Personalis at AMP 2020 Annual Meeting

Abstract Presentation

Sebastian Saldivar

Tuesday, November 17, 2020, 1:00 PM – 2:00 PM Eastern | Online

Title: An Exome- and Transcriptome-Based NeXT Dx Test Enables Therapy Selection for Cancer Patients and Offers Insight into Emerging Composite Biomarkers for Immunotherapy

Location: Online
Abstract Number: ST18
Presenter: Sebastian Saldivar

Introduction: Diagnostic biomarkers that consistently predict patient response to immunotherapies have remained elusive in spite of increased use of these treatments. There is an unmet need for the development of integrative, composite biomarkers that can model the complex biology driving response and/or resistance to immunotherapy more effectively than existing single-analyte approaches. However, many of the current cancer diagnostic panels, with their focus on a small set of genes, have limited scope and variability in tumor mutational burden (TMB) assessments for certain cancer types, and limited utility to support emerging composite biomarkers.

Methods: To address these limitations, we developed and validated NeXT Dx, a comprehensive whole exome and transcriptome based diagnostic test designed to simultaneously characterize tumor and immune genomics from a single limited formalin fixed, paraffin-embedded (FFPE) sample. We developed an augmented exome assay that improves uniformity of coverage across all ~20,000 genes, including boosted coverage of 248 cancer related genes. TMB was calculated using gold-standard whole exome data from non-synonymous variants (SNVs and indels). We validated this assay using tumor derived cell-lines, constructs, clinical FFPE samples, and proficiency testing samples. The test requires >4 FFPE slides to co-extract DNA and RNA which were sequenced using Illumina NovaSeq instruments at our CAP accredited, CLIA-certified laboratory. Additional assay enhancements for HLA, immune repertoire, and oncoviruses were designed to further optimize the platform for immunotherapy biomarker discovery applications.

Results: Validation of NeXT Dx demonstrated overall >99% specificity for all DNA variant types and 99.5% sensitivity for SNVs at ≥5% AF; 98.7% sensitivity for indels at ≥10% AF; 97.2% sensitivity for CNAs in samples with ≥30% tumor content for 248 genes footprint; and a 97.9% concordance rate for MSI compared to IHC/PCR. RNA fusion testing showed a 94.9% sensitivity and specificity. Typical median coverage depth was >1,000X for 248 cancer related genes, and ~300X for the remaining (whole exome) footprint.

Conclusions: We have developed an efficient, cost-effective and highly accurate NeXT Dx test that reports clinically actionable variants present in 248 cancer related genes and exomewide TMB for standard of care treatment selection. Additionally, whole-exome and transcriptome data offer an opportunity to further research novel biomarkers which may enable improved stratification of patient response to immunotherapies for all cancer types.