Cancer Res Treat.  2020 Apr;52(2):645-654. 10.4143/crt.2019.509.

Impact of Angiotensin Receptor Blockers, Beta Blockers,Calcium Channel Blockers and Thiazide Diuretics on Survivalof Ovarian Cancer Patients

Affiliations
  • 1Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 2Statistics and Data Center, Samsung Medical Center, Seoul, Korea

Abstract

Purpose
We investigated the impact of four types of antihypertensive medications, angiotensin receptor blockers (ARBs), beta blockers (BBs; both selective and non-selective), calcium channel blockers (CCBs), and thiazide diuretics (TDs) on survival outcomes in epithelial ovarian cancer (EOC).
Materials and Methods
A single-institutional retrospective chart review of 878 patients with EOC was performed. Survival was compared according to use of the four antihypertensive medications during primary treatment. Propensity score matching (ratio 1:3) was performed to control possible associated covariates, such as age, International Federation of Gynecology and Obstetrics stage, residual status after primary debulking surgery, and co-morbidity.
Results
Among 878 patients, 56 patients (6.4%) were ARB users, 62 (7.1%) were BB users, 107 (12.2%) were CCBs users and 32 (3.6%) used TDs. Median progression-free survival (PFS) for ARB, BB, and CCB users was 37.8, 27.2, and 23.6 months compared with 33.6 months for non-users. ARB was associated with 35% decreased risk of disease progression (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.42 to 0.99; p=0.046) in multivariate analysis. After propensity score matching, median PFS for ARB users was 37.8 months and ARB use remained to be associated with lower recurrence rate in univariate (p=0.035) and multivariate analysis (HR, 0.60; 95% CI, 0.39 to 0.93; p=0.022).
Conclusion
In this study, ARBs use during primary treatment is associated with lower recurrence in EOC patients. However, CCBs, BBs, and TDs did not show beneficial impact.

Keyword

Ovarian neoplasms; Antihypertensive agents; Angiotensin II type 1 receptor blockers; Adrenergic beta-antagonists; Calcium channel blockers; Thiazides

Figure

  • Fig. 1. Kaplan-Meier curve for progression-free survival according to angiotensin receptor blocker (A), beta blocker (B), and calcium channel blocker (C).

  • Fig. 2. Kaplan-Meier curve for progression-free survival after propensity score matching in angiotensin receptor blocker group (A), beta blocker group (B), and calciumchannel blocker group (C).


Reference

References

1. Lim MC, Won YJ, Ko MJ, Kim M, Shim SH, Suh DH, et al. Incidence of cervical, endometrial, and ovarian cancer in Korea during 1999-2015. J Gynecol Oncol. 2019; 30:e38.
Article
2. Jung KW, Won YJ, Kong HJ, Lee ES. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2016. Cancer Res Treat. 2019; 51:417–30.
Article
3. Dolley-Hitze T, Jouan F, Martin B, Mottier S, Edeline J, Moranne O, et al. Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma? Br J Cancer. 2010; 103:1698–705.
Article
4. Roder K, Werdich AA, Li W, Liu M, Kim TY, Organ-Darling LE, et al. RING finger protein RNF207, a novel regulator of cardiac excitation. J Biol Chem. 2014; 289:33730–40.
Article
5. Leung PS, Chappell MC. A local pancreatic renin-angiotensin system: endocrine and exocrine roles. Int J Biochem Cell Biol. 2003; 35:838–46.
Article
6. Liu WB, Wang XP, Wu K, Zhang RL. Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. World J Gastroenterol. 2005; 11:6489–94.
Article
7. Gong Q, Davis M, Chipitsyna G, Yeo CJ, Arafat HA. Blocking angiotensin II type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells. Pancreas. 2010; 39:581–94.
Article
8. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A. 2011; 108:2909–14.
Article
9. Zhao Y, Cao J, Melamed A, Worley M, Gockley A, Jones D, et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc Natl Acad Sci U S A. 2019; 116:2210–9.
Article
10. Hwang SH, Noh SJ, Kwak HJ, Kim KR, Park HS, Moon WS, et al. Expression of angiotensin II receptor type 1 and 2 in ovarian epithelial tumors. Basic Appl Pathol. 2008; 1:131–8.
Article
11. Ino K, Shibata K, Kajiyama H, Yamamoto E, Nagasaka T, Nawa A, et al. Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br J Cancer. 2006; 94:552–60.
Article
12. Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S, et al. Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin Cancer Res. 2005; 11:2686–94.
13. Park YA, Choi CH, Do IG, Song SY, Lee JK, Cho YJ, et al. Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma. Gynecol Oncol. 2014; 135:108–17.
Article
14. Watkins JL, Thaker PH, Nick AM, Ramondetta LM, Kumar S, Urbauer DL, et al. Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer. Cancer. 2015; 121:3444–51.
Article
15. Baek MH, Kim DY, Kim SO, Kim YJ, Park YH. Impact of beta blockers on survival outcomes in ovarian cancer: a nationwide population-based cohort study. J Gynecol Oncol. 2018; 29:e82.
Article
16. Heitz F, Hengsbach A, Harter P, Traut A, Ataseven B, Schneider S, et al. Intake of selective beta blockers has no impact on survival in patients with epithelial ovarian cancer. Gynecol Oncol. 2017; 144:181–6.
Article
17. Harding BN, Delaney JA, Urban RR, Weiss NS. Post-diagnosis use of antihypertensive medications and the risk of death from ovarian cancer. Gynecol Oncol. 2019; 154:426–31.
Article
18. Chehl N, Gong Q, Chipitsyna G, Aziz T, Yeo CJ, Arafat HA. Angiotensin II regulates the expression of monocyte chemoattractant protein-1 in pancreatic cancer cells. J Gastrointest Surg. 2009; 13:2189–200.
Article
19. Wzgarda A, Kleszcz R, Prokop M, Regulska K, Regulski M, Paluszczak J, et al. Unknown face of known drugs - what else can we expect from angiotensin converting enzyme inhibitors? Eur J Pharmacol. 2017; 797:9–19.
Article
20. Matsui T, Chiyo T, Kobara H, Fujihara S, Fujita K, Namima D, et al. Telmisartan inhibits cell proliferation and tumor growth of esophageal squamous cell carcinoma by inducing S-phase arrest in vitro and in vivo. Int J Mol Sci. 2019; 20:E3197.
Article
21. Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res. 2006; 12:369–75.
Article
22. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol. 2011; 29:2645–52.
Article
23. Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol. 2012; 127:375–8.
Article
24. Jang HI, Lim SH, Lee YY, Kim TJ, Choi CH, Lee JW, et al. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: a pilot study. Obstet Gynecol Sci. 2017; 60:170–7.
Article
25. Eskander R, Bessonova L, Chiu C, Ward K, Culver H, Harrison T, et al. Beta blocker use and ovarian cancer survival: a retrospective cohort study. Gynecol Oncol. 2012; 127:S21.
Article
26. Heitz F, du Bois A, Harter P, Lubbe D, Kurzeder C, Vergote I, et al. Impact of beta blocker medication in patients with platinum sensitive recurrent ovarian cancer-a combined analysis of 2 prospective multicenter trials by the AGO Study Group, NCIC-CTG and EORTC-GCG. Gynecol Oncol. 2013; 129:463–6.
Article
27. Li W, Zhang SL, Wang N, Zhang BB, Li M. Blockade of T-type Ca(2+) channels inhibits human ovarian cancer cell proliferation. Cancer Invest. 2011; 29:339–46.
28. Jang SJ, Choi HW, Choi DL, Cho S, Rim HK, Choi HE, et al. In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers. Bioorg Med Chem Lett. 2013; 23:6656–62.
Article
29. Sun H, Zhuang RY, Li T, Zheng YT, Cai WM. No association between calcium channel blockers and survival in patients with cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2016; 17:3917–21.
30. Huang T, Sood AK, Tworoger SS. Abstract 4252: Antihypertensive medication use and ovarian cancer survival. Cancer Res. 2018; 78:4252.
Article
Full Text Links
  • CRT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr