“…Durvalumab treatment after chemoradiotherapy in stage III NSCLC further supported this trend 94 . The other oncogene‐driven NSCLCs also did not show the same responses as driver mutation‐negative tumours 95,96 …”
Section: Immune Check ‐point Inhibitors and Oncogene‐driven Nsclcmentioning
confidence: 85%
“…94 The other oncogene-driven NSCLCs also did not show the same responses as driver mutation-negative tumours. 95,96 In contrast, KRAS mutations in ICI treatments represent an exception to the other driver mutations. NSCLCs with KRAS mutations typically develop in smokers, and KRAS mutation incidence increases in parallel with the smoking dose.…”
Section: Immune Check-point Inhibitors and Oncogene-driven Nsclcmentioning
Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large‐scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular‐targeted therapy and treatment with immune check‐point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD‐1/PD‐L1‐positive subsets, e.g. the kinase inhibitors target driver mutation‐positive tumours, whereas driver mutation‐negative tumours respond to ICI treatment. These therapeutic efficacy‐related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check‐point treatment. These pathogenic differences are explained well by the two‐compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air‐conducting system.
“…Durvalumab treatment after chemoradiotherapy in stage III NSCLC further supported this trend 94 . The other oncogene‐driven NSCLCs also did not show the same responses as driver mutation‐negative tumours 95,96 …”
Section: Immune Check‐point Inhibitors and Oncogene‐driven Nsclcmentioning
confidence: 85%
“…94 The other oncogene-driven NSCLCs also did not show the same responses as driver mutation-negative tumours. 95,96 In contrast, KRAS mutations in ICI treatments represent an exception to the other driver mutations. NSCLCs with KRAS mutations typically develop in smokers, and KRAS mutation incidence increases in parallel with the smoking dose.…”
Section: Immune Check-point Inhibitors and Oncogene-driven Nsclcmentioning
Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large‐scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular‐targeted therapy and treatment with immune check‐point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD‐1/PD‐L1‐positive subsets, e.g. the kinase inhibitors target driver mutation‐positive tumours, whereas driver mutation‐negative tumours respond to ICI treatment. These therapeutic efficacy‐related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check‐point treatment. These pathogenic differences are explained well by the two‐compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air‐conducting system.
“…Emerging evidence suggests that different oncogenic drivers have different effects on tumor immune microenvironment, which may lead to the different clinical benefits of ICIs. Patients with BRAF mutations or co‐occurring KRAS and TP53 mutations derive the greatest benefit from ICIs, while EGFR mutations or ALK fusions or ROS1 rearrangements are typically associated with lower tumor PD‐L1 levels and TMB, limited immune cell infiltration in the tumor microenvironment, and resistance to ICIs [59]. Clinical question: How to effectively select drugs for uncommon/rare oncogenic drivers?Consensus 5: Encourage innovative clinical trial methods to accommodate clinical research on rare oncogenic drivers.…”
Section: Level or Strength Evidence Recommendationsmentioning
The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.
“…Non-small cell lung cancer is a common and deadly disease ( 7 ). An emerging understanding of the tumor immune microenvironment, and the introduction of immunotherapy, has led to improved outcomes for many non-small cell lung cancer (NSCLC) patients ( 8 ). Yet, the majority of patients progress due to resistance mechanisms.…”
IntroductionNon-small cell lung carcinomas (NSCLC) exhibit different microvessel patterns (MVPs). Basal (BA), diffuse (DA) and papillary (PA) patterns show signs of angiogenesis (new blood vessels), while an alveolar pattern indicates that tumors are co-opting existing normal vessels (non-angiogenic alveolar, NAA). NAA tumor growth is known to exist in NSCLC, but little is known about its prognostic impact in different histological subgroups, and about associations between MVPs and immune cell infiltration.MethodsDetailed patterns of angiogenic and non-angiogenic tumor growth were evaluated by CD34 immunohistochemistry in whole tissue slides from 553 surgically treated patients with NSCLC stage I-IIIB disease. Associations with clinicopathological variables and markers related to tumor immunology-, angiogenesis- and hypoxia/metabolism were explored, and disease-specific survival (DSS) was analyzed according to histological subtypes.ResultsThe predominant MVP was angiogenic in 82% of tumors: BA 40%, DA 34%, PA 8%, while a NAA pattern dominated in 18%. A contribution of the NAA pattern >5% (NAA+), i.e., either dominant or minority, was observed in 40.1% of tumors and was associated with poor disease-specific survival (DSS) (p=0.015). When stratified by histology, a significantly decreased DSS for NAA+ was found for adenocarcinomas (LUAD) only (p< 0.003). In multivariate analyses, LUAD NAA+ pattern was a significant independent prognostic factor; HR 2.37 (CI 95%, 1.50-3.73, p< 0.001). The immune cell density (CD3, CD4, CD8, CD45RO, CD204, PD1) added prognostic value in squamous cell carcinoma (LUSC) and LUAD with 0-5% NAA (NAA-), but not in LUAD NAA+. In correlation analyses, there were several significant associations between markers related to tumor metabolism (MCT1, MCT4, GLUT1) and different MVPs.ConclusionThe NAA+ pattern is an independent poor prognostic factor in LUAD. In NAA+ tumors, several immunological markers add prognostic impact in LUSC but not in LUAD.
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