Abstract 1754: Test-the-test: Clinical utility of comprehensive whole exome sequencing (WES) and RNA-seq for lymphoma patients
Authors: Dai Chihara, Kumudha Balakrishnan, Gita Masand, Anna Novokreshchenova, Alexander Bagaev, Nikita Kotlov, Ekaterina Postovalova, Eduardo Shugaev-Mendosa, Yuliya Gracheva, Anna Love, Krystle Nomie, Nathan Fowler, Christopher R. Flowers, Jason Westin
Journal: Cancer Research (2024)

Abstract Background: Due to the rapidly evolving landscape of targeted therapies, there is an unmet need for comprehensive molecular profiling to guide treatment decisions for patients with lymphoma. To meet this need, we designed a pilot study to assess the feasibility and turnaround time (TAT) of a comprehensive WES and whole transcriptome sequencing (RNA-seq) assay (BostonGene Tumor PortraitTM test) in large B-cell lymphoma (LBCL) patients for clinical decision-making (NCT05464823). Design: Patients aged ≥18 years with histologically documented LBCL requiring therapy were eligible. Formalin-fixed paraffin-embedded tissues underwent WES, RNA-seq, and copy number analysis (CNA) with concomitant peripheral blood or saliva for germline DNA sequencing. Samples with &amp;lt;20% tumor purity and median coverage of &amp;lt;142x for tumor and/or &amp;lt;95x for normal samples were labeled as quantity not sufficient (QNS). Genomic and transcriptomic data were profiled to uncover clinically relevant biomarkers and match patients with clinical trials on ClinicalTrials.gov. Results: To date, 63 patients received WES and RNA-seq, with 45 full Tumor PortraitTM test clinical reports delivered and 3 partial reports for QNS samples. Cell of origin (COO, n = 41), LymphGen (n = 41), and lymphoma microenvironment (LME, n = 42) classifications were applied. The median TAT was 8 days for advanced reports, and 76% of reports had a TAT ≤9 days. WES identified frequent TP53 (n = 13) and CDK2NA (n = 5) alterations. COOs were designated as activated (n = 16, 39%) or germinal center (n = 25, 61%) LBCL. The LymphGen classifier showed the EZB MYC- (n = 9, 22%), A53 (n = 6, 15%), and MCD (n = 6, 15%) subtypes as the most prevalent. LME classification revealed most LMEs as mesenchymal (n = 30, 71%). Immune-depleted (n = 7, 17%), immune-inflamed (n = 4, 10%), and germinal center-like (n = 1, 2%) LMEs were less prevalent, but the immune-depleted LME was more common in patients with relapse. Clinically significant findings, such as ABC COO (n = 16), TP53 loss (n = 13), DHITsig+ (n = 6), and CARD11 mutations associated with ibrutinib resistance (n = 3), were identified in 33 samples. On average, 8 clinical trials were identified per delivered report. Conclusion: Our results show the clinical utility and acceptable TAT of using a comprehensive WES and RNA-seq assay on a cohort of lymphoma patients. The produced BostonGene Tumor PortraitTM test reports included findings on significant alterations, LymphGen and LME subtypes, COOs, and potential clinical trial matches. These robust findings, coupled with the rapid TAT, demonstrate the feasibility of using integrated WES and RNA-seq to guide clinical decision-making in lymphoma patients. Citation Format: Dai Chihara, Kumudha Balakrishnan, Gita Masand, Anna Novokreshchenova, Alexander Bagaev, Nikita Kotlov, Ekaterina Postovalova, Eduardo Shugaev-Mendosa, Yuliya Gracheva, Anna Love, Krystle Nomie, Nathan Fowler, Christopher R. Flowers, Jason Westin. Test-the-test: Clinical utility of comprehensive whole exome sequencing (WES) and RNA-seq for lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1754.