Gene Profiling of Clinical Routine Biopsies and Prediction of Survival in Non–Small Cell Lung Cancer

Baty, Florent; Facompré, Michaël; Kaiser, Sérgio; Schumacher, M.; Pless, Miklos; Bubendorf, Lukas; Savic, Spasenija; Marrer, Estelle; Budach, W.; Buess, Martin; Kehren, Jeanne; Tamm, Michael; Brutsche, Martin

doi:10.1164/rccm.200812-1807oc

Cited by 42 publications

(26 citation statements)

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“…These results seem to be consistent with a more aggressive phenotype for the EGFR-2 and wt/wt-1 high-risk groups, as suggested by their overall higher CIN70 metagene expression, higher number of copy number alterations/amplifications, and association with a poorly differentiated tumor phenotype. In addition, our results, combined with previous reports (26,48,49), show the potential of applying prognostic/predictive gene expression signatures to small biopsy specimens from patients with nonoperable disease, provided that enough tissue material could be sampled.…”

Section: Discussionsupporting

confidence: 70%

Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

Planck

Isaksson

Veerla

et al. 2013

Clinical Cancer Research

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Purpose: In lung adenocarcinoma, EGFR and KRAS mutations dominate the mutational spectrum and have clear therapeutic implications. We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS wild-type (EGFRwt/KRASwt) adenocarcinomas.Experimental Design: Gene expression profiles from 1,186 adenocarcinomas, including 215 EGFRmutated, 84 KRAS-mutated, and 219 EGFRwt/KRASwt tumors, were assembled and divided into four discovery (n ¼ 522) and four validation cohorts (n ¼ 664). Subgroups within the mutation groups were identified by unsupervised consensus clustering, significance analysis of microarrays (SAM) analysis, and centroid classification across discovery cohorts. Genomic alterations in identified mutation subgroups were assessed by integration of genomic profiles for 158 cases with concurrent data. Multicohort expression subgroup predictors were built for each mutation group using the discovery cohorts, and validated in the four validation cohorts.Results: Consensus clustering within the mutation groups identified reproducible transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt tumors, but not in KRAS-mutated tumors. Subgroups displayed differences in genomic alterations, clinicopathologic characteristics, and overall survival. Multicohort gene signatures derived from the mutation subgroups added independent prognostic information in their respective mutation group, for adenocarcinoma in general and stage I tumors specifically, irrespective of mutation status, when applied to the validation cohorts. Consistent with their worse clinical outcome, high-risk subgroups showed higher expression of proliferation-related genes, higher frequency of copy number alterations/amplifications, and association with a poorly differentiated tumor phenotype.Conclusions: We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathologic characteristics and patient outcome, not limited to a mutation-specific setting.

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Section: Discussionsupporting

confidence: 70%

Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

Planck

Isaksson

Veerla

et al. 2013

Clinical Cancer Research

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“…Attempts to detect gene expression in bronchoscopic or fine needle aspiration biopsies have emerged lately and not yet been applied broadly. Encouragingly, several recent studies have suggested that the limited amount of bronchoscopic or fine needle aspiration biopsies would allow establishing gene profiling and molecular tumor classification and might become a powerful adjunct for the daily clinical practice [31, 32]. Recently, Suwinski et al [33] have successfully integrated multiple molecular signatures from bronchoscopic biopsies into predicting clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

A prospective study of biomarker-guided chemotherapy in patients with non-small cell lung cancer

Zhang

Zhu

Zhang

et al. 2014

Cancer Chemother Pharmacol

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Purpose To assess the therapeutic value of biomarker-guided chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).MethodsEighty-five NSCLC patients at stage IIIb or IV were divided into two groups based on the feasibility of biomarker analysis. Group A included patients with biomarker data (n = 41); Group B were patients without biomarker results (n = 44). Tumor samples obtained by fiberoptic bronchoscopy and computerized tomography-guided needle biopsy were analyzed by immunohistochemistry for intratumoral level of excision repair cross-complementing gene 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and β-tubulin III. Chemotherapy regimens in Group A were determined according to the status of molecular signatures, whereas a standard gemcitabine plus cisplatin regimen was used for Group B. Tumor response, patient survival, and adverse effects were monitored for both groups.ResultsThe overall response rate, defined as complete response plus partial response, was 56.1 % for Group A, significantly higher than that in Group B (31.8 %; P = 0.024). The median progression-free survival (PFS) time was 5.2 months for Group A, significantly longer than that of Group B (4.1 months; P = 0.026). The 1-year survival rate of Group A was 65.9 %, significantly higher than that of Group B (40.9 %; P = 0.021), whereas the median overall survival times were 13.5 versus 12.5 months for Groups A and B, respectively (P = 0.483). The adverse effects in the two groups were essentially the same.ConclusionsBiomarker-tailored chemotherapy based on ERCC1, RRM1, and β-tubulin III expression showed significantly increased response rate, median PFS time, and 1-year survival rate in patients with NSCLC.

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“…The gene expression profiles obtained from this set of microarray data are derived, however, from highly heterogeneous clinical biopsies consisting of both tumor and activated stromal cells. In a previous study, Baty and colleagues revealed that prediction of survival was independent of tumor cell content present in each NSCLC biopsy (22). This suggests a strong predictive contribution from the tumor microenvironment compartments in NSCLC.…”

Section: Introductionmentioning

confidence: 95%

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non–Small Cell Lung Cancer Patients (SAKK 19/05 trial)

Franzini

Baty

Macovei

et al. 2015

Clinical Cancer Research

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Purpose: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients.Experimental Design: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumorshrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome.Results: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P ¼ 0.005), and median TTP 6.9 months versus 2.9 months (P ¼ 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P ¼ 0.001).Conclusions: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.

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Gene Profiling of Clinical Routine Biopsies and Prediction of Survival in Non–Small Cell Lung Cancer

Abstract: Integration of functional genomics from small bronchoscopic biopsies allows molecular tumor classification and prediction of survival in NSCLC and might become a powerful adjunct for the daily clinical practice.

Cited by 42 publications

References 42 publications

Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

A prospective study of biomarker-guided chemotherapy in patients with non-small cell lung cancer

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non–Small Cell Lung Cancer Patients (SAKK 19/05 trial)

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