scholarly journals PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations

2016 ◽  
Vol 5 (5) ◽  
pp. e1131379 ◽  
Author(s):  
Andreas H. Scheel ◽  
Sascha Ansén ◽  
Anne M. Schultheis ◽  
Matthias Scheffler ◽  
Rieke N. Fischer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung

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.

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

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]

scholarly journals Role of Immunotherapy for Oncogene-Driven Non-Small Cell Lung Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 245 ◽  
Author(s):  
Yosuke Miura ◽  
Noriaki Sunaga
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Future Direction ◽  
Nsclc Patients

The clinical application of immune checkpoint inhibitors (ICIs) has led to dramatic changes in the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Despite the observation of improved overall survival in NSCLC patients treated with ICIs, their efficacy varies greatly among different immune and molecular profiles in tumors. Particularly, the clinical significance of ICIs for oncogene-driven NSCLC has been controversial. In this review, we provide recent clinical and preclinical data focused on the relationship between oncogenic drivers and immunological characteristics and discuss the future direction of immunotherapy in NSCLC patients harboring such genetic alterations

scholarly journals Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 690 ◽  
Author(s):  
Arik Bernard Schulze ◽  
Georg Evers ◽  
Andrea Kerkhoff ◽  
Michael Mohr ◽  
Christoph Schliemann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Molecular Pathways ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
Therapeutic Concept ◽  
Platinum Based Chemotherapy

Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called ‘poly-(ADP)-ribose polymerases’ (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of ‘enhancer of zeste homolog 2’ (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.

Co-occurring genetic alterations and primary EGFR T790M mutations detected by next-generation sequencing in pre-TKI treated patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13128-e13128
Author(s):  
Yuan Tang ◽  
Bing Wei ◽  
Yang Yu ◽  
Yun Gao ◽  
Nanying Che ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Development ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Resected Nsclc ◽  
Egfr T790m

e13128 Background: With the development of targeted drugs, there are more therapeutic options for patients with non-small cell lung cancer (NSCLC) harboring corresponding genetic alterations. However, cancers are frequently caused by alterations on multiple genes, which collaborate to promote tumor development. Methods: A total of 1353 NSCLC patients from five different clinical institutions were enrolled in this study. Concurrent DNA and RNA NGS analysis was performed using the Ion Ampliseq Colon and Lung Cancer gene panel v2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel using FFPE samples from surgically resected NSCLC tumors. Results: Of the 1293 mutations that were detected, 2338 variants were identified in 24 genes, while 27 of the tumor samples were identified to have co-occurring DNA mutations (including insertions, deletions and point mutations) and RNA fusion mutations. Analysis of the 975 patients with EGFR-gene mutations revealed that the incidence of dual EGFR L858R/T790M mutations were higher compared to EGFR 19del/T790M, and the MAF of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. Conclusions: Even with the non-random cohort of patients in this study, the genetic alterations detected in this study had a certain degree of representation of NSCLC (especially lung adenocarcinoma) in the Chinese population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.

Impact of large-scale nationwide genomic screening project for small cell lung cancer (LC-SCRUM-Japan).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8559-8559
Author(s):  
Naoki Furuya ◽  
Shigeki Umemura ◽  
Hibiki Udagawa ◽  
Tadasuke Shimokawaji ◽  
Takashi Seto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Large Scale ◽  
Genetic Alterations ◽  
Small Cell ◽  
Clinical Samples ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Genomic Screening

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9589-9589 ◽  
Author(s):  
Yutaro Tamiya ◽  
Yoshitaka Zenke ◽  
Shingo Matsumoto ◽  
Naoki Furuya ◽  
Tomohiro Sakamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kras Mutation ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Genomic Screening

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p < 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.

scholarly journals Highlights on the morphology, prognostic factors, diagnostics, and treatment (chemotherapy, chemotherapy + radiation, targeted therapy, immunotherapy, and surgery) in small cell lung cancer

2020 ◽  
Vol 25 (4) ◽  
pp. 127-135
Author(s):  
Mark B. Bychkov ◽  
A. E. Kuzminov
Keyword(s):  
Lung Cancer ◽  
Prognostic Factors ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Algorithm ◽  
Genetic Alterations ◽  
Small Cell ◽  
Line Treatment ◽  
Small Cell Lung

The article present a review and experience from a a single institution on the morphology, diagnostics, and treatment (chemotherapy, radiation, targeted therapy, and immunotherapy)) of small cell lung cancer (SCLC). The characteristic molecular, genetic, histological, and immunohistochemical features of NSCLC and SCLC are compared. An important issue of SCLC histogenesis is highlighted, taking into account its neuroendocrine characteristics. Paraneoplastic syndromes associated with SCLC and other clinical features of SCLC are discussed. The algorithm of examination of a patient with histologically or cytologically confirmed SCLC, staging schemes, and main prognostic factors are presented. The following aspects of chemoradiotherapy of localized SCLC are considered: features of early, late, simultaneous, and sequential therapy, and the need for whole brain radiotherapy in patients with localized and extensive SCLC. The article discusses the treatment algorithm for extensive disease SCLC, taking into account the recent success of chemoimmunotherapy in the first-line treatment of SCLC. As is known, the combinations of atezolizumab, etoposide, carboplatin and durvalumab, etoposide, cisplatin, or carboplatin showed a real benefit compared to chemotherapy alone. Although the second line treatment has not changed, it is now possible to prescribe a third line therapy because of the proven effectiveness of immunotherapy. Targeted therapy, although not shown to be effective in SCLC, is discussed in terms of the key features of genetic alterations as a possible target for therapy. An important issue in the treatment of patients with superior vena cava syndrome is considered separately. The tasks of future prospective research in SCLC are described.

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