Predictive test for chemotherapy response in resectable gastric cancer

a multi-cohort, retrospective analysis

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, WooJin Hyung, Eunji Jang, Hyeseon Kim & 2 others yongmin Huh, Sung Hoon Noh

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 (p interaction =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.

Original languageEnglish
Pages (from-to)629-638
Number of pages10
JournalThe Lancet Oncology
Volume19
Issue number5
DOIs
Publication statusPublished - 2018 May 1

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Stomach Neoplasms
Cohort Studies
Drug Therapy
Adjuvant Chemotherapy
Survival
oxaliplatin
Gastrectomy
Paraffin
Formaldehyde
Genes
Neoplasms
Neoplasm Staging
Computational Biology
Transcriptome
Fluorouracil
Real-Time Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Cheong, J. H., Yang, H. K., Kim, H., Kim, W. H., Kim, Y. W., Kook, M. C., ... Noh, S. H. (2018). Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis. The Lancet Oncology, 19(5), 629-638. https://doi.org/10.1016/S1470-2045(18)30108-6
Cheong, Jae Ho ; Yang, Han Kwang ; Kim, Hyunki ; Kim, Woo Ho ; Kim, Young Woo ; Kook, Myeong Cherl ; Park, Young Kyu ; Kim, Hyung Ho ; Lee, Hye Seung ; Lee, Kyung Hee ; Gu, Mi Jin ; Kim, Ha Yan ; Lee, Jinae ; Choi, Seung Ho ; Hong, Soonwon ; Kim, Jong Won ; Choi, Yoon Young ; Hyung, WooJin ; Jang, Eunji ; Kim, Hyeseon ; Huh, yongmin ; Noh, Sung Hoon. / Predictive test for chemotherapy response in resectable gastric cancer : a multi-cohort, retrospective analysis. In: The Lancet Oncology. 2018 ; Vol. 19, No. 5. pp. 629-638.
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title = "Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis",
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 (p interaction =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.",
author = "Cheong, {Jae Ho} and Yang, {Han Kwang} and Hyunki Kim and Kim, {Woo Ho} and Kim, {Young Woo} and Kook, {Myeong Cherl} and Park, {Young Kyu} and Kim, {Hyung Ho} and Lee, {Hye Seung} and Lee, {Kyung Hee} and Gu, {Mi Jin} and Kim, {Ha Yan} and Jinae Lee and Choi, {Seung Ho} and Soonwon Hong and Kim, {Jong Won} and Choi, {Yoon Young} and WooJin Hyung and Eunji Jang and Hyeseon Kim and yongmin Huh and Noh, {Sung Hoon}",
year = "2018",
month = "5",
day = "1",
doi = "10.1016/S1470-2045(18)30108-6",
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Cheong, JH, Yang, HK, Kim, H, Kim, WH, Kim, YW, Kook, MC, Park, YK, Kim, HH, Lee, HS, Lee, KH, Gu, MJ, Kim, HY, Lee, J, Choi, SH, Hong, S, Kim, JW, Choi, YY, Hyung, W, Jang, E, Kim, H, Huh, Y & Noh, SH 2018, 'Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis', The Lancet Oncology, vol. 19, no. 5, pp. 629-638. https://doi.org/10.1016/S1470-2045(18)30108-6

Predictive test for chemotherapy response in resectable gastric cancer : a multi-cohort, retrospective analysis. / Cheong, Jae Ho; Yang, Han Kwang; Kim, Hyunki; Kim, Woo Ho; Kim, Young Woo; Kook, Myeong Cherl; Park, Young Kyu; Kim, Hyung Ho; Lee, Hye Seung; Lee, Kyung Hee; Gu, Mi Jin; Kim, Ha Yan; Lee, Jinae; Choi, Seung Ho; Hong, Soonwon; Kim, Jong Won; Choi, Yoon Young; Hyung, WooJin; Jang, Eunji; Kim, Hyeseon; Huh, yongmin; Noh, Sung Hoon.

In: The Lancet Oncology, Vol. 19, No. 5, 01.05.2018, p. 629-638.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Predictive test for chemotherapy response in resectable gastric cancer

T2 - a multi-cohort, retrospective analysis

AU - Cheong, Jae Ho

AU - Yang, Han Kwang

AU - Kim, Hyunki

AU - Kim, Woo Ho

AU - Kim, Young Woo

AU - Kook, Myeong Cherl

AU - Park, Young Kyu

AU - Kim, Hyung Ho

AU - Lee, Hye Seung

AU - Lee, Kyung Hee

AU - Gu, Mi Jin

AU - Kim, Ha Yan

AU - Lee, Jinae

AU - Choi, Seung Ho

AU - Hong, Soonwon

AU - Kim, Jong Won

AU - Choi, Yoon Young

AU - Hyung, WooJin

AU - Jang, Eunji

AU - Kim, Hyeseon

AU - Huh, yongmin

AU - Noh, Sung Hoon

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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 (p interaction =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.

AB - 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 (p interaction =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.

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