No-cost next generation sequencing of advanced cancer patients within the Strata Precision Oncology Network supports clinical trial enrollment.

3073 Background: Widespread integration of systematized next generation sequencing (NGS)-based precision oncology is hindered by numerous barriers. Hence, we developed the Strata trial (NCT03061305), a screening protocol to determine the impact of scaled precision oncology. Methods: We implemented no-cost NGS on formalin fixed paraffin embedded (FFPE) clinical samples for all patients with advanced tumors, a common portfolio of partnered therapeutic clinical trials, and robust infrastructure development across the Strata Precision Oncology Network. Results: Across the network of 17 centers, specimens from 8673/9222 (94%) patients were successfully tested in the Strata CLIA/CAP/NCI-MATCH accredited laboratory using comprehensive amplicon-based DNA and RNA NGS. Patients were tested with one of three StrataNGS test versions; the most recent panel assesses all classes of actionable alterations (mutations, copy number alterations, gene fusions, microsatellite instability, tumor mutation burden and PD-L1 expression). Median surface area of received FFPE tumor samples was 25mm2 (interquartile range 9-95mm2), and the median turnaround time from sample receipt to report was 6 business days. 2577 (27.9%) patients had highly actionable alterations, defined as alterations associated with within-cancer type FDA approved or NCCN guideline recommended therapies (1072 patients), NCI-MATCH trial arms (1467 patients), Strata-partnered therapeutic trials (327 patients), or specific alteration-matched FDA approved therapies in patients with cancers of unknown primary (71 patients). Of the 1467 patients matched to an NCI-MATCH trial arm, 15 enrolled. Of the 327 patients matched to one of nine Strata-partnered clinical trials, 77 (24%) were screen failures, while 250 (76%) have either enrolled or are being actively followed for enrollment upon progression. Conclusions: Through streamlined consent methods, electronic medical record queries, and high throughput laboratory testing at no cost to patients, we demonstrate that scaled precision oncology is feasible across a diverse network of healthcare systems when paired with access to relevant clinical trials. Clinical trial information: NCT03061305.

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PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.685 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii164-ii164

Author(s):

Mary Jane Lim-Fat ◽

Gilbert Youssef ◽

Mehdi Touat ◽

Bryan Iorgulescu ◽

Eleanor Woodward ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Immune Checkpoint Blockade ◽

Next Generation ◽

Single Nucleotide Variants ◽

Dana Farber Cancer Institute ◽

Clinical Records ◽

Ngs Data ◽

Generation Sequencing

Abstract BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

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GeneMed: An Informatics Hub for the Coordination of Next-Generation Sequencing Studies that Support Precision Oncology Clinical Trials

Cancer Informatics ◽

10.4137/cin.s17282 ◽

2015 ◽

Vol 14s2 ◽

pp. CIN.S17282 ◽

Cited By ~ 7

Author(s):

Yingdong Zhao ◽

Eric C. Polley ◽

Ming-Chung Li ◽

Chih-Jian Lih ◽

Alida Palmisano ◽

...

Keyword(s):

Clinical Trial ◽

Next Generation Sequencing ◽

Treatment Selection ◽

Control Treatment ◽

Precision Oncology ◽

Next Generation ◽

Multiple Cancer ◽

Randomized Design ◽

Sequencing Studies ◽

Generation Sequencing

We have developed an informatics system, GeneMed, for the National Cancer Institute (NCI) molecular profiling-based assignment of cancer therapy (MPACT) clinical trial (NCT01827384) being conducted in the National Institutes of Health (NIH) Clinical Center. This trial is one of the first to use a randomized design to examine whether assigning treatment based on genomic tumor screening can improve the rate and duration of response in patients with advanced solid tumors. An analytically validated next-generation sequencing (NGS) assay is applied to DNA from patients’ tumors to identify mutations in a panel of genes that are thought likely to affect the utility of targeted therapies available for use in the clinical trial. The patients are randomized to a treatment selected to target a somatic mutation in the tumor or with a control treatment. The GeneMed system streamlines the workflow of the clinical trial and serves as a communications hub among the sequencing lab, the treatment selection team, and clinical personnel. It automates the annotation of the genomic variants identified by sequencing, predicts the functional impact of mutations, identifies the actionable mutations, and facilitates quality control by the molecular characterization lab in the review of variants. The GeneMed system collects baseline information about the patients from the clinic team to determine eligibility for the panel of drugs available. The system performs randomized treatment assignments under the oversight of a supervising treatment selection team and generates a patient report containing detected genomic alterations. NCI is planning to expand the MPACT trial to multiple cancer centers soon. In summary, the GeneMed system has been proven to be an efficient and successful informatics hub for coordinating the reliable application of NGS to precision medicine studies.

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Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute–Designated Cancer Program

Journal of Oncology Practice ◽

10.1200/jop.2015.008433 ◽

2016 ◽

Vol 12 (4) ◽

pp. e396-e404 ◽

Cited By ~ 8

Author(s):

Kalyan C. Mantripragada ◽

Adam J. Olszewski ◽

Andrew Schumacher ◽

Kimberly Perez ◽

Ariel Birnbaum ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

National Cancer Institute ◽

Next Generation ◽

Genomic Alterations ◽

Cancer Centers ◽

Cancer Program ◽

Clinical Trial Accrual ◽

Generation Sequencing

Purpose: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)–designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non–NCI-designated cancer programs. Materials and Methods: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board–approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers. Results: Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physician's choice of a different therapy (6.8%), or stable disease (11%). Conclusion: This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.

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Clinical application of comprehensive next generation sequencing in the management of metastatic cancer in adults.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.101 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 101-101 ◽

Cited By ~ 6

Author(s):

Erin Frances Cobain ◽

Dan R. Robinson ◽

Yi-Mi Wu ◽

Jessica Everett ◽

Erica Rabban ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Metastatic Cancer ◽

Tumor Board ◽

Next Generation ◽

Genomic Alterations ◽

Targeted Ngs ◽

Generation Sequencing ◽

Over Time

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.

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An observational study profiling biospecimens from 10,000 metastatic prostate cancer (mPCa) patients to screen for molecular alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.tps402 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. TPS402-TPS402

Author(s):

Won Kim ◽

Kat Kwiatkowski ◽

Justin Brown ◽

Dan R Rhodes ◽

Scott A Tomlins ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Observational Study ◽

Large Scale ◽

Screening Program ◽

Next Generation ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

TPS402 Background: Despite recent success in development and use of targeted agents in patients with solid tumors, there is a paucity of such therapies approved for use in prostate cancer. This observational study provides next-generation sequencing (NGS) to men with mPCa to evaluate the proportion of patients available for targeted therapy clinical trials in mPCa and to assess the feasibility of using a large-scale NGS screening program to match patients for eligibility criteria in clinical trials. Methods: Using a virtual clinical trial model to maximize patient access and enrollment, this study is providing next-generation sequencing (NGS) to 10,000 men with mPCa. Patients with histologically-documented mPCa and surplus formalin-fixed paraffin-embedded tumor tissue are eligible for enrollment. Leftover archival tissue is submitted for NGS to Strata Oncology, a clinical laboratory improvement amendments (CLIA)-certified lab. The StrataNGS assay sequences DNA and RNA, and simultaneously detects a range of actionable genomic alterations including gene mutations, small insertions and deletions, copy number changes, and gene fusions in 87 cancer-related genes. Microsatellite instability status is determined via the number of length variant alleles observed in NGS sequencing data at several microsatellite loci. Test reports presented to the clinician include all positive and negative variants detected, and information about potential matching therapeutic protocols. Clinical trial information: NCT03061305.

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Comparison of Annotation Services for Next-Generation Sequencing in a Large-Scale Precision Oncology Program

JCO Precision Oncology ◽

10.1200/po.19.00118 ◽

2020 ◽

pp. 212-221 ◽

Cited By ~ 1

Author(s):

Evangelia Katsoulakis ◽

Jill E. Duffy ◽

Bradley Hintze ◽

Neil L. Spector ◽

Michael J. Kelley

Keyword(s):

Next Generation Sequencing ◽

Precision Oncology ◽

Cancer Type ◽

Gene Variant ◽

Next Generation ◽

Unique Gene ◽

Moderate Agreement ◽

Level 1 ◽

Generation Sequencing ◽

Multigene Panel

PURPOSE Next-generation sequencing (NGS) multigene panel testing has become widespread, including the Veterans Affairs (VA), through the VA National Precision Oncology Program (NPOP). The interpretation of genomic alterations remains a bottleneck for realizing precision medicine. We sought to examine the concordance for pathogenicity determination and clinical actionability of annotation services in NPOP. METHODS Unique gene variants were generated from NGS gene panel results using two sequencing services. For each unique gene variant, annotations were provided through N-of-One (NoO), IBM Watson for Genomics (WfG), and OncoKB. Annotations for pathogenicity (all three sources) and actionability (WfG and OncoKB) were examined for concordance. Cohen’s kappa statistic was calculated to measure agreement between annotation services. RESULTS Among 1,227 NGS results obtained between 2015 and 2017, 1,388 unique variants were identified in 117 genes. The genes with the largest number of variants included TP53 (270), STK11 (92), and CDKN2A (81). The most common cancer type was lung adenocarcinoma (440), followed by colon adenocarcinoma (113). For pathogenic and likely pathogenic variants, there was 30% agreement between WfG and NoO (kappa, −0.26), 76% agreement between WfG and OncoKB (kappa, 0.22), and 42% agreement between NoO and OncoKB (kappa, −0.07). For level 1 drug actionability of gene variant–diagnosis combinations, there was moderate agreement between WfG and OncoKB (96.9%; kappa, 0.44), with 27 combinations identified as level 1 by both services, 58 by WfG alone, and 6 variants by OncoKB alone. CONCLUSION There is substantial variability in pathogenicity assessment of NGS variants in solid tumors by annotation services. In addition, there was only moderate agreement in level 1 therapeutic actionability recommendations between WfG and OncoKB. Improvement in the precision of NGS multigene panel annotation is needed.

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