Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy

Abstract

Background: Although both seminomatous and nonseminomatous testicular germ cell tumors (TGCTs) have favorable outcomes with chemotherapy, a subset is chemorefractory, and novel therapeutic options are needed.

Objective: To molecularly characterize chemotherapy-refractory TGCTs.

Design, setting, and participants: Archival tissues from 107 chemotherapy-treated and relapsed TGCT patients (23 seminomas; 84 nonseminomas) underwent hybrid-capture-based genomic profiling to evaluate four classes of genomic alterations (GAs). Tumor mutational burden (TMB) and microsatellite instability (MSI) were also measured.

Intervention: Genomic profiling on tumor samples from chemotherapy-refractory TGCTs.

Outcome measurements and statistical analysis: Descriptive analyses and differences between seminoma and nonseminoma subgroups were reported.

Results and limitations: The mean GA/tumor was 2.9 for seminomas and 4.0 for nonseminomas (p=0.04). KRAS alterations (mainly amplifications) were the most common GAs at the single-gene level (47.8% of seminomas and 51.2% of nonseminomas). RAS-RAF pathway (56.5% vs 52.3%) and cell-cycle pathway (52.2% vs 56.0%) were the most common GA classes in seminomas and nonseminomas, respectively. Receptor tyrosine kinase pathway and PI3K pathway GAs were more frequent in seminomas (p=0.02). Median TMB was 1.8 mutations/Mb for seminomas and 2.7 mutations/Mb for nonseminomas (p=0.098), and MSI-high status was found in one nonseminoma only (1.2%). A lack of clinical outcome correlation is a limitation of the present analyses.

Conclusions: In chemotherapy-refractory TGCTs, trials with agents targeting the KRAS pathway may be pursued due to the high frequency of KRAS GAs. Overall, the GAs found in refractory seminomas and nonseminomas differ significantly. Considering the frequency of high TMB or MSI-high status, immunotherapy may benefit a small subset of nonseminomas.

Patient summary: Testicular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially druggable, particularly in the clinical trial setting, and genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients.

Keywords: Chemorefractory tumor; Genomic alterations; Germ cell tumor; Testicular cancer.