Abstract PO5-13-05: Comparison of whole exome, whole transcriptome genomic profiling and targeted sequencing with 50-gene panels
Authors: Thakkar Snehal , Hall David , Hoag Jess , Flannery Cynthia , Therala Nishitha , Tharayanil Anson , Ortendahl Jesse , Carter Gebra Cuyun , Basu Gargi 
Published: May 2024

Abstract
Introduction
Genomic profiling to identify targetable genomic alterations is the standard of care in the management of advanced cancers, including breast cancer (BC), and is recommended by ASCO provisional clinical guidelines. Genomic panels of ≤50 genes are generally less expensive than larger panels but may miss targetable alterations. This study compared a comprehensive tumor-normal whole-exome, whole-transcriptome panel to four 50-gene panels. In addition, for triple-negative BC (TNBC), the budget impact of using a comprehensive panel versus 50-gene panels was estimated.
Methods
Gene lists derived from three commercially available 50-gene panels (A, B and C) and a customized pan-cancer gene panel list (D) were used. The genes listed on the custom panel were chosen by medical experts. Samples from BC patients that underwent OncoExTraTM testing from May 2018 through March 2023 were included. The OncoExTra assay uses tumor-normal whole exome and whole transcriptome sequencing to detect somatic single base substitutions, indels, copy number alterations, gene fusions and alternative transcripts. In this analysis, the focus was actionable biomarkers, defined as those with associated FDA-approved targeted therapies in any cancer type, those that made patients eligible for an active clinical trial, or those with evidence in guidelines or the literature for possible matched therapies in any cancer. The frequencies of patients who would have been missed (no actionable alterations identified) using only the genes on each 50-gene panel were summarized. It was assumed that any alteration involving a listed gene would be detected, maximizing the potential utility of each panel. For TNBC, the budget impact of shifting the 20% of patients currently tested with 50-gene panels to OncoExTra testing was estimated using a previously published model.
Results
A total of 2161 BC patient samples were included. Across all samples, between 11.9% and 28.1% of patients would have been missed by restricting to only 50 genes (Table 1). The proportion of missed patients across panels was highest in TNBC and lowest in HER2+ cancers. Major drivers of missed patients included absence of FGF3/4/19 (A-D), MAP3K1 (A-D), BRCA1/2 (A, B, C), CCND1 (B, C, D), and PTEN (A, D). Across the four panels, patients were missed due to actionable alterations in 96 to 126 genes. Tumor mutational burden and microsatellite instability, which are not reported in 50-gene panels, were high in 35 (1.6%) and 7 (0.3%) BC patient samples, respectively.
Within a 1-million-member plan, 44 TNBC patients would be eligible for testing. If all these patients were tested with OncoExtra rather than a 50-gene panel, the increase in per-member-per-month costs ranges from $0.0104-0.0172, driven predominantly by increased matched therapy costs. Between two and five TNBC patients would be eligible to receive a different treatment with a comprehensive panel.
Conclusions
In BC, between 11.9% and 28.1% of patients with actionable alterations would have been missed by restricting analysis to the 50 genes found in these panels. Using a comprehensive profiling assay such OncoExTra led to the identification of additional TNBC patients with actionable alterations at a minimal budget impact.
Table 1. BC patients (pts) with actionable alterations missed by each 50-gene panel. NS = subtype not specified.
Citation Format: Snehal Thakkar, David Hall, Jess Hoag, Cynthia Flannery, Nishitha Therala, Anson Tharayanil, Jesse Ortendahl, Gebra Cuyun Carter, Gargi Basu. Comparison of whole exome, whole transcriptome genomic profiling and targeted sequencing with 50-gene panels [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-05.