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Updated: Jun 29, 2025
Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma
Published on: April 11, 2018
Best Overall Response-Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from
Jiangang Liu1, David S Moura2, Robin L Jones3
1Eli Lilly and Company, Indianapolis, Indiana.
Purpose:
This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers.
Experimental Design:
RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation.
Results:
A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e-7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma.
Conclusions:
The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.
Insights
Researchers identified a 25-gene signature (REDSARC) that predicts response to doxorubicin in soft tissue sarcomas (STS). This signature, associated with histologic subtype and grade, shows potential for guiding doxorubicin treatment decisions in various sarcoma subtypes.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Advanced soft tissue sarcomas (STS) present complex treatment challenges.
- Doxorubicin is a standard chemotherapy, but its efficacy varies.
- Predictive markers for doxorubicin response in STS are needed.
Purpose of the Study:
- To explore tumor complexity in advanced STS from the ANNOUNCE trial.
- To identify predictive markers for doxorubicin treatment efficacy.
- To understand response patterns in patients treated with doxorubicin.
Main Methods:
- RNA sequencing of pretreatment tumor samples (n=273) from the ANNOUNCE trial.
- Development of a Best Overall Response (BOR)-associated signature (REDSARC) for doxorubicin.
- Validation using an external cohort from the Spanish Group for Research on Sarcomas (GEIS).
Main Results:
- A BOR-associated signature (REDSARC) was identified and associated with STS histologic subtype and grade.
- REDSARC predicted progression-free survival (PFS) and overall survival (OS).
- A refined 25-gene signature predicted PFS and OS in leiomyosarcoma, liposarcoma, and other STS subtypes, but not undifferentiated pleomorphic sarcoma.
Conclusions:
- The refined REDSARC signature offers a potential tool for directing doxorubicin application in sarcomas.
- Further validation in prospective, subtype-specific cohorts is recommended.
- This signature may aid in personalizing STS treatment strategies.
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