Melanoma: Recent Advances and Future Possibilities

 

Melanoma: Recent Advances and Future Possibilities
By Cather McKay MD, FAAD

The incidence of invasive melanoma increases each year. Deaths from melanoma steadily rose until 2014, decreased until 2019, but have been on the rise again. As of 2024, the American Cancer Society predicts the lifetime risk of melanoma is 1 in 33 for White Americans, 1 in 1,000 for Black Americans, and 1 in 200 for Hispanic Americans.¹ Despite lower incidence in patients with skin of color, diagnosis tends to occur later with poorer survival as a result.

We as dermatologists aim to improve diagnostic accuracy and correctly stage our patients so they can be referred to appropriate specialists. Melanoma staging and National Comprehensive Cancer Network (NCCN) guidelines are important for every dermatologist to review and are available with a free NCCN account. Here are some of the recent updates²:

 

Biopsy principles

• Biopsy via saucerization/deep shave removal, punch for small diameter lesions, or elliptical excision is recommended so that complete assessment of the lesion and Breslow depth can be performed. Including the diameter of the pigmented lesion on the requisition form provides helpful information to your dermatopathologist, particularly if the biopsy of the entire lesion is not possible and a smaller sample is taken.
• If a shave removal shows residual pigment at the base, a deeper biopsy (punch or elliptical) should be performed immediately and submitted in a separate specimen container noting possible transection of the first biopsy.

 

Sentinel lymph node biopsy (SLNB)

• SLNB is not recommended if the risk of positivity is <5%. T1a melanomas (Breslow depth <0.8mm, nonulcerated) do not necessitate SLNB consideration unless there is uncertainty of the Breslow depth due to transection or limited sampling of a larger lesion.
• If the risk is 5-10%, SLNB should be discussed and considered. T2b (Breslow depth 0.8-1.0mm or <0.8mm with ulceration), or T1a melanomas with Breslow depth >0.5mm with other adverse features (age ≤42 years, head/neck location, lymphovascular invasion, and/or ≥2 mitoses/mm²), may fall into this category.³
• Calculators for SLNB risk prediction exist at no cost online:
• https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_
• melanomarisk.org.au/snlland
• SLNB should be considered if microscopic satellites are present in wide excision specimens, even if other criteria for SLNB are not met.

 

Treatment

• Mohs surgery is not recommended for invasive melanoma if appropriate margins can be obtained. However, Mohs may be considered for T1a (<0.8mm Breslow depth without ulceration) in areas such as the face, ears, or acral sites. Staged excision with permanent sections is an option, or if Mohs is performed, the central debulking specimen should be sent for permanent sections with immunostaining (preferred) or frozen sections if necessary.
• For stage IIB (Breslow depth >2-4mm with ulceration) or IIC (Breslow depth >4mm), adjuvant pembrolizumab or nivolumab (category 1 recommendation with a high level of evidence), and/or primary tumor site radiation therapy to reduce local recurrence (category 2B recommendation), should be considered. Stage IIB or IIC melanomas that are desmoplastic or display neurotropism have an increased risk of local recurrence and may be candidates for radiation.
• The MSLT and DeCOG phase 3 trials failed to show survival benefit with complete lymph node dissection (CLND) for patients with positive SLNB and as a result, fewer of these procedures are being performed.
• Tumor-infiltrating lymphocyte therapy (Lifileucel) and the combination of nivolumab and relatlimab, a lymphocyte activation gene-3 (LAG-3) inhibitor, were added as options for patients who progressed on immunotherapy or BRAF/MEK inhibitor combination therapy.
• An emphasis on neoadjuvant (pre-surgery) plus adjuvant (post-surgery) immunotherapy is made for advanced melanoma. When neoadjuvant therapy is given and patients experience excellent clinical/pathologic responses, complete excision may not be necessary, especially when there is a high risk of morbidity.

 

Diagnostic and prognostic tools

The NCCN guidelines do not currently recommend use of the commercially available gene expression profiling (GEP) testing to guide clinical decision making for melanoma. Ongoing independent, prospective studies are needed, but for now, these tests “do not provide clinically actionable prognostic information when combined or compared to known clinicopathologic features (eg, sex, age, primary tumor location, thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and/or SLNB status”. Even so, many dermatologists use GEP testing and consider it to be a helpful tool in appropriate situations.

For aid in diagnosis, DermTech has a 2- or 3-GEP pigmented lesion assay performed using stickers to collect skin cells from the lesion to test for expression of PRAME, LINC, +/- mutations in the TERT promoter. A recent study found a negative predictive value of the 2-GEP to be more than 99%.⁴ Nevertheless, biopsy is the gold standard for melanoma diagnosis.

For dermatopathologists, Castle Biosciences has a 23-GEP called MyPath to aid in the diagnosis of indeterminate melanocytic lesions. This test is acknowledged in the NCCN guidelines as a potential ancillary test to be used in conjunction with expert dermatopathologist review.

DecisionDx-Melanoma is a 31-GEP by Castle Biosciences marketed as a tool for risk stratification. Potential applications include identification of patients at risk of poor outcomes who may need closer surveillance, as well as patients who may be more likely to have a favorable outcome who may consider foregoing SLNB. In February, Quest Diagnostics released a 31-GEP called MelaNodal Predict in conjunction with SkylineDx and Dermpath Diagnostics with similar intended use.

AMBLor from Avero Diagnostics is yet another test but with a goal of identifying early melanomas at low risk of progression. The test identifies presence or absence of two biomarker proteins, AMBRA1 and loricrin. Presence of one or both proteins suggests a lower risk for progression.

 

Future possibilities

Ongoing research into the following topics may one day change our practice:

• Use of circulating tumor DNA or RNA as a serum biomarker, also known as a “liquid biopsy”, to detect minimal disease or relapse, may one day be available.⁵
• Therapeutic cancer vaccines are on the horizon. Phase 2b results of a personalized mRNA vaccine (mRNA-4157/V940) plus pembrolizumab vs pembrolizumab alone for completely resected stage IIIB-IV show a reduction in recurrence risk or death by 49%, and a reduction in risk for distant metastasis by 62% at 3 years. Phase 3 trials started last year.^6,7 Phase 3 trials are also underway for a personalized vaccine made from autologous tumor lysate.⁸
• Chimeric antigen receptor (CAR) T-cell-based immunotherapy using genetically engineered versions of a patient’s immune cells to target cancer cells may also one day be available.⁹
  

 

References

1. Cancer Facts and Figures 2024. American Cancer Society.
2. NCCN Guidelines for Cutaneous Melanoma v.2.2024. https://www.nccn.org
3. Shannon AB, et al. J Am Acad Dermatol 2023;88:52-59.
4. Ferris LK, et al. Large U.S. registry study confirms 2-GEP negative predictive value over 99%. Presented at: Winter Clinical Conference; Feb. 16-19, 2024; Miami.
5. Kamińska P, Buszka K, Zabel M, et al. Liquid Biopsy in Melanoma: Significance in Diagnostics, Prediction and Treatment Monitoring. Int J Mol Sci. 2021 Sep 8;22(18):9714
6. Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644.
7. Moderna And Merck Announce mRNA-4157 (V940) In Combination with Keytruda(R) (Pembrolizumab) Demonstrated Continued Improvement in Recurrence-Free Survival and Distant Metastasis-Free Survival in Patients with High-Risk Stage III/IV Melanoma Following Complete Resection Versus Keytruda at Three Years. News release. Moderna. December 14, 2023.
8. Carpenter EL, Van Decar S, Adams AM, et al. Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis. J Immunother Cancer. 2023 Aug;11(8):e006665.
9. Jilani, S., Saco, J.D., Mugarza, E. et al. CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes. Nat Commun 15, 1244 (2024).