Genomic Landscape of Uterine Sarcomas Defined Through Prospective Clinical Sequencing.

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 2021;26(14):3881-3888

PMID: 32299819

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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 ( = 80), high-grade non-leiomyosarcoma ( = 22), low-grade endometrial stromal sarcoma (LG-ESS, = 4), and smooth muscle tumor of uncertain malignant potential (STUMP, = 2). Genomic profiling influenced histologic diagnosis in three cases. Common uterine leiomyosarcoma alterations were loss-of-function mutations in (56%), (51%), and (31%). Homozygous deletions of were present in 5% of these patients. 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 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 alterations treated with PARP inhibitors.

Address: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected].; Weill Cornell Medical College, New York, New York.; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

DOI: 10.1158/1078-0432.CCR-19-3959