37O - Plasma circulating tumor DNA (ctDNA) as a clinically relevant biomarker for disease monitoring and prognostication in metastatic pheochromocytoma and paraganglioma (mPPGL)

Background

Approximately 15% of pheochromocytomas and paragangliomas (PPGLs) progress to metastatic disease (mPPGL). These metastatic tumors often remain stable for prolonged periods but can undergo sudden rapid progression, frequently resulting in poor patient outcomes and reduced survival. Currently, there are no validated prognostic biomarkers available for monitoring mPPGL or predicting disease progression. In this study, we investigate the potential of liquid biopsy as a novel approach to identify aggressive disease phenotypes and predict clinical outcomes in patients with mPPGL.

Methods

We performed shallow whole-genome sequencing (shWGS) combined with the ICHOR-CNA bioinformatics pipeline to quantify circulating tumor DNA (ctDNA) in plasma samples from patients with metastatic pheochromocytoma and paraganglioma.

Results

We analyzed 232 plasma cfDNA samples from 146 mPPGL patients through the ENSAT and A5 networks using the ICHOR-CNA pipeline. ctDNA was detected in 19% of cases, with 78.4% showing progressive disease or death, while 80% of ctDNA-negative patients had stable disease. ctDNA positivity was associated with poorer prognosis (HR=7.14) and lower 24-month survival (38% vs. 85%). Outcomes also correlated with ctDNA levels: undetectable ctDNA (HR reference), 2%-10% ctDNA (HR=5.4), and >10% ctDNA (HR=27.3). Among ctDNA-positive patients, those treated with targeted therapies (RET inhibitors, HIF2α inhibitors, TKIs) had better survival than those receiving chemotherapy or watch-and-wait management (HR=8.3). These findings support ctDNA as a prognostic biomarker and a tool for guiding treatment in mPPGL.

Conclusions

Our findings underscore the value of ctDNA as a non-invasive biomarker with significant potential for predicting clinical outcomes and guiding patient management in mPPGL. By demonstrating its association with disease progression and survival, our study establishes ctDNA as a novel and reliable prognostic biomarker for patients with mPPGL, paving the way for its integration into routine clinical practice to enhance disease monitoring and treatment stratification.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Paradifference Foundation.

Disclosure

M. Fassnacht: Financial Interests, Institutional, Invited Speaker, Clinical trial on adrenocortical carcinoma and malignant pheochromocytoma: Enterome Bioscience; Financial Interests, Institutional, Invited Speaker, Clinical trial in Cushing's syndrome: HRA Pharma, Corcept; Financial Interests, Institutional, Invited Speaker, Clinical trial in malignant paraganglioma: MSD; Non-Financial Interests, Personal, Leadership Role: European Network for the Study of Adrenal Tumor; Non-Financial Interests, Personal, Member of Board of Directors: European Society of Endocrinology; Non-Financial Interests, Personal, Member: European Network for the Study of Adrenal Tumors; Other, Personal, Other, Data safety board for a clinical trail (compensation is paid to the Institution): Bayer Pharma. J. Capdevila: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono, Esteve, ITM; Financial Interests, Personal, Research Grant: AstraZeneca, Advanced Accelerator Applications, Bayer, Eisai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Roche, Gilead; Financial Interests, Institutional, Invited Speaker: ITM, Boeringher. All other authors have declared no conflicts of interest.