Dataset Information

BESPOKE Study of ctDNA Guided Immunotherapy

ABSTRACT: This is a prospective data collection study of patients with advanced solid tumors who will receive standard of care immunotherapy (IO) and will be monitored with SIGNATERA testing. SIGNATERA test will be performed at baseline and during routine care. The test results will be part of assessing tumor response. The correlation between SIGNATERA test results and subsequent treatment decisions will be examined to compare actual treatment delivered against treatment decisions potentially impacted by SIGNATERA results. Treatment administered, tumor assessment results, time to progression, overall survival, physician questionnaires, and patient-reported outcomes will be collected/recorded.

DISEASE(S): Melanoma,Colorectal Cancer,Non-small Cell Lung Cancer,Colorectal Neoplasms,Carcinoma, Non-small-cell Lung

PROVIDER: 2367927 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background & Aims: Patients with beta-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) have demonstrated limited clinical benefit to first-line immunotherapy (IO). Animal models of HCC expressing mutant-beta-catenin and additional aberrations via hydrodynamic tail vein injection with sleeping beauty transposon/transposase (SB-HDTVI) represent clinically relevant human HCC subsets. Here, we perform transcriptomic analysis on multiple beta-catenin-mutated and non-mutated HCC animal models to identify Mutated beta-catenin Gene Signature (MBGS) for HCC patient stratification for CTNNB1-mutations and IO response. Methods: We co-expressed in mice mutant-NFE2L2 and hMET +- mutant-CTNNB1 via SB-HDTVI and monitored for HCC development. Bulk RNA-sequencing was assessed for transcriptional differences between various beta-catenin-mutated and non-mutated models. MBGS was generated for predictive ability of CTNNB1 mutations and IO resistance in multiple HCC patient cohorts. Results: Co-expression of S45Y-beta-catenin + G31A-NFE2L2 + hMet (beta-N-M) resulted in HCC development by 4.5 weeks while co-expression of G31A-NFE2L2 + hMet (N-M) led to HCC by 14 weeks with tumors being positive for expected targets by immunohistochemistry (IHC). Bulk RNA-sequencing comparing beta-catenin-driven versus non-beta-catenin driven models yielded 95 common upregulated genes. Differential gene expression analysis of the common genes comparing CTNNB1-mutated vs non-mutated TCGA patients narrowed the gene panel to 13-(or 10-) genes. This MBGS predicted CTNNB1-mutation status in TCGA (n=374) and French (n=398) patient cohorts (with ROC AUC of 0.90 and 0.94). High MBGS expression was also associated with no overall and progression-free survival benefit when comparing atezolizumab + bevacizumab versus sorafenib arms in IMbrave150 cohort implying fewer treatment effects. Conclusions: In an era of patient molecular stratification for HCC, MBGS may aid in optimally selecting patients for IO through diagnosis of a molecular subset which lacks optimal response.

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BESPOKE Study of ctDNA Guided Immunotherapy

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