Functional Loss Defines a Targetable Subset in Leiomyosarcoma.

Background: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for 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 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition.

Results: In an unselected STS study population, alterations were identified in 15 (1%) patients, and homozygous loss was detected in 9 (<1%). However, subset analysis revealed that these alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with loss.

Conclusion: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for 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 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 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and 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 alterations and may benefit from treatment targeted to these alterations.