Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study

Area of Science:

• Genomic Medicine
• Oncology
• Endocrinology

Background:

• Clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) present limited therapeutic avenues.
• Identifying actionable genomic alterations is crucial for developing targeted treatments for these neuroendocrine tumors.

Purpose of the Study:

• To compare genomic alterations (GA) in CA-Para and CA-Pheo using comprehensive genomic profiling (CGP).
• To identify potential therapeutic targets for patients with advanced paraganglioma and pheochromocytoma.

Main Methods:

• Eighty-three CA-Para and 45 CA-Pheo samples underwent hybrid-capture-based CGP on a 324-gene panel.
• Tumor mutational burden (TMB) and microsatellite instability (MSI) were assessed.
• Genomic alterations and germline mutations in cancer predisposition genes were analyzed.

Main Results:

• Low frequencies of genomic alterations were observed (1.9/tumor in CA-Para, 2.3/tumor in CA-Pheo).
• Frequent potentially targetable GA included FGFR1 (CA-Para, CA-Pheo), RET (CA-Pheo), NF1 (CA-Pheo), PTEN, NF2, and CDK4 (CA-Para).
• Germline mutations were more frequent in CA-Para (45%) than CA-Pheo (30%), notably involving SDHA/B genes. Low TMB, PD-L1 expression, and no high MSI status were observed in both.

Conclusions:

• CGP identified specific, potentially targetable genomic alterations in both CA-Para and CA-Pheo.
• Germline alterations were more prevalent in CA-Para, suggesting hereditary components.
• Low PD-L1 and MSI status indicate limited efficacy for current immune checkpoint inhibitors, underscoring the importance of targeted therapies.