From the Journals

Targetable genetic alterations found in 41% of soft tissue sarcomas



Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.

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