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PSM

PSM Parallel Session

69: Detection and Concordance of Actionable Mutations in Solid Tumor and Circulating DNA Samples in Appendiceal Cancer

Thursday, March 21, 2024
2:02pm – 2:12pm ET
Location: C105-C106
Disclosure(s):
Sefali Patel, DO: No financial relationships to disclose
Introduction:

Circulating tumor DNA (ctDNA) has shown promise as a biomarker in appendiceal cancer (AC) and other peritoneal surface malignancies (PSM), in which conventional radiographic and serologic indicators of disease status are unreliable. ctDNA assays rely heavily on the concordant identification of patient-specific genomic variants in solid tumor and blood. In this study, we utilized a comprehensive genomic profiling pipeline to identify concordant variants in paired tumor and blood samples from patients undergoing treatment for AC. 


Methods:

AC patients (n=37) who consented to a pan-cancer circulating biomarker study at Allegheny Health Network Cancer Institute provided solid tumor and blood samples. Blood was collected in a membrane stabilizer, courier transported within 72 hours, separated via differential centrifugation, extracted with magnetic beads, and next-generation sequencing (NGS) was performed using the ct-TSO500 assay. NGS results from the solid tumor were compared to ctDNA. Clinical actionability of variants was determined using the OncoKB database at levels 1, 2, and R1. Variant yield and concordance were then assessed for correlation with clinical and pathologic factors. 


Results:

Of 1,894,528 positions interrogated, 1,132.1 +/- 90.7 variants per case were found, with 97.4% concordance between ctDNA and tumor. Coding oncogenic variants were 163.8 +/- 15.6 (95.5% concordance), and 6.6 +/- 1.8 were clinically actionable (79.1% concordance). Every patient had at least one oncogenic mutation; 18 (48.6%) had potential for pharmacotherapy. Correlation was noted between overall variants detected and disease volume (peritoneal carcinomatosis index/PCI, r2=0.22, p=0.013 on linear regression); while coding variant counts were correlated with low vs. high grade (mean, 173.25 vs 159.94, p=0.035) and intra-tumoral CD8 lymphocyte density (r2=0.18, p=0.024). Overall, the assay demonstrated 95.9% sensitivity and 99.9% specificity of detecting coding oncogenic variants.  


Conclusions:

In this study, we demonstrate the feasibility of an in-house NGS pathway to yield patient-specific ctDNA variants with high fidelity between solid and ctDNA for patients undergoing AC treatment at a high-volume center. We identified predictors of ctDNA variant yield in AC based on disease volume (PCI), tumor grade, and CD8+ lymphocyte infiltration. Future studies are underway to explore the utility of this pathway to inform patient-specific ctDNA assays as biomarkers of response to therapy, minimal residual disease, and disease recurrence in AC patients. 

 

Learning Objectives:

  • Upon completion participants will be able to understand our ctDNA and solid tumor sequencing pathway.
  • Upon completion participants will learn about the fidelity of the mutations captured in solid tumors versus ctDNA.
  • Upon completion participants will be able to recognize the differences in coding variant mutations with regards to histological grade, disease burden and CD8 infiltration into the tumor microenvironment.