Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets

Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non–small-cell lung cancer (NSCLC). Over the last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patient's clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patient's tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.

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New drug and multimodality combinations in the treatment of advanced non[ndash ]small cell lung cancer

Seminars in Oncology ◽

10.1053/sonc.2001.24600 ◽

2001 ◽

Vol 28 (3 Suppl 9) ◽

pp. 1-4

Author(s):

Masaaki Kawahara ◽

Mark G. Kris ◽

Mark Green ◽

Hideo Kunitoh

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

New Drug

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Liquid Biopsy for Small Cell Lung Cancer either De Novo or Transformed: Systematic Review of Different Applications and Meta-Analysis

Cancers ◽

10.3390/cancers13092265 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2265

Author(s):

Elio Gregory Pizzutilo ◽

Martino Pedrani ◽

Alessio Amatu ◽

Lorenzo Ruggieri ◽

Calogero Lauricella ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Liquid Biopsy ◽

De Novo ◽

Meta Analysis ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Lung

Background: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). Methods: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Results: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71–4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. Conclusions: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling.

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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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Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

Cell ◽

10.1016/j.cell.2013.09.041 ◽

2013 ◽

Vol 155 (3) ◽

pp. 552-566 ◽

Cited By ~ 115

Author(s):

Hyun Seok Kim ◽

Saurabh Mendiratta ◽

Jiyeon Kim ◽

Chad Victor Pecot ◽

Jill E. Larsen ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Molecular Subtype ◽

Small Cell ◽

Small Cell Lung ◽

Systematic Identification ◽

Subtype Selective

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Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.59 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 59-59

Author(s):

Woojung Lee ◽

Scott Spencer ◽

Josh John Carlson ◽

Tam Dinh ◽

Victoria Dayer ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genetic Alterations ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Lung ◽

Eligibility Criteria ◽

Comprehensive Genomic Profiling

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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