Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma

Abstract

ImportanceMerkel 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.ObjectiveTo identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB).Design, Setting, and ParticipantsThis 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 MeasuresThe main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations.ResultsA 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 RelevanceIn 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.

The Role of Neoadjuvant Immunotherapy in the Management of Merkel Cell Carcinoma with Clinically Detected Regional Lymph Node Metastasis

“…Other predictive markers such as PD-L1 or tumor mutational burden, which are not available in the NCDB, should be included in the decision to initiate immunotherapy in a multidisciplinary setting. Currently, multiple ongoing clinical trials are exploring this, 16 although in the KEY-NOTE-017 trial, tumor viral or PD-L1 status was not associated with improved overall survival. 25 This is in contrast to a study demonstrating that patients with positive MCPyV status were more likely to express PD-L1 and have improved overall survival.…”

“…gov ID NCT04975152; and neoadjuvant nivolumab and relatlimab, ClinicalTrials.gov ID NCT06151236) together with predictive markers such as MCPyV status, PD-L1, or tumor mutational status to determine MCC immunotherapy efficacy are ongoing. 15,16 Also of future interest is an optimal regimen for NIO and the prognostic and practice-changing implications for patients who may have a complete pathologic response to NIO.…”

“…Currently, multiple other clinical trials are ongoing to evaluate different dosages and regimens of NIO. 15,16 This study aimed to understand the trends of NIO use in MCC with CDRLNM on a national level using a cancer registry and to describe the impact of NIO on OS outcomes. We hypothesized that in line with findings from melanoma studies, offering neoadjuvant therapy to MCC patients who have CDRLNM with the tumor in situ provides better long-term OS than upfront excision and adjuvant therapy.…”

The effect of GP-2250 on cultured virus-negative Merkel cell carcinoma cells: preliminary results

“…Hence, it is not surprising that the intra-tumoral T cell receptor repertoire in virus-positive MCC is clonal whereas virus-negative MCC is characterized by a diverse T cell receptor reservoir. Virus-negative MCC is characterized by a high number of UV-induced DNA mutations being 90-fold increased compared to virus-positive MCC (Stachyra et al 2021 ; Wardhani et al 2019 ; Brazel et al 2023 ; Horny et al 2021 ; Harms et al 2015 ; Becker et al 2017b ). Apart from RB1 and TP53 mutations , aberrations occur also frequently in Notch genes as well as in the PI3K/AKT/mTOR signaling pathway which we have addressed in the present study (Dobson et al 2020 ; Temblador et al 2022 ; Stachyra et al 2021 ; Wu et al 2021 ; Iwasaki et al 2015 ; Lin et al 2014 ).…”

“…Both pathways have been shown to be affected in MCC. About ¾ of virus-negative MCC show alterations in Notch , thus Notch1 mutations are observed in up to 90% of MCC cases (Goh et al 2016 ; Panelos J et al 2009 ; Wardhani et al 2019 ; Brazel et al 2023 ). Again, most mutations in MCC are characterized by UV signatures (Horny et al 2021 ; Harms et al 2015 ).…”