Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients with non-seminomatous germ-cell tumor (NSGCT).
Authors: Hassoun Rebecca , Cary Clint , Masterson Timothy A. , Laliotis George , Sharma Shruti , Dutta Punashi , Malhotra Meenakshi , ElNaggar Adam , Liu Minetta C. , Sfakianos John P. , King Jennifer , Einhorn Lawrence H. , Adra Nabil 
Published: January 2024

500

Background: Serum tumor markers (STM) are currently utilized in the management of testicular NSGCT. However, STMs are normal in a substantial proportion of patients with NSGCT (up to 40%) and can be falsely elevated in certain other clinical conditions. Therefore, a highly sensitive and specific biomarker for NSGCT can be helpful for disease monitoring with diagnostic and therapeutic implications. Herein, we test the clinical utility of ctDNA to predict patient outcomes and monitor treatment response in stage II-III NSGCT. Methods: A total of 106 plasma samples were collected from a cohort of 25 Stage II-III NSGCT patients post-orchiectomy with a median age of 29 years (IQR: 26.8-38.8) and a median follow-up of 10 months (IQR: 7.2-17.5). Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera bespoke mPCR-NGS assay). ctDNA results were analyzed and evaluated for their correlation with clinical outcomes (event-free survival [EFS]) during surveillance after first-line therapy (retroperitoneal lymph node dissection [RPLND] or chemotherapy) or after salvage chemotherapy. EFS is described as the interval from orchiectomy to the date of recurrence or evidence of residual/persistent disease after the completion of RPLND or chemotherapy. Results: Of 25 patients, 28% (7/25) had stage II and 72% (18/25) had stage III disease. Five patients with stage II disease underwent RPLND, and all tested positive for ctDNA prior to RPLND. Of the 18 patients with stage III disease, 83.3% (15/18) tested ctDNA positive pre-chemotherapy. For patients who completed 1st line treatment with RPLND or chemotherapy and had ctDNA testing post-completion of therapy, none of the patients who tested negative for ctDNA experienced relapse (recurrence rate: 0%, 0/6) compared to a recurrence rate of 30.8% (4/13) in patients who had normal STM levels. The detection of ctDNA was associated with a significantly shorter EFS (HR=11.4, 95%Cl 1.09-1537, p=0.041) while elevated STM results were not (HR=2.14, 95%Cl 0.51-8.94, p=0.298). ctDNA-positivity remained strongly associated with poor EFS (HR=12.98, 95%CI 1.17-1869, p=0.035) when adjusted for STM status. For patients who progressed after 1st line therapy and were treated with salvage chemotherapy, no events were seen in those who were ctDNA negative after therapy (0/6) compared with an event rate of 25% (2/8) in patients with normal STMs. Conclusions: Personalized monitoring of ctDNA seems predictive for recurrence in patients with NSGCT. To the best of our knowledge, this is one of the first reports presenting the clinical implications of ctDNA monitoring in this patient population. Our findings suggest that ctDNA monitoring may help optimize clinical decision-making, however, larger prospective studies are needed to validate the findings of this study.