DNA damage response pathway alterations and clinical outcome in leiomyosarcoma.

Abstract

11048 Background: Leiomyosarcoma (LMS) is a complex karyotype sarcoma with frequent alterations in the homologous recombination (HR) pathway. Genomically unstable tumors with DNA damage repair (DDR) deficiencies may have improved responses to DNA damaging therapies, such as cytotoxic chemotherapy or PARP inhibitors. Methods: We retrospectively reviewed LMS patients treated at MSKCC who had targeted somatic DNA sequencing (MSK-IMPACT) performed on tumor tissue. 33 DDR genes, including 16 HR genes, were analyzed for oncogenic alterations. A composite HR deficiency (HRD) score measured tumor genomic scarring for each patient. To determine if DDR alteration status is prognostic of outcome, we analyzed the recurrence-free survival (RFS) of patients who underwent complete resection, and the overall survival (OS) of the whole cohort. Results: 211 patients had IMPACT testing between March 2014 and October 2018; 48% of samples were primary tumors and 52% recurrent/metastatic sites. Among soft tissue LMS (stLMS), there were 35 men and 55 women. 20% of patients had an oncogenic DDR gene alteration, 72% of which were in the HR pathway (table below). Uterine LMS (uLMS) had more DDR alterations than stLMS, though not statistically significant (p = 0.084). BRCA2 (n = 14 cases), RAD51B (8), and ERCC5 (4) were most frequently altered. HRD score significantly correlated with HRD alteration status (p = 0.004). DDR or HRD altered status and HRD score were associated with shorter RFS in patients with resectable disease, independent of age (p < 0.05). Median OS for the cohort was 75 months (95% CI: 64 – 84). Men with stLMS had shorter OS compared to women (p = 0.025). OS did not significantly differ based on DDR or HRD status (p > 0.05). Conclusions: One-fifth of LMS patients have one or more oncogenic somatic alterations in the DDR pathway, predominantly in effectors of HR. DDR status may be prognostic of recurrence risk. Further analyses to determine the association between DDR status and response to cytotoxic chemotherapy are ongoing. [Table: see text]