Clinically Relevant Genomic Alterations Identified In Two-Fifths of Soft-Tissue Sarcomas

Molecular analysis suggests that many adults with soft-tissue sarcoma might benefit from targeted therapy

medwireNews: Two-fifths of adult soft-tissue sarcomas have genetic alterations that might be amenable to targeted therapy, next-generation sequencing has revealed.

“Given the poor prognosis of [soft-tissue sarcomas] treated by nontargeted conventional therapies, comprehensive genomic profiling shows promise to identify targeted therapeutic approaches to improve outcomes for this devastating disease”, the investigators write in JAMA Oncology.

The majority (57%) of the 584 patients registered in the AACR GENIE database had complex genomics sarcomas with multiple karyotypic abnormalities, such as leiomyosarcoma or pleomorphic liposarcoma, explain Antoine Italiano, from Institut Bergonié in Bordeaux, France, and co-authors.

A further 25% of the patients had translocation-related sarcomas (eg, synovialosarcoma or myxoid round cell liposarcoma), while the remaining 18% of patients had other types of sarcomas, namely tumours with specific oncogenic mutations (eg, epithelioid sarcoma) or recurrent amplification (eg, well-differentiated or dedifferentiated liposarcoma).

The researchers identified 2697 genetic alterations in 451 different genes, with a median of four abnormalities per patient. The most commonly affected genes were TP53, MDM2, CDK4, RB1, ATRX, CDKN2A, PTEN, NF1, CDKN2B, KMT2D and GLI1. These were followed by mutations in ATM, TERT, PI3KCA, NOTCH1, MAP2K4, ERBB4, ARID1A, TSC2 and TNFAIP3.

While 41% of patients in the study had at least one clinically relevant genetic alteration that might be suitable for targeted therapy, the rate varied from 82% of the 89 patients with a specific oncogenic mutation or recurrent amplification to 40% of the 131 patients with complex genomic sarcomas and 13% of the 19 patients with translocation-type disease.

Of note, 107 patients had genetic abnormalities that are used as standard of care biomarkers for prediction of response to drugs that are not currently approved for the treatment of soft-tissue sarcomas. These included CDK4 amplifications in 84 patients, MET amplifications or mutations in 10, and BRCA1 or BRCA2 truncating mutations in four patients.

A further 148 patients had genetic abnormalities that are “associated with compelling clinical evidence of predictive value”, and 121 patients had alterations “associated with compelling biological evidence of predictive value” for targeted therapy, the researchers add.

Antoine Italiano et al believe their findings provide support for the upcoming launch of the MULTISARC trial, which will compare conventional management and next-generation sequence-guided treatment for patients with advanced soft-tissue sarcomas

“Thanks to a public-private partnership, 16 targeted therapies will be included in the program”, the authors say.

“One of the objectives of the MULTISARC study will be to demonstrate that use of [next-generation sequencing] data can improve [overall survival] of advanced [soft-tissue sarcomas] by allowing in at least a proportion of them the identification of 1 or more additional appropriate lines of treatment”, they explain.

 

Reference

Lucchesi C, Khalifa E, Laizet Y, et al. Targetable alterations in adult patients with soft-tissue sarcomas. Insights for personalized therapy . JAMA Oncol; Advance online publication 3 May 2018.
DOI:10.1001/jamaoncol.2018.0723

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