Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) is detected in the majority of MCCs while MCPyV-negative cases are thought to arise through progressive accumulation of ultraviolet-light induced somatic mutations. In a non-selected cohort of stage IV MCC patients, treatment with Avelumab(an anti-PD-L1 monoclonal antibody), showed durable responses in less than a third of patients, regardless of their PD-L1 or MCV status. We hypothesized that there are significant differences in other predictors of response to I-O therapy in MCC related to their oncogenic origins.
Forty-seven MCC samples were analyzed for the presence of MCPyV using immunohistochemistry for detection of the large T-antigen (CM2B4 clone). Biomarkers of I-O therapy response included: expression of PD-L1 (IHC), total mutational burden (TMB) and microsatellite instability (MSI). NGS was performed on genomic DNA isolated from FFPE tumor samples using either NextSeq(592-whole gene panel) or MiSeq(45-gene hot-spot panel).
Overall, MCPyV was detected in 16/46 cases using IHC (35%). TMB in MCPyV-positive cases (available for 9 cases) averaged 6/Mb (range 4-11/Mb), while in MCPyV-negative cases (N=21) it was significantly (p<0.0001) higher and averaged 25/Mb (range 4-68/Mb). Similarly, MCPyV-negative cases exhibited significantly more pathogenic mutations than MCPyV-positive carcinomas (p<0.001). No microsatellite instability was detected in any of the cases (0/22). The most commonly mutated gene in MCPyV-negative cohort was TP53detected in 20 cases, with co-mutation of RB1in 11 cases. Other more prevalent mutations included PIK3CA(12%), NOTCH1(9%), KMT2Dand KMT2C(5% each). Only one pathogenic mutation (ARID1A) was detected in any of the nine MCPyV-positive cases. A single (MCPyV-positive) case exhibited PD-L1 expression in 5% of tumor cells.
MCPyVassociated MCC was present in a significantly lower proportion of cases in our data set (35%) than previously reported in the non-selected cases (70-80%), potentially due to the preselection of advanced disease cases. Successes of Avelumabtherapy in MCC may be related to the high mutational load in MCPyV-negative cases and mediated through PD-L1+ immune cell infiltrate (IC) influence on effector (PD-1) lymphocytes, or some other mechanism. Further analysis of the status of these (and potentially other) biomarkers of response to immune checkpoint inhibitors is recommended to refine the subgroups of patients responding to therapy.Download Publication