels in patients with stage IV melanoma (cancer that has spread throughout the body) were associated with lower chances of survival. They also established that changes in ctDNA measurements during treatment could be used to identify patients with better or worse survival prognoses.
The current investigation’s statistical analysis was robust, accounting for factors that could influence recurrence, such as sex, age, and the specific type of therapy received. This meticulous approach strengthens the validity of the ctDNA findings.
A Direct Measure of Disease
Dr. David Polsky, MD, PhD, the study’s senior author and a dermatologist at NYU Langone Health, emphasized the advantage of ctDNA over traditional methods. "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," he explained. Dr. Polsky holds the Alfred W. Kopf, M.D., Professor of Dermatologic Oncology in the Ronald O. Perelman Department of Dermatology and is also a professor in NYU Grossman School of Medicine’s Department of Pathology.
The ctDNA assessment was found to be as good as, or even better than, other experimental tests that examine the tumor itself, such as those measuring immune activity within cancer cell populations, in predicting recurrence. This suggests that ctDNA analysis offers a distinct and powerful diagnostic capability.
Future Directions and Refinements
While the study presents a significant leap forward, the researchers acknowledge that challenges remain. Dr. Polsky cautioned that in some instances, cancer recurred even in patients who had a negative ctDNA test result before initiating therapy. To address this limitation, the team plans to focus on improving the sensitivity of their ctDNA test.
Furthermore, the researchers intend to explore, within a clinical setting, whether proactively using ctDNA biomarker results to guide treatment decisions can indeed lead to improved patient survival rates and enhanced quality of life. This prospective research will be crucial in translating these promising findings into standard clinical care.
A Collaborative Effort
The research was supported by funding from Novartis Pharmaceuticals Corporation. Dr. Polsky has disclosed advisory board memberships for Novartis and Merck, as well as honoraria and research contracts with several other pharmaceutical and diagnostic companies, with all relationships managed according to NYU Langone Health’s policies.
The study involved a broad international collaboration, with key investigators including Jennifer Wiggins-Crosby, PhD, and Saim Ali, BA from NYU Langone Health. Other significant contributors included Georgina Long, MD, PhD, from the University of Sydney; James Garrett, PhD, from Novartis Pharmaceuticals Corporation; Victoria Atkinson, MD, from the University of Queensland; Mario Santinami, MD, from the National Cancer Institute of Milan; Dirk Schadendorf, MD, from the University of Duisburg-Essen; Axel Hauschild, MD, from the University Hospital, Campus Kiel; Michael Millward, MD, from the University of Western Australia; Mario Mandala, MD, from the University of Perugia; Vanna Chiarion-Sileni, MD, from the Veneto Institute of Oncology; Michael Smylie, MD, from the Cross Cancer Institute; Georgy Manikhas, MD, from St. Petersburg Oncology Hospital; Reinhard Dummer, MD, from the University Hospital Zurich Skin Cancer Center; Sachin Bajirao Adnaik, PhD, from Novartis Healthcare Pvt. Ltd.; and Monique Tan, MD, MPH, and Maya Dajee, PhD, from Novartis Pharmaceuticals.
The Broader Impact on Cancer Care
The implications of this research extend beyond melanoma. The successful application of ctDNA as a predictive biomarker in a challenging cancer like stage III melanoma suggests its potential to revolutionize cancer monitoring across a spectrum of malignancies. As cancer detection and treatment continue to evolve, minimally invasive liquid biopsies like ctDNA analysis are poised to play an increasingly central role in personalized medicine, offering oncologists more precise tools to guide patient care, optimize treatment outcomes, and ultimately, improve survival rates and quality of life for individuals battling cancer. The ability to swiftly track treatment progress and detect early signs of cancer growth, as highlighted by Syeda, is paramount in managing a disease as dangerous as melanoma, which has historically been notoriously difficult to treat once it has spread. Early feedback from a ctDNA analysis holds the promise of saving lives by enabling timely intervention and adaptive treatment strategies.
