1. 1674 Mo Gli antagonisti del sistema renina- angiotensina hanno effetti anticancro? Alberto Morganti Centro Fisiologia Clinica e Ipertensione Ospedale Policlinico, Università Milano 5°Congresso Nazionale ASIAM Riccione 15-17 Maggio 2015

2. 2800 Mo Antihypertensive drugs and cancer DrugReserpineBeta-blockers Calcium antagonists Thiazide diuretics Anti-HT drugs Cancer site BreastLung Cancer in general Kidney / Colon Brain glioma

3. 2801 Mo Cancer occurrence reported in trials of ARBs in which cancer was a prespecified endpoint TrialTRANSCENDONTARGETONTARGETLIFEMeta-analysis Sipahi I et al., Lancet Oncology 2010; 11: 627-656 RR1.171.051.141.121.11 Risk ratio (95% CI) 0.51.02.0 ARB worse Control worse

4. 2802 Mo Methodological limitations of Sipahi meta-analysis Arbitrary selection of included trials (short follow-up, # of patients) Lack of information on individual patient data Adjudication of cancer diagnosis not uniform Results driven by a single study (ONTARGET) Overall cancer death similar in ARB and control patients

5. 2806 Mo Tumours expressing Angiotensin II receptors MelanomaBrainLungPancreasKidneyOvaryBladderProstate

6. 2805 Mo RAS and tumour proliferation Wilop S et al., J Cancer Res Clin Oncol 2009; 135: 1429-1435 AII AT 2 R AT 1 R EGF Tumor cells VEGF Stromal cells Proliferation ↑ Angiogenesis ↑ Tumour growth ↑ ?++

7. 2807 Mo Influence of components of RAS on tumour growth Angiotensin II Angio (1-7) Angio (1-5) AT 1 R AT 2 R AT 4 R Prorenin / Renin receptors (PRR) FacilitationInhibitionUnknownFacilitation Mostly inhibition FacilitationFacilitation Factors whereby facilitation or inhibition is exerted: vascular endothelial growth factor (VEGF), angiopoietin 2, basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), hepatocyte growth factor (HEGF), nuclear factor KB (NF-KB), endothelin, nitric oxide (NO), monocyte chemoattractant protein (MCP 1-2), seryl-aspartil-lysyl-proline (SAKP)

8. 2809 Mo Effect of AT 2 receptor overexpression on human lung cancer cell growth Pievel L et al., Cancer Biol Ther 2010; 9: 277-285 -A549 cell -H358 cell 0 0.1 0.2 0.3 0.4 0.5 0.6 0 0.1 0.2 0.3 0.4 0.5 Cell growth Control AT 2 Control Human Mouse *** *** *** **

9. 2808 Mo Cell line / animal models in which RAS blockade effectively reduces tumour volume or metastases Cell line / Model Lung carcinoma Fibrocarcinoma Renal carcinoma Hepatocellular carcinoma Ovarian carcinoma Bladder cancer Colorectal / liver metastases Gastric cancer AgentCaptoprilCaptoprilCaptoprilPerindoprilCandesartanCandesartanCaptoprilCandesartan Ager EI et al., Carcinogenesis 2008; 28: 1675-1684

10. 2820 Mo Incident and fatal cancer in patients on ACEI vs age- and sex-matched patients on other antiHT drugs Lever AR et al., Lancet 1998; 352: 179-184 % without cancer Fatal cancer Incident cancer Follow-up (years) Cumulative survival (%) Follow-up (years) ACEI (n = 1559) Other antiHT drugs (n = 3468) RR: 0.72 RR: 0.65 100 98 96 94 92 90 100 98 96 94 012345678910012345678910

11. 2803 Mo ARB, cancer risk and cancer related death Studies1520 Bangalore S et al., Lancet Oncology 2011; 12: 65-82 OR0.980.99 Cases / Pts on ARB 3108 / 49996 (6.2%) 942 / 56991 (1.6%) Mean follow-up 3.5 years (minimum 1 year), patients enrolled 100 or more Cases / Controls 3167 / 49779 (6.3%) 952 / 57291 (1.6%) Cancer risk Cancer related death

12. 2804 Mo Incidence of cancer by specific ARB vs non-ARB controls in 15 RC ARB trials DrugTelmisartanIrbesartanValsartanCandesartanLosartan Grand total ARB Trialist Collaboration, J Hypertens 2011; 29: 623-635 OR1.070.910.921.111.091.00Studies3344115 Data from 138.769 patients, follow-up 24-57 months Pts on ARB 1823 (6.3%) 491 (6.8%) 491 (6.8%) 1441 (5.9%) 451 (5.0%) 451 (5.0%) 343 (7.4%) 343 (7.4%) 4549 (6.2%) Cancer cases Pts not on ARB 1112 (5.3%) 536 (7.5%) 536 (7.5%) 1484 (7.6%) 408 (4.5%) 408 (4.5%) 316 (6.9%) 316 (6.9%) 3856 (6.3%) p value 0.090.120.020.130.100.88

13. 2814 Mo Incidence of lung cancer in patients treated vs not treated with ARBs Rao GA et al., J Hypertens 2013; 31: 1669-1675 Time in years Lung cancer incidence (%) n = 6577 / 1155826 Treated Not treated n = 346 / 78075 HR: 0.74 Follow-up: 3-5 years 0.700.60 0.50 0.40 0.30 0.20 0.10 0.00 -0.10 -0.20 1234567 *

14. 2815 Mo Relationship between ARB subtype and lung cancer incidence Rao GA et al., J Hypertens 2012; 31: 1669-1675 Stratified by smoking status All current smokers All former smokers All never smoked Stratified ARB subtype in a cohort of all ARB users LosartanCandesartanIrbesartanValsartan HR for ARB 0.720.860.42 HR for ARB subtype 1 (ref) 1.000.940.94 P < 0.001 0.1750.06P0.790.950.99

15. 3048 Mo Colorectal cancer risk associated with increasing dose and duration of antiHT agents Makar GA, J Natl Cancer Inst 2014 AntiHT agent ACEI/ARB therapy < 3 years ≥ 3 years CCB therapy < 3 years ≥ 3 years OR0.891.010.901.03 Low dose p0.03ns0.04nsn5155196273963667OR0.870.590.910.94 High dose pns0.01nsnsn551431269157

16. 2811 Mo Overall survival in patients with advanced pancreatic cancer with and without ACEI/ARB treatment Nakai Y et al., BJC 2010; 103; 1644-1648 Non HT group (n = 103) Time (months) Overall survival rate (%) p < 0.03 6.2 months increase p < 0.03 6.2 months increase 100 80 60 40 20 0 012243648 Non ACEI/ARB with HT group (n = 25) ACEI/ARB group (n = 27)

17. 2813 Mo Overall survival of patients with advanced gastric cancer on platinum therapy with and without ACEI/ARB treatment Kim ST et al., Oncology 2012; 83: 354-360 Time (months) Survival rate (%) ACEI/ARB (n = 30) Non-ACEI/ARB (n = 33) p = 0.009 5.7 months increase 1.0 0.8 0.6 0.4 0.2 0.0 01224364860

18. 3049 Mo Cancer risk among patients with essential hypertension with and without ACEI/ARB treatment Chiang YY et al., J Clin Hypertens 2014; 16: 27-33 Variables vs Control Age, years ≤ 39 40-4950-5960-6970-79 ≥ 80 Adjusted HR 0.8012.13.56.48.17.9 0.511 2.7 2.7 5.0 5.0 8.2 8.213.511.7 ARB vs Control (n = 6969 vs 143887) ACEI vs Control (n = 4388 vs 143887) p0.0230.002<0.001<0.001<0.001<0.001p<0.0010.004<0.001<0.001<0.001<0.001

19. Control 3050 Mo Probability of cancer occurrence and duration of ACEI-ARB exposure among patients with essential HT Chiang YY et al., J Clin Hypertens 2014; 16: 27-33 Cumulative probability of cancer occurrence 0.10 0.08 0.06 0.04 0.02 0.00 0246810 Control ACEIs ARBs 0.08 0.06 0.04 0.02 0.00 0246810 Duration of exposure (years)

20. 2823 Mo Comparison of risk of incident cancer between users of specific ARB and of ACEI Pasternak B et al., Circulation 2011; 123: 1729-1736 LosartanCandesartanIrbesartanValsartanTelmisartan Eprosartan / OlmesartanAdjustedRR0.980.750.950.900.970.76 Incident cancer cases (n) 175191353949421255 Incident cancer cases (n) per 100.000 pers-ys 130511791233134412401354 0.51.01.5 ARB better ACEI better

21. 2799 Mo Conclusions Results of large observational studies do not support the hypothesis that patients on treatment with RAS antagonists are at greater risk of cancer Actually the majority of animal and "in vitro" studies suggest the opposite, i.e. that RAS antagonists may protect against cancer incidence and progression Few, small, non randomized studies have shown that treatment with RAS antagonists in men is associated with lower incidence and progression of cancer, specifically of gastro-intestinal origin More controlled, prospective studies are needed to confirm the antiblastic potentialities of RAS antagonists