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Multi-layered molecular profiling informs the diagnosis and targeted therapy of desmoplastic small round cell tumor
Marcus Renner1,2,3, Małgorzata Oleś4, Nagarajan Paramasivam4
1Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. Here, we show that comprehensive molecular profiling informs diagnosis and individualized therapy in this disease. We report the results of whole-genome/exome, transcriptome, and DNA methylome analyses performed in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling in nine, within a nationwide precision oncology program. In eight patients (27%), DSRCT was diagnosed only after molecular profiling. Although DSRCTs have "quiet" genomes, 28 patients (93%) received 107 molecular-based management recommendations, including assessment of clinical trial eligibility in 17 (57%). Most recommendations are informed by overexpression of tyrosine kinases, SSTR3/5, and CLDN6, detected in 45%, 33%, and 20% of cases, respectively. Thirteen patients (46%) received recommended therapies, yielding disease control in eight (62%), including three long-lasting responses to pazopanib and trastuzumab deruxtecan, the latter administered based on ERBB2 overexpression in the absence of aberrant ERBB2 kinase activation. These findings demonstrate that multi-omics profiling provides clinically actionable insights for DSRCT management.
Insights
Comprehensive molecular profiling aids diagnosis and treatment for desmoplastic small round cell tumor (DSRCT), an ultra-rare cancer. Multi-omics analysis identified actionable targets and guided therapy, improving outcomes for patients with limited options.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with few treatment options.
- Molecular profiling is crucial for diagnosing and personalizing therapy in rare cancers.
Purpose of the Study:
- To evaluate the utility of comprehensive multi-omics profiling in diagnosing and guiding treatment for refractory DSRCT patients.
- To identify actionable molecular alterations and assess their therapeutic implications in DSRCT.
Main Methods:
- Whole-genome/exome, transcriptome, and DNA methylome analyses were performed on 30 DSRCT patients.
- (Phospho)proteomic profiling was conducted in nine patients.
- Molecular data was used to generate management recommendations and assess clinical trial eligibility.
Main Results:
- Molecular profiling confirmed DSRCT diagnosis in 27% of cases.
- 93% of patients received molecular-based management recommendations, including 57% for clinical trials.
- Overexpression of tyrosine kinases (45%), SSTR3/5 (33%), and CLDN6 (20%) were common findings.
- 46% of patients received recommended therapies, with 62% achieving disease control, including responses to pazopanib and trastuzumab deruxtecan.
Conclusions:
- Multi-omics profiling is essential for accurate DSRCT diagnosis and identifying personalized treatment strategies.
- Molecularly guided therapies can lead to significant disease control in DSRCT patients.
- This approach offers actionable insights for managing this rare and challenging sarcoma.
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