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Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse
Roman Groisberg1,2, David S Hong1, Vijaykumar Holla3
1Department of Investigational Cancer Therapeutics (A Phase I Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Background:
There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed. We analyzed genomic profiling results in patients referred to MD Anderson Cancer Center with advanced sarcomas to elucidate the frequency of potentially actionable genomic alterations in this population.
Methods:
We reviewed charts of patients with advanced sarcoma who were referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling (CGP) of 236 or 315 cancer genes in at least 50ng of DNA. Actionable alterations were defined as those identifying anti-cancer drugs on the market, in registered clinical trials, or in the Drug-Gene Interaction Database.
Results:
Among the 102 patients analyzed median age was 45.5 years (range 8-76), M: F ratio 48:54. The most common subtypes seen in our study were leiomyosarcoma (18.6%), dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%). Ninety-five out of 102 patients (93%) had at least one genomic alteration identified with a mean of six mutations per patient. Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%). Notable co-segregating amplifications included MDM2-CDK4 and FRS2-FGF. Sixteen percent of patients received targeted therapy based on CGP of which 50% had at least stable disease.
Conclusions:
Incorporating CGP into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease, as well as personalized matching of patients to targeted therapies such as those available in basket clinical trials.
Insights
Genomic profiling identified actionable mutations in 93% of advanced sarcoma patients, guiding targeted therapy. This approach offers personalized treatment options for rare and diverse sarcoma subtypes.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Sarcomas lack FDA-approved molecularly matched therapies, except for gastrointestinal stromal tumors.
- The diversity, heterogeneity, and rarity of sarcomas present significant therapeutic challenges.
- Limited options exist for relapsed and refractory sarcoma cases.
Purpose of the Study:
- To analyze genomic profiling results in advanced sarcoma patients.
- To determine the frequency of potentially actionable genomic alterations.
- To guide personalized treatment strategies for sarcomas.
Main Methods:
- Reviewed charts of 102 advanced sarcoma patients.
- Utilized CLIA-certified comprehensive genomic profiling (CGP) of 236 or 315 cancer genes.
- Defined actionable alterations based on drug availability, clinical trials, or databases.
Main Results:
- 93% of patients (95/102) had at least one genomic alteration, with an average of six mutations per patient.
- Most common alterations involved TP53, CDK4, MDM2, RB1, and CDKN2A/B genes.
- 16% of patients received targeted therapy based on CGP, with 50% achieving stable disease.
Conclusions:
- Comprehensive genomic profiling (CGP) can aid in precise sarcoma diagnosis and sub-classification.
- CGP facilitates personalized matching of patients to targeted therapies, including those in basket clinical trials.
- Integrating CGP into sarcoma management enhances treatment precision for rare and diverse neoplasms.