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Journal ArticleDOI: 10.1158/0008-5472.CAN-20-3991

Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer.

02 Mar 2021-Cancer Research (American Association for Cancer Research (AACR))-Vol. 81, Iss: 9, pp 2566-2573
Abstract: Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRASG12C and less frequent EGFRdel19 and EGFRL858R mutations, whereas doubling smoking-free months was associated with more frequent EGFRL858R . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.

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Topics: Lung cancer (61%), Adenocarcinoma (53%), Carcinogenesis (51%) ... read more
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10 results found


Journal ArticleDOI: 10.1093/JNCI/DJAB116
Abstract: BACKGROUND Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive. METHODS This study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patient smoking history, clinicopathological characteristics, tumor mutation burden (TMB) by clinical targeted next generation sequencing, and PD-L1 tumor proportion score (TPS) by immunohistochemistry were prospectively collected. The association of smoking history with clinical outcomes of ICI monotherapy in metastatic NSCLC patients was evaluated after adjusting for other potential predictors. All statistical tests were 2-sided. RESULTS Of 644 advanced NSCLC patients 105 (16.3%) were never smokers, 375 (58.2%) were former smokers (median pack-years = 28), and 164 (25.4%) were current smokers (median pack-years = 40). Multivariable logistic and Cox proportional hazards regression analyses suggested that doubling of smoking pack-years is statistically significantly associated with improved clinical outcomes of patients treated with ICI monotherapy (objective response rate odds ratio = 1.21, 95% confidence interval [CI] = 1.09-1.36, P < .001; progression-free survival hazard ratio = 0.92, 95% CI = 0.88-0.95, P < .001; overall survival hazard ratio = 0.94, 95% CI = 0.90-0.99, P = .01). Predictive models incorporating pack-years and PD-L1 TPS yielded additional information and achieved similar model performance compared to using TMB and PD-L1 TPS. CONCLUSIONS Increased smoking exposure had a statistically significant association with improved clinical outcomes in metastatic NSCLC treated with ICI monotherapy independent of PD-L1 TPS. Pack-years may serve as a consistent and readily obtainable surrogate of ICI efficacy when TMB is not available to inform prompt clinical decisions and allow more patients to benefit from ICIs.

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Topics: Hazard ratio (55%), non-small cell lung cancer (NSCLC) (53%), Progression-free survival (52%) ... read more

6 Citations


Open accessJournal ArticleDOI: 10.1111/CAS.15031
11 Jul 2021-Cancer Science
Abstract: There could be two carcinogenetic pathways for lung adenocarcinoma (LADC), that are, the non-smokers' pathway and the smokers' pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the non-smokers' pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers' pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the non-smokers' pathway is mostly driven by EGFR mutations, whereas in the smokers' pathway, approximately one-quarter of LADCs have KRAS mutations, but the other three-quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression, chromosome 12p13-21 amplification in the non-smokers' pathway, and HNF4α expression and TTF1 mutations in the smokers' pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight into better understanding the nature of LADCs.

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2 Citations


Open accessJournal ArticleDOI: 10.3389/FONC.2021.672677
Peipei Wang1, Yueyun Chen1, Chun Wang1Institutions (1)
Abstract: Immunotherapy has significantly improved the clinical outcome of patients with cancer. However, the immune response rate varies greatly, possibly due to lack of effective biomarkers that can be used to distinguish responders from non-responders. Recently, clinical studies have associated high tumor neoantigen burden (TNB) with improved outcomes in patients treated with immunotherapy. Therefore, TNB has emerged as a biomarker for immunotherapy and other types of therapy. In the present review, the potential application of TNB as a biomarker was evaluated. The methods of neoantigen prediction were summarized and the mechanisms involved in TNB were investigated. The impact of high TNB and increased number of infiltrating immune cells on the efficacy of immunotherapy was also addressed. Finally, the future challenges of TNB were discussed.

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Topics: Immunotherapy (51%)

1 Citations


Open accessJournal ArticleDOI: 10.1002/CAM4.4197
Li-Yue Sun1, Wen-Jian Cen1, Wen-Ting Tang1, Ya-Kang Long1  +7 moreInstitutions (1)
01 Sep 2021-Cancer Medicine
Abstract: BACKGROUND This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy. METHODS We conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. RESULTS We enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05). CONCLUSIONS The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.

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Topics: Lung cancer (58%), Combination therapy (52%), Immune checkpoint (50%)

Open accessJournal ArticleDOI: 10.21037/TLCR-21-734
Haitang Yang1, Wenyan Ma1, Beibei Sun1, Liwen Fan1  +8 moreInstitutions (4)
Abstract: Background There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated. Methods We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemo-immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. Clinicopathological factors associated with pathological response were analyzed. Results A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure. Conclusions These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.

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Topics: Lung cancer (57%), Adenocarcinoma (51%)

References
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29 results found


Open accessJournal ArticleDOI: 10.1038/NATURE10738
Li Ding1, Timothy J. Ley1, David E. Larson1, Christopher A. Miller1  +35 moreInstitutions (1)
26 Jan 2012-Nature
Abstract: Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

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1,772 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2018.03.035
05 Apr 2018-Cell
Abstract: Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

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Topics: Wnt signaling pathway (55%), DNA methylation (51%), Cell cycle (50%)

1,079 Citations


Journal ArticleDOI: 10.1097/00001648-199507000-00005
Sander Greenland1Institutions (1)
01 Jul 1995-Epidemiology
Abstract: Standard categorical analysis is based on an unrealistic model for dose-response and trends and does not make efficient use of within-category information This paper describes two classes of simple alternatives that can be implemented with any regression software: fractional polynomial regression and spline regression These methods are illustrated in a problem of estimating historical trends in human immunodeficiency virus incidence Fractional polynomial and spline regression are especially valuable when important nonlinearities are anticipated and software for more general nonparametric regression approaches is not available

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Topics: Nonparametric regression (63%), Regression (51%)

972 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2012.08.024
14 Sep 2012-Cell
Abstract: We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

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Topics: Cancer (54%), KRAS (53%), Lung cancer (52%) ... read more

918 Citations


Open accessJournal ArticleDOI: 10.1101/GR.239244.118
Anand Mayakonda1, Anand Mayakonda2, De-Chen Lin3, Yassen Assenov4  +5 moreInstitutions (4)
19 Oct 2018-Genome Research
Abstract: Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of data from somatic mutations entails a number of computational and statistical approaches, requiring usage of independent software and numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers a multitude of analysis and visualization modules that are commonly used in cancer genomic studies, including driver gene identification, pathway, signature, enrichment, and association analyses. Maftools only requires somatic variants in Mutation Annotation Format (MAF) and is independent of larger alignment files. With the implementation of well-established statistical and computational methods, Maftools facilitates data-driven research and comparative analysis to discover novel results from publicly available data sets. In the present study, using three of the well-annotated cohorts from The Cancer Genome Atlas (TCGA), we describe the application of Maftools to reproduce known results. More importantly, we show that Maftools can also be used to uncover novel findings through integrative analysis.

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Topics: Bioconductor (58%)

671 Citations


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