For the first time, melanoma mortality in the USA has diminished! This likely reflects improved therapies, which are now based upon new ways of classifying the various types of melanomas (pathologically and clinically).
Therefore, there are two 2021 top melanoma stories that together have impacted the improved survival of our melanoma patients:
Acceptance of Histopathology of Melanoma Based Upon Oncogenic Triggers and Mutations Rather Than Pattern Analysis Alone
Although I trained with Bernie Ackerman, for whom pattern analysis was sacred, melanoma clinically and histopathologically is now classified based upon causal mechanisms, oncogenic triggers, and mutations rather than cellular and architectural pattern. The new classifications of melanoma include1: 1) low cumulative sun damage melanoma (superficial spreading melanoma); 2) high cumulative sun damage melanoma (lentigo maligna melanoma); 3) desmoplastic melanoma; 4) Spitz melanoma (malignant Spitz); 5) acral melanoma; 6) mucosal melanoma; 7) melanoma arising in congenital nevus; 8) melanoma arising in blue nevus; and 9) uveal melanoma.
Additionally, the roles of immunohistochemistry and molecular diagnostics in melanoma have expanded and are now used for both diagnosis and treatment selection. There is a mutation-specific antibody2 for BRAFV600E, immunohistochemistry to detect the kinase domain of the native protein to screen for kinase fusions, and immunohistochemical stains used to infer loss of tumor suppressors, including BAP1 (BRCA1-associated protein), PRKAR1A (cAMP-dependent protein kinase type I-alpha regulatory subunit), p16 (also known as cyclin-dependent kinase inhibitor 2A, CDKN2A), and NF1. There are even multiple new platforms for detecting mutations in DNA. Because many melanomas demonstrate multiple DNA copy number changes, specific gains or losses can be assessed by fluorescence in situ hybridization (FISH).
Combined Targeted Therapies
For decades, we have sought a treatment for melanoma that would target the melanoma cells but not healthy cells. Many thought the answer would be found in small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway. Initially, a speciﬁc inhibitor of V600E-mutant BRAF (the mutation that occurs in a high percentage of melanomas) was thought to represent the magic bullet.3 Unfortunately, melanomas tended to relapse after this single-agent therapy. The subsequent successful combination of BRAF and MEK suppression therapeutically avoided or at least delayed resistance to BRAF inhibition.3 These targeted treatments resulted in a rapid decrease in tumor burden and thereby relieved melanoma-related symptoms within one to a few weeks, and conferred an 11.1- to 14.9-month median progression-free survival and a 22.5- to 33.6-month median overall survival.3 Although this was a vast improvement, it failed to achieve long-lasting responses. Additionally, we need therapies that would also address those melanomas that were not BRAF mutated.4
The answer was found in enhancing the patients’ own immune response to the tumor in ways that would prohibit the melanoma cells from immune escape. Immune checkpoint surface proteins attenuated the T-cell response, allowing melanoma cells to escape the immune response.5 Therapeutic antibodies to nonselective biological response modifiers (cytotoxic T lymphocyte-associated protein 4 [CTLA4] and programmed cell death protein 1 [PD-1] inhibitors) enhanced melanoma cell and immune cell engagement. This proved successful, often resulting in durable responses that even tended to persist after the discontinuation of therapy. However, this breakthrough only resulted in a 50% 5-year survival rate. Also, these new drugs came at a price: a host of autoimmune diseases impacting the skin, other organs, and patient’s quality of life.
In the past year, several preclinical studies based upon the synergistic responses with combination regimens of BRAF/MEK inhibitors with immune checkpoint blockade got underway.4
What therapies are there beside MAPK pathway and immune checkpoint inhibitors in 2021? Intralesional oncolytic virotherapy, T-VEC, transfects tumor cells with a granulocyte macrophage colony-stimulating (GM-CSF) factor encoding plasmid, resulting in high local concentrations in the tumor microenvironment that has resulted in significantly improved durable response rates compared with systemically administered GM-CSF.4 It has also been noted recently that the melanoma glycome is composed of complex carbohydrates, termed glycans, and it has been suggested that glycans may play a major role in influencing melanoma progression and could be used for prognostication of metastatic activity as well as therapeutic targets.6
Because epigenetic markers have been noted to be able to predict response to cancer immunotherapy, what is their role in melanoma immunotherapy? Histone methyltransferase EZH2 has been associated with treatment resistance to anti-CTLA4 or interleukin (IL)-2 therapy.4 A potential for combining immunotherapy with epigenetic modulators to achieve better treatment efficacy is being explored and hopefully will be news in the top story of melanoma in 2022.
Genetic testing and personalized medicine are almost here! Although not yet FDA approved, a 31-gene two-class molecular test is available for cutaneous melanoma. Finally, the measurement of circulating tumor DNA is gaining in popularity for melanoma surveillance and to measure response to therapy.5 My hope is that in future melanoma updates, this kind of testing will be part of melanoma management protocol improving patient care.