Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
Yunfei Shi,Youming Lei,Li Liu,Shiyue Zhang,Wen-Jing Wang,Juan Zhao,Songhui Zhao,Xiaowei Dong,Ming Yao,Kai Wang,Qing Zhou +10 more
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TLDR
Wang et al. as discussed by the authors explored the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1).Abstract:
Objectives This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1). Materials and methods Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. Results EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007). Conclusion We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC. Implications for practice Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.read more
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Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications
Daniel Kazdal,Véronique Hofman,Petros Christopoulos,Marius Ilie,Albrecht Stenzinger,Paul Hofman +5 more
TL;DR: The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.
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Artificial Intelligence-based Prediction of Clinical Outcome in Immunotherapy and Targeted Therapy of Lung Cancer.
TL;DR: Wang et al. as mentioned in this paper reviewed the application of AI in predicting the outcomes of immunotherapy and targeted therapy in lung cancer patients, and discussed the challenges and future directions in this field.
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Efficacy of immune checkpoint inhibitor therapy in patients with RET fusion-positive non-small-cell lung cancer.
TL;DR: In this article, outcomes of patients with rear-raned during transfection (RET) fusion-positive non-small-cell lung cancer (NSCLC) who received immune checkpoint inhibitor (ICI)-based treatments in the US were described.
Journal ArticleDOI
TP53 Co-Mutations in Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy
TL;DR: The prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients is described, the mechanisms of this co- mutation affecting the response to EGFR-TKIs are investigated, and optimal regimens effectively are explored to prolong the survival time of the NSCLc patients harboring this co,mutation.
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Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma
TL;DR: In this article, the authors reviewed the evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response and found that only a small subset of MPM patients respond to checkpoint inhibition, and this response has varied and unpredictable across several clinical trials.
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