Malignant pheochromocytoma (MP): A comprehensive genomic profiling (CGP) study

4584 Background: We CGP to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 201,766 consecutive clinical cases, 44 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. 23 patients were females and 21 patients were males. There were 34 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site where the exact primary site was unknown. The primary tumor was used for sequencing in 14 (32%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (68%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (25%), TP53 (21%), SDHB (13%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 8 (18%) of cases involving SDHB (5 cases) and BRCA1, MEN1, and MSH2 (1 case each). The genomic signatures of primary MP were not significantly different from that obtained from sequencing of metastatic site biopsies. 0 (0%) of 5 MP stained positively for PD-L1 expression. The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. There 2 (5%) of MP with TMB ≥ 10 mutations/MB and 0 (0%) with TMB ≥ 20 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: Although the GA/tumor is relatively low for MP, CGP can reveal important potential therapy targets including RET, NF1 and FGFR1. MP do not reveal strong potential for immunotherapies with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies.