Transcriptome based individualized therapy of refractory pediatric sarcomas: feasibility, tolerability and efficacy

Abstract

Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient’s tumor and guide the choice of therapy.Twenty patients with refractory pediatric sarcomas (age 8-35 years) were assessed with array profiling: ten had Ewing sarcoma, five osteosarcoma, and five soft tissue sarcoma. Overexpressed genes and deregulated pathways were identified as actionable targets and an individualized combination of targeted therapies was recommended. Disease status, survival, adverse events (AEs), and quality of life (QOL) were assessed in patients receiving targeted therapy (TT) and compared to patients without targeted therapy (non TT).Actionable targets were identified in all analyzed biopsies. Targeted therapy was administered in nine patients, while eleven received no targeted therapy. No significant difference in risk factors between these two groups was detected. Overall survival (OS) and progression free survival (PFS) were significantly higher in the TT group (OS: P=0.0014, PFS: P=0.0011). Median OS was 8.83 versus 4.93 months and median PFS was 6.17 versus 1.6 months in TT versus non TT group, respectively. QOL did not differ at baseline as well as at four week intervals between the two groups. TT patients had less grade 1 AEs (P=0.009). The frequency of grade 2-4 AEs did not differ.Overall, expression based targeted therapy is a feasible and likely beneficial approach in patients with refractory pediatric sarcomas that warrants further study.

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

“…This study showed that patients treated with therapy targeting genetic alterations are likely to benefit. 55 In a study of 71 OGS samples from 66 adults and paediatric patients, next-generation sequencing (NGS) was used to identify potentially actionable mutations. Out of these 71 samples, 32 were from metastatic or recurrent lesions.…”

Integrated Genomic and Transcriptomic Analysis Revealed Mutation Patterns of De-differentiated Liposarcoma and Leiomyosarcoma

“…Previous study indicated that immune infiltration in tumor is prognostic for anticancer therapies [4,5]. Genomics and transcriptome based individualized therapy in sarcoma have shown a survival benefit [6]. The results of our analysis can potentially be correlated to the response of LMS and DDLPS to chemotherapy, targeted therapy, or immunotherapy, and can be used to develop biomarkers of therapeutic choice.…”

“…Tumor Mutational Burden And Microsatellite Status 6 Tumor mutational burden (TMB) was calculated from the total number of nonsynonymous somatic mutation using a published algorithm [14]. All autosomal microsatellite tracts containing 1-5 bp repeating subunits in length and comprising five or more repeats in GRCh37/hg19 were identified using MISA (http://pgrc.ipk-gatersleben.de/misa/misa.html) [15].…”

Precision Medicine in Pediatric Cancer: Current Applications and Future Prospects

“…Despite the lower prevalence of actionable mutations, targeted therapy gives pediatric oncologists further hope in the treatment of refractory or relapsed pediatric cancers. In a case-controlled study of nine pediatric patients with refractory sarcoma, targeted therapy resulted in improvement of the overall survival to 8.83 months versus 4.93 months, and improvement of the progression-free survival to 6.17 months versus 1.6 months in the control group [23]. However, because of a possible increase in the number of mutations and changes in the mutational spectrum, the importance of testing relapsed or metastatic rather primary tumors cannot be over-emphasized [24].…”