Development and validation of a multigene variant profiling assay to guide targeted and immuno therapy selection in solid tumors

Dadasaheb Akolkar; Darshana Patil; Navin Srivastava; Revati Patil; Vineet Datta; Sachin Apurwa; Nitin Yashwante; Raja Dhasarathan; Rahul Gosavi; Jinumary John; Shabishta Khan; Ninad Jadhav; Priti Mene; Dhanashri Ahire; Sushant Pawar; Harshal Bodke; Subhraline Sahoo; Arun Nile; Dinesh Saindane; Harshal Darokar; Pradip Devhare; Ajay Srinivasan; Rajan Datar

doi:10.1371/journal.pone.0246048

Development and validation of a multigene variant profiling assay to guide targeted and immuno therapy selection in solid tumors

PLoS One. 2021 Feb 8;16(2):e0246048. doi: 10.1371/journal.pone.0246048. eCollection 2021.

Authors

Dadasaheb Akolkar¹, Darshana Patil¹, Navin Srivastava¹, Revati Patil¹, Vineet Datta¹, Sachin Apurwa¹, Nitin Yashwante¹, Raja Dhasarathan¹, Rahul Gosavi¹, Jinumary John¹, Shabishta Khan¹, Ninad Jadhav¹, Priti Mene¹, Dhanashri Ahire¹, Sushant Pawar¹, Harshal Bodke¹, Subhraline Sahoo¹, Arun Nile¹, Dinesh Saindane¹, Harshal Darokar¹, Pradip Devhare¹, Ajay Srinivasan¹, Rajan Datar¹

Affiliation

¹ Datar Cancer Genetics, Nashik, Maharashtra, India.

Abstract

We present data on analytical validation of the multigene variant profiling assay (CellDx) to provide actionable indications for selection of targeted and immune checkpoint inhibitor (ICI) therapy in solid tumors. CellDx includes Next Generation Sequencing (NGS) profiling of gene variants in a targeted 452-gene panel as well as status of total Tumor Mutation Burden (TMB), Microsatellite instability (MSI), Mismatch Repair (MMR) and Programmed Cell Death-Ligand 1 (PD-L1) respectively. Validation parameters included accuracy, sensitivity, specificity and reproducibility for detection of Single Nucleotide Alterations (SNAs), Copy Number Alterations (CNAs), Insertions and Deletions (Indels), Gene fusions, MSI and PDL1. Cumulative analytical sensitivity and specificity of the assay were 99.03 (95% CI: 96.54-99.88) and 99.23% (95% CI: 98.54% - 99.65%) respectively with 99.20% overall Accuracy (95% CI: 98.57% - 99.60%) and 99.7% Precision based on evaluation of 116 reference samples. The clinical performance of CellDx was evaluated in a subsequent analysis of 299 clinical samples where 861 unique mutations were detected of which 791 were oncogenic and 47 were actionable. Indications in MMR, MSI and TMB for selection of ICI therapies were also detected in the clinical samples. The high specificity, sensitivity, accuracy and reproducibility of the CellDx assay is suitable for clinical application for guiding selection of targeted and immunotherapy agents in patients with solid organ tumors.

Publication types

Validation Study

MeSH terms

Genetic Variation / genetics*
High-Throughput Nucleotide Sequencing*
Humans
Immunotherapy*
Limit of Detection
Molecular Targeted Therapy*
Multigene Family / genetics*
Mutation
Neoplasms / genetics*
Neoplasms / immunology
Neoplasms / therapy*

Grants and funding

All author except RD2 are employees of the DCG, which is the Funding Institution and has commercial interests. The funding institution provided support in the form of salaries for authors [DA1, DP, NS, RP, VD, SA, NY, RD1, SK, NJ, PM, DA2, SP, HB, SS, AN, DS, PD, AS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.