Malignant pheochromocytomas harbor a variety of genomic alterations

SAN FRANCISCO — Malignant pheochromocytomas appeared to feature a variety of genomic alterations, some of which, including RET, NF1 and FGFR1, may be potential targets for therapy in the metastatic setting, according to results of a comprehensive genomic profiling study presented at Genitourinary Cancers Symposium.

“Malignant pheochromocytomas are a rare form of endocrine malignancy that can occur in familial and sporadic clinical settings,” Gennady Bratslavsky, MD, professor and chair of urology at Upstate Medical Center and urologic surgeon and oncologist at Upstate Cancer Center, said during his presentation. “We performed comprehensive genomic profiling to characterize genomic alterations in malignant pheochromocytoma and to enable the search for potential therapy targets.”

Researchers reviewed data from 181,782 consecutive clinical cases, 43 of which had clinically advanced disease and underwent comprehensive genomic profiling using a hybrid-capture based commercial assay.

Thirty-three (77%) of the malignant pheochromocytomas originated in the adrenal gland and 10 (23%) were sequenced from a metastatic site.

Researchers used primary tumor for sequencing 13 (30%) of the cases and a nonprimary tumor metastatic site — liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity and chest wall — for 30 (70%) of the cases.

Overall, there were 2.3 genomic alterations per tumor.

The most frequent genomic alterations that are currently untargetable included ATRX (26%), TP53 (21%), SDHB (11%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%).

Potentially targetable genomic alterations included RET (9%), NF1 (9%) and FGFR1 (5%).

Researchers observed PBRM1 genomic alterations in 2% of cases.

Seven cases (16%) harbored germline mutations in known cancer predisposition genes, including SDHB (n = 4), and BRCA1, MEN1 and MSH2 (n = 1 for each).

Researchers also calculated tumor mutational burden on 1.1 Mbp of sequencing DNA and they determined microsatellite instability on 114 loci.

The mean tumor mutational burden was 2.95 mutations/Mb, and the median tumor mutational burden was 2.4 mutations/Mb.

None of the 33 cases evaluated for microsatellite instability had a microsatellite instability-high status.

“Based on these data, further study of comprehensive genomic profiling as a method of developing precision therapies for malignant pheochromocytoma appears warranted,” Bratslavsky said. – by Alexandra Todak

Reference:

Bratslavsky G, et al. Abstract 508. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: Bratslavsky reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.