1674 Mo1674 Mo

Gli antagonisti del sistema renina-Gli antagonisti del sistema renina-angiotensina hanno effetti anticancro?angiotensina hanno effetti anticancro?

Alberto MorgantiAlberto MorgantiCentro Fisiologia Clinica e Ipertensione Centro Fisiologia Clinica e Ipertensione Ospedale Policlinico, Università MilanoOspedale Policlinico, Università Milano

5°Congresso Nazionale ASIAM 5°Congresso Nazionale ASIAM Riccione 15-17 Maggio 2015Riccione 15-17 Maggio 2015

2800 Mo2800 Mo

Antihypertensive drugs and cancerAntihypertensive drugs and cancer

DrugDrug

ReserpineReserpine

Beta-blockersBeta-blockers

Calcium antagonistsCalcium antagonists

Thiazide diureticsThiazide diuretics

Anti-HT drugsAnti-HT drugs

Cancer siteCancer site

BreastBreast

LungLung

Cancer in generalCancer in general

Kidney / ColonKidney / Colon

Brain gliomaBrain glioma

2801 Mo2801 Mo

Cancer occurrence reported in trials of ARBs Cancer occurrence reported in trials of ARBs in which cancer was a prespecified endpointin which cancer was a prespecified endpoint

TrialTrial

TRANSCENDTRANSCEND

ONTARGETONTARGET

ONTARGETONTARGET

LIFELIFE

Meta-analysisMeta-analysis

Sipahi I et al., Lancet Oncology 2010; 11: 627-656Sipahi I et al., Lancet Oncology 2010; 11: 627-656

RRRR

1.171.17

1.051.05

1.141.14

1.121.12

1.111.11

Risk ratio (95% CI)Risk ratio (95% CI)

0.50.5 1.01.0 2.02.0ARB worseARB worseControl worseControl worse

2802 Mo2802 Mo

Methodological limitations of Sipahi meta-analysisMethodological limitations of Sipahi meta-analysis

Arbitrary selection of included trials (short follow-up, # of Arbitrary selection of included trials (short follow-up, # of patients)patients)

Lack of information on individual patient dataLack of information on individual patient data

Adjudication of cancer diagnosis not uniformAdjudication of cancer diagnosis not uniform

Results driven by a single study (ONTARGET)Results driven by a single study (ONTARGET)

Overall cancer Overall cancer deathdeath similar in ARB and control patients similar in ARB and control patients

2806 Mo2806 Mo

Tumours expressing Angiotensin II receptors Tumours expressing Angiotensin II receptors

MelanomaMelanoma

BrainBrain

LungLung

PancreasPancreas

KidneyKidney

OvaryOvary

BladderBladder

ProstateProstate

2805 Mo2805 Mo

RAS and tumour proliferationRAS and tumour proliferation

Wilop S et al., J Cancer Res Clin Oncol 2009; 135: 1429-1435Wilop S et al., J Cancer Res Clin Oncol 2009; 135: 1429-1435

AIIAII

ATAT22RR ATAT11RR ATAT11RR

EGFEGFTumor cellsTumor cells

VEGFVEGFStromal cellsStromal cells

Proliferation ↑Proliferation ↑Angiogenesis ↑Angiogenesis ↑

Tumour growth ↑Tumour growth ↑

?? ++ ++

2807 Mo2807 Mo

Influence of components of RAS on tumour growthInfluence of components of RAS on tumour growth

Angiotensin IIAngiotensin II

Angio (1-7)Angio (1-7)

Angio (1-5)Angio (1-5)

ATAT11RR

ATAT22RR

ATAT44RR

Prorenin / Renin receptors (PRR)Prorenin / Renin receptors (PRR)

FacilitationFacilitation

InhibitionInhibition

UnknownUnknown

FacilitationFacilitation

Mostly inhibitionMostly inhibition

FacilitationFacilitation

FacilitationFacilitation

Factors whereby facilitation or inhibition is exerted:Factors whereby facilitation or inhibition is exerted:vascular endothelial growth factor (VEGF), angiopoietin 2, basic fibroblast growth factor (b-FGF), 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), 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 endothelin, nitric oxide (NO), monocyte chemoattractant protein (MCP 1-2), seryl-aspartil-lysyl-proline (SAKP)(SAKP)

2809 Mo2809 Mo

Effect of ATEffect of AT22 receptor overexpression on receptor overexpression on

human lung cancer cell growthhuman lung cancer cell growth

Pievel L et al., Cancer Biol Ther 2010; 9: 277-285Pievel L et al., Cancer Biol Ther 2010; 9: 277-285

-A549 cell-A549 cell-A549 cell-A549 cell -H358 cell-H358 cell-H358 cell-H358 cell

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

Cel

l gro

wth

Cel

l gro

wth

ControlControl ATAT22 ControlControl ATAT22

HumanHuman

MouseMouse

************

****** ****

2808 Mo2808 Mo

Cell line / animal models in which RAS blockade Cell line / animal models in which RAS blockade effectively reduces tumour volume or metastaseseffectively reduces tumour volume or metastases

Cell line / ModelCell line / Model

Lung carcinomaLung carcinoma

FibrocarcinomaFibrocarcinoma

Renal carcinomaRenal carcinoma

Hepatocellular carcinomaHepatocellular carcinoma

Ovarian carcinomaOvarian carcinoma

Bladder cancerBladder cancer

Colorectal / liver metastasesColorectal / liver metastases

Gastric cancerGastric cancer

AgentAgent

CaptoprilCaptopril

CaptoprilCaptopril

CaptoprilCaptopril

PerindoprilPerindopril

CandesartanCandesartan

CandesartanCandesartan

CaptoprilCaptopril

CandesartanCandesartan

Ager EI et al., Carcinogenesis 2008; 28: 1675-1684Ager EI et al., Carcinogenesis 2008; 28: 1675-1684

2820 Mo2820 Mo

Incident and fatal cancer in patients on ACEI vs Incident and fatal cancer in patients on ACEI vs age- and sex-matched patients on other antiHT drugsage- and sex-matched patients on other antiHT drugs

Lever AR et al., Lancet 1998; 352: 179-184Lever AR et al., Lancet 1998; 352: 179-184

% without cancer% without cancer

Fatal cancerFatal cancerFatal cancerFatal cancerIncident cancerIncident cancerIncident cancerIncident cancer

Follow-up (years)Follow-up (years)

Cumulative survival (%)Cumulative survival (%)

Follow-up (years)Follow-up (years)

ACEI (n = 1559)ACEI (n = 1559)Other antiHT drugs (n = 3468)Other antiHT drugs (n = 3468)

RR: 0.72RR: 0.72 RR: 0.65RR: 0.65

100100

9898

9696

9494

9292

9090

100100

9898

9696

9494

00 11 22 33 44 55 66 77 88 99 1010 00 11 22 33 44 55 66 77 88 99 1010

2803 Mo2803 Mo

ARB, cancer risk and cancer related deathARB, cancer risk and cancer related death

StudiesStudies

1515

2020

Bangalore S et al., Lancet Oncology 2011; 12: 65-82Bangalore S et al., Lancet Oncology 2011; 12: 65-82

OROR

0.980.98

0.990.99

Cases / Pts on ARBCases / Pts on ARB

3108 / 49996 (6.2%)3108 / 49996 (6.2%)

942 / 56991 (1.6%)942 / 56991 (1.6%)

Mean follow-up 3.5 years (minimum 1 year), patients enrolled 100 or moreMean follow-up 3.5 years (minimum 1 year), patients enrolled 100 or more

Cases / ControlsCases / Controls

3167 / 49779 (6.3%)3167 / 49779 (6.3%)

952 / 57291 (1.6%)952 / 57291 (1.6%)

Cancer riskCancer risk

Cancer related deathCancer related death

2804 Mo2804 Mo

Incidence of cancer by specific ARB vs non-ARB controls Incidence of cancer by specific ARB vs non-ARB controls in 15 RC ARB trialsin 15 RC ARB trials

DrugDrug

TelmisartanTelmisartan

IrbesartanIrbesartan

ValsartanValsartan

CandesartanCandesartan

LosartanLosartan

Grand totalGrand total

ARB Trialist Collaboration, J Hypertens 2011; 29: 623-635ARB Trialist Collaboration, J Hypertens 2011; 29: 623-635

OROR

1.071.07

0.910.91

0.920.92

1.111.11

1.091.09

1.001.00

StudiesStudies

33

33

44

44

11

1515

Data from 138.769 patients, follow-up 24-57 monthsData from 138.769 patients, follow-up 24-57 months

Pts on ARBPts on ARB

1823 (6.3%)1823 (6.3%)

491 (6.8%)491 (6.8%)

1441 (5.9%)1441 (5.9%)

451 (5.0%)451 (5.0%)

343 (7.4%)343 (7.4%)

4549 (6.2%)4549 (6.2%)

Cancer cases Cancer cases Pts not on ARBPts not on ARB

1112 (5.3%)1112 (5.3%)

536 (7.5%)536 (7.5%)

1484 (7.6%)1484 (7.6%)

408 (4.5%)408 (4.5%)

316 (6.9%)316 (6.9%)

3856 (6.3%)3856 (6.3%)

p valuep value

0.090.09

0.120.12

0.020.02

0.130.13

0.100.10

0.880.88

2814 Mo2814 Mo

Incidence of lung cancer Incidence of lung cancer in patients treated vs not treated with ARBsin patients treated vs not treated with ARBs

Rao GA et al., J Hypertens 2013; 31: 1669-1675Rao GA et al., J Hypertens 2013; 31: 1669-1675

Time in yearsTime in years

Lu

ng

can

cer

inci

den

ce (

%)

Lu

ng

can

cer

inci

den

ce (

%)

n = 6577 / 1155826n = 6577 / 1155826

TreatedTreatedNot treatedNot treated

n = 346 / 78075n = 346 / 78075

HR: 0.74HR: 0.74Follow-up: 3-5 yearsFollow-up: 3-5 years

0.700.70

0.600.60

0.500.50

0.400.40

0.300.30

0.200.20

0.100.10

0.000.00

-0.10-0.10

-0.20-0.20

11 22 33 44 55 66 77

**

2815 Mo2815 Mo

Relationship between ARB subtype Relationship between ARB subtype and lung cancer incidenceand lung cancer incidence

Rao GA et al., J Hypertens 2012; 31: 1669-1675Rao GA et al., J Hypertens 2012; 31: 1669-1675

Stratified by smoking statusStratified by smoking status

All current smokersAll current smokersAll former smokersAll former smokersAll never smokedAll never smoked

Stratified ARB subtype Stratified ARB subtype in a cohort of all ARB usersin a cohort of all ARB users

LosartanLosartanCandesartanCandesartanIrbesartanIrbesartanValsartanValsartan

HR for ARBHR for ARB

0.720.720.860.860.420.42

HR for ARB subtypeHR for ARB subtype

1 (ref)1 (ref)1.001.000.940.940.940.94

PP

< 0.001< 0.0010.1750.1750.060.06

PP

0.790.790.950.950.990.99

3048 Mo3048 Mo

Colorectal cancer risk associated with Colorectal cancer risk associated with increasing dose and duration of antiHT agentsincreasing dose and duration of antiHT agents

Makar GA, J Natl Cancer Inst 2014Makar GA, J Natl Cancer Inst 2014

AntiHT agentAntiHT agent

ACEI/ARB therapyACEI/ARB therapy< 3 years< 3 years≥ ≥ 3 years3 years

CCB therapyCCB therapy< 3 years< 3 years≥ ≥ 3 years3 years

OROR

0.890.891.011.01

0.900.901.031.03

Low doseLow dosepp

0.030.03nsns

0.040.04nsns

nn

5155515519621962

7396739636673667

OROR

0.870.870.590.59

0.910.910.940.94

High doseHigh dosepp

nsns0.010.01

nsnsnsns

nn

551551431431

269269157157

2811 Mo2811 Mo

Overall survival in patients with advanced pancreatic cancer Overall survival in patients with advanced pancreatic cancer with and without ACEI/ARB treatmentwith and without ACEI/ARB treatment

Nakai Y et al., BJC 2010; 103; 1644-1648Nakai Y et al., BJC 2010; 103; 1644-1648

Non HT groupNon HT group(n = 103)(n = 103)

Time (months)Time (months)

Ove

rall

surv

ival

rat

e (%

)O

vera

ll su

rviv

al r

ate

(%)

p < 0.03 p < 0.03 6.2 months increase6.2 months increasep < 0.03 p < 0.03 6.2 months increase6.2 months increase

100100

8080

6060

4040

2020

0000 1212 2424 3636 4848

Non ACEI/ARB with HT groupNon ACEI/ARB with HT group(n = 25)(n = 25)

ACEI/ARB group (n = 27)ACEI/ARB group (n = 27)

2813 Mo2813 Mo

Overall survival of patients with advanced gastric cancer on Overall survival of patients with advanced gastric cancer on platinum therapy with and without ACEI/ARB treatmentplatinum therapy with and without ACEI/ARB treatment

Kim ST et al., Oncology 2012; 83: 354-360Kim ST et al., Oncology 2012; 83: 354-360Time (months)Time (months)

Su

rviv

al r

ate

(%)

Su

rviv

al r

ate

(%)

ACEI/ARB (n = 30)ACEI/ARB (n = 30)

Non-ACEI/ARB (n = 33)Non-ACEI/ARB (n = 33)

p = 0.009p = 0.0095.7 months increase5.7 months increase

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

00 1212 2424 3636 4848 6060

3049 Mo3049 Mo

Cancer risk among patients with essential hypertension Cancer risk among patients with essential hypertension with and without ACEI/ARB treatmentwith and without ACEI/ARB treatment

Chiang YY et al., J Clin Hypertens 2014; 16: 27-33Chiang YY et al., J Clin Hypertens 2014; 16: 27-33

VariablesVariables

vs Controlvs Control

Age, yearsAge, years≤ ≤ 393940-4940-4950-5950-5960-6960-6970-7970-79≥ ≥ 8080

Adjusted HRAdjusted HR

0.800.80

1 1 2.12.13.53.56.46.48.18.17.97.9

Adjusted HRAdjusted HR

0.510.51

1 1 2.72.7 5.05.0 8.28.213.513.511.711.7

ARB vs ControlARB vs Control(n = 6969 vs 143887)(n = 6969 vs 143887)

ACEI vs ControlACEI vs Control(n = 4388 vs 143887)(n = 4388 vs 143887)

pp

0.0230.023

0.0020.002<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

pp

<0.001 <0.001

0.0040.004<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

ControlControl

3050 Mo3050 Mo

Probability of cancer occurrence and duration of ACEI-ARB Probability of cancer occurrence and duration of ACEI-ARB exposure among patients with essential HTexposure among patients with essential HT

Chiang YY et al., J Clin Hypertens 2014; 16: 27-33Chiang YY et al., J Clin Hypertens 2014; 16: 27-33

Cu

mu

lati

ve p

rob

abili

ty o

f ca

nce

r oc

curr

ence

Cu

mu

lati

ve p

rob

abili

ty o

f ca

nce

r oc

curr

ence

0.100.10

0.080.08

0.060.06

0.040.04

0.020.02

0.000.00

00 22 44 66 88 1010

ControlControlACEIsACEIs ARBsARBs

0.080.08

0.060.06

0.040.04

0.020.02

0.000.00

00 22 44 66 88 1010

Duration of exposure (years)Duration of exposure (years) Duration of exposure (years)Duration of exposure (years)

2823 Mo2823 Mo

Comparison of risk of incident cancer Comparison of risk of incident cancer between users of specific ARB and of ACEIbetween users of specific ARB and of ACEI

Pasternak B et al., Circulation 2011; 123: 1729-1736Pasternak B et al., Circulation 2011; 123: 1729-1736

LosartanLosartanCandesartanCandesartanIrbesartanIrbesartanValsartanValsartanTelmisartanTelmisartanEprosartan / Eprosartan / OlmesartanOlmesartan

Adjusted Adjusted RRRR

0.980.980.750.750.950.950.900.900.970.970.760.76

Incident cancerIncident cancercases (n)cases (n)

175117519139135395394944942122125555

Incident cancerIncident cancercases (n) per cases (n) per

100.000 pers-ys100.000 pers-ys

130513051179117912331233134413441240124013541354

0.50.5 1.01.0 1.51.5ARB betterARB better ACEI betterACEI better

2799 Mo2799 Mo

ConclusionsConclusions

Results of large observational studies do not support the hypothesis that Results of large observational studies do not support the hypothesis that patients on treatment with RAS antagonists are at greater risk of cancerpatients on treatment with RAS antagonists are at greater risk of cancer

Actually the majority of animal and "in vitro" studies suggest the Actually the majority of animal and "in vitro" studies suggest the opposite, i.e. that RAS antagonists may protect against cancer incidence opposite, i.e. that RAS antagonists may protect against cancer incidence and progressionand progression

Few, small, non randomized studies have shown that treatment with Few, small, non randomized studies have shown that treatment with RAS antagonists in men is associated with lower incidence and RAS antagonists in men is associated with lower incidence and progression of cancer, specifically of gastro-intestinal originprogression of cancer, specifically of gastro-intestinal origin

More controlled, prospective studies are needed to confirm the More controlled, prospective studies are needed to confirm the antiblastic potentialities of RAS antagonistsantiblastic potentialities of RAS antagonists