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Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy
Andrea Necchi1, Gennady Bratslavsky2, Robert J Corona2
1Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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.
Insights
Chemotherapy-refractory testicular germ cell tumors (TGCTs) show distinct genomic alterations. Targeting the KRAS pathway may benefit patients, while a subset of nonseminomas could respond to immunotherapy.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Testicular germ cell tumors (TGCTs) generally respond well to chemotherapy.
- A subset of TGCTs, however, is refractory to chemotherapy, necessitating novel therapeutic strategies.
Purpose of the Study:
- To perform molecular characterization of chemotherapy-refractory TGCTs.
- To identify potential therapeutic targets in refractory TGCTs.
Main Methods:
- Hybrid-capture-based genomic profiling was performed on archival tissues from 107 chemotherapy-refractory TGCT patients.
- Genomic alterations (GAs), tumor mutational burden (TMB), and microsatellite instability (MSI) were evaluated.
Main Results:
- Seminomas and nonseminomas exhibited different genomic profiles, with a mean of 2.9 GAs/tumor in seminomas and 4.0 in nonseminomas (p=0.04).
- KRAS alterations were the most frequent single-gene GAs (47.8% in seminomas, 51.2% in nonseminomas).
- RAS-RAF and cell-cycle pathways were commonly altered in both subtypes; receptor tyrosine kinase and PI3K pathways were more frequent in seminomas (p=0.02).
Conclusions:
- The high frequency of KRAS GAs suggests potential efficacy of KRAS-targeting agents in clinical trials for refractory TGCTs.
- Immunotherapy may benefit a subset of nonseminomas with high TMB or MSI-high status.
- Genomic profiling can guide clinical research and identify therapeutic opportunities for patients with refractory TGCTs.
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