Genomic Landscape of Merkel Cell Carcinoma
Researchers have developed the largest descriptive genomic analysis of patients with Merkel cell carcinoma to date. Their analysis, published by Knepper et al in Clinical Cancer Research, will provide important information to improve the care and treatment of patients with Merkel cell carcinoma.
Researchers are beginning to learn more about how Merkel cell carcinoma develops and its associated risk factors. Many patients with Merkel cell carcinoma have genetic mutations associated with UV radiation exposure, demonstrating that exposure to natural or artificial sunlight increases a person’s risk. Additionally, DNA and proteins from the Merkel cell polyomavirus (MCPyV) are present in many patients with Merkel cell carcinoma, and it is now accepted that MCPyV plays an important role in the development of some cases of Merkel cell carcinoma.
In the past, patients with Merkel cell carcinoma had few effective treatment options, resulting in a poor prognosis with a 5-year survival rate of only 20%. However, first study author Todd Knepper, PharmD, explained that patients with Merkel cell carcinoma now have hope for improved outcomes. “Just a few years ago, there were no U.S. Food and Drug Administration–approved treatments for Merkel cell carcinoma, but recently the treatment paradigm for advanced Merkel cell carcinoma has shifted dramatically with immune checkpoint inhibitors demonstrating remarkable efficacy in this disease,” said Dr. Knepper. “Indeed, since 2017, several immune checkpoint inhibitors have been approved for the treatment of patients with Merkel cell carcinoma, and clinical data have demonstrated their ability to improve patient response rates and survival.”
Methods
With these improvements in the understanding of Merkel cell carcinoma biology and therapeutic advances in immunotherapy, researchers wanted to generate a more comprehensive analysis of patients with Merkel cell carcinoma to understand its genetic landscape and how these genetic differences affect treatment responses. They performed a comprehensive genomic analysis of 317 patients with Merkel cell carcinoma and also analyzed the outcomes of 57 treated patients with Merkel cell carcinoma. Importantly, they also compared these genetic profiles to other skin cancers showing that MCPyV-positive Merkel cell carcinoma resembles other viral cancers, whereas MCPyV-negative Merkel cell carcinoma resembles other neuroendocrine cancers.
Analysis Results
The researchers reported that there were two distinct populations among the 317 patients—patients with a high tumor mutational burden (TMB) and those with a low TMB. Of the patients with a high TMB, 94% had a UV-signature mutation in their tumor DNA, and none of these patients had evidence of MCPyV. Patients with a low TMB did not have a UV-signature mutation, but rather 63% of these patients had evidence of MCPyV virus within their tumors. Among both TMB-high and TMB-low tumor populations, mutations in the genes TP53 and RB1 were the most prevalent.
In their analysis of treatment outcomes, the researchers discovered that immunotherapies were highly effective for patients with both a high TMB and a low TMB; 50% of patients with TMB-high/UV-driven tumors had a response to therapy, while 41% of patients with TMB-low/MCPyV-positive tumors had a response to therapy. Researchers also found that the earlier the patients were treated with immunotherapy, the better they responded to therapy. The percent of patients who responded to first-line immunotherapy was 75%, but the response rate decreased to 39% for those treated with second-line immunotherapy and 18% for those treated with third-line or later immunotherapy. The researchers also reported that patients who expressed the biomarker programmed cell death protein 1 (PD-1) had a better response to immunotherapy than patients who did not express PD-1.
Prior to this analysis, the largest analysis of a Merkel cell carcinoma population included fewer than 50 patients.
According to senior author Andrew Brohl, MD, “This study represents the largest description of the genomic landscape of Merkel cell carcinoma. The magnitude of this study provides a more definitive landscape of the disease, demonstrating the distinctive mutational spectra of MCPyV-positive/TMB-low and UV-driven Merkel cell carcinoma subgroups. While there are two distinct molecular subsets of this disease, interestingly, they exhibit similar response rates to checkpoint inhibitor therapy.”
Disclosure: The study was supported in part by the National Cancer Institute Cancer Center Support Grant, the Campbell Family Foundation, the DFCI Helen Pappas Merkel Cell Research Fund, and the Claudia Adams Barr Program in Cancer Research. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
