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Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis

Authors
 Jae-Ho Cheong  ;  Han-Kwang Yang  ;  Hyunki Kim  ;  Woo Ho Kim  ;  Young-Woo Kim  ;  Myeong-Cherl Kook  ;  Young-Kyu Park  ;  Hyung-Ho Kim  ;  Hye Seung Lee  ;  Kyung Hee Lee  ;  Mi Jin Gu  ;  Ha Yan Kim  ;  Jinae Lee  ;  Seung Ho Choi  ;  Soonwon Hong  ;  Jong Won Kim  ;  Yoon Young Choi  ;  Woo Jin Hyung  ;  Eunji Jang  ;  Hyeseon Kim  ;  Yong-Min Huh  ;  Sung Hoon Noh 
Citation
 Lancet Oncology, Vol.19(5) : 629-638, 2018 
Journal Title
 Lancet Oncology 
ISSN
 1470-2045 
Issue Date
2018
Abstract
BACKGROUND: Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer. METHODS: In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. FINDINGS: We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83.2% (95% CI 75.2-92.0), 74.8% (69.9-80.1), and 66.0% (60.1-72.4), respectively (p=0.012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73.5-87.1] vs 64.5% [56.8-73.3]; univariate hazard ratio 0.47 [95% CI 0.30-0.75], p=0.0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72.9% [66.5-79.9] in patients who received chemotherapy plus surgery vs 72.5% [65.8-79.9] in patients who only had surgery; 0.93 [0.62-1.38], p=0.71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0.036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. INTERPRETATION: The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. FUNDING: Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.
Full Text
https://www.sciencedirect.com/science/article/pii/S1470204518301086
DOI
10.1016/s1470-2045(18)30108-6
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
김하얀(Kim, Ha Yan)
김현기(Kim, Hyunki) ORCID logo https://orcid.org/0000-0003-2292-5584
노성훈(Noh, Sung Hoon) ORCID logo https://orcid.org/0000-0003-4386-6886
이진애(Lee, Jinae)
정재호(Cheong, Jae Ho) ORCID logo https://orcid.org/0000-0002-1703-1781
최승호(Choi, Seung Ho) ORCID logo https://orcid.org/0000-0002-9872-3594
최윤영(Choi, Yoon Young) ORCID logo https://orcid.org/0000-0002-2179-7851
허용민(Huh, Yong Min) ORCID logo https://orcid.org/0000-0002-9831-4475
형우진(Hyung, Woo Jin) ORCID logo https://orcid.org/0000-0002-8593-9214
홍순원(Hong, Soon Won) ORCID logo https://orcid.org/0000-0002-0324-2414
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/161927
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