BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma

Author:

Seligson Nathan D.12,Kautto Esko A.3,Passen Edward N.4,Stets Colin4,Toland Amanda E.5,Millis Sherri Z.6,Meyer Christian F.7,Hays John L.89,Chen James L.48

Affiliation:

1. Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

2. Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA

3. Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA

4. Division of Bioinformatics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, USA

5. Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, Ohio, USA

6. Foundation Medicine Inc., Cambridge, Massachusetts, USA

7. Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

8. Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA

9. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, Columbus, Ohio, USA

Abstract

Abstract Background Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). Materials and Methods DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. Results In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. Conclusion HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS.

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3