Predictive values of genomic variation, tumor mutational burden, and PD-L1 expression in advanced lung squamous cell carcinoma treated with immunotherapy

Xu, Yanjun; Li, Hui; Huang, Zhiyu; Chen, Kaiyan; Yu, Xiaoqing; Sheng, Jing; Zhang, Hanhan; Fan, Yun

doi:10.21037/tlcr-20-1130

Cited by 21 publications

(18 citation statements)

References 42 publications

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“…The mechanisms MMR deficiencies result in high TMB remain unclear, which might relate to microsatellite instability, which is important in mutation number increase via repeated sequences and cancer immunity alteration. Smoking was considered contributing to high TMB ( 46 ). Given the exclusion of relevant EGFR/ALK driver gene alterations, as many patients with oncogene target mutations were non-smokers, further study on the relationships between DDR gene alterations or smoking and TMB was conducted.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Dai

Jiang

et al. 2021

Front. Oncol.

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DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients’ prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692–0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.

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Section: Discussionmentioning

confidence: 99%

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Dai

Jiang

et al. 2021

Front. Oncol.

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“…Additionally, two studies aiming to develop nomograms to predict the prognosis of NSCLC patients treated with anti-PD-1 inhibitors both showed that smoking was associated with improved prognosis and incorporated it into the model (8,14). Smokers were more likely to exhibit positive PD-L1 expression and higher TMB, which may improve the therapeutic efficacy of PD-1 inhibitors (31). The potential mechanism involved recruitment of tumor-infiltrating lymphocytes (TILs) and release of interferon-g (IFN-g) under a chronic inflammatory microenvironment caused by tobacco exposure, which induced PD-L1 expression and enhanced the stability of PD-L1 (8).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Nomogram for Predicting Prognosis to Immune Checkpoint Inhibitors Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer

et al. 2021

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BackgroundImmune checkpoint inhibitors (ICIs) plus chemotherapy improved the prognosis of patients with non-small cell lung cancer (NSCLC); however, reliable prognostic biomarkers are lacking. We explored factors associated with prognosis and developed a predictive model.MethodsWe retrospectively analyzed 130 consecutive stage IIIA–IVB NSCLC patients treated with ICIs combined with chemotherapy. Cox univariate and multivariate proportional hazards regression analyses were used to identify prognostic factors associated with progression-free survival (PFS). A nomogram was developed based on key factors in the training cohort (n = 86) and evaluated in the validation cohort (n = 44). According to the nomogram-based total point scores, we divided patients into low- and high-risk groups.ResultsIn the training cohort, bone metastases (p = 0.017) and an increased derived neutrophil-to-lymphocyte ratio (p = 0.018) were significantly associated with poor PFS, while smoking (p = 0.007) and programmed death-ligand 1 (PD-L1) ≥50% (p = 0.001) were associated with improved PFS. A nomogram based on these factors was developed to predict PFS at 3, 6, and 12 months. The C-index of the nomogram to predict PFS was 0.725 (95% CI: 0.711–0.739) in the training cohort and 0.688 (95% CI: 0.665–0.711) in the validation cohort. The area under the curve (AUC) exhibited an acceptable discriminative ability, and calibration curves demonstrated a consistency between the actual results and predictions. In the training cohort, the median PFS (mPFS) was 12.3 and 5.7 months in the low- and high-risk groups, respectively (p < 0.001). In the validation cohort, the mPFS was 12.6 and 6.2 months in the low- and high-risk groups, respectively (p = 0.021).ConclusionsA predictive nomogram was developed to help clinicians assess prognosis early for advanced NSCLC patients who received ICI plus chemotherapy.

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“…The incidence of BM is lower in patients with lung squamous cell carcinoma (LUSC) compared to those with non-squamous cell carcinoma (NSCC) and there are few studies on BM of LUSC (15,16). Efficient tools are urgently needed to facilitate the early diagnosis of BM in patients with LUSC (17).…”

Section: Introductionmentioning

confidence: 99%

The development and validation of a nomogram for predicting brain metastases in lung squamous cell carcinoma patients: an analysis of the Surveillance, Epidemiology, and End Results (SEER) database

Zhang¹,

Xu²,

Jin³

et al. 2021

J Thorac Dis

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Background: The incidence of brain metastasis (BM) in patients suffering from lung squamous cell carcinoma (LUSC) is lower than that in patients suffering from non-squamous cell carcinoma (NSCC) and there are few studies on BM of LUSC. The purpose of this investigation was to ascertain the risk factors of LUSC, as well as to establish a nomogram prognostic model to predict the incidence of BM in patients with LUSC. Methods: Patients diagnosed with LUSC between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database and the patient data were collated. All patients diagnosed from 2010-2012 were allocated into the training cohort, and the remaining patients diagnosed from 2013-2015 formed the test cohort. Using factors that were screened out through logistic regression analyses, the nomogram in the training cohort was established. It was then evaluated for discrimination and calibration using the test cohort. The performance of the nomogram was assessed by quantifying the area under the receiver operating characteristic (ROC) curve and evaluating the calibration curve. Results: A total of 26,154 LUSC patients were included in the study. The training cohort consisted of 16,543 patients and there were 8611 patients in the test cohort. Age, marital status, insurance status, histological grade, tumor location, laterality, stage of the cancer, number of metastatic organs, chemotherapy, surgery, and radiotherapy were highly correlated with the incidence of BM. The area under the ROC curve (AUC) of the nomogram for the training cohort and the test cohort were 0.810 [95% confidence interval (CI): 0.796 to 0.823] and 0.805 (95% CI: 0.784 to 0.825), respectively. The slope of the calibration curve was close to 1. Conclusions:The nomogram was able to accurately predict the incidence of BM. This may be beneficial for the early identification of high-risk LUSC patients and the establishment of individualized treatments.

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Predictive values of genomic variation, tumor mutational burden, and PD-L1 expression in advanced lung squamous cell carcinoma treated with immunotherapy

Cited by 21 publications

References 42 publications

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Development and Validation of a Nomogram for Predicting Prognosis to Immune Checkpoint Inhibitors Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer

The development and validation of a nomogram for predicting brain metastases in lung squamous cell carcinoma patients: an analysis of the Surveillance, Epidemiology, and End Results (SEER) database

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