Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas

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.

Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers

“…MDM2 amplification and chromosomal gains were relatively frequent in RMS, with up to 32% of cases in one study [14]. While the incidence of MDM2 alterations were similar between the alveolar and embryonal RMS subtypes [15,16], TP53 mutations usually occurred in PAX fusion negative RMS but in generally less than 15% of those cohorts [17,18]. In OS, MDM2 amplifications could be detected in up to 83% of patient samples in individual reports and were more frequent in the parosteal subtype [19,20].…”

Individualizing systemic therapy for advanced soft tissue sarcomas based on tumor histology and biology

“…While the value of universal molecular profiling to guide STS management has been debated, retrospective studies do suggest that targeted next-generation sequencing can identify alternative treatment options [23,24]. The ongoing randomized, phase III MULTISARC clinical trial (NCT03784014) compares the standard of care therapy with the utilization of next-generation sequencing (NGS) to enroll patients into sub-arms of targeted therapies.…”

Role of Molecular Profiling in Soft Tissue Sarcoma

“…4 In another study of 102 patients who had profiling on a 236-or 315gene panel, 61% were considered to have an actionable mutation and 16% were able to be treated with targeted therapy. 46 It is important to note that "actionable" in this particular study was loosely defined as "any gene alteration that is either directly targeted or a pathway component of a directly targeted gene by an approved or investigational drug." Nonetheless, there are ongoing developments to use information from molecular profiling to direct new and investigational therapies (see next section), and results from recent molecular-based trials are highlighted in Table 2.…”