<i>Helicobacter pylori</i> infection is associated with favorable outcome in advanced gastric cancer patients treated with S‐1 adjuvant chemotherapy

Nishizuka, Satoshi; Tamura, Gen; Nakatochi, Masahiro; Fukushima, Noriyoshi; Ohmori, Yukimi; Sumida, Chihiro; Iwaya, Takeshi; Takahashi, Takashi; Koeda, Keisuke

doi:10.1002/jso.24977

Cited by 24 publications

(38 citation statements)

References 43 publications

(111 reference statements)

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“…Infection with Helicobacter pylori ( H. pylori ), a bacterial carcinogen, contributed to ~75% of the global gastric cancer burden and its eradication therapy during early stages of the precancerous cascade can prevent gastric cancer development 2 . Recently, a multicenter study further confirmed that post-operative S-1 (oral fluoropyrimidine comprised of tegafur, gimeracil, and oteracil) adjuvant chemotherapy led to an increase in both overall survival and disease-free survival in H. pylori -positive advanced gastric cancer patients than H. pylori -negative patients 3 . Thus, unveiling the precise mechanisms that regulate cancer development in response to H. pylori infection is urgently required for improving the prognosis of gastric cancer patients.…”

Section: Introductionmentioning

confidence: 91%

The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway

et al. 2021

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Helicobacter pylori (H. pylori) is listed as a class I carcinogen in human gastric cancer; however, the underlying mechanisms are poorly understood. In this study, we identified Protogenin (PRTG) was upregulated in both gastric cancer tissues and H. pylori-infected tissues by analyzing dysregulated genes in TCGA and GEO databases. Importantly, upregulated PRTG predicted poor prognosis of gastric cancer patients and integrative analysis revealed that PRTG served as an oncogenic protein in gastric cancer and was required for H. pylori-mediated tumorigenic activities in in vitro cellular and in vivo tumor-bearing mouse models. Mechanistically, H. pylori infection enhanced PRTG expression by promoting transcriptional factor ZEB1 stabilization and recruitment to the PRTG promoter, and which then activated the sub-following cGMP/PKG signaling pathway in bioinformatic and cellular studies. Cellular studies further confirmed that PRTG depended on activating cGMP/PKG axis to promote proliferation, metastasis, and chemoresistance of gastric cancer cells. The PKG inhibitor KT5823 played synergistic anti-tumor effects with cisplatin and paclitaxel to gastric cancer cells in in vitro cellular and in vivo tumor-bearing mouse models. Taken together, our findings suggested that H. pylori infection depends on ZEB1 to induce PRTG upregulation, and which leading to the development and progression of gastric cancer through activating cGMP/PKG signaling pathway. Blocking PRTG/cGMP/PKG axis, therefore, presents a promising novel therapeutic strategy for gastric cancer.

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Section: Introductionmentioning

confidence: 91%

The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway

et al. 2021

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“…These results suggested that the TP53 codon 72 polymorphisms could be a useful index to assess the efficacy of postoperative adjuvant chemotherapy using S‐1, an oral fluoropyrimidine . However, the TP53 codon 72 polymorphism did not appear to be a strong biomarker for predicting S‐1 efficacy in surgery alone and S‐1 treated stage II/III patients with gastric cancer, suggesting that 5‐FU sensitivity in gastric cancer cell lines may not exclusively depend on a TP53 codon 72 polymorphism . We then hypothesized that the TP53 genotype might have simply reflected the degree of biological malignancy.…”

Section: Discussionmentioning

confidence: 98%

“…The study included 658 patients who underwent gastrectomy with curative intent (R0 surgery) from October 2000 to November 2009 followed by survival outcome survey until April 2014. The patients were histologically diagnosed as primary adenocarcinoma of the stomach and enrolled in the Northern Japan Gastric Cancer Study Consortium (NCT 01905969) . Formalin fixed paraffin embedded (FFPE) tissue samples and corresponding patient information were collected.…”

Section: Methodsmentioning

confidence: 99%

Recurrence risk evaluation in T1N1M0/T2N0M0/T3N0M0 gastric cancer with TP53 codon 72 polymorphisms

Ohmori

Nomura

Fukushima

et al. 2019

Journal of Surgical Oncology

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Background: Postoperative adjuvant chemotherapy is not indicated for T1N1M0/ T2N0M0/T3N0M0 gastric cancer. However, approximately 10% to 30% of these patients experience recurrence and metastasis.Methods: Among 658 patients with gastric cancer who received gastrectomy with curative intent, 130 T1N1M0/T2N0M0 and 73 T3N0M0 patients were enrolled.Overall survival (OS) and relapse-free survival (RFS) were analyzed based on TP53 codon 72 polymorphisms Arg/Arg, Arg/Pro, and Pro/Pro. The hazard ratio (HR) for each subgroup was compared by TP53 codon 72 polymorphisms.Results: Of the 189 patients for whom polymorphism analysis results were available, the 5-and 10-year OS was 84.9% and 65.1%, respectively. The 5-and 10-year RFS was 81.8% and 65.4%, respectively. When the study cohort was divided into two groups according to polymorphism status (ie, "Arg/Arg and Arg/Pro" vs Pro/Pro), both the OS (HR, 2.799; 95% confidence interval [CI], 1.071-7.315; P = .036) and RFS (HR, 2.639; 95% CI, 1.025-6.794; P = .044) of the Pro/Pro group were significantly lower than those for the Arg/Arg and Arg/Pro groups across the entire observation period. Conclusions:The TP53 codon 72 Pro/Pro polymorphism may isolate a relatively high-risk patient group in T1N1M0/T2N0M0/T3N0M0 gastric cancer. K E Y W O R D S gastric cancer, postoperative adjuvant chemotherapy, T1N1M0/T2N0M0/T3N0M0, TP53 codon 72 polymorphism Members of Northern Gastric Cancer Study Consortium:

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“…[26,27] However, Nishizuka et al reported that H. pyloriinfected patients had superior survival rates when treated with adjuvant S-1, which was compatible with our results. [28] Host antitumor immunity may be enhanced by H. pylori infection and uoropyrimidine-mediated eradication of myeloid-derived suppressor cells, which may contribute to a survival advantage. [29] Furthermore, we noticed that the survival outcomes in stage IB-IIIA or N0-1 disease were better with S-1, whereas platinum-based doublets led to additional bene ts in the more advanced diseases.…”

Section: Factors Associated With Adjuvant S-1mentioning

confidence: 99%

Surgery Alone, Adjuvant Tegafur/gimeracil/octeracil (S-1), or Platinum-based Chemotherapies For Resectable Gastric Cancer: Real-world Experience and A Propensity Score Matching Analysis

Yen

Shan

Chao

et al. 2021

Preprint

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Background: Adjuvant chemotherapy has changed the paradigm in resectable gastric cancer. S-1 is an oral chemotherapeutic with promising efficacy in Asia. However, comparisons with close observation or platinum-based doublets post D2 gastrectomy have been less reported.Methods: We retrospectively evaluated patients with D2-dissected stage IB-III gastric cancer who received S-1 (S-1, n=64), platinum-based doublets (P, n=95) and operation with close observation (OBS, n=110) from Jan 2013 to Oct 2018. A propensity score matching was used to compare for recurrence-free (RFS) and overall survivals (OS). Adverse reactions, dosage, and associated factors for S-1 are also discussed.Results: In a median follow-up of 42.5 months, Group S-1 had a comparable survival to that of P and OBS. (median RFS/OS: S-1 vs. P, 24.4/37.4 vs. 39.1/62.1 months, HR=1.12/1.22, p=0.667/0.514; S-1 vs. OBS, 23.6/37.4 vs. 24.0/64.6 months, HR=1.17/1.23, p=0.554/0.499). However, in patients with N2-3 or stage IIIB/IIIC disease, P significantly improved survival as compared with S-1. Conversely, S-1 was comparable to P and superior to OBS in stage IB-IIIA or N0-1 disease. S-1 was well-tolerated with a relative dose intensity of 73.6%, a median duration of 8.3 months and associated with less adverse reactions as compared with P. In the subgroup analysis, P was favored in stage III, N2-3 or T3-4 disease wherase patients with Helicobacter Pylori infection had a better survival when treated with S-1.Conclusions: Adjuvant S-1 correlated with comparable survival rates but fewer adverse reactions as compared with platinum-based doublets. Patients with low to moderate risk of recurrence and Helicobacter pylori infection derived benefits from S-1 while platinum-based doublets were favored in advanced cases. The study provides additional information about adjuvant S-1 in patients with selected risk of recurrence.

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Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S‐1 adjuvant chemotherapy

Abstract: The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

Cited by 24 publications

References 43 publications

The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway

The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway

Recurrence risk evaluation in T1N1M0/T2N0M0/T3N0M0 gastric cancer with TP53 codon 72 polymorphisms

Surgery Alone, Adjuvant Tegafur/gimeracil/octeracil (S-1), or Platinum-based Chemotherapies For Resectable Gastric Cancer: Real-world Experience and A Propensity Score Matching Analysis

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