ctDNA as a predictive biomarker for disease monitoring in non-seminomatous germ-cell tumours
Although serum tumour markers (STM) are frequently used in the management of testicular non-seminomatous germ cell tumours (NSGCT), their limitations in terms of sensitivity and specificity underscore the need for more reliable biomarkers. In this study, the detection of circulating tumour DNA (ctDNA) was significantly associated with shorter event-free survival, in contrast to elevated STM. These results suggest the potential utility of ctDNA as a predictive biomarker for effective disease monitoring in NSGCT patients.
Serum tumour markers (STM) are currently used in the diagnosis and management of testicular non-seminomatous germ cell tumours (NSGCT). However, STM levels remain within normal ranges in a significant proportion of NSGCT patients (up to 40%), and can be falsely elevated in certain other clinical conditions. Therefore, there is an unmet clinical need for highly sensitive and specific biomarkers in NSGCT that ensure effective disease monitoring. This study assessed the clinical utility of circulating tumour DNA (ctDNA) in predicting patient outcomes, aiming to enhance the precision of NSGCT diagnosis and management.
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 and a median follow-up of 10 months. Longitudinal ctDNA testing was performed using a personalised, tumour-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). ctDNA results were analysed and evaluated for their correlation with event-free survival (EFS) during surveillance after first-line therapy (retroperitoneal lymph node dissection [RPLND] or chemotherapy) or after salvage chemotherapy. EFS was 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
This study included 25 patients, with 28% (7/25) having stage II and 72% (18/25) having stage III disease. Of note, three patients underwent RPLND only as primary treatment, seventeen completed chemotherapy and five patients had a combination of both chemotherapy and RPLND. Pre-orchiectomy tumour markers were elevated in 56% of patients, while 64% of patients had elevated tumour markers at any point during the disease course.
CtDNA rates were evaluated in three different windows. Within 1 to 12 weeks post-orchiectomy and prior to any therapy (MRD window, n=7), the ctDNA detection rate was 85.7% in stage III patients (non-evaluable in stage II with only one patient). In the surveillance window, defined as patients who had ctDNA tests post-primary RPLND or chemotherapy, the ctDNA detection rate was 40% for stage II and 50% for stage III. In the overall population, ctDNA detection rate was 85.7% in stage II and 82.4% in stage III disease at any time point.
The association of conventional STM and ctDNA with EFS was evaluated in patients post RPLND, orchiectomy, or chemotherapy. The results show that ctDNA detection significantly correlated with a shorter EFS (HR=11.4, 95%Cl 1.09- 1537, p=0.029), while elevated STM levels did not (HR=2.14, 95%Cl 0.51-8.94, p=0.298). Among patients with normal serum tumour markers, 4 out of 13 had progression, while among patients with elevated serum tumour markers, six out of seven had progression. Among patients with negative ctDNA post RPLND or chemotherapy, zero out of six had progression, while among patients with a positive ctDNA test, three out of five had progression.
Conclusions
In conclusion, this is one of the first reports outlining the clinical implications of ctDNA monitoring in patients with NSGCT. The significant association between ctDNA status post-RPLND and/or chemotherapy and EFS underscores its potential as a predictive tool for recurrence in NSGCT patients. Nevertheless, larger prospective studies are needed to validate the findings of this study.
Reference
Hassoun R, et al. Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients with non-seminomatous germ-cell tumor (NSGCT). Presented at ASCO GU 2024; Abstract 500.
