BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma

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. Implications for Practice Soft‐tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP‐ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

“…The recurrent onco-suppressors genes involved in uLMS including BRCA2 , coupled with the frequent inactivation of genes implicated in DNA damage and homologous recombination repair, further depict this disease as a tumor with defects in proper DNA repair and reinforce the role of PARP inhibitors in the treatment of uLMS [ 31 ]. Indeed, Seligson and coworkers have already shown that HRR pathway alterations are enriched in uLMS by means of BRCA2 loss and that PARP inhibitors demonstrated durable clinical benefit in uLMS patients with BRCA2 inactivation [ 32 ]. Furthermore, Hensley et al reported clinical benefit in all five BRCA2 -mutant uLMS patients treated with PARP inhibitors, further supporting the potential actionability of HRR alterations in uterine leiomyosarcoma [ 19 ].…”

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

“…Data from The Cancer Genome Atlas (TCGA) , including 57 patients with DDLPS who were part of the soft tissue sarcoma cohort, were downloaded from the Genomics Data Commons (https://gdc.cancer.gov/). Sequencing data overlapping the MDM2 or GAPDH regions of the genome were selected as previously described . MDM2 amplification was determined by quantifying the ratio of the uniquely mapped reads for MDM2 region (tumor tissue) to the uniquely mapped reads of GAPDH region (tumor tissue) per patient.…”

Identifying Opportunities and Challenges for Patients With Sarcoma as a Result of Comprehensive Genomic Profiling of Sarcoma Specimens

“… 17 A developing example would be that in leiomyosarcoma, where we have previously reported that homologous recombination alterations are a common feature of uterine leiomyosarcomas and may be amenable to PARP inhibition. 18 …”