Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors

Abstract

Background: Metastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy. Objective: To perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets. Design, setting, and participants: Ten patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture-based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Intervention: CGP on tumor samples. Outcome measurements and statistical analysis: Descriptive analyses and differences between histological subgroups were reported. Results and limitations: In these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of !10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses. Conclusions: Rare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies. Patient summary: Genomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.

A comparison of stage-specific all-cause mortality between testicular sex cord stromal tumors and germ cell tumors: results from the National Cancer Database

“…Imatinib, a selective tyrosine kinase inhibitor, has been shown to decrease viability of Leydig tumor cell lines [19]. Furthermore, with the advent of the use of genomics and precision medicine, future therapeutic regimens could potentially be tailored for these patients and may help improve treatment outcomes in patients with advanced disease [20]. Necchi et al performed comprehensive genome profiling on the tumors of 10 patients with metastatic SCSTs and reported that, although uncommon, several tumors expressed targetable genomic alterations indicating the potential efficacy of cell-cycle, mTOR, hedgehog, and polymerase inhibitors [20].…”

“…Furthermore, with the advent of the use of genomics and precision medicine, future therapeutic regimens could potentially be tailored for these patients and may help improve treatment outcomes in patients with advanced disease [20]. Necchi et al performed comprehensive genome profiling on the tumors of 10 patients with metastatic SCSTs and reported that, although uncommon, several tumors expressed targetable genomic alterations indicating the potential efficacy of cell-cycle, mTOR, hedgehog, and polymerase inhibitors [20]. A case-series by Calaway et al reported that two patients with disseminated SCSTs had tumor genetic susceptibility testing following retroperitoneal lymph This study is not without limitations.…”

Sertoli Cell Tumors of the Testes: Systematic Literature Review and Meta-Analysis of Outcomes in 435 Patients

“…Given the limited life expectancy of patients with metastastic disease, as well as limited experience with systemic cancer therapies versus germ-cell cancer therapies, experimental targeted approaches or immunotherapy could be considered. However, exploratory findings show only limited, targetable genomic alterations and low tumor mutational burden, arguing against checkpoint inhibition [23].…”

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy

“…Necchi et al explored the genomic changes in malignant TSCSTs and found that the microsatellite instability mutation rate is low and that it has the characteristics of a low TMB. Thus, they speculated that the response to immunotherapy would be limited (22). However, Aguilar et al found that the growth rate of TSCSTs in mice could be significantly decreased by injecting an inhibin-a vaccine in advance.…”

“…explored the genomic changes in malignant TSCSTs and found that the microsatellite instability mutation rate is low and that it has the characteristics of a low TMB. Thus, they speculated that the response to immunotherapy would be limited ( 22 ). However, Aguilar et al.…”