Unknown,Transcriptomics,Genomics,Proteomics

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Prognostic and Predictive Gene Signature for Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer

ABSTRACT: Background: The JBR.10 trial demonstrated significant survival benefit from adjuvant cisplatin/vinorelbine (ACT) in stage IB-II NSCLC (HR 0.69, p=0.04), but stage IB patients did not derive significant benefit (HR: 0.94, p= 0.79). We hypothesized that expression profiling could identify stage-independent subgroups of patients who might benefit from adjuvant chemotherapy. Methods: Gene expression profiling was conducted on mRNA isolated from frozen JBR.10 tumor samples (either from patients under observation [OBS], or treated with ACT). The minimum gene set that selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified and this gene signature was used to classify patients into high and low risk for death after surgery, and predict ACT effect. The prognostic gene signature was additionally tested on ACT patients and publicly available microarray datasets. Results: A 15-gene signature separated OBS patients into equal high and low risk subgroups with significantly different prognoses (HR 15.02, 95% CI 5.12-44.04, p=0.0001). The signature was prognostic in both stage IB and II. It was also predictive of improved survival following ACT treatment in high-risk patients (HR 0.33, 95% CI 0.17-0.63, p=0.0005), but not in low risk patients (HR 3.67, 95% CI 1.22-11.06, p=0.0133; interaction p=0.0001). The prognostic effect of the signature was validated in two independent gene expression datasets of 169 stage I-II adenocarcinoma and 106 squamous cell carcinoma patients. Conclusions: This microarray-based 15-gene prognostic expression signature is stage and histology independent and may select early stage NSCLC patients who are most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine. Keywords: Expression profiling by microarray; prognosis prediction 90 samples

ORGANISM(S): Homo sapiens

SUBMITTER: Ming-Sound Tsao

PROVIDER: E-GEOD-14814 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer.

Zhu Chang-Qi CQ Ding Keyue K Strumpf Dan D Weir Barbara A BA Meyerson Matthew M Pennell Nathan N Thomas Roman K RK Naoki Katsuhiko K Ladd-Acosta Christine C Liu Ni N Pintilie Melania M Der Sandy S Seymour Lesley L Jurisica Igor I Shepherd Frances A FA Tsao Ming-Sound MS

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100907 29

<h4>Purpose</h4>The JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT.<h4>Patients and methods</h4>Gene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis pat ...[more]

PMID: 20823422

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Project description:Introduction: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented. Methods: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n=71) or no adjuvant treatment (OBS, n=62) [GSE14814] and 2) formalin-fixed paraffin-embedded (FFPE) pre-treatment tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine. Results: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p=0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p=0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR=0.138 (95% CI:0.035-0.537), p=0.004) and multivariate analysis (HR=0.14 (95% CI:0.030-0.6), p=0.0081). No discrimination was found in the OBS cohort (HR=1.328, p=0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p=0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p=0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis. Conclusions: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

Project description:Background: Accurate survival stratification in early-stage NSCLC could inform the use of adjuvant therapy. We developed a clinically-implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables. Methods: Gene expression profiles from 1106 non-squamous NSCLCs were used for generation and internal validation of a 9-gene molecular prognostic index (MPI). Expression of the MPI genes was determined within sorted tumor cell subpopulations. A quantitative PCR (qPCR) assay was developed and validated on an independent cohort of FFPE tissues. A prognostic score using clinical variables was generated using Surveillance Epidemiology and End Results (SEER) data and combined with the MPI. Results: The MPI stratified stage I patients into prognostic categories in four independent validation datasets, including three microarray and one FFPE qPCR cohorts (HR=2.4, 95% CI, 1.8-3.3, P=7x10-9 in the largest microarray cohort; and HR=2.5, 95% CI 1.1-6.0, P=.03 in stage I patients of the qPCR validation cohort). Prognostic genes were expressed in distinct tumor cell subpopulations and expression of genes implicated in cellular proliferation and stem cells portended poor outcomes, while expression of genes involved in normal lung differentiation and immune infiltration was associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR=3.3, 95% CI 2.4-4.6; P=2x10-15 in the largest microarray cohort; and HR=3.6, 95% CI 1.5-8.8, P=.003 in stage I patients of the qPCR validation cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK. Conclusion: The MPI incorporates genes expressed in the tumor and its microenvironment, and designates risk of death for patients with early-stage non-squamous NSCLC. The MPI can be implemented clinically using qPCR assays on FFPE tissues and a composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

Project description:Purpose Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for individual non-small-cell lung cancer (NSCLC) patients. Most current molecular signatures for lung cancer are prognostic only and provide limited information with regard to the functional importance of the genes selected. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefit of ACT in NSCLC. Experimental Design An 18-hub-gene prognosis signature was developed through a systems biology approach using a large NSCLC dataset from the Director’s Challenge Consortium. The prognostic value of this signature was tested in NSCLC patients from UT Lung SPORE cohort and additional five public datasets. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefit in NSCLC. Results We showed that the 18-hub-gene set can robustly predict the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The refined 12-gene functional set was successfully validated in two independent datasets. The predicted benefit group showed significant improvement in survival after ACT (JBR.10 clinical trial data: hazard ratio=0.36, p=0.038; UT Lung SPORE data: hazard ratio=0.34, p=0.017), while the predicted non-benefit group showed no survival improvement. Conclusions This is the first study to integrate genetic aberration, genome-wide RNAi functional data, and mRNA expression data to identify a functional gene set that is predictive for ACT benefits. This 12-gene predictive signature has been validated in two independent NSCLC cohorts. Patients were eligible to enter the study if they underwent curative resection for NSCLC at MD Anderson Cancer Center between December 1996 and June 2007, and patients with radiation therapy were excluded from the study. All tissue samples were obtained by surgical resection from patients who had provided written informed consent. Tissues were stored at −140°C after being snap frozen in liquid nitrogen. Serial sectioning of each sample was used to histologically evaluate tumor and malignant cells content before RNA extraction. The primary tumor tissues from 176 patients were selected randomly from similar samples in the UT Lung SPORE tumor collection based on stringent, predefined quality control procedures before any data analysis, including the presence of ≥70% tumor tissue and ≥50% malignant cells in the frozen tissue used for RNA extraction. In this cohort, 133 patients are adenocarcinomas (ADCs) and 43 patients are squamous cell carcinomas (SCCs); 49 patients received ACT (mainly Carboplatin plus Taxanes) and 127 patients did not receive ACT.

Dataset Information

Prognostic and Predictive Gene Signature for Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer

Publications

Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer.

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