Potential therapeutic genomic alterations in desmoplastic small round blue cell tumor.

Abstract

11066 Background: Desmoplastic Small Round Blue Cell Tumor (DSRCT) originates from a cell with multilineage potential. A molecular hallmark of DSCRT is the EWS-WT1 reciprocal translocation. Ewing’s and DSRCT are treated similarly due to similar oncogene activation pathways and DSRCT has been represented in very limited numbers in sarcoma studies. Methods: Thirty-five DSRCT tumors were tested with a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Specific tests performed included sequencing (NextGen), protein expression (IHC) and gene amplification (CISH or FISH). Tumor mutational load (TML) was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Molecular alterations were compared to 88 Ewing sarcomas (ES). Chi-square tests were used for comparison and statistical significance was determined as p < 0.05. Results: In the 35 DSRCT tumors, high expression of TOP2A were seen in 63%, TOPO1 in 63%, PTEN in 62%, androgen receptor (AR) in 59%, EGFR in 42% of tumors; low expression of TUBB3 was seen in 44%, MGMT in 45%, TS in 48%, RRM1 in 57% and ERCC1 in 76% of tumors. When compared to ES, no significant difference was seen in protein expressions with the exception of a significantly higher overexpressson of AR in DSRCT (59% vs. 3%, p = 1.7E-10) and TUBB3 (56% vs. 29%, p = 0.03). Tumor expression of PD-L1 (Ab: SP142) was not seen in the 4 DSRCT and 10 ES tested. NextGen revealed a TP53 mutation (7%) and a FOXO3 mutation (L382fs) in DSCRT, while 6 TP53 mutations (13%), 2 APC mutations (L1129S and I1307K), 1 BRCA1(c.301+1G > A) and 1 CTNNB1 (T41A) mutation were identified in ES. Tumor mutational load evaluated in the 3 DSRCT and 11 ES tumors averaged 6 and 5 mutations per megabase, respectively. Conclusions: Molecular profiling on 35 DSRCT tumors and comparison with Ewing’s sarcoma revealed low immunogenicity ( < 10 Mutations/MB) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more effective in Ewing’s sarcoma compared to DSCRT based on TUBB3 expression. Genomic and Molecular assessment may help determine the ideal regimen that will help achieve maximal tumor debulking.

Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations

“…Molecular profiling on 35 DSRCTs sampled from patients having surgery for DSRCT (Caris Life Sciences, Phoenix, AZ) that were compared with Ewing sarcoma revealed low immunogenicity (<10 mutations/Mb) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more effective in Ewing sarcoma compared to DSRCT based on TUBB3 expression [ 43 ]. Given the male predominance of this subset of disease, it is not surprising that, when compared to Ewing sarcoma, no significant difference was seen in protein expressions with the exception of a significantly higher overexpression of AR in DSRCT (59% versus 3%, p =1.7E-10) and TUBB3 (56% versus 29%, p =0.03) [ 43 ].…”

“…A phase II study (SARC028) is evaluating the role of pembrolizumab across various sarcoma histologies ( NCT02301039 ) [ 47 ]. None of the patients in a recently reported DSRCT cohort had identifiable tumoral PD-L1 expression by SP142 antibody testing, and the significance of PD-1-positive TILs is unclear at this time [ 43 ]. The composite of tumoral PD-L1 positivity and PD-1 positivity among tumor-infiltrating lymphocytes has been suggested as an indicator of prognosis in soft tissue sarcoma patients [ 45 ].…”

Value-based genomics

“…Not surprisingly, genome sequencing is undergoing widespread implementation into routine cancer patient care ( Supplementary Table 1 ). Molecular profiling is now incorporated into standard practice guidelines recommended by the NCCN while offering research value through facilitating the investigation of potential biomarkers of interest in breast [ 102 – 110 ], colorectal [ 111 – 115 ], gastroesophageal [ 116 – 122 ], hepatobiliary [ 123 – 127 ], pancreatic [ 128 – 130 ], gynecologic [ 131 – 143 ], prostate [ 144 – 152 ], other genitourinary (kidney, germ cell, and bladder) [ 153 – 166 ], lung [ 167 – 179 ], head and neck [ 180 – 187 ], melanoma [ 188 – 194 ], soft tissue sarcomas [ 195 – 204 ], and central nervous system cancers [ 205 – 212 ].…”

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy

“…However, one important molecular aberration that distinguishes DSRCT from ES is the increased Androgen Receptor (AR) expression. In a comprehensive analysis of 35 patients [20] with diagnosis of DSRCT using next-generation sequencing, immunohistochemistry and gene amplification tests it was found that the most common alterations that distinguished DSRCTs from ES included higher expression of AR, TUBB3, EGFR, and TOPO2A expression. Independent analysis using RNAseq confirmed higher AR expression from an independent data set of EWS-WT1 fusion-positive DSRCTs compared with ES and a pan-cancer analysis [20].…”