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Brief Report
October 2018

Targetable Alterations in Adult Patients With Soft-Tissue Sarcomas: Insights for Personalized Therapy

Author Affiliations
  • 1Bioinformatics Unit, Institut Bergonié, 229 Cours de L'Argonne, 33076 Bordeaux, France
  • 2Department of Pathology, Institut Bergonié, 229 Cours de L'Argonne, 33076 Bordeaux, France
  • 3Clinical and Epidemiological Research Unit, Institut Bergonié, Comprehensive Cancer Center, F-33000 Bordeaux, France
  • 4Institut national de la santé et de la recherche médicale (INSERM),Clinical Epidemiology, Bordeaux, France
  • 5INSERM, Institut de Santé Publique, d' Épidémiologie et de Développement (ISPED), Centre INSERM U1219 Bordeaux Population Health Center, Epicene Team, F-33000 Bordeaux, France
  • 6University of Bordeaux, ISPED, Centre INSERM U1219 Bordeaux Population Health, Epicene Team, F-33000 Bordeaux, France
  • 7L'Institut Thématique Multiorganisme Cancer, Bordeaux, France
  • 8Department of Medical Oncology, Institut Bergonié, Bordeaux, France
  • 9University of Bordeaux, France
JAMA Oncol. 2018;4(10):1398-1404. doi:10.1001/jamaoncol.2018.0723
Key Points

Question  Can next-generation sequencing reveal potentially actionable alterations in a significant proportion of patients with soft-tissue sarcoma?

Findings  In this analysis of next-generation sequencing data from 584 patients, actionable genomic alterations in up to 41% of cases were identified.

Meaning  Comprehensive genomic profiling can identify novel therapeutic strategies to address the limited options and poor prognoses of patients with soft-tissue sarcoma.

Abstract

Importance  Patients with advanced soft-tissue sarcomas (STS) have a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving patient outcomes.

Objective  To characterize targetable genomic alterations (GAs) in patients with STS.

Design, Setting, and Participants  This cross-sectional study of next-generation sequencing results from 584 patients with STS included in the AACR GENIE Database.

Main Outcomes and Measures  Presence of targetable GAs in STS.

Results  Of 584 patients included in the analysis, 294 (50.3%) were men and 290 (49.7%) were women, with a median age of 56 years (range, 18-89 years). There were 331 (57%) patients with complex genomics sarcomas, 144 (25%) with translocation-related sarcomas, and 112 (18%) with other sarcomas (inactivating mutation, simple amplicon). A total of 2697 alterations were identified in 451 genes (1154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) with a median of 4 (1-53) per case. In order of frequency, the 20 genes most often altered were: TP53, MDM2, CDK4, RB1, ATRX, CDKN2A, PTEN, NF1, CDKN2B, KMT2D, GLI1, ATM, TERT, PI3KCA, NOTCH1, MAP2K4, ERBB4, ARID1A, TSC2, and TNFAIP3. At least 1 targetable GA was found in 239 cases (41%) with a statistically significant higher number in other and complex genomics sarcomas than in translocation-related sarcomas (respectively other: n=89, 82%, complex: n = 131, 40%, translocation: n = 19, 13%; χ2 test, P < .001).

Conclusions and Relevance  Up to 41% of STS harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with STS.

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