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Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma
Danielle Brazel1, Priyanka Kumar1, Hung Doan2
1Department of Medicine, University of California, Irvine, Orange.
Importance:
Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence. Cytotoxic chemotherapy and checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy treatment options.
Objective:
To identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB).
Design, Setting, And Participants:
This is a retrospective, cross-sectional study using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, a multicenter international cancer consortium database. Patients with MCC were enrolled in participating institutions between 2017 and 2022. Data from version 11.0 of the database were released in January 2022 and analyzed from April to June 2022.
Main Outcomes And Measures:
The main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations.
Results:
A total of 324 tumor samples from 313 patients with MCC (107 women [34.2%]; 287 White patients [91.7%]; 7 Black patients [2.2%]) were cataloged in the database. The median (range) number of alterations was 4.0 (0.0-178.0), with a mean (SD) of 13.6 (21.2) alterations. Oncogenic alterations represented 20.2% of all alterations (862 of 4259 alterations). Tissue originated from primary tumor in 55.0% of patients (172 patients) vs metastasis in 39.6% (124 patients). TMB-high (≥10 mutations per megabase) was present in 26.2% of cases (82 patients). Next-generation sequencing identified 55 patients (17.6%) with a level 3B variation for a Food and Drug Administration-approved drug for use in a biomarker-approved indication or approved drug in another indication. An additional 8.6% of patients (27 patients) had a level 4 variation. Actionable alterations were more common among high TMB cases, with 37 of 82 patients (45.1%) harboring level 3 alterations compared with only 18 of 231 patients (7.8%) with low TMB. The most common level 3B gene variants included PIK3CA (12 patients [3.8%]), BRCA1/2 (13 patients [4.2%]), ATM (7 patients [2.2%]), HRAS (5 patients [1.6%]), and TSC1/2 (6 patients [1.9%]). The most common level 4 variants include PTEN (13 patients [4.1%]), ARID1A (9 patients [2.9%]), NF1 (7 patients [2.2%]), and CDKN2A (7 patients [2.2%]). Copy number alterations and fusions were infrequent. In 61.0% of cases (191 cases), a PanCancer pathway was altered, and 39.9% (125 cases) had alterations in multiple pathways. Commonly altered pathways were RTK-RAS (119 patients [38.0%]), TP53 (103 patients [32.9%]), cell cycle (104 patients [33.2%]), PI3K (99 patients [31.6%]), and NOTCH (93 patients [29.7%]). In addition, oncogenic DNA mismatch repair gene alterations were present in 8.0% of cases (25 patients).
Conclusions And Relevance:
In this cross-sectional retrospective study of alterations and TMB in MCC, a minority of patients had potentially actionable alterations. These findings support the investigation of targeted therapies as single agent or in combination with immunotherapy or cytotoxic chemotherapy in selected MCC populations.
Insights
A study found that a small percentage of Merkel cell carcinoma (MCC) patients have actionable genetic alterations. These findings suggest that targeted therapies could be beneficial for selected MCC patients, potentially combined with existing treatments.
Area of Science:
- Oncology
- Genomics
- Medical Informatics
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with rising incidence.
- Current treatments like chemotherapy and checkpoint inhibitors are used for metastatic disease, but targeted therapies lack approval.
- Identifying actionable genetic alterations is crucial for developing new treatment strategies.
Purpose of the Study:
- To identify actionable genetic alterations in MCC.
- To correlate these alterations with tumor mutational burden (TMB).
- To assess the therapeutic evidence level of these alterations using the OncoKB database.
Main Methods:
- Retrospective analysis of 324 MCC tumor samples from the AACR GENIE database (2017-2022).
- Utilized next-generation sequencing data to identify genetic alterations.
- Assessed tumor mutational burden (TMB) and OncoKB therapeutic evidence levels (3B and 4).
Main Results:
- 26.2% of MCC cases had high TMB (≥10 mutations/Mb).
- 17.6% of patients had OncoKB level 3B alterations and 8.6% had level 4 alterations.
- Actionable alterations were more frequent in high TMB cases (45.1%) compared to low TMB cases (7.8%).
- Commonly altered pathways included RTK-RAS, TP53, cell cycle, PI3K, and NOTCH.
Conclusions:
- A minority of MCC patients possess potentially actionable genetic alterations.
- These findings support further investigation into targeted therapies for MCC.
- Targeted therapies may be effective as single agents or in combination with immunotherapy or chemotherapy for specific MCC patient groups.
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