Researchers have identified seven blood biomarkers that appear to help predict the risk of a patient's melanoma metastasizing. The Yale Cancer Center and Yale University School of Medicine team found elevated levels of one or more of the proteins CEACAM, ICAM-1, osteopontin, MIA, GDF-15, TIMP-1, or S100B in the vast majority of patients with metastatic disease.
Conversely, none of the biomarkers were elevated in over three-quarters of patients with early-stage disease. The researchers, led by Harriet Kluger, M.D., associate professor of medicine at the School of Medicine, suggest a panel of these biomarkers could be used to monitor patients for disease recurrence and potentially compliment currently used lactate dehydrogenase and imaging studies. Their results are published in Clinical Cancer Research in a paper titled “Plasma Markers for Identifying Patients with Metastatic Melanoma.”
Melanoma is the fifth most common cancer in men and the seventh in women, and the risk of death rises from 10% to 80% dependent on the stage of the disease, the authors write. However, there are currently no reliable methods for predicting which patients within a particular staging group will relapse and if they do, when, or who will remain disease-free.
Current monitoring methods include physical examinations, blood tests, and imaging studies, but there is no clear consensus regarding selection and timing of laboratory and imaging studies when following patients with resected melanoma. Serum LDH is the only blood-based biomarker in clinical use for melanoma monitoring, and elevated serum LDH levels do sometimes correlate with metastatic relapse. “However, the sensitivity and specificity for LDH as a predictor of metastatic relapse is low,” the authors state.
Studies have suggested that levels of other blood-based markers are associated with melanoma disease burden and/or prognosis. These include VEF-R3, serum S100B, and secretory CSE1L/CAS. To try and verify a link between plasma protein concentrations and melanoma relapse risk, the researchers carried out ELISA assays to measure proteins in the plasma of 216 individuals including 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease.
The cohort was divided into training and test cohorts. Plasma from healthy donors, defined as individuals who had no diagnosis of cancer, and matched by age and gender to the two melanoma cohorts, was also assayed to determine biologically normal values for the plasma markers.
The markers evaluated were chosen based on gene-expression data and literature searches for candidates that have a known association with cancer. Of these, CEACAM, ICAM-1, OPN, MIA, GDF-15, TIMP-1, and S100B were selected for further analysis.
In fact, none of the individual markers was enough to distinguish the resected stage I/II patients from the unresected stage IV patients, so the researchers assessed the distribution of positive markers in their training and test sets. In the training set, 70% of patients with stage IV disease had elevations in at least one marker. In the test set this figure was 78%. Conversely, among patients with resected stage I/II disease in the training set, 76% of patients had no marker elevation, while 81% of resected stage I/II patients in the test set had no marker elevation.
The authors claim that if elevated levels of at least one marker is considered a positive result for abnormality, then the assay is 74–79% sensitive, 79% specific, and has a positive and negative predictive rate of 78% and 75%, respectively. If high levels of 2 or more markers are considered positive for abnormality, then the assay has a sensitivity of 57.4% specificity, of 94.4% sensitivity, and has positive and negative predictive rates of 89% and 70%, respectively.
Area under the curve for the melanoma panel was 0.898, which suggests the seven biomarker melanoma assay compares favourably in terms of reliability, with other clinically used cancer assays such as those employed for breast cancer, the researchers state. While they stress that prospective validation of their findings will need to be carried out, the panel could represent a useful predictive tool.
“To the best of our knowledge, this is the first published study that assesses these biomarkers in combination," the researchers note. "Particularly when used in combination, these markers can be used to monitor patients for disease recurrence and might be useful for complimenting surveillance imaging for resected stage I to III patients or increasing the interval between imaging studies, particularly in high-risk stage IIC and III patients.”