Comprehensive Genomic and Transcriptomic Analysis to Guide Therapy for Patients with Metastatic Solid Tumors
Authors
Burak Uzunparmak¹, Fei Su¹, Amber M. Johnson¹, Krystle Nomie², Lile Kontselidze², Alexander Bagaev², Ecaterina E. Dumbrava¹, Jordi Rodon-Ahnert¹, Siqing Fu¹, David S. Hong¹, Timothy A. Yap¹, Aung Naing¹, Sarina A. Piha-Paul¹, Daniel D. Karp¹, Paula R. Pohlmann¹, Apostolia M. Tsimberidou¹, Keyur P. Patel¹, Funda Meric-Bernstam¹
- The University of Texas MD Anderson Cancer Center, Houston, TX, US
- BostonGene, Corp., Waltham, MA, US
Abstract
Introduction: Precision oncology which aims to profile tumors for identifying actionable alterations to guide therapy is rapidly developing and has become mainstream in cancer clinics. While most approaches focus on DNA abnormalities on targeted panels, not all patients’ tumors exhibit targetable genomic alterations in these limited gene sets, indicating a need for more comprehensive methodologies combining whole genome (WES) and whole transcriptome sequencing (RNAseq) to direct a larger fraction of patients to therapies. Here, we aimed to compare the feasibility and utility of a comprehensive analytical platform with WES and RNAseq, BostonGene (BG), to two targeted exome panels in identifying actionable alterations and therapy selection for patients with metastatic solid tumors.
Methods: Study enrolled patients with solid tumors who have had next-generation-sequencing (NGS) testing with one of two tissue-based targeted exome sequencing panels, Oncomine (ThermoFisher, 148 genes), or MDA-MAPP (615 genes) with identification of no College of American Pathologists Tier-1 actionable DNA alterations between August 2022 and November 2023. Patients’ tissue and blood/saliva samples were subjected to BG’s NGS platform. An alteration-level actionability analysis was performed upon receipt of NGS results to inform treatment decision making, based on functional and therapeutic effects of the alterations detected.
Results: A total of 64 patients were enrolled; testing was cancelled for 7 patients (10.9%) with specimens showing <10% tumor cellularity, while 5 patients’ reports were pending at the time of data analysis. Median turn-around time from consent to sample acquisition (SA) and from SA to available genomic profile were 5.5 and 20.5 days, respectively. 52 patients had NGS results representing a diverse group of tumor types, including sarcoma (n=11, 21.2%), head and neck (n=9, 17.3%) and mesothelioma (n=5, 9.6%). In 94.2% (49/52) of patients, BG identified additional DNA alterations (mean: 3.75; median: 4) not shown by prior testing, whereby the most common alteration types included SNVs (43.1%), deletions (23.6%) and amplifications (11.8%). BG identified additional tier 1 actionable DNA alterations (referred to as “AAs”; mean: 1.9, median: 2) in 32 (61.5%) patients, whereby majority of AAs were deletions (59.7%) and amplifications (27.4%). BG detected AAs in 58.8% (10/17) vs 62.9% (22/35) of patients for whom the same vs different samples were used across different tests compared (P=0.8). Of 32 patients with AAs, 7 (21.9%) were subsequently directed to DNA-informed treatments within 6 months based upon the new genomic findings reported by BG, 14 (43.8%) are being followed for treatment matching, while 11 (34.4%) were deceased.
Discussion: Our results show the feasibility and utility of comprehensive molecular profiling to match patients to WES-informed treatments within a clinically relevant time frame. The high rate of additional actionable findings suggest comprehensive testing may offer benefit over traditional targeted panels in solid tumor patients. Larger prospective validation studies to confirm clinical utility are planned.
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Methods: Study enrolled patients with solid tumors who have had next-generation-sequencing (NGS) testing with one of two tissue-based targeted exome sequencing panels, Oncomine (ThermoFisher, 148 genes), or MDA-MAPP (615 genes) with identification of no College of American Pathologists Tier-1 actionable DNA alterations between August 2022 and November 2023. Patients’ tissue and blood/saliva samples were subjected to BG’s NGS platform. An alteration-level actionability analysis was performed upon receipt of NGS results to inform treatment decision making, based on functional and therapeutic effects of the alterations detected.
Results: A total of 64 patients were enrolled; testing was cancelled for 7 patients (10.9%) with specimens showing <10% tumor cellularity, while 5 patients’ reports were pending at the time of data analysis. Median turn-around time from consent to sample acquisition (SA) and from SA to available genomic profile were 5.5 and 20.5 days, respectively. 52 patients had NGS results representing a diverse group of tumor types, including sarcoma (n=11, 21.2%), head and neck (n=9, 17.3%) and mesothelioma (n=5, 9.6%). In 94.2% (49/52) of patients, BG identified additional DNA alterations (mean: 3.75; median: 4) not shown by prior testing, whereby the most common alteration types included SNVs (43.1%), deletions (23.6%) and amplifications (11.8%). BG identified additional tier 1 actionable DNA alterations (referred to as “AAs”; mean: 1.9, median: 2) in 32 (61.5%) patients, whereby majority of AAs were deletions (59.7%) and amplifications (27.4%). BG detected AAs in 58.8% (10/17) vs 62.9% (22/35) of patients for whom the same vs different samples were used across different tests compared (P=0.8). Of 32 patients with AAs, 7 (21.9%) were subsequently directed to DNA-informed treatments within 6 months based upon the new genomic findings reported by BG, 14 (43.8%) are being followed for treatment matching, while 11 (34.4%) were deceased.
Discussion: Our results show the feasibility and utility of comprehensive molecular profiling to match patients to WES-informed treatments within a clinically relevant time frame. The high rate of additional actionable findings suggest comprehensive testing may offer benefit over traditional targeted panels in solid tumor patients. Larger prospective validation studies to confirm clinical utility are planned.
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