Statin Use Decreases the Risk of Metachronous Gastric Cancer in Patients without Helicobacter pylori Infection
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics of the Study Cohort
2.2. Factors Associated with Metachronous GC
2.3. Duration and Dose-Response Effects of Statin Use on the Occurrence of Metachronous GC
3. Discussion
4. Materials and Methods
4.1. Study Design and Patient Selection
4.2. Study Outcomes
4.3. Statin Exposure
4.4. Covariates
4.5. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
- Thrift, A.P.; El-Serag, H.B. Burden of Gastric Cancer. Clin. Gastroenterol. Hepatol. 2020, 18, 534–542. [Google Scholar] [CrossRef]
- Maehata, Y.; Nakamura, S.; Fujisawa, K.; Esaki, M.; Moriyama, T.; Asano, K.; Fuyuno, Y.; Yamaguchi, K.; Egashira, I.; Kim, H.; et al. Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer. Gastrointest. Endosc. 2012, 75, 39–46. [Google Scholar] [CrossRef] [PubMed]
- Kwon, Y.H.; Heo, J.; Lee, H.S.; Cho, C.M.; Jeon, S.W. Failure ofHelicobacter pylorieradication and age are independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer in 283 patients. Aliment. Pharmacol. Ther. 2014, 39, 609–618. [Google Scholar] [CrossRef]
- Correa, P.; Piazuelo, M.B.; Camargo, M.C. The future of gastric cancer prevention. Gastric Cancer 2004, 7, 9–16. [Google Scholar] [CrossRef]
- A Helicobacter and Cancer Collaborative Group Gastric cancer and Helicobacter pylori: A combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001, 49, 347–353. [CrossRef] [PubMed] [Green Version]
- Lee, Y.-C.; Chiang, T.-H.; Chou, C.-K.; Tu, Y.-K.; Liao, W.-C.; Wu, M.-S.; Graham, D.Y. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterol. 2016, 150, 1113–1124. [Google Scholar] [CrossRef] [Green Version]
- Bae, S.E.; Jung, H.-Y.; Kang, J.; Park, Y.S.; Baek, S.; Jung, J.-H.; Choi, J.Y.; Kim, M.-Y.; Ahn, J.Y.; Choi, K.-S.; et al. Effect of Helicobacter pylori Eradication on Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasm. Am. J. Gastroenterol. 2014, 109, 60–67. [Google Scholar] [CrossRef] [PubMed]
- Choi, I.J.; Kook, M.-C.; Kim, Y.-I.; Cho, S.-J.; Lee, J.Y.; Kim, C.G.; Park, B.; Nam, B.-H. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N. Engl. J. Med. 2018, 378, 1085–1095. [Google Scholar] [CrossRef]
- Boudreau, D.M.; Yu, O.; Johnson, J. Statin use and cancer risk: A comprehensive review. Expert Opin. Drug Saf. 2010, 9, 603–621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Singh, S.; Singh, A.G.; Singh, P.P.; Murad, M.H.; Iyer, P.G. Statins Are Associated With Reduced Risk of Esophageal Cancer, Particularly in Patients With Barrett’s Esophagus: A Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol. 2013, 11, 620–629. [Google Scholar] [CrossRef] [Green Version]
- Pisanti, S.; Picardi, P.; Ciaglia, E.; D’Alessandro, A.; Bifulco, M. Novel prospects of statins as therapeutic agents in cancer. Pharmacol. Res. 2014, 88, 84–98. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Lee, S.H.; Hur, K.Y.; Woo, S.Y.; Kim, S.W.; Kang, W.K. Statins and the risk of gastric cancer in diabetes patients. BMC Cancer 2012, 12, 596. [Google Scholar] [CrossRef] [Green Version]
- Graaf, M.R.; Beiderbeck, A.B.; Egberts, A.C.G.; Richel, D.J.; Guchelaar, H.-J. The Risk of Cancer in Users of Statins. J. Clin. Oncol. 2004, 22, 2388–2394. [Google Scholar] [CrossRef]
- Abe, S.; Oda, I.; Suzuki, H.; Nonaka, S.; Yoshinaga, S.; Nakajima, T.; Sekiguchi, M.; Mori, G.; Taniguchi, H.; Sekine, S.; et al. Long-term surveillance and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection. Endoscopy 2015, 47, 1113–1118. [Google Scholar] [CrossRef] [PubMed]
- Kato, M.; Nishida, T.; Yamamoto, K.; Hayashi, S.; Kitamura, S.; Yabuta, T.; Yoshio, T.; Nakamura, T.; Komori, M.; Kawai, N.; et al. Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: A multicentre retrospective cohort study by Osaka University ESD study group. Gut 2012, 62, 1425–1432. [Google Scholar] [CrossRef]
- Min, B.-H.; Kim, E.R.; Kim, K.-M.; Park, C.K.; Lee, J.H.; Rhee, P.-L.; Kim, J.J. Surveillance strategy based on the incidence and patterns of recurrence after curative endoscopic submucosal dissection for early gastric cancer. Endoscopy 2015, 47, 784–793. [Google Scholar] [CrossRef] [Green Version]
- Pyo, J.H.; Lee, H.; Min, B.-H.; Lee, J.H.; Choi, M.G.; Sohn, T.S.; Bae, J.M.; Kim, K.M.; Ahn, J.H.; Carriere, K.C.; et al. Long-Term Outcome of Endoscopic Resection vs. Surgery for Early Gastric Cancer: A Non-inferiority-Matched Cohort Study. Am. J. Gastroenterol. 2016, 111, 240–249. [Google Scholar] [CrossRef] [PubMed]
- Ryu, S.J.; Kim, B.-W.; Kim, B.G.; Kim, J.H.; Kim, J.S.; Park, J.-M.; Oh, J.-H.; Kim, T.H.; Park, S.-M.; Park, C.H.; et al. Endoscopic submucosal dissection versus surgical resection for early gastric cancer: A retrospective multicenter study on immediate and long-term outcome over 5 years. Surg. Endosc. 2016, 30, 5283–5289. [Google Scholar] [CrossRef]
- Park, C.H.; Lee, H.; Kim, D.W.; Chung, H.; Park, J.C.; Shin, S.K.; Hyung, W.J.; Kil Lee, S.; Lee, Y.C.; Noh, S.H. Clinical safety of endoscopic submucosal dissection compared with surgery in elderly patients with early gastric cancer: A propensity-matched analysis. Gastrointest. Endosc. 2014, 80, 599–609. [Google Scholar] [CrossRef]
- Choi, I.J.; Lee, J.H.; Kim, Y.-W.; Kim, C.G.; Cho, S.-J.; Lee, J.Y.; Ryu, K.W.; Nam, B.-H.; Kook, M.-C. Long-term outcome comparison of endoscopic resection and surgery in early gastric cancer meeting the absolute indication for endoscopic resection. Gastrointest. Endosc. 2015, 81, 333–341.e1. [Google Scholar] [CrossRef] [PubMed]
- Cholesterol Treatment Trialists’ (CTT) Collaboration Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy. PLoS ONE 2012, 7, e29849. [CrossRef] [Green Version]
- Chung, H.; Kim, H.J.; Jung, H.C.; Kil Lee, S.; Kim, S.G. Statins and metachronous recurrence after endoscopic resection of early gastric cancer: A nationwide Korean cohort study. Gastric Cancer 2020, 23, 659–666. [Google Scholar] [CrossRef]
- Chiu, H.-F.; Ho, S.-C.; Chang, C.-C.; Wu, T.-N.; Yang, C.-Y. Statins Are Associated With a Reduced Risk of Gastric Cancer: A Population-Based Case–Control Study. Am. J. Gastroenterol. 2011, 106, 2098–2103. [Google Scholar] [CrossRef] [PubMed]
- Singh, P.; Singh, S. Statins are associated with reduced risk of gastric cancer: A systematic review and meta-analysis. Ann. Oncol. 2013, 24, 1721–1730. [Google Scholar] [CrossRef]
- Cheung, K.S.; Chan, E.W.; Wong, A.Y.S.; Chen, L.; Seto, W.-K.; Wong, I.C.K.; Leung, W.K. Statins were associated with a reduced gastric cancer risk in patients with eradicated Helicobacter pylori infection: A territory-wide propensity score matched study. Cancer Epidemiol. Biomark. Prev. 2019, 29, 493–499. [Google Scholar] [CrossRef]
- Patrick, A.R.; Shrank, W.H.; Glynn, R.J.; Solomon, D.H.; Dormuth, C.R.; Avorn, J.; Cadarette, S.M.; Mogun, H.; Brookhart, M.A. The Association between Statin use and Outcomes Potentially Attributable to an Unhealthy Lifestyle in Older Adults. Value Heal. 2011, 14, 513–520. [Google Scholar] [CrossRef] [Green Version]
- Chey, W.D.; Wong, B.C.Y. Practice Parameters Committee of the American College of Gastroenterology American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am. J. Gastroenterol. 2007, 102, 1808–1825. [Google Scholar] [CrossRef]
- Newman, T.B.; Hulley, S.B. Carcinogenicity of Lipid-Lowering Drugs. JAMA 1996, 275, 55. [Google Scholar] [CrossRef]
- Oliver, M. Might treatment of hypercholesterolaemia increase non-cardiac mortality? Lancet 1991, 337, 1529–1531. [Google Scholar] [CrossRef]
- Ridker, P.M.; Rifai, N.; Pfeffer, M.A.; Sacks, F.M.; Moye, L.A.; Goldman, S.; Flaker, G.C.; Braunwald, E. Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels. Circulation 1998, 98, 839–844. [Google Scholar] [CrossRef] [PubMed]
- Gazzerro, P.; Bifulco, M. Statins and Cancer in Gastroenterology: New Insight? Gastroenterol. 2013, 144, 1572–1573. [Google Scholar] [CrossRef] [PubMed]
- Demierre, M.-F.; Higgins, P.D.R.; Gruber, S.B.; Hawk, E.T.; Lippman, S.M. Statins and cancer prevention. Nat. Rev. Cancer 2005, 5, 930–942. [Google Scholar] [CrossRef] [PubMed]
- Panani, A.D. Cytogenetic and molecular aspects of gastric cancer: Clinical implications. Cancer Lett. 2008, 266, 99–115. [Google Scholar] [CrossRef]
- Cao, Z.; Fan-Minogue, H.; Bellovin, D.I.; Yevtodiyenko, A.; Arzeno, J.; Yang, Q.; Gambhir, S.S.; Felsher, D.W. MYC Phosphorylation, Activation, and Tumorigenic Potential in Hepatocellular Carcinoma Are Regulated by HMG-CoA Reductase. Cancer Res. 2011, 71, 2286–2297. [Google Scholar] [CrossRef] [Green Version]
- Follet, J.; Corcos, L.; Baffet, G.; Ezan, F.; Morel, F.; Simon, B.; Le Jossic-Corcos, C. The association of statins and taxanes: An efficient combination trigger of cancer cell apoptosis. Br. J. Cancer 2012, 106, 685–692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El-Zimaity, H.M. Accurate Diagnosis of Helicobacter pylori with Biopsy. Gastroenterol. Clin. North Am. 2000, 29, 863–869. [Google Scholar] [CrossRef]
- Asano, K.; Kubo, M.; Yonemoto, K.; Doi, Y.; Ninomiya, T.; Tanizaki, Y.; Arima, H.; Shirota, T.; Matsumoto, T.; Iida, M.; et al. Impact of serum total cholesterol on the incidence of gastric cancer in a population-based prospective study: The Hisayama study. Int. J. Cancer 2007, 122, 909–914. [Google Scholar] [CrossRef]
Variables | Total Patients (N = 2153) | Statin Users (N = 228) | Statin Nonusers (N = 1925) | p Value |
---|---|---|---|---|
Age, year | 64 (57–71) | 66 (60–74) | 64 (57–71) | <0.001 |
Male | 1699 (78.9) | 195 (85.5) | 1504 (78.1) | 0.01 |
Tumor size, mm | 12 (8–19) | 12 (8–17) | 12 (8–20) | 0.09 |
Tumor location | 0.22 | |||
Lower | 1357 (63.0) | 73 (62.9) | 1224 (63.6) | |
Middle | 749 (34.8) | 42 (36.2) | 658 (34.2) | |
Upper | 47 (2.2) | 1 (0.9) | 43 (2.2) | |
Tumor macroscopic type | 0.003 | |||
Elevated | 270 (12.5) | 27 (11.8) | 243 (12.6) | |
Flat | 310 (14.4) | 45 (19.7) | 265 (13.8) | |
Depressed | 1009 (46.9) | 117 (51.3) | 892 (46.3) | |
Mixed | 564 (26.2) | 39 (17.1) | 525 (27.3) | |
Depth of invasion | 0.49 | |||
Mucosa (T1a) | 1963 (91.2) | 212 (93.0) | 1751 (91.0) | |
Submucosa (T1b) | 190 (8.8) | 16 (7.0) | 174 (9.0) | |
Histologic differentiation | 049 | |||
Differentiated | 2148 (99.8) | 227 (99.6) | 1921 (99.8) | |
Undifferentiated | 5 (0.2) | 1 (0.4) | 4 (0.2) | |
Histologic heterogeneity | 0.40 | |||
Absent | 2011 (93.4) | 210 (92.1) | 1801 (93.6) | |
Present | 142 (6.6) | 18 (7.9) | 124 (6.4) | |
Lymphovascular invasion | 43 (2.0) | 6 (2.6) | 37 (1.9) | 0.46 |
Comorbidities | ||||
Hypertension | 378 (17.6) | 153 (67.1) | 225 (11.7) | <0.001 |
Diabetes mellitus | 240 (11.1) | 96 (42.1) | 144 (7.5) | <0.001 |
Myocardial infarction | 32 (1.5) | 17 (7.5) | 15 (0.8) | <0.001 |
Heart failure | 58 (2.7) | 29 (12.7) | 29 (1.5) | <0.001 |
Chronic kidney disease | 87 (4.0) | 40 (17.5) | 47 (2.4) | <0.001 |
Liver cirrhosis | 56 (2.6) | 8 (3.5) | 48 (2.5) | 0.36 |
Cerebrovascular accident | 206 (9.6) | 87 (38.2) | 119 (6.2) | <0.001 |
Comorbidities (≥2) | 380 (17.6) | 200 (87.8) | 180 (10.4) | <0.001 |
Aspirin | 252 (11.7) | 132 (57.8) | 120 (6.2) | <0.001 |
Metformin | 199 (9.2) | 57 (25.6) | 142 (7.4) | <0.001 |
Factors | Univariable Analysis | Multivariable Analysis | ||
---|---|---|---|---|
HR (95% CI) | p Value | HR (95% CI) | p Value | |
Age (per year) | 1.03 (1.01–1.05) | <0.001 | 1.03 (1.02–1.05) | <0.001 |
Male sex | 1.20 (0.86–1.79) | 0.36 | ||
Tumor size, mm | 1.01 (0.99–1.02) | 0.07 | 1.005 (0.99–1.02) | 0.505 |
Tumor location | ||||
Lower | Reference | Reference | ||
Middle | 1.32 (0.96–1.81) | 0.08 | 1.35 (0.99–1.85) | 0.056 |
Upper | 1.06 (0.033–3.34) | 0.92 | 0.93 (0.29–2.95) | 0.91 |
Tumor macroscopic type | ||||
Elevated | Reference | Reference | ||
Flat | 0.70 (0.42–1.25) | 0.23 | 0.75 (0.42–1.33) | 0.33 |
Depressed | 0.64 (0.40–1.02) | 0.06 | 0.74 (0.47–1.19) | 0.22 |
Mixed | 0.91 (0.56–1.48) | 0.72 | 0.98 (0.60–1.58) | 0.93 |
Depth of invasion | ||||
Mucosa (T1a) | Reference | |||
Submucosa (T1b) | 1.00 (0.60–1.69) | 0.97 | ||
Histologic differentiation | ||||
Differentiated | Reference | |||
Undifferentiated | 0.05 (0– ) | 0.66 | ||
Histologic heterogeneity | ||||
Absent | Reference | |||
Present | 1.49 (0.89–2.49) | 0.12 | ||
Lymphovascular invasion | 1.44 (0.53–3.89) | 0.46 | ||
Comorbidities | ||||
Hypertension | 0.85 (0.58–1.26) | 0.44 | ||
Diabetes mellitus | 1.19 (0.76–1.85) | 0.38 | ||
Myocadiac infarction | 0.67 (0.16–2.73) | 0.58 | ||
Heart failure | 1.07 (0.47–2.42) | 0.87 | ||
Chronic kidney disease | 0.97 (0.47–1.98) | 0.93 | ||
Liver cirrhosis | 1.16 (0.51–2.62) | 0.72 | ||
Cerebrovascular disease | 1.03 (0.64–1.67) | 0.87 | ||
Statin use | 0.50 (0.28–0.85) | 0.017 | 0.46 (0.26–0.82) | 0.008 |
Aspirin use | 1.21 (0.80–1.82) | 0.35 | ||
Metformin use | 1.37 (0.85–2.21) | 0.19 |
Factors | Multivariable Analysis a | |
---|---|---|
HR (95% CI) | p Value | |
Duration | ||
Non-statin use | Reference | |
<2 years | 0.87 (0.41–1.87) | 0.73 |
2–4 years | 0.48 (0.15–1.51) | 0.21 |
>4 year | 0.25 (0.08–0.79) | 0.019 |
cDDD | ||
Non-statin use | Reference | |
<500 | 0.91 (0.46–1.79) | 0.79 |
500–1000 | 0.64 (0.20–2.01) | 0.44 |
>1000 | 0.08 (0.01–0.58) | 0.013 |
Factors | HR (95% CI) | p Value |
---|---|---|
Statin use | 0.34 (0.17–0.71) | 0.004 |
Duration | ||
Non-statin use | Reference | |
<2 years | 0.57 (0.23–1.44) | 0.235 |
2–4 years | 0.31 (0.07–1.27) | 0.104 |
>4 year | 0.18 (0.04–0.75) | 0.018 |
cDDD | ||
Non-statin use | Reference | |
<500 | 0.63 (0.27–1.48) | 0.286 |
500–1000 | 0.39 (0.09–1.60) | 0.191 |
>1000 | 0.09 (0.01–0.62) | 0.015 |
Variables | Statin Users (n = 197) | Statin Nonusers (n = 425) | p Value |
---|---|---|---|
Age, year | 66 (59–73) | 65 (58–72) | 0.788 |
Male | 168 (85.3) | 339 (79.8) | 0.124 |
Tumor size, mm | 12 (8–18) | 12 (8–19) | 0.671 |
Tumor location | 0.960 | ||
Lower | 117 (59.4) | 248 (58.4) | |
Middle | 77 (39.1) | 171 (40.2) | |
Upper | 3 (1.5) | 6 (1.4) | |
Tumor macroscopic type | 0.830 | ||
Elevated | 45 (10.6) | 45 (10.6) | |
Flat | 79 (18.7) | 79 (18.6) | |
Depressed | 212 (49.9) | 212 (49.9) | |
Mixed | 89 (20.9) | 89 (20.9) | |
Depth of invasion | 0.763 | ||
Mucosa (T1a) | 182 (92.4) | 388 (91.3) | |
Submucosa (T1b) | 15 (7.6) | 37 (8.7) | |
Histologic differentiation | 0.936 | ||
Differentiated | 196 (99.5) | 421 (99.1) | |
Undifferentiated | 1 (0.5) | 4 (0.9) | |
Histologic heterogeneity | 0.802 | ||
Absent | 184 (93.4) | 393 (92.5) | |
Present | 13 (6.6) | 32 (7.5) | |
Lymphovascular invasion | 6 (3.0) | 10 (2.4) | 0.814 |
Comorbidities | |||
Hypertension | 92 (46.7) | 166 (39.1) | 0.174 |
Diabetes mellitus | 49 (24.9) | 100 (23.5) | 0.860 |
Myocadiac infarction | 10 (5.1) | 15 (3.5) | 0.427 |
Heart failure | 16 (8.1) | 26 (6.1) | 0.423 |
Chronic kidney disease | 27 (13.7) | 38 (8.9) | 0.110 |
Liver cirrhosis | 8 (4.1) | 16 (3.8) | 1.000 |
Cerebrovascular disease | 61 (31.0) | 107 (25.2) | 0.145 |
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Kwon, T.J.; Kim, T.J.; Lee, H.; Min, Y.W.; Min, B.-H.; Lee, J.H.; Kim, J.J. Statin Use Decreases the Risk of Metachronous Gastric Cancer in Patients without Helicobacter pylori Infection. Cancers 2021, 13, 1020. https://doi.org/10.3390/cancers13051020
Kwon TJ, Kim TJ, Lee H, Min YW, Min B-H, Lee JH, Kim JJ. Statin Use Decreases the Risk of Metachronous Gastric Cancer in Patients without Helicobacter pylori Infection. Cancers. 2021; 13(5):1020. https://doi.org/10.3390/cancers13051020
Chicago/Turabian StyleKwon, Tae Jin, Tae Jun Kim, Hyuk Lee, Yang Won Min, Byung-Hoon Min, Jun Haeng Lee, and Jae J. Kim. 2021. "Statin Use Decreases the Risk of Metachronous Gastric Cancer in Patients without Helicobacter pylori Infection" Cancers 13, no. 5: 1020. https://doi.org/10.3390/cancers13051020