Originally published as JCO Early Release 10.1200/JCO.2005.03.3399 on March 20 2006

This Article Full Text Full Text (PDF) Supplementary Data Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Petty, R. D. Articles by Collie-Duguid, E. S.R. Search for Related Content PubMed PubMed Citation Articles by Petty, R. D. Articles by Collie-Duguid, E. S.R.

Tumor Transcriptome Reveals the Predictive and Prognostic Impact of Lysosomal Protease Inhibitors in Non–Small-Cell Lung Cancer

Russell D. Petty, Keith M. Kerr, Graeme I. Murray, Marianne C. Nicolson, Patrick H. Rooney, Donald Bissett, Elaina S.R. Collie-Duguid

From the Oncology Research Group, Department of Medicine and Therapeutics, Institute of Medical Sciences, School of Medicine, University of Aberdeen; Department of Oncology, ANCHOR Unit, Aberdeen Royal Infirmary; Department of Pathology, University of Aberdeen, Aberdeen, United Kingdom.

Address reprint requests to Elaina Collie-Duguid BSc (Hons), PhD, or Russell Petty, BMSc (Hons), MBCh, BMRCF (UK), Department of Medicine and Therapeutics, IMS, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom; e-mail: e.collie-duguid{at}abdn.ac.uk or r.d.petty{at}abdn.ac.uk

PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non–small-cell lung cancer (NSCLC).

METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.

RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = –0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).

CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

R.D.P. is supported by a Clinical Research Fellowship from The Friends of ANCHOR, Aberdeen, United Kingdom. E.C.D. is supported by the Association for International Cancer Research. This work was also supported by grants from National Health Service Grampian University Hospitals Trust Endowments, Tenovus Scotland, and The James Alexander Mearns' Trust.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.