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.

Figure 1.

A) Composition of the MSK uterine sarcoma cohort by histology, grade, and stage. B) Distribution of the biopsied primary and metastatic disease sites and sample numbers in the cohort. C) Overall survival of high grade uterine sarcoma cohort split by leiomyosarcoma (LMS) and high-grade non-leiomyosarcoma (HG non-LMS).

Figure 2.

A) Oncoprint of genomic alterations in the cohort split by histology. Alterations represented were selected by the following criteria: 1) All actionable alterations (OncoKB); 2) All genes with oncogenic alterations (OncoKB) in at least 5% of cases; 3) An alteration type in a given gene was found to be most frequent in uterine sarcomas when compared to the contemporary MSK-IMPACT clinical series cohort of prospectively sequenced cancers (n=15816). B) Frequency of PDCD1 homozygous deletions in the MSK-IMPACT clinical sequencing cohort compared to other cancer types with at least 25 cases and 1% altered cases. C) and D) Frequency of MAP2K4 and RIT1 amplifications in the MSK-IMPACT clinical sequencing cohort compared to other cancer types with at least 25 cases and 1% altered cases.

Figure 3.

A) Comparison of genomic alterations across MSK uterine-LMS, MSK non-uterine LMS, and TCGA uterine-LMS. B) All clinically actionable alterations identified via MSK-IMPACT or MSK-Fusion, split by OncoKB levels of evidence.