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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.

SUBMITTER: Hensley ML 

PROVIDER: S-EPMC7367750 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Genomic Landscape of Uterine Sarcomas Defined Through Prospective Clinical Sequencing.

Hensley Martee L ML   Chavan Shweta S SS   Solit David B DB   Murali Rajmohan R   Soslow Robert R   Chiang Sarah S   Jungbluth Achim A AA   Bandlamudi Chaitanya C   Srinivasan Preethi P   Tap William D WD   Rosenbaum Evan E   Taylor Barry S BS   Donoghue Mark T A MTA   Hyman David M DM  

Clinical cancer research : an official journal of the American Association for Cancer Research 20200416 14


<h4>Purpose</h4>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.<h4>Experimental design</h4>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  ...[more]

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