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 suffer severe adverse events.¹

Melanoma, representing only about 1% of all skin cancers, is a rare but among the most aggressive and heterogeneous skin tumors.² It has the highest mortality rate, with only 15% of metastatic patients surviving three 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, due to the heterogeneous nature of the disease, an increased number of patients show no response to the treatment and suffer from severe adverse effects.¹ Knowledge of inter-tumor 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 improves 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.

While explaining the role of precision medicine in the treatment of melanoma, Trevan D. Fischer, MD, surgical oncologist and assistant professor of surgical oncology for Saint's John's Cancer Institute at Providence Saint John's Health Center in Santa Monica, California says, "Not all tumors are the same, and some may respond to other treatments not traditionally used in that specific type of cancer. 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 further explains.

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 multi-staged 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 15-20% 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. "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", Fischer explains.

Recent advances in multi-omics 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. Regarding the importance of biomarkers, Fischer says, "Biomarkers can help us predict the response to therapy and be used to follow the response over time."

When asked about the limitations of precision medicine, Fischer says, "Personalize, 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."

While concluding the discussion, Fischer provides insights on the future of precision medicine and says, "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. Published 2021 Apr 7. doi:10.3390/ijms22083837
2. Melanoma skin cancer research: Melanoma studies. American Cancer Society. https://www.cancer.org/cancer/melanoma-skin-cancer/about/new-research.html#references. Accessed September 16, 2022.
3. Gurzu, S.; Beleaua, M.A.; Jung, I. The role of tumor microenvironment in development and progression of malignant melanomas—A systematic review. Rom. J. Morphol. Embryol. 2018, 59, 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 does chemo work?: Types of chemotherapy. American Cancer Society. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html. Accessed September 16, 2022.
6. Gilson P, Merlin JL, Harlé A. Deciphering Tumour Heterogeneity: From Tissue to Liquid Biopsy. Cancers (Basel). 2022;14(6):1384. Published 2022 Mar 8. doi:10.3390/cancers14061384
7. Hachey SJ, Boiko AD. Therapeutic implications of melanoma heterogeneity. Exp Dermatol. 2016;25(7):497–500.
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 2021 Jan 22. doi:10.1016/j.csbj.2021.01.009