Future directions in the treatment of osteosarcoma

Abstract

Purpose of review: Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies.

Recent findings: Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies.

Summary: Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.

Figures

Figure 1

A CIRCOS plot demonstrates genomic complexity within a single osteosarcoma tumor sample. Chromosomes are depicted on the outer most track. A blue-red heatmap circle indicates copy number ratio estimates from whole genome sequencing. Interchromosomal and intrachromosomal rearrangements are represented by lines and arcs within the heat-map circle. C>T (green) and C>G (yellow) mutations are plotted outside the heat-map circle. An area of numerous C>T and C>G mutations in concert with significant intrachromosomal rearrangements at chromosome 15 suggests a focal area of hypermutation or “kataegis”.

Figure 2

A karyotype of a patient with osteosarcoma demonstrates multiple structural and numeric abnormalities.