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Enhancing the Anti-angiogenic Effect of Bevacizumab with ACE Inhibition on mCRC

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Abstract

Introduction

Angiotensin 2 has been shown to promote angiogenesis through multiple pathways. Reduction of angiotensin 2 production by angiotensin-converting enzyme inhibitors (ACEi) could enhance the antiangiogenic effect of bevacizumab and lead to improved survival.

Methods

Data from metastatic colorectal cancer (mCRC) patients treated with bevacizumab in our hospital were retrospectively collected. Patients were divided into groups taking ACEi or angiotensin receptor blockers (ARB) or neither. We performed survival analysis and COX proportional hazard modelling and calculated the hazard ratio (HR). Multivariate analyses were performed to measure the impact of factors affecting survival, and subgroup analyses were performed for patients younger than 65 years.

Results

We enrolled 133 patients who received bevacizumab therapy. Eighty patients were male, and 53 were female. Twenty-three patients received ACEi treatment, and 34 patients received ARB. The median age was 58 years. Progression-free survival was higher in the ACEi group than in the ARB group or in the group receiving neither (7.66 vs. 5.98 vs. 5.0 months; p < 0.01), corresponding to a HR of 0.44 for the ACEi group (95% CI 0.26–0.74). Overall survival was not significantly longer in the ACEi group than in the ARB group or in the group receiving neither (22.0 vs. 23.5 vs. 19.7 months; p = 0.30), HR 0.66 (95% CI 0.38–1.2). In a subgroup analysis, overall survival was higher in patients younger than 65 years in the ACEi group (45.0 vs. 16.2 months; p = 0.02).

Conclusion

In the final analysis, ACEi use in patients treated with bevacizumab resulted in prolonged progression-free survival, but this did not affect overall survival. Because our study is the first to look at the enhancement of the effect of bevacizumab by ACEi treatment and ACEi receiving patients are older, it would be useful to confirm our results by randomized trials.

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References

  1. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. 2009;350(23):2335–42. https://doi.org/10.1056/NEJMoa032691.

  2. Munk VC, De Miguel LS, Petrimpol M, et al. Angiotensin II induces angiogenesis in the hypoxic adult mouse heart in vitro through an AT2-B2 receptor pathway. Hypertension. 2007;[cited 2022 Jan 9];49(5):1178–85. Available from: https://doi.org/10.1161/HYPERTENSIONAHA.106.080242.

  3. Si W, Xie W, Deng W, et al. Angiotensin II increases angiogenesis by NF-κB–mediated transcriptional activation of angiogenic factor AGGF1. The FASEB J 2018 [cited 2022 Jan 9];32(9):5051. Available from: https://www.pmc/articles/PMC6103173/.

  4. Shen Y, Wang X, Lu J, et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell. 2020;37(6):800-817.e7.

    Article  CAS  PubMed  Google Scholar 

  5. Chen X, Yi CH, Ya KG. Renin–angiotensin system inhibitor use and colorectal cancer risk and mortality: a dose–response meta analysis. J Renin Angiotensin Aldosterone Syst. [Internet] 2020 [cited 2022 Jan 17];21(3). Available from: https://www.pmc/articles/PMC7338647/.

  6. Neo JH, Malcontenti-Wilson C, Muralidharan V, Christophi C. Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases. J Gastroenterol Hepatol. 2007;22(4):577–84.

    Article  CAS  PubMed  Google Scholar 

  7. Roth IM, Wickremesekera AC, Wickremesekera SK, Davis PF, Tan ST. Therapeutic targeting of cancer stem cells via modulation of the renin-angiotensin system. Front Oncol. 2019;9(AUG):745.

  8. Tabatabai E, Khazaei M, Asgharzadeh F, et al. Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer. EXCLI J. 2021;20:863.

    PubMed  PubMed Central  Google Scholar 

  9. Stokes WA, Molina E, McDermott JD, et al. Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer. Head Neck. 2021;43(11):3255–75.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xiong L, Wei Y, Zhou X, et al. AGTR1 inhibits the progression of lung adenocarcinoma. Cancer Manag Res. 2021;13:8535–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wu C-N, Wu S-C, Chen W-C, et al. Angiotensin II receptor blockers and oral squamous cell carcinoma survival: a propensity-score-matched cohort study. PLoS ONE. 2021;16(12): e0260772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ren T, Jia H, Wu Q, et al. Inhibition of angiogenesis and extracellular matrix remodeling: synergistic effect of renin-angiotensin system inhibitors and bevacizumab. Front Oncol. 2022;12.

  13. Makar GA, Holmes JH, Yang YX. Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk. JNCI J Nat Canc Inst. 2014;106(2).

  14. Ozawa T, Hashiguchi Y, Yagi T, et al. Angiotensin I-converting enzyme inhibitors/angiotensin II receptor blockers may reduce tumor recurrence in left-sided and early colorectal cancers. Int J Colorectal Dis. 2019;34(10):1731–9.

    Article  PubMed  Google Scholar 

  15. Cui Y, Wen W, Zheng T, et al. Use of antihypertensive medications and survival rates for breast, colorectal, lung, or stomach cancer. Am J Epidemiol. 2019;188(8):1512–28.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Osumi H, Matsusaka S, Wakatsuki T, Suenaga M, Shinozaki E, Mizunuma N. Angiotensin II type-1 receptor blockers enhance the effects of bevacizumab-based chemotherapy in metastatic colorectal cancer patients. Mol Clin Oncol. 2015 [cited 2022 Jan 17];3(6):1295–300. Available from: https://doi.org/10.3892/mco.2015.630.

  17. Zeman M, Skałba W, Wilk AM, Cortez AJ, Maciejewski A, Czarniecka A. Impact of renin-angiotensin system inhibitors on the survival of patients with rectal cancer. BMC Cancer. 2022;22(1).

  18. Engineer DR, Burney BO, Hayes TG, Garcia JM. Exposure to ACEI/ARB and β-blockers is associated with improved survival and decreased tumor progression and hospitalizations in patients with advanced colon cancer. Transl Oncol. 2013;6(5):539–45.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Deng Y, Xie Y, Wang M, et al. Effects of antihypertensive drugs use on risk and prognosis of colorectal cancer: a meta-analysis of 37 observational studies. Front Pharmacol. 2022;12.

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Authors and Affiliations

  1. Department of Medical Oncology, Faculty of Medicine, Ankara University, Balkiraz Mah. Tip Fakultesi Cad. No: 1, Mamak, Ankara, Turkey

    Efe Cem Erdat, Elif Berna Koksoy & Gungor Utkan

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  1. Efe Cem Erdat
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  2. Elif Berna Koksoy
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  3. Gungor Utkan
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All authors contributed equally, and all authors have reviewed the manuscript.

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Correspondence to Efe Cem Erdat.

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Erdat, E.C., Koksoy, E.B. & Utkan, G. Enhancing the Anti-angiogenic Effect of Bevacizumab with ACE Inhibition on mCRC. J Gastrointest Canc 54, 897–902 (2023). https://doi.org/10.1007/s12029-022-00890-4

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  • DOI: https://doi.org/10.1007/s12029-022-00890-4

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