Top

Journal of Cancer Research and Clinical Oncology

Published in:

Open Access 01-01-2021 | NSCLC | Review – Clinical Oncology

Risk of lung cancer and renin–angiotensin blockade: a concise review

Authors: Tobias Rachow, Helmut Schiffl, Susanne M. Lang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2021

Abstract

Purpose

The blockade of the renin–angiotensin–aldosterone system (RAAS) by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is one of the most common treatments for hypertension, heart failure and renal diseases. However, concerns have been raised about a possible link between RAAS-blockers and an increased risk of cancer, particularly of lung cancer. This narrative review aims to give a critical appraisal of current evidence and to help physicians understand potential links between RAAS blockade and de novo lung cancer development.

Methods

Numerous pharmaco-epidemiologic studies, mostly retrospective cohort analyses, evaluated the association of RAAS blockade with lung cancer incidence and reported inconsistent findings. Meta-analyses could not further clarify a possible link between RAAS blockade and the risk of lung cancer.

Results

International regulatory agencies (FDA, EMA) have concluded that the use of RAAS blockers is not associated with an increased risk of developing lung cancer. Co-administration of RAAS blockers to systemic therapy of advanced non-small cell lung cancer seems to have positive effects on the outcome.

Conclusion

Until more comprehensive analyses have been completed, there is no need to change clinical practise. Additional prospective randomized trials with long-term follow-up are needed to investigate the effects of these drugs on the development and progression of lung cancer.

Alvarez A et al (2004) Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood 104:402–408. https://doi.org/10.1182/blood-2003-08-2974CrossRefPubMed

Arrieta O et al (2008) Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 99:160–166. https://doi.org/10.1038/sj.bjc.6604431CrossRefPubMedPubMedCentral

Aydiner A, Ciftci R, Sen F (2015) Renin-Angiotensin system blockers may prolong survival of metastatic non-small cell lung cancer patients receiving erlotinib. Medicine (Baltimore) 94:e887. https://doi.org/10.1097/MD.0000000000000887CrossRef

Azoulay L, Assimes TL, Yin H, Bartels DB, Schiffrin EL, Suissa S (2012) Long-term use of angiotensin receptor blockers and the risk of cancer. PLoS ONE 7:e50893. https://doi.org/10.1371/journal.pone.0050893CrossRefPubMedPubMedCentral

Bangalore S et al (2011) Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol 12:65–82. https://doi.org/10.1016/s1470-2045(10)70260-6CrossRefPubMed

Bhaskaran K, Douglas I, Evans S, van Staa T, Smeeth L (2012) Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ 344:e2697. https://doi.org/10.1136/bmj.e2697CrossRefPubMedPubMedCentral

Chang CH, Lin JW, Wu LC, Lai MS (2011) Angiotensin receptor blockade and risk of cancer in type 2 diabetes mellitus: a nationwide case-control study. J Clin Oncol 29:3001–3007. https://doi.org/10.1200/JCO.2011.35.1908CrossRefPubMed

Chiang YY, Chen KB, Tsai TH, Tsai WC (2014) Lowered cancer risk with ACE inhibitors/ARBs: a population-based cohort study. J Clin Hypertens (Greenwich) 16:27–33. https://doi.org/10.1111/jch.12228CrossRef

Collaboration ARBT (2011) Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens 29:623–635. https://doi.org/10.1097/HJH.0b013e328344a7deCrossRef

Cronin-Fenton D (2018) Angiotensin converting enzyme inhibitors and lung cancer. BMJ 363:k4337. https://doi.org/10.1136/bmj.k4337CrossRefPubMed

Danilov SM, Metzger R, Klieser E, Sotlar K, Trakht IN, Garcia JGN (2019) Tissue ACE phenotyping in lung cancer. PLoS ONE 14:e0226553. https://doi.org/10.1371/journal.pone.0226553CrossRefPubMedPubMedCentral

Datzmann T, Fuchs S, Andree D, Hohenstein B, Schmitt J, Schindler C (2019) Systematic review and meta-analysis of randomised controlled clinical trial evidence refutes relationship between pharmacotherapy with angiotensin-receptor blockers and an increased risk of cancer. Eur J Intern Med 64:1–9. https://doi.org/10.1016/j.ejim.2019.04.019CrossRefPubMed

Egami K et al (2003) Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest 112:67–75. https://doi.org/10.1172/jci16645CrossRefPubMedPubMedCentral

Feng Y et al (2011) Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro. Oncol Rep 26:1157–1164. https://doi.org/10.3892/or.2011.1394CrossRefPubMed

Friis S, Sorensen HT, Mellemkjaer L, McLaughlin JK, Nielsen GL, Blot WJ, Olsen JH (2001) Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark. Cancer 92:2462–2470. https://doi.org/10.1002/1097-0142(20011101)92:9%3c2462::aid-cncr1596%3e3.0.co;2-lCrossRefPubMed

George AJ, Thomas WG, Hannan RD (2010) The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 10:745–759. https://doi.org/10.1038/nrc2945CrossRefPubMed

Gokhale M, Girman C, Chen Y, Pate V, Funk MJ, Sturmer T (2016) Comparison of diagnostic evaluations for cough among initiators of angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Pharmacoepidemiol Drug Saf 25:512–520. https://doi.org/10.1002/pds.3977CrossRefPubMedPubMedCentral

Goldstein B, Trivedi M, Speth RC (2017) Alterations in gene expression of components of the renin-angiotensin system and its related enzymes in lung cancer. Lung Cancer Int 2017:6914976. https://doi.org/10.1155/2017/6914976CrossRefPubMedPubMedCentral

Greco S et al (2003) Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells. J Cell Physiol 196:370–377. https://doi.org/10.1002/jcp.10313CrossRefPubMed

Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L (2018) Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 363:k4209. https://doi.org/10.1136/bmj.k4209CrossRefPubMedPubMedCentral

Huang CC, Chan WL, Chen YC, Chen TJ, Lin SJ, Chen JW, Leu HB (2011) Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertension. Am J Cardiol 107:1028–1033. https://doi.org/10.1016/j.amjcard.2010.11.026CrossRefPubMed

Ishikane S, Takahashi-Yanaga F (2018) The role of angiotensin II in cancer metastasis: potential of renin-angiotensin system blockade as a treatment for cancer metastasis. Biochem Pharmacol 151:96–103. https://doi.org/10.1016/j.bcp.2018.03.008CrossRefPubMed

Lever AF et al (1998) Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 352:179–184. https://doi.org/10.1016/s0140-6736(98)03228-0CrossRefPubMed

Li YF et al (2012) Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis. PLoS ONE 7:e37396. https://doi.org/10.1371/journal.pone.0037396CrossRefPubMedPubMedCentral

Lin SY et al (2020) Association between angiotensin-converting enzyme inhibitors and lung cancer-a nationwide, population-based, propensity score-matched cohort study. Cancers (Basel). https://doi.org/10.3390/cancers12030747CrossRefPubMedPubMedCentral

Menter AR et al (2017) Effect of angiotensin system inhibitors on survival in patients receiving chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer 18(189–197):e183. https://doi.org/10.1016/j.cllc.2016.07.008CrossRef

Miao L, Chen W, Zhou L, Wan H, Gao B, Feng Y (2016) Impact of angiotensin I-converting enzyme inhibitors and angiotensin II type-1 receptor blockers on survival of patients with NSCLC. Sci Rep 6:21359. https://doi.org/10.1038/srep21359CrossRefPubMedPubMedCentral

Pasternak B, Svanstrom H, Callreus T, Melbye M, Hviid A (2011) Use of angiotensin receptor blockers and the risk of cancer. Circulation 123:1729–1736. https://doi.org/10.1161/circulationaha.110.007336CrossRefPubMed

Pei N et al (2017) Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer. J Exp Clin Cancer Res 36:77. https://doi.org/10.1186/s13046-017-0542-0CrossRefPubMedPubMedCentral

Pinter M, Jain RK (2017) Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aan5616CrossRefPubMedPubMedCentral

Rao GA et al (2013) Angiotensin receptor blockers: are they related to lung cancer? J Hypertens 31:1669–1675. https://doi.org/10.1097/HJH.0b013e3283621ea3CrossRefPubMedPubMedCentral

Romer FK (1981) Angiotensin-converting enzyme and its association with outcome in lung cancer. Br J Cancer 43:135–142. https://doi.org/10.1038/bjc.1981.21CrossRefPubMedPubMedCentral

Sedgwick B (2004) Repairing DNA-methylation damage. Nat Rev Mol Cell Biol 5:148–157. https://doi.org/10.1038/nrm1312CrossRefPubMed

Shirotake S, Miyajima A, Kosaka T, Tanaka N, Maeda T, Kikuchi E, Oya M (2011) Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer. Urology 77:1009.e1019-1025. https://doi.org/10.1016/j.urology.2010.11.002CrossRef

Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC (2010) Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 11:627–636. https://doi.org/10.1016/s1470-2045(10)70106-6CrossRefPubMedPubMedCentral

Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J (2003) Inflammation and angiotensin II. Int J Biochem Cell Biol 35:881–900. https://doi.org/10.1016/s1357-2725(02)00271-6CrossRefPubMed

Tascilar K, Azoulay L, Dell’Aniello S, Bartels DB, Suissa S (2016) The use of telmisartan and the incidence of cancer. Am J Hypertens 29:1358–1365. https://doi.org/10.1093/ajh/hpw095CrossRefPubMedPubMedCentral

Tawinwung S, Ninsontia C, Chanvorachote P (2015) Angiotensin II increases cancer stem cell-like phenotype in lung cancer cells. Anticancer Res 35:4789–4797PubMed

Tsutamoto T et al (2000) Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure. J Am Coll Cardiol 35:714–721. https://doi.org/10.1016/s0735-1097(99)00594-xCrossRefPubMed

Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD (2020) Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med 382:1653–1659. https://doi.org/10.1056/NEJMsr2005760CrossRefPubMed

Varela AS, Bosco Lopez Saez JJ (1993) Utility of serum activity of angiotensin-converting enzyme as a tumor marker. Oncology 50:430–435. https://doi.org/10.1159/000227224CrossRefPubMed

Wang N, Liu J, Wang W, Qin J, Lin D (2017) The impact of Renin-angiotensin system blockers on lung cancers prognosis: a prisma-compliant systematic review and meta-analysis. Allied J Med Res 1:28–34CrossRef

Wei J et al (2019) Retrospective clinical study of renin-angiotensin system blockers in lung cancer patients with hypertension. PeerJ 7:e8188. https://doi.org/10.7717/peerj.8188CrossRefPubMedPubMedCentral

Wilop S, von Hobe S, Crysandt M, Esser A, Osieka R, Jost E (2009) Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol 135:1429–1435. https://doi.org/10.1007/s00432-009-0587-3CrossRefPubMed

Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473. https://doi.org/10.1038/onc.2016.304CrossRefPubMed

Zhang J et al (2015) Angiotensin receptor blockers (ARBs) reduce the risk of lung cancer: a systematic review and meta-analysis. Int J Clin Exp Med 8:12656–12660PubMedPubMedCentral

Title: Risk of lung cancer and renin–angiotensin blockade: a concise review
Authors: Tobias Rachow
Helmut Schiffl
Susanne M. Lang
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
Lung Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2021
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03445-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Elevated ZBTB7A expression in the tumor invasive front correlates with more tumor budding formation in gastric adenocarcinoma

B-MYB—p53-related relevant regulator for the progression of clear cell renal cell carcinoma

BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis

Association between the use of aspirin and risk of lung cancer: results from pooled cohorts and Mendelian randomization analyses

An immune-related gene signature for determining Ewing sarcoma prognosis based on machine learning

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials