Melanoma

Director
Dr. Donald L. Morton

Goals and Areas of Research

As one of the largest melanoma centers in the United States, the John Wayne Cancer Institute conducts landmark research to identify new or recurring melanoma at its earliest stages, predict and monitor the response to systemic treatments, and develop active and passive immunotherapies for surgical and nonsurgical patients.

Lymphatic Mapping and Sentinel Lymphadenectomy

Cutaneous melanoma is increasing in incidence faster than all other malignancies in the United States except for lung cancer in women. While most cases are discovered early when cure is likely, about 30% of patients will die of the disease. Patient prognosis is determined by primary tumor thickness, ulceration and the presence of regional lymph node metastases. Unfortunately, no blood test has been shown to be completely accurate for determining patient prognosis.

Over the last year, scientists in our melanoma laboratories have focused on early detection methods in the areas of genetics and proteomics; they are also working on making the sentinel node biopsy more effective. This surgical technique, developed here at the Institute, has become the standard of care for melanoma and breast cancer patients around the world.

What is a sentinel node? Simply put, the sentinel node is the first target of tumor cells spreading from the tumor. If the sentinel node contains tumor cells, then metastasis (spread) has occurred and further nodal surgery should be undertaken. However, if the sentinel node is tumor-free, then no further surgery is necessary. This surgical innovation is saving thousands of patients from unnecessary surgery.

Innovative work in the melanoma program focuses on the idea that the sentinel node (SN) and primary melanoma are intimately related through a local regional immune response that is initiated by antigen-presenting dendritic cells. This interaction of primary skin tumor and regional lymph nodes is important for understanding the natural history and potentially the prognosis in individual patients.

JWCI physicians and scientists have observed physical features of the SN that suggest it may be functionally different than non-SN from the same patient and that SN with melanoma metastases differ from similar SN without disease. While understanding altered lymph node status may lead to more individualized staging, methods to reverse these changes may be necessary for creating clinically relevant therapies. Our research shows that the deficit of dendritic cell activation and presence of immunosuppressive type cytokines from the SN are important for the initiation of the process of metastasis of melanoma, and dendritic cell activating agents may prevent the metastasis.

In the Operating Room: Sentinel Node Biopsy

JWCI’s first Multicenter Selective Lymphadenectomy Trial (MSLT-I) is the largest and most important study of SN biopsy to date. As recently reported in the New England Journal of Medicine (September 28, 2006), it shows that surgical management based on analysis of the regional SN can significantly improve the survival of patients with early melanoma.

Before Dr. Donald L. Morton introduced sentinel node biopsy, patients with no clinical evidence of metastasis either underwent extensive nodal surgery (which usually proved unnecessary) or an anxiety-provoking "watch-and-wait" observation period. Neither was satisfactory, which is why Dr. Morton’s SN concept has been greeted enthusiastically by patients and physicians. However, only recently has SN biopsy been conclusively validated as the standard of care for melanoma.

Underway is the second MSLT (MSLT-II), a randomized trial that will accrue 4,500 patients from more than 30 countries. Results of MSLT-II will indicate whether removal of the SN alone is adequate nodal surgery in certain patients with regional metastatic melanoma. The Melanoma Department is also conducting a clinical trial using a novel mapping agent which may facilitate the SN procedure.

In the Laboratory: Molecular Assays

Conventional polymerase chain reaction (PCR) assay is a well-known lab test for detecting tumor markers in a blood or tissue specimen. Quantitative real-time PCR (qRT) quantifies individual markers rather than merely determining a marker’s presence or absence. Investigators in JWCI’s Department of Molecular Oncology have developed multimarker panels for qRT assay of nodal tissue. They recently reported significantly higher rates of disease recurrence among patients whose nodes contained at least one positive marker; they also found that survival decreased as the number of markers increased.

These findings indicate the potential of qRT marker-panels for risk stratification; patients at highest risk of melanoma recurrence after treatment may benefit from more rigorous follow-up and adjuvant treatment, whereas those at lowest risk may be followed less aggressively and avoid unnecessary adjuvant treatment. This hypothesis is being examined in MSLT-II; in fact, MSLT-II is the first major melanoma clinical study to randomize patients according to qRT assessment of the SN.

Molecular oncologists at JWCI are also detecting and measuring genetic markers that circulate in the serum of melanoma patients. One such marker is DNA that has been inactivated by methylation. In a recent study, researchers showed that the presence of hypermethylated DNA in a blood specimen could be used to predict a patient’s response to biochemotherapy for advanced melanoma. Knowing in advance which patients are more likely to respond to a specific treatment would allow clinicians to tailor each patient’s treatment more appropriately.