Melanoma medicine in the new millennium
Authors: H. Tsao
Journal: British Journal of Dermatology (2021)

In this issue, the BJD has compiled four timely and ‘state-of-the-art’ reviews on melanoma for the contemporary dermatologist. Over the last 20 years, the practice of treating melanoma has evolved into what I call ‘mechanism-minded medicine’. At the turn of the new millennium, there was one major oncogene known in melanoma: NRAS. Tumour suppressor genes were just coming into fashion and there was one that was all the rage: CDKN2A, or p16. On the treatment front, interferon (IFN)-α, interleukin (IL)-2 and dacarbazine were the only tenable agents, none of which are routinely used today. So how did we get to where we are now? At the dawn of the twenty-first century, the Human Genome Project ushered in an unprecedented technological explosion. In terms of genetic analyses, one gene became many genes, which expanded to all genes. In 2001, the National Institutes of Health challenged the scientific community to imagine life in 2020 and the idea of a $1000 genome was born. For those of us who laboured over sequencing gels, the $1000 genome contest seemed like an unattainable dream, only to realize later that it had been reached before 2020. The spark in melanoma genetics and therapeutics was ignited when the Wellcome Trust Sanger Institute systematically sequenced cancer cell lines to better understand the genetic aetiology of cancer.1 The Sanger team discovered that a single point mutation in BRAF (i.e. p.V600E) was present in a large percentage of tumours, especially melanoma. Fast forward 20 years and the completion of The Cancer Genome Atlas project has now revealed a long list of commonly mutated genes in melanoma (see Figure 1 in Guhan et al.)2 and what was once thought to be one disease is now accepted to be a collection of distinct, but related, genetic entities. With ‘next-generation sequencing’, many genetic black boxes have been systematically opened: NRAS/BRAF/NF1 for acquired naevi and superficial spreading and nodular melanomas; GNAQ11 for blue naevi and uveal melanomas; and KIT and PDGFR for acral and mucosal melanomas, to name just a few. One of the greatest impacts that genetic classification has had on melanoma falls in the domain of dermatopathology. In the review by Yeh and Bastian,3 the authors lay out a bold new approach to classifying melanoma based on mechanism rather than pattern. The ‘path’ in ‘dermpath’ has now been transformed from ‘pathology’ to ‘pathway’. Without giving away the punchline, the traditional morphological groupings (e.g. superficial spreading melanoma and lentigo maligna melanoma) has given way to pathways of development and oncogenic triggers (Table 1 in Yeh and Bastian).3 A new World Health Organization classification has embraced mechanism-minded medicine by leading pathologists away from pure pattern recognition towards a map of the melanomagenesis. It is now routine in many hospitals to sequence tumours comprehensively to render a clinical diagnosis based on panel of mutations rather than cellular and architectural features. The profiling of RNA has also exploded onto the clinical scene. Twenty years ago, certain laboratories were particularly deft at in situ hybridization, which characterized a single gene on a melanoma slide. Gene expression profiling (GEP), as described by Yeh and Bastian,3 has the potential to probe concurrently a multiplicity of genes beyond mutations. But have these innovations actually helped the patient with melanoma? Progress in cancer treatments, including melanoma, has never been so rapid in the history of cancer therapeutics. Let us return to the BRAF moment in 2002. The BRAF gene product is a protein kinase, which is a class of enzymes that has been functionally credentialed with tremendous detail. These proteins transfer a phosphate moiety from ATP to a serine, threonine or tyrosine residue, thereby changing the charge properties and conformation of the modified protein. Many in the field immediately recognized the therapeutic implications of the V600E finding. As the BRAFV600E mutation occurs in a high percentage of melanoma tumours, but not in normal cells, a specific inhibitor of V600E-mutant BRAF could represent the desideratum of all cancer – the ‘magic bullet’. Vemurafenib became the poster child for targeted therapies in 2011 when it beat dacarbazine hands down in progression-free and overall survival.4 However, relapse was generally the rule with single-agent BRAF inhibition and soon dual BRAF + MEK suppression proved to be indispensable as the combination prevented the melanoma cell from negotiating the BRAF signal blockade.5 Again, enabling technologies allowed the scientific community to dissect rapidly the mechanisms that underpinned resistance to BRAF inhibitors thereby providing clinicians with a series of front-line therapies carefully described in the review by Bai and Flaherty.6 However, technology is not only the privilege of molecular therapeutics, but has also helped to unleash a veritable immune rage on melanoma cells. In the early 1990s, James Allison and Tasuku Honjo discovered two proteins in mice – cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1), respectively – that would revolutionize our approach to melanoma immunotherapy.7 These ‘immune checkpoint’ surface proteins attenuate the T-cell response thereby offering the tumour cell a route of immune escape. Early studies in mice showed the strong antitumour effects of immune checkpoint blockade (ICB), but it was the vanguard protein technologies that arose over the last several decades that promulgated ‘humanized antibodies’ for clinical use. While BRAF + MEK dual inhibition worked well for BRAF-mutated melanomas, there was little to offer for individuals with BRAF wild-type tumours. As elegantly reviewed by Gault et al.,8 the era of nonselective biological response modifiers (e.g. IFN, granulocyte macrophage colony-stimulating factor and IL-2) has now been replaced by mechanistically based therapeutic antibodies that block the precise surface engagement between the melanoma cell and the immune cell thereby thwarting the tumour’s attempts at immune escape. The results are clinically spectacular. With 5-year data now available,9 the overall survival rates for metastatic melanoma are approaching 50% with ICBs. For the first time in history, melanoma mortality in the USA has diminished,10 partly because of the biologically inspired treatments such as dual BRAF + MEK and immune checkpoint inhibition. However, as with man’s discovery of fire, with great power comes great risks. One of the most popular areas of focus for trainees is a new branch of dermatology called ‘oncodermatology’. Rather than ‘cutaneous oncology’, which deals more with skin cancer treatment, oncodermatology contends with the skin reactions from immune drugs. With the initial introduction of targeted molecular therapies, there have been descriptions of cutaneous adverse events. For example, vemurafenib, as a single agent, induced squamous proliferations and carcinomas on the skin – a complication that has largely been eliminated with the addition of MEK inhibitors. However, with immune checkpoint inhibitors, the range of autoimmune skin disease has spawned a new cadre of dermatologists who focus specifically on managing these unwanted immune-related adverse events (irAEs). Once again, the article by Gault et al. extensively summarizes the extraordinary range of cutaneous irAEs reported for ICBs.8 While it has been incredibly exciting for dermatologists to witness the birth of a new subspecialty in our profession, we are all approaching this complex area with newfound trepidation. Perhaps it is only appropriate to end with a front-row view of the next 10 years. Single-cell sequencing, rather than the current bulk sequencing, will change our fundamental view of tumour composition much in the same way as quantum mechanics has deconstructed matter into particles. Robust gene expression programming platforms, in combination with clinicopathological models, may, in fact, supplant the sentinel lymph node biopsy and allow for judicious choice of adjuvant treatments. Cellular therapy, such as chimeric antigen receptor T cells, will move the field from immune cell manipulation (i.e. with drug and antibody therapies) to immune cell creation. Lastly, no review is complete without mentioning the potential power of artificial intelligence. Resident data in our entire healthcare infrastructure – from single practices to national systems – may soon be digitally accessible and leveraged for clinical gain. For those science fiction fans out there, we may soon be taking orders from that all-knowing benevolent computer. Hensin Tsao: Conceptualization (lead); Writing-original draft (lead); Writing-review & editing (lead).