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

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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Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC)

Cancers ◽

10.3390/cancers13040609 ◽

2021 ◽

Vol 13 (4) ◽

pp. 609

Author(s):

Caterina Fumagalli ◽

Elena Guerini-Rocco ◽

Massimo Barberis

Keyword(s):

Lung Cancer ◽

Small Cell ◽

Tumor Board ◽

Genomic Profiling ◽

Small Cell Lung ◽

Molecular Alterations ◽

Comprehensive Genomic Profiling ◽

Molecular Tumor Board ◽

Personalized Cancer Therapy ◽

Personalized Cancer

Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...]

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How clinically useful is comprehensive genomic profiling for patients with non-small cell lung cancer? A systematic review

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2021.103459 ◽

2021 ◽

pp. 103459

Author(s):

Gabriel Fernando Torres ◽

Carlos Eduardo Bonilla ◽

Giancarlo Buitrago ◽

Oscar Arrieta ◽

Umberto Malapelle ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Lung ◽

Comprehensive Genomic Profiling

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Impact of Comprehensive Genomic Profiling of Patients With First Line Non-Small Cell Lung Cancer In The UK

Value in Health ◽

10.1016/j.jval.2017.08.1004 ◽

2017 ◽

Vol 20 (9) ◽

pp. A575

Author(s):

R Anhorn ◽

G Roberts ◽

M Skovhus ◽

M Khorshid

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Lung ◽

First Line ◽

Comprehensive Genomic Profiling ◽

The Uk

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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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