Precision Medicine Considerations in Melanoma: Identifying Patients and Optimizing Genetic, Molecular Testing

Genetic and molecular testing may lead to earlier detection of melanoma and potentially other cancers, as well as guide decision-making on use of immunotherapies and targeted therapies. But deciding which tests to use and who would benefit from such testing warrants consideration among dermatologists.

Jeffrey P. North, MD, FAAD, managing director and associate professor of Pathology and Dermatology, University of California San Francisco, discussed the current availability of molecular tests in dermapathology and how they can help assess difficult biopsies during a Saturday session at a 2022 American Academy of Dermatology (AAD) Annual Meeting.

“Prior study findings on 120 million melanomas examined by experienced dermapathologists showed there was disagreement on diagnosis in a quarter of the cases,” noted North. “It’s not that some dermapathologists are lazy or worse than others—it's just a limitation of the human brain and eye, some of these tumors defy classification routines.”

There are currently several molecular tests available for melanoma, of which fluorescence in situ hybridization (FISH) tests are typically the most well known and used, along with comparative genomic hybridization (CGH), gene expression profiling, and next-generation sequencing (NGS).

Although FISH and gene expression tests like MyPath perform well in unequivocal cases of melanoma, North said that the specificity and sensitivity of these assays lowers when tasked with assessing challenging cases of ambiguous tumors, particularly for spitzoid regions.

“We stratified lesions that people commonly requested molecular testing for and the vast majority are atypical spitzoid proliferations.”

CGH’s assessment of the whole genome was noted to be advantageous, but its inability to evaluate individual parts of a tumor makes the test less effective in evaluating specific cells vs FISH.

North expressed his excitement at the potential of NGS, which examines all potentially actionable mutations. The approach allows for both the assessment of the whole genome and individual cells, but it can be an onerous approach due to the amount of data generated.

“There's going to be some tumor DNA and nontumor DNA so you can actually get a sense of how many mutations are in a gene by the sequencing of many molecules. A study of 70 tumors examined by 20 expert dermapathologists showed that agreement on what was a conventional melanoma and what was a benign vs non-benign tumor increased when NGS data was provided," he said.

Deciding which patients would benefit from genetic testing is another issue to consider for dermatologists. Sancy Leachman, MD, PhD, professor and chair, Department of Dermatology, Oregon Health & Science University, noted that there are several risk factors linked with melanoma, particularly inheriting an autosomal dominant gene by being a member of a family with a history of melanoma.

These patients are at the highest relative risk of melanoma, ranging from 35% to 70%, and are at risk for other tumors such as pancreatic cancer.

“It's probably a good idea to test these populations. But importantly, the screening that comes along with the identification of these patients isn't harmless either, especially if you're going to be screening for pancreatic cancer. You really want to make sure that what you're doing is in alignment with what overall is believed to be the best screening program for them,” said Leachman.

She recommended the “rule of 3” that can be leveraged as selection criteria for genetic assessment of patients with familial melanoma, in which only 1 criteria needs to be met:

• greater than or equal to 3 invasive melanomas in blood relatives
• greater than or equal to 3 melanomas in an individual
• greater than or equal to 3 melanoma plus pancreateic or astrocytoma in first-degree relatives
  

In accounting for the emergence of panel testing, the “rule of 3” was further expanded to examine for incidence of other cancers, such as colon, breast, and ovarian, to decide whether to move forward with genetic testing in patients with hereditary melanoma.

A tailored approach of management and screening that accounts for each patient’s history of cancer, genetics, and other cancers in their family was touted by Leachman.

“The environment, the ultraviolet radiation, and the geography that causes the exposure to that environment superimposes additional risks. So does the invasiveness of the melanoma and age,” she added.

“If you're doing those appropriate screenings, you'll likely detect the cancer as early as you possibly can. And everyone knows that tends to give you an advantage when it comes to treatment.”

Now that patient selection has been considered, mutations identified by genetic testing can be applied in guiding treatment decision-making. The dominant mutations in melanoma are BRAF (50%), NRAS (20%), and NF-1 (10%).

For patients with advanced disease, Justine Cohen, DO, clinical assistant professor of Medicine, Hematology and Medical Oncology, University of Pennsylvania Perelman School of Medicine, addressed the myriad of immunotherapy and targeted therapy options available:

• immunotherapies: ipilimumab, pembrolizumab, nivolumab, ipilimumab plus nivolumab, atezolizumab plus cobimetinib plus vemurafenib
• targeted therapies: dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, binimetinib

“We know that BRAF and MEK (BRAF/MEK) inhibitors, when given to certain patients, will have a rapid response to therapy. Which treatment regimen we choose is really just distinguished based on the number of pills patients take per day, the timing of administration, what's approved by their insurance, the toxicities, and pharmacokinetics,” said Cohen.

Other considerations for treatment decision-making include a history of autoimmune diseases, transplant, and immunosuppression.

“Molecular profiling of melanomas gives us the ability to select patients who will respond to treatment, at least initially, and particularly if they have BRAF mutations…biomarkers like circulating tumor DNA will play a role as we move forward in also identifying who's going to respond to treatments.”