700P - Detection of circulating tumor DNA and chromosome 3p25.3 gain in relapsed/refractory germ cell tumors and impact of salvage high-dose chemotherapy: Results from the Italian Germ Cell Cancer Group 04 study

Background

The gain 3p25.3 was identified as a predictor of poor prognosis and platinum-resistance in germ cell tumors (GCTs) (Timmerman et al - J Clin Oncol 2022). High-dose chemotherapy (HDCT) with autologous stem cell transplantation represents a main option for relapsed/resistant GCTs after cisplatin-based chemotherapy. In this observational retrospective study, we evaluated the role of 3p25.3 gain in liquid biopsy in correlation with HDCT clinical outcome in relapsed/refractory GCTs.

Methods

Relapsed/refractory GCTs underwent HDCT were enrolled in the Italian Germ cell cancer Group 04 (IGG-04) study. 2 ml of plasma collected prior to the mobilizing chemotherapy was used for ctDNA extraction. 20ng of ctDNA was used for whole genome libraries preparation using KAPA Hyper Prep (Roche) and sequenced on Novaseq6000 (Illumina)at ∼5× coverage. IchorCNA was used for the detection of tumor specific copy number alterations (CNAs) and for circulating tumor fraction (TF) estimation.

Results

72 assessable cases were analyzed, 74% were non seminoma (NS). NS histology was associated with lower progression-free survival (PFS) and overall survival (OS) (PFS: HR=3.85, 95%CI=1.17-12.7, P=0.026; OS: HR=3.52, 95%CI=1.06-11.6, P=0.039). ctDNA was successfully extracted and processed from all patients, ctDNA was detectable in 73.6% of cases, with a mean TF of 0.18 in seminoma patients and 0.04 in NS (p<0.001). Tumor specific CNAs were identified, including chr12p amplification in 94.7% of plasma with detectable TF. Amplifications or gains affecting chr3p25.3 region were identified in 37.5% of patients. If only plasma with detectable TF was considered the presence of chr3p25.3 increases to 44.7% of patients. PFS and OS after HDCT were not significantly associated with the presence of chr3p25.3 gain, even if a trend of worse outcome was observed in NS cases (PFS: HR=1.70, CI 95%0.61-4.69, P=0.3; OS: HR=1.64, 95%CI=0.58-4.62, P=0.3).

Conclusions

Analysis of ctDNA is feasible in GCTs and it can be used for the detection of tumor specific CNAs. HDCT activity seems independent from the presence of chr3p25.3 gain, even if gain-positive NS tends to have lower PFS/OS.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

U. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Merck; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. All other authors have declared no conflicts of interest.