Molecular Testing Making Strides in Melanoma Care

Unlike most other cancer types, rates of melanoma are increasing. Melanoma rates doubled between 1982 and 2011, according to data from the U.S. Centers for Disease Control and Prevention (CDC). When diagnosed early, melanoma is highly survivable, but survival rates for advanced, stage IV melanoma remain below 20 percent. As new therapeutic options enter the commercial market, it is hoped these survival rates will improve. According to the CDC, the annual cost of treating new melanoma cases is projected to nearly triple from $457 million in 2011 to $1.6 billion in 2030. Given the increasing cost of treating record numbers of melanoma patients with expensive new therapies, payers are particularly interested in identifying the subset of patients most likely to achieve clinical benefit from the treatment.

Academic centers like Vanderbilt University (Nashville, Tenn.) have initiated extensive molecular testing in patients with advanced melanoma. Jeffrey Sosman, M.D., director of Vanderbilt's melanoma program, tells DTET that using a next-generation sequencing (NGS) platform the medical center is testing 300 genes (including point mutations, deletions, and amplifications in expression levels).

"We are looking at a broad number of genes that are not all targetable right now, but hopefully, in the future we will use more and more of this information and it will tell us what treatment to give or not give," Sosman says. "I see that there will be a shift towards more intense molecular definition of tumors, possibly reaching the point where many patients are getting whole exome sequencing. But, there will probably be a pull-back after we learn from it, we will pick patterns that are most important in affecting treatment and outcomes and retarget genetic profiling in a less encompassing way."

While molecular testing has entered the clinical realm to target therapies to specific mutations, experts expect advanced laboratory testing to play a prominent role across the spectrum of melanoma care in the coming years—identifying those at risk for the condition, diagnosing the lesion, selecting treatment, and assessing prognosis for recurrence or metastasis.

Targeted Therapies
Molecular testing has made greatest inroads into clinical care of melanoma patients in the area of targeting therapy based on tumor mutation analysis. Several targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) and have shown promise in extending the lives of patients with advanced melanoma. Immunotherapy has similarly shown promise in patients with advanced melanoma, although research continues to identify biomarkers indicating which patients are more likely to see benefit from the therapy. New studies are showing that this molecular testing is both feasible to guide treatment decisions and gaining traction in actual practice.

Melanoma Mutations Are Actionable - NGS studies have revealed a significant number of actionable mutations in patients with advanced melanoma. Researchers from Fox Chase Cancer Center (Philadelphia) conducted mutational analysis on 60 archived tumor samples from patients with high-risk and recurrent melanoma. They sequenced targeted regions of 50 cancer-related genes and identified 101 mutations in 25 genes. At the American Society for Clinical Oncology's (ASCO) annual meeting (Chicago; June 3-7) the researchers revealed that two or more mutations were uncovered in 43.3 percent of samples (n = 26), while 13.3 percent of studied samples (n = 8) had no identifiable genetic alterations. Of the identified mutations more than twothirds (68.3 percent, n = 41) were potentially actionable mutations (BRAF, KIT, or NRAS) with commercially available drugs, while another 21 genes could be targetable with a compound in a clinical trial, the authors said.

Mutational Testing Adopted Quickly - Two studies presented at ASCO suggested that there is considerable use of BRAF testing in clinical care. In a retrospective analysis of Canadian patients diagnosed with stage IV melanoma between 2012 and 2014, investigators found the trend for BRAF testing has grown, but that a significant percentage of patients remain untested prior to their first treatment (43 of 125 patients in 2014). Furthermore, a "surprisingly high percentage" of patients with BRAF mutations are still treated with chemotherapy (nine of 34), rather than targeted treatments.

In a larger U.S. study, researchers from Flatiron Health (New York) found that testing patterns for BRAF mutations show "fast and stable" adoption with testing rates ranging from 85 percent to 88 percent from 2012 through 2014. Examination of medical records from 760 patients show similar rates of testing across U.S. geographic regions. In contrast to BRAF mutational analysis, testing for KIT and NRAS were "sparsely performed" over the same time period (overall testing rates of 14 percent and 7 percent, respectively).

Other Prognostic Markers
In addition to determining which therapies are likely to be most effective for a particular patient, clinicians are searching for prognostic information as to which patients are at highest risk of recurrence or metastatic disease. Currently prognostic assessment is "crude" and based on the thickness of melanoma tumors.

Predicting Metastasis Risk - A 31-gene expression profile test (GEP) can accurately identify high-risk disease in patients with melanoma tumors of intermediate thickness (T2/T3), independent of sentinel lymph node biopsy status or tumor ulceration. The validation of the DecisionDX-Melanoma GEP test (Castle Biosciences; Friendswood, Texas) was presented at ASCO. Based on gene expression levels, 555 patients' tumors were retrospectively classified as either low risk (Class 1) or high risk (Class 2) of distant metastasis. Current risk assessment utilizes nodal metastasis, which the authors note is an imperfect predictor.

The multicenter study found that classification as low risk was a significant predictor of distant metastasis free survival and overall survival. Across validation cohorts the GEP test identified more than 80 percent of those patients who were at risk of disease progression or death both overall in T2/T3 patients, as well as in a lymph node-negative subgroup that might typically mistakenly be considered at lower risk for metastasis. The company says that this test can complement conventional staging, particularly in patients with intermediate-grade lesions.

"Not only does the DecisionDx-Melanoma test accurately identify these high-risk patients that are missed by today's staging system, but it also identifies patients who are at very low risk of metastasis with a Class 1 designation," said Derek Maetzold, CEO of Castle Biosciences, in a statement. "These data provide further validation that DecisionDx- Melanoma is a clinically important tool to identify tumors of intermediate thickness that are at high risk of metastasizing."

Total Mutation Burden May Predict Outcomes - Researchers from MD Anderson Cancer Center (Houston) and Lion Biotechnologies (Tampa, Fla.) developed an algorithm to estimate total tumor mutation burden in cutaneous melanoma using genes assessed in two NGS panels. The Predicted Total Mutation Load (PTML) of the tumor correlated strongly with the actual whole-exome sequencing mutation load of each tumor in three datasets. Low PTML was defined as a score of 100 or less, while high PTML was over 100. High PTML significantly predicted both increased progression-free survival and overall survival among patients, including those treated with immunotherapy.

Inflammatory Markers May Also Be Tied to Outcomes - In cutaneous tissue there is an established link between tissue damage, inflammation, and cancer development. Furthermore, there is evidence that melanoma is immunogenic. Yet, the correlation between inflammatory mediators, immunosuppressive cells and clinical outcomes in melanoma patients is still a matter of intense research, according to a review published in March 27 in Discoveries Journal. In the article, the Romanian-based researchers say there is a prototype of intratumor inflammatory infiltrate associated with a good prognosis in melanoma. That infiltrate is composed of numerous T cells CD3+, Langerhans cells, few/ absent B cells CD20+ and few/absent plasma cells. They say that circulating immune cells with activated or suppressor phenotype would give the physician a more detailed immune status of the patient.

"A panel of tissue/circulatory immune markers can complete the immune status, can add value to the overall prognostic of the patient and, as a result direct/redirect the therapy choice," write the authors, led by Monica Neagu, from University of Bucharest (Romania). "The future lies within establishing low-cost, affordable/available, easily reproducible assays that will complete the pre-clinical parameters of the patient."

While immunotherapies are FDA-approved for the treatment of melanoma, clinicians are awaiting identification of markers that will clarify the prognostic value of immune cells.

Risk Assessment
Comprehensive skin cancer prevention programs could prevent 20 percent of new cases between 2020 and 2030, according to the CDC. Yet, other than skin-protecting measures there are currently few means to assess an average individual's risk of melanoma.

Family History Is Small Percent of Cases - Familial melanoma accounts for approximately 10 percent of all melanoma cases and even then a minority of these cases are attributable to a single genetic factor, CDKN2A (p16). Experts say that even with this known link to some hereditary melanoma cases, the clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with melanoma and there are no standard medical management guidelines for the mutation. Genome-wide association studies have identified numerous low-risk alleles, but again, they have not been incorporated into any meaningful risk assessment tools.

Risk Data Can Inform Prevention Efforts - New research that shows patients act on insights from genomic risk assessments is encouraging to melanoma prevention experts. Screening for common genetic risk factors for melanoma could increase preventive behaviors among individuals who are at increased risk for hereditary melanoma, according to a study published in February in the Journal of Personalized Medicine. As part of the Coriell Personalized Medicine Collaborative, participants received a personalized risk assessment based upon information related to their own self-reported family history of melanoma as well as a genetic risk variant showing a moderate effect size. The researchers found that participants with reported family risk of melanoma, personal genetic risk, or both risk factors were significantly more likely to increase skin cancer preventive behaviors compared to participants with neither risk factor.

Takeaway: Molecular testing is already informing treatment selection for melanoma patients with BRAF mutations. Over the next five years, experts expect advanced laboratory testing to further improve identification of those at risk for melanoma, determine who will benefit most from immunotherapy, and predict risk of metastasis.