A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial.
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Date
2018-12-01Author
Smyth, EC
Nyamundanda, G
Cunningham, D
Fontana, E
Ragulan, C
Tan, IB
Lin, SJ
Wotherspoon, A
Nankivell, M
Fassan, M
Lampis, A
Hahne, JC
Davies, AR
Lagergren, J
Gossage, JA
Maisey, N
Green, M
Zylstra, JL
Allum, WH
Langley, RE
Tan, P
Valeri, N
Sadanandam, A
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. PATIENTS AND METHODS: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. RESULTS: Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. CONCLUSIONS: These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.
Collections
Subject
Esophagus
Stomach
Humans
Esophageal Neoplasms
Stomach Neoplasms
Neoplasm Recurrence, Local
Antineoplastic Combined Chemotherapy Protocols
Prognosis
Treatment Outcome
Chemotherapy, Adjuvant
Neoadjuvant Therapy
Esophagectomy
Gastrectomy
Risk Assessment
Prospective Studies
Gene Expression Profiling
Adult
Aged
Middle Aged
Female
Male
Kaplan-Meier Estimate
Transcriptome
Biomarkers, Tumor
Research team
Medicine (RMH Smith Cunningham)
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Systems and Precision Cancer Medicine
Language
eng
License start date
2018-12
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2018, 29 (12), pp. 2356 - 2362
Publisher
OXFORD UNIV PRESS