Yonsei Med J.  2019 Feb;60(2):132-139. 10.3349/ymj.2019.60.2.132.

Single Patient Classifier Assay, Microsatellite Instability, and Epstein-Barr Virus Status Predict Clinical Outcomes in Stage II/III Gastric Cancer: Results from CLASSIC Trial

• Roh CK
• Choi YY
• Choi S
• Seo WJ
• Cho M
• Jang E
• Son T
• Kim HI
• Kim H
• Hyung WJ
• Huh YM
• Noh SH
• Cheong JH

• KMID: 2431629
• DOI: http://doi.org/10.3349/ymj.2019.60.2.132

Abstract

PURPOSE
Clinical implications of single patient classifier (SPC) and microsatellite instability (MSI) in stage II/III gastric cancer have been reported. We investigated SPC and the status of MSI and Epstein-Barr virus (EBV) as combinatory biomarkers to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer.
MATERIALS AND METHODS
Tumor specimens and clinical information were collected from patients enrolled in CLASSIC trial, a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. The results of nine-gene based SPC assay were classified as prognostication (SPC-prognosis) and prediction of chemotherapy benefit (SPC-prediction). Five quasimonomorphic mononucleotide markers were used to assess tumor MSI status. EBV-encoded small RNA in situ hybridization was performed to define EBV status.
RESULTS
There were positive associations among SPC, MSI, and EBV statuses among 586 patients. In multivariate analysis of disease-free survival, SPC-prognosis [hazard ratio (HR): 1.879 (1.101-3.205), 2.399 (1.415-4.067), p=0.003] and MSI status (HR: 0.363, 95% confidence interval: 0.161-0.820, p=0.015) were independent prognostic factors along with age, Lauren classification, TNM stage, and chemotherapy. Patient survival of SPC-prognosis was well stratified regardless of EBV status and in microsatellite stable (MSS) group, but not in MSI-high group. Significant survival benefit from adjuvant chemotherapy was observed by SPC-Prediction in MSS and EBV-negative gastric cancer.
CONCLUSION
SPC, MSI, and EBV statuses could be used in combination to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer.

Keyword

Gastric cancer; microsatellite instability; single patient classifier; EBV

MeSH Terms

Biomarkers
Capecitabine
Chemotherapy, Adjuvant
Classification
Disease-Free Survival
Drug Therapy
Herpesvirus 4, Human*
Humans
In Situ Hybridization
Microsatellite Instability*
Microsatellite Repeats*
Multivariate Analysis
Prognosis
RNA
Stomach Neoplasms*
Biomarkers
Capecitabine
RNA

Figure

• 

  Fig. 1 Kaplan-Meier and log-rank comparisons of DFS in patients with stage II/III gastric cancer according to (A) status of MSI and SPC-prognosis, (B) status of EBV and SPC-prognosis, (C) EBV status and treatment. DFS, disease-free survival; MSI, microsatellite instability; SPC, single patient classifier; MSS, microsatellite stable; MSI-L, microsatellite instability-low; MSI-H, microsatellite instability-high; EBV, Epstein-Barr virus; CTx, adjuvant chemotherapy (capecitabine plus oxaliplatin).

• 

  Fig. 2 Kaplan-Meier and log-rank comparisons of DFS in patients with stage II/III gastric cancer following treatment in subgroups of (A) MSS/MSI-L and SPC responder group, (B) MSS/MSI-L and SPC non-responder group, (C) EBV-negative and SPC responder group, and (D) EBV-negative and SPC non-responder group. DFS, disease-free survival; CTx, adjuvant chemotherapy (capecitabine plus oxaliplatin); MSS, microsatellite stable; MSI-L, microsatellite instability-low; SPC, single patient classifier; EBV, Epstein-Barr virus.

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