Abstract 3534: Analytical performance of a comprehensive genomic profiling system to detect actionable genetic alterations in NSCLC

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

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Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations

Modern Pathology ◽

10.1038/s41379-020-0581-5 ◽

2020 ◽

Vol 33 (12) ◽

pp. 2397-2406 ◽

Cited By ~ 1

Author(s):

Erik A. Williams ◽

Meagan Montesion ◽

Nikunj Shah ◽

Radwa Sharaf ◽

Dean C. Pavlick ◽

...

Keyword(s):

Cutaneous Melanoma ◽

Molecular Subtype ◽

Genetic Alterations ◽

Experimental Models ◽

Genomic Profiling ◽

Missense Mutations ◽

Wild Type ◽

Single Nucleotide Variants ◽

Sequencing Platform ◽

Comprehensive Genomic Profiling

AbstractWhile the genomics of BRAF, NRAS, and other key genes influencing MAP kinase (MAPK) activity have been thoroughly characterized in melanoma, mutations in MAP2K1 (MEK1) have received significantly less attention and have consisted almost entirely of missense mutations considered secondary oncogenic drivers of melanoma. Here, we investigated melanomas with in-frame deletions of MAP2K1, alterations characterized as MAPK-activating in recent experimental models. Our case archive of clinical melanoma samples with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform was searched for MAP2K1 genetic alterations. Clinical data, pathology reports, and histopathology were reviewed for each case. From a cohort of 7119 advanced melanomas, 37 unique cases (0.5%) featured small in-frame deletions in MAP2K1. These included E102_I103del (n = 11 cases), P105_A106del (n = 8), Q58_E62del (n = 6), I103_K104del (n = 5), I99_K104del (n = 3), L98_I103del (n = 3), and E41_F53del (n = 1). All 37 were wild type for BRAF, NRAS, and NF1 genomic alterations (“triple wild-type”), representing 2.0% of triple wild-type melanomas overall (37/1882). Median age was 66 years and 49% were male. The majority arose from primary cutaneous sites (35/37; 95%) and demonstrated a UV signature when available (21/25; 84%). Tumor mutational burden was typical for cutaneous melanoma (median = 9.6 mut/Mb, range 0–35.7), and frequently mutated genes included TERTp (63%), CDKN2A (46%), TP53 (11%), PTEN (8%), APC (8%), and CTNNB1 (5%). Histopathology revealed a spectrum of appearances typical of melanoma. For comparison, we evaluated 221 cases with pathogenic missense single nucleotide variants in MAP2K1. The vast majority of melanomas with missense SNVs in MAP2K1 showed co-mutations in BRAF (58%), NF1 (23%), or NRAS (18%). In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.

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P3.13-25 Development of a Comprehensive Genomic Profiling System to Detect Actionable Genetic Alterations and Tumor Mutation Burden

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.1866 ◽

2018 ◽

Vol 13 (10) ◽

pp. S985-S986

Author(s):

S. Jones ◽

S. Angiouli ◽

K. Gerding ◽

L. Keefer ◽

J. Hernandez ◽

...

Keyword(s):

Genetic Alterations ◽

Genomic Profiling ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Comprehensive Genomic Profiling

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Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.558 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 558-558

Author(s):

Xin Huang ◽

Huanwen M. Wu ◽

Changbin Zhu ◽

Di Shao ◽

Dan Guo ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Copy Number ◽

Triple Negative ◽

Genetic Data ◽

Genetic Alterations ◽

Clinicopathological Parameters ◽

Genomic Profiling ◽

Cyclin E1 ◽

Comprehensive Genomic Profiling

558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]

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Advanced Lung Adenocarcinoma Patient with ERBB2 Amplification Identified by Comprehensive Genomic Profiling Benefits from Trastuzumab

Case Reports in Oncological Medicine ◽

10.1155/2020/9072173 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Chi-Wei Tao ◽

Mei-Yin Chen ◽

Ching-Min Tseng ◽

Nina Lapke ◽

Shu-Jen Chen ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number Variants ◽

Genetic Alterations ◽

Lung Lesion ◽

Genomic Profiling ◽

Comprehensive Genomic Profiling ◽

Lung Adenocarcinoma Patient ◽

Nsclc Patients ◽

Next Generation Sequencing Ngs ◽

Erbb2 Amplification

For non-small-cell lung cancer (NSCLC) patients without established actionable alterations in genes such as EGFR or ALK, options for targeted therapy remain limited in clinical practice. About 5% of lung adenocarcinoma patients have tumors with ERBB2 genetic alterations, with even fewer patients harboring ERBB2 amplification. Currently, clinical trials mainly use IHC, FISH, or mutation testing to identify potential responders to ERBB2-targeting agents. The use of next-generation sequencing (NGS) to detect ERBB2 alterations, including copy number variants, is rare. In this study, we present an EGFR- and ALK-negative advanced NSCLC case for which we conducted comprehensive tumor genomic profiling to identify potentially actionable alterations. The tumor harbored an ERBB2 amplification, and trastuzumab-based therapy resulted in an excellent response, with a necrotic regression of the patient’s lung lesion. Although he developed brain metastasis four months after trastuzumab initiation, he survived for an additional period of eight months without local recurrence or other systemic metastasis. This case report shows that the use of comprehensive genetic testing enables the identification of rare actionable alterations in NSCLC patients without other options for targeted treatment.

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Clinical utility of comprehensive genomic profiling and targeted therapy in biliary tract cancers: A real-world experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16671 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16671-e16671

Author(s):

Mahum Shahid ◽

Mohamed A. Abdallah ◽

Moataz Ellithi ◽

Hafez Mohammad Abdullah ◽

Morgan Nelson ◽

...

Keyword(s):

Targeted Therapy ◽

Biliary Tract ◽

Medical Center ◽

Genetic Alterations ◽

Molecular Therapy ◽

Common Mutation ◽

Genomic Profiling ◽

Biliary Tract Cancers ◽

Comprehensive Genomic Profiling

e16671 Background: Biliary tract cancers (BTC) are a highly aggressive group of malignancies with high mortality and poor prognosis. Chemotherapy is the mainstay of treatment for advanced disease. The role of molecular targeted therapy and immunotherapy using comprehensive genomic profiling (CGP) is evolving. We investigated the role of CGP directed therapy in patients with BTC. Methods: A multi-center retrospective study of CGP done on 35 patients with BTC at Sanford USD Medical Center and Avera McKennan Hospital, Sioux Falls, SD, between 2014 and 2019. 27 patients had cholangiocarcinoma (fifteen intrahepatic, two extrahepatic and ten unclassified), two had gallbladder carcinoma and six had ampullary carcinoma. Results: 22 of 35 BTC (63%) had potentially actionable genetic alterations(GA). Nine of these 22 (41%) received molecular therapy based on CGP. Four patients had microsatellite instability (MSI-H) and two of them received immunotherapy (Table). CDKN2A/B was the most common mutation (23%) followed by PIK3CA (13%), ARID1A (13%) and Tp53(13%). By the end of the follow up period, median overall survival (OS) was 569 days(19 months) for those who received targeted therapy compared to 315 days(10.5 months) for those who did not. (P = 0.051). Conclusions: In this multi-center cohort, 63% of patients had at least one targetable GA. Furthermore, CGP guided treatment decisions in 41% of patients. CGP has the potential to provide clinically meaningful treatment options for patients with BTC. New studies are warranted to further investigate this promising prospect for BTC management. [Table: see text]

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Concurrent Genetic Alterations in Lung Cancer: a Comprehensive Genomic Profiling in a Japanese Cohort

Annals of Oncology ◽

10.1093/annonc/mdu357.10 ◽

2014 ◽

Vol 25 ◽

pp. iv545

Author(s):

T. Taira ◽

H. Kenmotsu ◽

M. Serizawa ◽

K. Wakuda ◽

H. Akamatsu ◽

...

Keyword(s):

Lung Cancer ◽

Genetic Alterations ◽

Genomic Profiling ◽

Japanese Cohort ◽

Comprehensive Genomic Profiling

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A scalable high-throughput targeted next-generation sequencing assay for comprehensive genomic profiling of solid tumors

PLoS ONE ◽

10.1371/journal.pone.0260089 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260089

Author(s):

Jeffrey M. Conroy ◽

Sarabjot Pabla ◽

Sean T. Glenn ◽

R. J. Seager ◽

Erik Van Roey ◽

...

Keyword(s):

Solid Tumors ◽

High Throughput ◽

Splice Variants ◽

Turnaround Time ◽

Analytical Performance ◽

Clinical Samples ◽

Genomic Profiling ◽

Accurate Identification ◽

Molecular Alterations ◽

Comprehensive Genomic Profiling

Timely and accurate identification of molecular alterations in solid tumors is essential for proper management of patients with advanced cancers. This has created a need for rapid, scalable comprehensive genomic profiling (CGP) systems that detect an increasing number of therapeutically-relevant variant types and molecular signatures. In this study, we assessed the analytical performance of the TruSight Oncology 500 High-Throughput assay for detection of somatic alterations from formalin-fixed paraffin-embedded tissue specimens. In parallel, we developed supporting software and automated sample preparation systems designed to process up to 70 clinical samples in a single NovaSeq 6000TM sequencing run with a turnaround time of <7 days from specimen receipt to report. The results demonstrate that the scalable assay accurately and reproducibly detects small variants, copy number alterations, microsatellite instability (MSI) and tumor mutational burden (TMB) from 40ng DNA, and multiple gene fusions, including known and unknown partners and splice variants from 20ng RNA. 717 tumor samples and reference materials with previously known alterations in 96 cancer-related genes were sequenced to evaluate assay performance. All variant classes were reliably detected at consistent and reportable variant allele percentages with >99% overall accuracy and precision. Our results demonstrate that the high-throughput CGP assay is a reliable method for accurate detection of molecular alterations in support of precision therapeutics in oncology. The supporting systems and scalable workflow allow for efficient interpretation and prompt reporting of hundreds of patient cancer genomes per week with excellent analytical performance.

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