Integrated molecular portrait of non-small cell lung cancers

Lazar, Vladimir; Suo, Chen; Oréar, Cédric; Oord, Joost van den; Balogh, Zsuzsanna; Guégan, Justine; Job, Bastien; Meurice, Guillaume; Ripoche, Hugues; Calza, Stefano; Hasmats, Johanna; Lundeberg, Joakim; Lacroix, Ludovic; Vielh, Philippe; Dufour, Fabienne; Lehtiö, Janne; Napieralski, Rudolf; Eggermont, Alexander M.M.; Schmitt, Manfred; Cadranel, Jacques; Besse, Benjamin; Girard, Philippe; Blackhall, Fiona; Validire, Pierre; Soria, Jean‐Charles; Dessen, Philippe; Hansson, Johan; Pawitan, Yudi

doi:10.1186/1755-8794-6-53

Cited by 53 publications

(51 citation statements)

References 37 publications

(38 reference statements)

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“…Using gene expression profiling techniques, prior studies also demonstrated that adenocarcinoma and squamous cell NSCLCs have different expression portfolios (2,14), which is in line with our observation that the association between TP53 mutations and increased VEGF-A transcripts appears specific for adenocarcinoma of the lung. It is conceivable that the improved outcome that was previously reported by our group (5) in bevacizumab-treated patients who harbored TP53 mutations versus wild-type TP53 is due to the association between TP53 mutations and higher VEGF-A, the target for bevacizumab.…”

Section: Resultssupporting

confidence: 77%

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VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Schwaederlé¹,

Lazar

Validire³

et al. 2015

Cancer Research

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Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P ¼ 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types. Cancer Res; 75(7);

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Section: Resultssupporting

confidence: 77%

“…A diagnosis of NSCLC carries a grim prognosis; 5-year survival is less than 15% (2). Bevacizumab is an antibody that targets vascular endothelial growth factor-A (VEGF-A).…”

Section: Introductionmentioning

confidence: 99%

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Schwaederlé¹,

Lazar

Validire³

et al. 2015

Cancer Research

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“…Finally, the biomarker testing was limited to NGS. Integration of transcriptomic and/or proteomic biomarkers may provide additional information in future studies (39,40).…”

Section: Discussionmentioning

confidence: 99%

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience

Schwaederlé¹,

Parker²,

Schwab³

et al. 2016

Molecular Cancer Therapeutics

159

136

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By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy, 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved stable disease (SD) ! 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P ¼ 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P ¼ 0.009); however, this shortening was not observed in the matched patients (P ¼ 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/ PFS1 ratio !1.3 compared with 19.3% of patients (11/57) in the unmatched group (P ¼ 0.004 univariable and P ! 0.057 in multivariable/propensity score analysis). Patients with a "matching-score" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was 0.2, (P ¼ 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ! 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743-52. Ó2016 AACR.

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“…Non-small cell lung cancer (NSCLC) is the primary histological classification of lung cancer [2]. There are three histologic subtypes of NSCLC: squamous cell carcinoma (SCC), adenocarcinoma (AC), and large-cell carcinoma (LCC) [3]. Overall, 5-year survival of NSCLC has remained at 15 % for the last two decades and the prognosis of patients with NSCLC principally correlates with tumor invasion and metastasis [4].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of LATS2 in non-small cell lung cancer promoted the growth and motility of cancer cells

Yao

Liu

et al. 2014

Tumor Biol.

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LATS2 (Large tumor suppressor) has been reported to be dys-regulated in several cancer types. However, its function in non-small cell lung cancer (NSCLC) remains poorly understood. Here, it was found that the expression level of LATS2 was decreased in NSCLC tissues. Moreover, forced expression of LATS2 in NSCLC cells inhibited cell growth and migration, while knockdown of the expression of LATS2 promoted the tumorigenicity of NSCLC cells. Mechanistically, LATS2 was found to negatively regulate NF-κB signaling in NSCLC cells. Taken together, our study suggested that down-regulation of LATS2 was very important in the progression of NSCLC, and restoring the function of LATS2 might be a promising therapeutic strategy for NSCLC.

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Integrated molecular portrait of non-small cell lung cancers

Cited by 53 publications

References 37 publications

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience

Down-regulation of LATS2 in non-small cell lung cancer promoted the growth and motility of cancer cells

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