Abstract
BackgroundThere 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.MethodsWe 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.ResultsAmong 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.ConclusionsIncorporating 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.
Highlights
Recurrent and metastatic sarcomas are a rare and heterogeneous group of diseases
Incorporating comprehensive genomic profiling (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
All patients in this study had advanced or metastatic relapsed or refractory sarcoma or did not have any other standard care therapies available when they presented for clinical trials
Summary
Recurrent and metastatic sarcomas are a rare and heterogeneous group of diseases. With well over 70 subtypes, the exact diagnosis alone can be challenging to make [1]. When sarcomas progress beyond efficacious local control, the standard practice with few notable exceptions is to treat with cytotoxic agents until progression or intolerance [2]. These cytotoxic agents yield overall response rates of around 25% [3, 4]. 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. 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
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