Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study

SIMPLE SUMMARY: Clinically advanced pheochromocytomas and paragangliomas are a rare form of endocrine malignancy which can occur in familial and sporadic clinical settings and feature a variety of genomic alterations. Comprehensive genomic profiling (CGP) was performed to characterize the genomic alterations (GA) in clinically advanced disease to enable the search for potential therapy targets. Although the GA/tumor is relatively low for clinically advanced disease, CGP can reveal important potential targets for therapy in the metastatic setting including RET, NF1 and FGFR1. Based on this data, further study of CGP as a method of developing precision therapies for clinically advanced disease appears warranted. ABSTRACT: Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.