Pheochromocytomas are a relatively rare neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells) that secretes high amounts of catecholamines, leading to functional manifestations. Pretreatment with medical management followed by surgical excision is recommended. However, a small proportion of pheochromocytomas can have malignant potential – or the ability to metastases. Yet, if pheochromoctyomas are rare, malignant pheochromocytomas are rarer still. Unfortunately, malignancy cannot be determined at a histologic level – rather clinical manifestation with either local invasion of surrounding tissues or distant metastases indicate malignancy.
Survival of malignant pheochromocytomas are <50% in 5 years and treatment options are currently limited. It can occur in familial and sporadic clinical settings.
That leaves clinicians and surgeons in a bit of a quandary. How do we know which patients are malignant? Which ones are benign? Are there therapies that may be useful in prevent malignant spread? Perhaps genomics can help answer these questions.
In this study, Dr. Bratslavsky and colleagues performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in malignant pheochromocytoma (MP) cases to enable the search for potential therapy targets. To highlight the rarity of this condition, from a series of 181,782 consecutive clinical cases of pheochromocytomas, they identified only 43 cases of clinically advanced MP for assessment.
All 43 cases were underwent complete genomic profiling (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. IHC for PD-L1 expression was performed on a subset of patients (DAKO 22C3 antibody).
All 43 patients had clinically advanced recurrent and/or metastatic disease. There were 33 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site. The primary tumor was used for sequencing in 13 (30%) 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 (70%) of the MP cases.
Looking first at genomic alterations, there were 2.3 GA/tumor. Of these, the most frequent un-targetable GA were ATRX (26%), TP53 (21%), SDHB (11%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). He did note that while VHL isn’t targetable directly, there are many downstream targets that can be utilized – similar to patients with RCC.
The most frequent potentially targetable GA with current agents included RET (9%), NF1 (9%) and FGFR1 (5%).
Looking at germline mutations, known cancer predisposition genes were predicted in 7 (16%) of cases involving SDHB (4 cases) and BRCA1, MEN1, and MSH2 (1 case each).
Lastly, looking at tumor mutational burden, mean TMB was 2.95 mutations/Mb and the median TMB was 2.4 mutations/Mb. Unfortunately, none (0%) of 33 MP evaluated for MSI would be classified as MSI-high. Also, none of the 5 evaluable patients were PDL-1 positive. PBRM1 GA were found in 2% of MAP. Based on these results, he noted that these patients are unlikely to be responsive to immune checkpoint inhibition.
Based on these interesting results, the authors conclude that MP represents a very rare form of endocrine cancer that feature a variety of genomic alterations. Although the genomic alterations/tumor are relatively low for MP compared to other malignancies, CGP can reveal important potential targets for therapy in the metastatic setting including RET, NF1 and FGFR1. Unfortunately, due to low TMB and absence of MSI-high tumors, the potential for immunotherapy (such as immune checkpoint inhibitors) appears to be low.
It would have been interesting if they had also mapped clinically benign pheochromocytomas as a comparison, which may have helped predict patients who would progress to metastases.
Presented by: Gennady Bratslavsky, MD, SUNY Upstate Medical University, Syracuse, NY
Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA