The incidence of skin cancer is rising in the United States, making research on prevention and treatment more important than ever before. The John Wayne Cancer Institute is well known for its work on melanoma, the most serious form of skin cancer, under the direction of Mark B. Faries, MD, director of the Donald L. Morton, MD, Melanoma Research Program and director of therapeutic immunology. Dr. Faries and his team are producing findings that have appeared in some of the most prestigious and respected national and international scientific journals. Each study takes another step toward improving the treatment of skin cancer, and, collectively, this research has had a substantial impact on the field.
Here’s a look at some of the Institute’s multifaceted projects and their implications for improved patient care.
The Role of Sentinel Node Dissection
More than two decades ago, Donald L. Morton, MD, proposed that biopsy of sentinel nodes, the lymph nodes closest to a cancer, had a significant role in determining the prognosis and treatment of melanoma patients. In the culmination of a long-term study of more than 2,000 patients, Dr. Morton, Dr. Faries, Robert Elashoff, MD, and their collaborators at other institutions in the Multicenter Selective Lymphadenectomy Trial (MSLT) found that biopsy-based management prolongs disease-free survival for all patients and prolongs survival for patients whose melanomas have spread to their sentinel lymph nodes. The results were published last year in the New England Journal of Medicine.
Metastatic Melanoma and Ipilimumab
Achieving any improvement in overall survival for people whose melanomas have dispersed to distant sites has proved virtually impossible. In this research, John Wayne Cancer Institute researcher Steven J. O’Day, MD, reported on research with a monoclonal antibody called ipilimumab. Monoclonal antibodies are single-purpose immune system antibodies derived from a single cell line. This landmark study, published in the New England Journal of Medicine, involved more than 600 patients at 125 centers in a total of 13 countries and established that ipilimumab had a significant, positive impact on survival. The data resulted in the Food and Drug Administration’s approval of the medication and brought about a shift in thinking that has expressed itself as a burst of worldwide research on the use of medications to do what ipilimumab does—strengthen a patient’s own immune system so it is strong enough to overcome a tumor’s resistance.
Metastatic Melanoma and Vemurafenib
Cancers are good cells gone bad, usually due to one or more mutations in the cancer cell’s DNA. Such cells then multiply without detection or adequate response by the body’s immune system. This study, involving Dr. O’Day, was only the second to ever show that a medical therapy could produce a survival advantage in advanced metastatic melanoma. The research demonstrated the efficacy of a protein kinase inhibitor called vemurafenib in treating melanomas resulting from a specific mutation. Such an inhibitor blocks the action of an enzyme responsible for making chemical alterations to a protein by adding phosphate to its structure. This is necessary for some cancers to grow, and its inhibition can slow or stop the growth. The improvement in survival was so dramatic in this study that, at the halfway point, independent reviewers recommended switching people who’d been on a comparison medication to vemurafenib. There was a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression with vemurafenib compared to the standard medication. Vemurafenib is now an FDA-approved treatment. The data were published in the New England Journal of Medicine.
Surgery for Distant Metastatic Melanoma
This study, published in 2012 in Annals of Surgical Oncology, used the data derived from an earlier clinical trial to examine the value of surgery in the treatment of patients with stage IV metastatic melanoma. Dr. Faries and Dr. Morton worked with many international collaborators in the Multicenter Selective Lymphadenectomy Trial (MSLT) for this study. Most physicians believe that surgery is not effective once melanoma has traveled through the bloodstream and settled at distant sites. But this study demonstrated that patients with metastatic melanoma who are treated surgically have much better survival than those who are treated with only nonsurgical therapies. The median survival time of those treated surgically was more than twice that of patients who received only systemic medical treatment. While not all patients with advanced disease are appropriate surgical candidates, more than half are.
Genomic Classification of Melanomas
Institute researchers joined a large number of institutions to collaborate on the definitive study of the genetic makeup of melanomas. State-of-the-art gene sequencing technology was used to profile the genetic makeup of 333 melanomas, which resulted in defining four basic subtypes of melanoma based on the pattern of mutation of the genes that are most frequently mutated. This genomic classification provides a framework for identifying biomarkers that may permit earlier detection and genetic susceptibility to specific drugs. Published in June in the journal Cell, this landmark paper is the foundation for much of the potential now seen in individualized treatment of not only melanoma but also many other diseases. The Institute’s contribution was led by Dave S.B. Hoon, PhD, director of molecular oncology, chief of scientific intelligence and director of the genomics sequencing center.
New Combination Treatment for Melanoma
Harnessing a patient’s immune system to treat melanoma creates new opportunities to combine immunological agents. In a 2012 study, Dr. Morton, Dr. Faries, Delphine J. Lee, MD, PhD, Roderick Turner, MD, and Leland Foshag, MD, examined a combination of Bacille Calmette-Guérin (BCG), which is often used as a tuberculosis vaccine, and imiquimod, a relatively new immune response modifier medication. Of the nine patients studied, five had complete regression of their melanoma, one had a partial response and the three others had a complete response following surgical treatment of residual hot spots. Seven of the nine had not had the disease return at an average of three years post-treatment (two died of non-melanoma causes). The combination of the two drugs permitted researchers to address melanomas that would not have been fully accessible to BCG.
For more information on the Institute’s programs in skin cancer research, please contact Mary Byrnes in the Office of Development at 310-582-7102 or Mary.Byrnes@stjohns.org.