Clinical relevance of HRD score in pheochromocytomas and paragangliomas: molecular cluster distribution and prognostic implications.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential across molecular clusters. While the homologous recombination deficiency (HRD) score has been established as a surrogate for HRD-related genomic instability to guide prognostic evaluation and therapeutic options in multiple solid tumors, its relevance in PPGLs remains unexplored. Here, data from 133 PPGL patients in the TCGA database were extracted to assess relationships between the HRD score and molecular clusters, metastasis, metastasis-free survival (MFS), and other clinical characteristics. Subsequently, a real-world cohort of 54 matched blood-tumor pairs was subjected to whole-exome sequencing, with HRD scores calculated to confirm the prior observations. The median HRD score was 7.0 and 9.0 in the TCGA-PPGL dataset and the clinical cohort, respectively. In the TCGA dataset, an elevated HRD score significantly correlated with metanephrine secretion, C2 cluster, and metastasis. Multivariate analysis identified a higher HRD score as an independent risk factor for shorter MFS (HR = 1.33, P = 0.008). Patients with HRD scores ≥ 7 exhibited significantly shorter MFS (P = 0.037), which was observed exclusively within the C1A cluster (P = 0.007). Analyses of our clinical validation cohort corroborated this cluster-specific distribution and further revealed higher HRD scores in three temozolomide-treated PPGLs compared with those treatment-naive C1A tumors (P = 0.043). In conclusion, despite exhibiting lower levels in C1A clusters, an elevated HRD score emerges as a promising indicator for refined metastatic risk stratification in PPGLs. Futhermore, the substantial increase in HRD score following temozolomide treatment provides a rationale for PARP inhibitor sequential or combination therapy in metastatic PPGLs.