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29-01-2012 | Genetics | Article

Molecular assay predicts early-stage lung cancer prognosis

Abstract

Free abstract

MedWire News: A novel molecular assay developed by US researchers predicts the likelihood for death from early-stage lung cancer more accurately than conventional methods, show results from two independent validation cohorts.

The assay measures the expression of 14 genes in tumor tissue from individual patients. The pattern of gene activity level is then analyzed, yielding a risk score that categorizes the patient as having a high-, intermediate-, or low-risk for mortality following surgical resection.

"This assay provides prognostic differentiation of patients with early-stage disease and might be helpful in the identification of the most appropriate application of treatment guidelines to improve clinical outcomes," write Michael Mann (University of California, San Francisco, USA) and colleagues in The Lancet.

The researchers explain that outcomes after resection of early-stage non-small-cell lung cancer (NSCLC) are poor, even for patients with stage I disease in whom no nodal or other metastatic involvement can be detected at the time of surgery.

They therefore aimed to develop and validate a practical, reliable assay that improves risk stratification in patients with nonsquamous NSCLC who are deemed to have early-stage disease by conventional criteria but who have a high rate of treatment failure after resection.

The 14-gene expression assay was developed in a cohort of 361 patients with nonsquamous NSCLC. It uses quantitative polymerase chain reaction on formalin-fixed paraffin-embedded tissue samples to measure expression of 11 cancer-related target genes (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, and WNT3A) and three reference genes (ESD, TBP, and YAP1).

The assay validated in tissue samples from 433 patients with stage I nonsquamous NSCLC in northern California, and in 1006 patients with stage I-III nonsquamous NSCLC in China.

In the Californian cohort, 5-year overall survival rates decreased significantly with increasing risk category, from 71.4% in the low-risk group to 58.3% and 49.2% in the intermediate- and high-risk groups, respectively.

Similar results were observed in the Chinese cohort, with corresponding mortality rates of 74.1%, 57.3%, and 44.6%.

Multivariate analysis in both cohorts indicated that no standard clinical risk factors - including age, gender, smoking history, histology, and disease stage - could account for the prognostic information provided by the assay.

Furthermore, area under the receiver operating characteristic curve analysis showed that the molecular assay gave significantly better risk discrimination than National Comprehensive Cancer Network Criteria, at c-statistic values of 0.60 versus 0.54.

Mann and co-authors say that a prospective study is now planned in which patients with stage I disease identified as high risk by the molecular assay will be randomly allocated to observation or chemotherapy.

The study "will directly test the effectiveness of the application of guidelines for adjuvant treatment on the basis of this molecular enhancement of risk stratification in patients with stage I disease."

However, it will be some time before any results are available because the team predicts that the accrual phase alone will take between 5 and 7 years.

By Laura Cowen

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