The Role of Precision Medicine in the Management of Melanoma

A study published in the International Journal of Molecular Sciences found precision medicine to be fundamental in the treatment of patients with melanoma who do not respond to traditional therapies and experience severe adverse events.¹

Melanoma, representing only about 1% of all skin cancers, is rare but among the most aggressive and heterogeneous skin tumors.² It has the highest mortality rate, with only 15% of metastatic patients surviving 3 years after diagnosis.³ Early detection may help reduce the mortality and morbidity associated with the condition. Although melanoma mainly develops in melanocytes, in rare cases, it may also originate in melanin-producing cells found on various mucosal surfaces, including the gastrointestinal tract and leptomeninges.⁴

Although melanoma is among the first solid tumors that benefit from immunotherapy because of the heterogeneous nature of the disease, an increased number of patients show no response to the treatment and experience severe adverse effects.¹ Knowledge of intertumor heterogeneity and molecular backgrounds has formed the basis of personalized medicine in cancer prognosis, diagnosis, and management.

Chemotherapeutic drugs, the standard cancer treatment, are commonly used to kill cells that proliferate quickly, whether normal or cancerous, and may cause severe adverse effects by killing normal cells.⁵ However, precision medicine can improve clinical outcomes and predicts viable treatment options for individual patients by considering variability in genes and proteins in the patient’s body.

Precision medicine is an emerging approach that allows predicting responses to treatments or possible adverse events through the discovery and analysis of new predictive and/or prognostic biomarkers, reducing the gap between basic research and clinical management of the patient.

“Not all tumors are the same, and some may respond to other treatments not traditionally used in that specific type of cancer,” explained Trevan D. Fischer, MD, surgical oncologist and assistant professor of surgical oncology for Saint John’s Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California. “For example, we have specific targeted treatments for melanoma patients who have a specific mutation that we would not use in patients who do not have that mutation. This is a form of precision medicine.

“We do use precision or personalized medicine in the treatment of skin cancers and are learning more and more about the granular details we can get from the patient’s tumor to help direct therapy. There are developments using the analysis from the tumor itself to predict who is likely to have a recurrence or tumor that has already spread,” he continued.

Molecular characterization of various tumors has revealed that despite having the same histopathology, origin, and clinical stages, the potential for genetic and epigenetic heterogeneity is much higher in certain cancers.⁶

Studies have shown that the tumor-transformation process of melanoma is multistage and complex, exhibiting BRAF gene mutations in most lesions. However, mutations in the BRAF gene are not sufficient for disease progression and require alterations in targeted genes, including PTEN, TERT, and NF1. These genes alter the physiological functions of PI3K and MAPK pathways.¹ MAPK pathway, which is dysregulated in almost 80% of cases, may also be triggered by mutations in the NRAS gene, seen in about 15% to 20% of melanomas, and account for a more aggressive disease with greater invasive potential.⁷

Genetic abnormalities keep cancers from being detected and destroyed by the body’s immune system. Precision medicine has revolutionized the treatment of patients with metastatic melanoma with significant improvements in the life expectancy of patients. It targets specific genetic characteristics and helps tailor personalized therapies that are most cost-effective with fewer side effects. The approach is mainly based on knowing the impact of specific genetic mutations. “Testing a patient’s melanoma can tell us several things that drive therapy. Mutations in BRAF or c-Kit have specific targeted therapies one might use and understanding PD-L1 percentage positive or TMB (tumor mutational burden) may help predict response to immunotherapy,” said Fischer.

“It can guide the clinician to make the most appropriate treatment for the individual patient. It may also help us understand how to avoid treatments where adverse side effects are more likely to occur,” he said.

Recent advances in multiomics analyses, providing clear and precise insights into the relationship between different parts of cells, made it easier to identify and understand underlying cancer biology, thereby improving the treatment process.⁸ These approaches have identified potential biomarkers crucial to predict and improve treatment response and adverse events. “Biomarkers can help us predict the response to therapy and be used to follow the response over time.” Fischer said.

Asked about the limitations of precision medicine, Fischer said: “Personalized or precision medicine is very important in the fight against cancer. One drawback to this approach is that it is harder to prove statistical differences between the treatment. Clinical trials require statistical power to say that differences in treatment are not just by chance and due to a study drug or intervention. Many of these trials require hundreds or not thousands of patients to be able to tell if this difference exists. When we separate patients on a more individual basis, it’s hard, if not impossible, to get enough apples in the basket to compare apples to apples. For this, some people are advocating what is called N-of-1 clinical trials, which is a single subject clinical trial design.”

In conclusion, Fisher said, “More clinical trials are using the bench-side research in the clinics and seeing if the results improve outcomes.”

References

1. Valenti F, Falcone I, Ungania S, et al. Precision medicine and melanoma: multi-omics approaches to monitoring the immunotherapy response. Int J Mol Sci. 2021;22(8):3837. 2021;22(8):3837. doi:10.3390/ijms22083837
2. What’s new in melanoma skin cancer research? American Cancer Society. Revised August 14, 2019. Accessed September 16, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/about/new-research.html#references
3. Gurzu S, Beleaua MA, Jung, I. The role of tumor microenvironment in development and progression of malignant melanomas—a systematic review. Rom J Morphol Embryol. 2018;59(1): 23-28.
4. van der Weyden L, Brenn T, Patton EE, Wood GA, Adams DJ. Spontaneously occurring melanoma in animals and their relevance to human melanoma. J Pathol. 2020;252(1):4-21. doi:10.1002/path.5505
5. How chemotherapy drugs work. American Cancer Society. Revised November 22, 2019. Accessed September 16, 2022. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html
6. Gilson P, Merlin JL, Harlé A. Deciphering tumour heterogeneity: from tissue to liquid biopsy. Cancers (Basel). 2022;14(6):1384. doi:10.3390/cancers14061384
7. Hachey SJ, Boiko AD. Therapeutic implications of melanoma heterogeneity. Exp Dermatol. 2016;25(7):497-500. doi:10.1111/exd.13002
8. Menyhárt O, Győrffy B. Multi-omics approaches in cancer research with applications in tumor subtyping, prognosis, and diagnosis. Comput Struct Biotechnol J. 2021;19:949-960. Published January 22, 2021. doi:10.1016/j.csbj.2021.01.009