Somatic Genetic Alterations and Implications for Targeted Therapies in Cancer (GIST, CML, Lung Cancer)

2010 ◽  
pp. 205-220 ◽  
Author(s):  
Alice T. Shaw ◽  
Eyal C. Attar ◽  
Edwin Choy ◽  
Jeffrey Engelman
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Genetic Alterations

scholarly journals The Liquid Biopsy for Lung Cancer: State of the Art, Limitations and Future Developments

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3923
Author(s):  
Daniel Di Capua ◽  
Dara Bracken-Clarke ◽  
Karine Ronan ◽  
Anne-Marie Baird ◽  
Stephen Finn
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Targeted Therapies ◽  
Liquid Biopsy ◽  
Genetic Alterations ◽  
Rapid Progression ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Genetic Sequencing ◽  
Tissue Biopsy

Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9094-9094
Author(s):  
Shingo Matsumoto ◽  
Takaya Ikeda ◽  
Kiyotaka Yoh ◽  
Akira Sugimoto ◽  
Terufumi Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Targeted Therapies ◽  
Advanced Nsclc ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Gene Testing ◽  
Genomic Screening ◽  
Nsclc Patients

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p < 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p < 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p < 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

A Career in Lung Cancer: Pushing Beyond Chemotherapy

2019 ◽  
pp. 583-589
Author(s):  
Pradnya Dinkar Patil ◽  
Frances Shepherd ◽  
David H. Johnson
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Disease Biology ◽  
Formidable Challenge ◽  
Treatment Paradigm

The landscape of treatments for non–small cell lung cancer (NSCLC) has evolved dramatically over the past 3 decades. A better understanding of the disease biology and identification of actionable genetic alterations heralded an era of targeted therapies that has led to unprecedented survival benefits in patients with oncogene-driven NSCLC. More recent breakthroughs in immunotherapy led to the development of immune checkpoint inhibitors that have changed the treatment paradigm for patients with advanced NSCLC because of their ability to produce durable responses, resulting in improved survival outcomes. Despite the unparalleled success of these agents, primary and acquired resistance to these therapies pose a formidable challenge. In this article, we provide an overview of the therapeutic advances in the treatment of NSCLC, mechanisms of resistance, and potential strategies to overcome resistance to targeted therapies and immune checkpoint inhibitors.

Clinical features of squamous cell lung cancer with targetable gene alterations in a nationwide genomic screening network in Japan (LC-SCRUM-Japan).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9057-9057
Author(s):  
Eri Sugiyama ◽  
Shingo Matsumoto ◽  
Nobuaki Kobayashi ◽  
Hiromi Aono ◽  
Masato Shingyoji ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Features ◽  
Squamous Cell ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Clinical Characteristics ◽  
Genetic Alterations ◽  
Squamous Cell Lung Cancer ◽  
Genomic Screening ◽  
Gene Alterations

9057 Background: Molecular-targeted therapies for precision medicine in squamous cell lung cancer (SqLC) have not yet been established. To identify precise patients for targeted therapies and to reveal their clinical characteristics, we have operated clinical sequencing of advanced SqLCs in our nationwide genomic screening project in Japan (LC-SCRUM-Japan) since March 2015. Methods: As of December 2016, 190 institutions across Japan were participating and 263 advanced SqLC patients had been enrolled in this project. Submitted tumor samples were subjected to a next-generation sequencing system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: The median age of the 263 patients was 74 years (range, 27-87 years). Two hundred thirty (87%) were male and most patients (97%) were smokers. Among 211 available samples, potentially targetable gene alterations were detected in 58 (27%). Based on these gene alterations, the patients were subdivided into 4 groups, consisting of 25 (12%) with genetic alterations of FGFR family (FGFR type; 23 FGFR1 amplifications, 1 FGFR2 amplification and 1 FGFR3 fusion), 20 (9%) with genetic alterations of the PI3K pathway (PI3K type; 10 PIK3CA mutations, 8 PTEN mutations and 2 AKT mutations), 15 (7%) with other oncogene alterations (KRAS/EGFR/ALK type; 10 KRAS mutations, 3 EGFR mutations and 2 ALK fusions) and others. Comparative analyses of clinical characteristics between the 4 types showed that brain metastases were significantly more frequent in the FGFR type than the others (24% vs. 5%, p = 0.0007), and females (40% vs. 11%, p = 0.0009) and never-smokers (21% vs. 3%, p = 0.0004) were significantly frequent in the KRAS/EGFR/ALK type compared to the others. The prognostic significance of these genetic alterations has not yet been evaluated because of short follow-up time (median, 8.5 months). Conclusions: A series of potentially targetable gene alterations have been identified in SqLC patients. The SqLC patients had distinct clinical features according to the molecular subtypes, and genotype-directed therapeutic strategy should be developed for the individual subtypes.

scholarly journals Immunotherapy and Targeted Therapies in the Treatment of Non-small Cell Lung Cancer

2017 ◽  
Vol 13 (01) ◽  
pp. 35
Author(s):  
Tu Nguyen-Ngoc ◽  
Martin Reck ◽  
Daniel SW Tan ◽  
Solange Peters ◽  
◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

In the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti-PD-1 antibodies nivolumab and pembrolizumab. Several other anti-PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient.

scholarly journals Non-Small-Cell Lung Cancer: New Rare Targets—New Targeted Therapies—State of The Art and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1829
Author(s):  
Katarzyna Stencel ◽  
Izabela Chmielewska ◽  
Janusz Milanowski ◽  
Rodryg Ramlau
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Stage Iv ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Her2 Gene ◽  
Rapid Improvement

Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies.

scholarly journals Genetic and Biochemical Alterations in Non-Small Cell Lung Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Jackie L. Johnson ◽  
Smitha Pillai ◽  
Srikumar P. Chellappan
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Biological Significance ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Biochemical Alterations

Despite significant advances in the detection and treatment of lung cancer, it causes the highest number of cancer-related mortality. Recent advances in the detection of genetic alterations in patient samples along with physiologically relevant animal models has yielded a new understanding of the molecular etiology of lung cancer. This has facilitated the development of potent and specific targeted therapies, based on the genetic and biochemical alterations present in the tumor, especially non-small-cell lung cancer (NSCLC). It is now clear that heterogeneous cell signaling pathways are disrupted to promote NSCLC, including mutations in critical growth regulatory proteins (K-Ras, EGFR, B-RAF, MEK-1, HER2, MET, EML-4-ALK, KIF5B-RET, and NKX2.1) and inactivation of growth inhibitory pathways (TP53, PTEN, p16, and LKB-1). How these pathways differ between smokers and non-smokers is also important for clinical treatment strategies and development of targeted therapies. This paper describes these molecular targets in NSCLC, and describes the biological significance of each mutation and their potential to act as a therapeutic target.

scholarly journals Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer

2021 ◽  
Vol 22 (2) ◽  
pp. 612
Author(s):  
Sara S. Fois ◽  
Panagiotis Paliogiannis ◽  
Angelo Zinellu ◽  
Alessandro G. Fois ◽  
Antonio Cossu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Molecular Epidemiology ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung

Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes of modern targeted therapies, their global prognostic significance, and their mutual interaction in cases of co-occurrence.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

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