Genomic Landscape of Uterine Sarcomas Defined Through Prospective Clinical Sequencing.

Abstract

PURPOSE:

We examined whether prospective molecular characterization of advanced metastatic disease can reveal grade and/or histology-specific differences to inform diagnosis and facilitate enrollment onto clinical trials.

EXPERIMENTAL DESIGN:

Patients with uterine sarcoma consented to a prospective study of next-generation sequencing (NGS). Clinical annotations were extracted from their medical record. Tumor and matched normal DNA were subjected to NGS, and the genomic landscape was explored for survival correlations and therapeutic targetability.

RESULTS:

Tumors from 107 women were sequenced and included leiomyosarcoma (n = 80), high-grade non-leiomyosarcoma (n = 22), low-grade endometrial stromal sarcoma (LG-ESS, n = 4), and smooth muscle tumor of uncertain malignant potential (STUMP, n = 2). Genomic profiling influenced histologic diagnosis in three cases. Common uterine leiomyosarcoma alterations were loss-of-function mutations in TP53 (56%), RB1 (51%), and ATRX (31%). Homozygous deletions of BRCA2 were present in 5% of these patients. PTEN alteration frequency was higher in the metastases samples as compared with the primary samples. Genomes of low-grade tumors were largely silent, while 50.5% of high-grade tumors had whole-genome duplication. Two metastatic uterine leiomyosarcoma cases were hypermutated. Both had prolonged disease-free survival. Potentially actionable mutations were identified in 48 patients (45%), 8 (17%) of whom received matched therapy with 2 achieving clinical responses. Among patients with uterine leiomyosarcoma with somatic BRCA2 alterations, sustained partial responses were observed with PARP inhibitor-containing therapy.

DISCUSSION:

Prospective genomic profiling can contribute to diagnostic precision and inform treatment selection in patients with uterine sarcomas. There was evidence of clinical benefit in patients with uterine leiomyosarcoma with somatic BRCA2 alterations treated with PARP inhibitors.

• Authors: Martee L Hensley, Shweta S Chavan, David B Solit, Rajmohan Murali, Robert Soslow, Sarah Chiang, Achim A Jungbluth, Chaitanya Bandlamudi, Preethi Srinivasan, William D Tap, Evan Rosenbaum, Barry S Taylor, Mark T A Donoghue, David M Hyman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 14 Pg. 3881-3888 (07 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32299819 (Publication Type: Journal Article, Observational Study, Research Support, N.I.H., Extramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• BRCA2 Protein
• BRCA2 protein, human
• Biomarkers, Tumor
• Poly(ADP-ribose) Polymerase Inhibitors
• RB1 protein, human
• Retinoblastoma Binding Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Ubiquitin-Protein Ligases
• PTEN Phosphohydrolase
• PTEN protein, human
• ATRX protein, human
• X-linked Nuclear Protein

Topics

• Adolescent
• Adult
• BRCA2 Protein (genetics)
• Biomarkers, Tumor (genetics)
• Child
• DNA Mutational Analysis
• Female
• Gene Deletion
• High-Throughput Nucleotide Sequencing
• Humans
• Loss of Function Mutation
• Middle Aged
• PTEN Phosphohydrolase (genetics)
• Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use)
• Precision Medicine (methods)
• Prospective Studies
• Retinoblastoma Binding Proteins (genetics)
• Sarcoma (drug therapy, genetics, pathology)
• Tumor Suppressor Protein p53 (genetics)
• Ubiquitin-Protein Ligases (genetics)
• Uterine Neoplasms (drug therapy, genetics, pathology)
• X-linked Nuclear Protein (genetics)
• Young Adult