Analytical Validation of a Practical Molecular Assay Prognostic of Survival in Nonsquamous Non–Small Cell Lung Cancer

Kratz, Johannes R.; Tham, Patrick T.; Mulvihill, Michael S.; Ziaei, Fatemeh; Ray, M. Roshni; Hurst, Jerry W.; Segal, Mark R.; Berryman, David M.; Chu, W. K.; He, Biao; Jablons, David M.; Mann, Michael J.

doi:10.1097/pdm.0b013e318273fb61

Cited by 20 publications

(21 citation statements)

References 28 publications

(33 reference statements)

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“…These are myPlan® Lung Cancer (Myriad, Salt Lake City, UT) and Pervenio™ Lung RS platform (Life Technologies, West Sacrament, CA. Both signatures, focused on adenocarcinoma tumors, stratify patients into high- and low-risk groups with hazards ratios of approximately 1.5-2 [ 50 , 51 ] and 2 [ 52 , 53 ], respectively. However, we propose a simpler evaluation strategy (pERK in adenocarcinoma, and nuclear p53 in squamous cell carcinoma) for prognostic biomarkers using immunohistochemistry, a technique routinely performed in clinics and feasible in one FFPE sample sheet and thus requiring a very limited amount of tissue.…”

Section: Discussionmentioning

confidence: 99%

Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer

et al. 2018

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Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome. We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034). Regarding the prognostic potential of the expression of these proteins, high pERK levels proved to be an independent prognostic factor for overall (p<0.001) and progression-free survival (p<0.001) in adenocarcinoma patients, but not in those from the squamous histology, and high p53 nuclear levels were identified as independent prognostic factor for progression-free survival (p=0.031) only in squamous cell carcinoma patients. We propose a role as early prognostic biomarkers for pERK protein levels in adenocarcinoma, and for nuclear p53 levels in squamous cell lung carcinoma. The determination of these potential biomarkers in the adequate histologic context may predict the outcome of early stage NSCLC patients, and may offer a therapeutic opportunity to enhance survival of these patients.

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Section: Discussionmentioning

confidence: 99%

Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer

et al. 2018

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“…To date, most of the published prognostic profiles are gene expression profiles based on RNA levels [ 5 – 7 ]. In our view, our prognostic signature based on CNA may have stronger prospects of clinical utility due to the higher stability of DNA when compared to RNA.…”

Section: Discussionmentioning

confidence: 99%

“…A large number of studies have been developed to define a prognostic genomic signature in early stage lung cancer, most of them based on mRNA expression microarrays [ 5 – 7 ]. However, although clinical parameters are validated predictors for OS, most prognostic profiles do not provide a decision making algorithm combining both the molecular markers and the clinicopathologic features (sex, age, stage, etc.)…”

Section: Introductionmentioning

confidence: 99%

“…The need of a robust and reproducible genetic profile is especially apparent for SCC, as most of the genetic prognostic profiles described so far for lung cancer patients are restricted to ADC histology [ 8 ]. Indeed, the two commercially available prognostic tests for lung cancer (both RNA-based) are intended for ADC patients and are not valid for SCC [ 5 , 7 ]. Despite the efforts to characterize prognosis of SCC patients [ 9 – 11 ], the published information has not been translated into a validated clinically useful tool, partly due to the existence of several biological subtypes within the squamous lung tumors [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

et al. 2015

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BackgroundThe development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies.ResultsA new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC).ConclusionThe present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1935-0) contains supplementary material, which is available to authorized users.

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“…A subsequent study assessed the analytical validity of the assay by evaluating its precision and reproducibility in 2 large international cohorts [51]. A clinical trial to evaluate benefit of adjuvant therapy in high risk stage I non-squamous NSCLC identified by the signature has been initiated (NCT01817192 at www.clinicaltrials.gov) [24].…”

Section: Omics-based Diagnostic and Prognostic Lung Cancer Biomarkersmentioning

confidence: 99%

Integration of multiple “OMIC” biomarkers: A precision medicine strategy for lung cancer

Robles

Harris

2017

Lung Cancer

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More than half of all new lung cancer diagnoses are made in patients with locally advanced or metastatic disease, at which point therapeutic options are scarce. It is anticipated, however, that the widespread use of Low-Dose Computed Tomography (LDCT) screening, will lead to a greater proportion of lung cancers being diagnosed at an early, operable, stage. Still, the overall rate of recurrence for surgically treated Stage I lung cancer patients is up to 30% within 5 years of diagnosis. Thus, the identification and clinical application of biomarkers of early stage lung cancer is a pressing medical need. The integrative analysis of “omic,” clinical and epidemiological data for single patients is a core principle of precision medicine. Through rigorous bioinformatics and statistical analyses we have identified biomarkers of early-stage lung cancer based on DNA methylation, expression of mRNA and miRNA, inflammatory cytokines, and urinary metabolites. Beyond a more comprehensive understanding of the molecular taxonomy of lung cancer, these biomarkers can have very practical implications in the context of unmet clinical needs of early stage lung cancer patients: First, current guidelines for LDCT screening broadly include individuals based on age and history of heavy smoking. Tumor-derived circulating biomarkers in the blood and urine associated with lung cancer risk could narrow and prioritize individuals for LDCT screening. Second, a high number of nodules are identified by LDCT, of which fewer than 5% are finally diagnosed as lung cancer. Biomarkers may help discriminate malignant nodules from benign or indolent lesions. Third, the expected rise in the numbers of lung cancer patients diagnosed at an early stage will necessitate new treatment options. Circulating, urinary and tissue-based biomarkers that molecularly categorize Stage I patients after tumor resection can help identify high-risk patients who may benefit from adjuvant chemotherapy or innovative immunotherapy regimens.

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Analytical Validation of a Practical Molecular Assay Prognostic of Survival in Nonsquamous Non–Small Cell Lung Cancer

Cited by 20 publications

References 28 publications

Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer

Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer

Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

Integration of multiple “OMIC” biomarkers: A precision medicine strategy for lung cancer

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