Hormone therapy (HT)and breast cancer

Øjvind Lidegaard

Gynaecological ClinicRigshospitaletCopenhagen University

HT sale DK 2002. DDD/1,000 per day

0

50

100

150

200

250

15-39 40-44 45-49 50-54 55-59 60-64 65-69 70+

LocalMirenaComb contComb cyclProgestagenOestrogen

Danish Sex Hormone Register Study (DaHORS).

www.dachre.dk

HT sale DK 2004. DDD/1,000 per day

0

50

100

150

200

250

15-39 40-44 45-49 50-54 55-59 60-64 65-69 70+

LocalMirenaComb contComb cyclProgestagenOestrogen

Danish Sex Hormone Register Study (DaHORS).

www.dachre.dk

Breast cancer incidence rate by age

0 0 2 322

50

127

189

244271

352368

326 338 324342

0

50

100

150

200

250

300

350

400

<15

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

485

+

Total: 4,000 per yearLifetime risk: 10%

Health statistics, National Board of Health, DK 2003

Incidence per 100,000

80%20%

BC incidence rate in DK 1945-2000

61 62 6366

7278

8692

98

105

112

119

50

60

70

80

90

100

110

120

45 50 55 60 65 70 75 80 85 90 95 20

Oksbjerg S. Ugeskr Læger 1997; 159: 7134-40.

Incidence per 100,000 age standardised

Li/07

Family disposition and BC

1

1,8

2,9

3,9

1

1,5

2

2,5

3

3,5

4

0 1 2 3+

Risk of BC (95% CL)

Collaborative group, Lancet 2001; 358: 1389-99

Age at first birth and risk of BC

1

1,1

1,5

1,7

1

1,2

1,4

1,6

1,8

<20 20-24 25-29 30+

Risk of BC (95% CL)

Vatten LJ. Br J Cancer 2002, 86: 89-91

Case-control studyNorway373 cases1,150 controls

22,7

23,724

24,6

25,5

26,4

27,528,1

2928,9

22

23

24

25

26

27

28

29

30

1965 1970 1975 1980 1985 1990 1995 2000 2005 2008

Age at first birth Dk 1965-2008

Danmarks Statistik Online: www.dst.dk

Increase: 1 year/6 years

Li/09

Childless at 49 years 1995: 7.9%Childless at 49 years 2005: 12.7%

Alcohol intake and risk of breast cancer

drinks per day1

1,1

1,2

1,3

1,4

1,5

0 1 2 3 4

Risk of BC (95% CL)

Longnecker. Canc Causes and Control 1994; 5: 73-82Beral V et al. Lancet 2002; 87: 234-45.

Tjønneland et al. Canc Causes Control 2003; 14: 277-84

13%/drink

7.1%/drink

10%/drink

Can we explain the increase?

Yes:

• Increase in age at first birth 22→30 years

• Higher birth weight

• Less physical activity

• Fewer children per woman

• Increase in daily alcohol consumption

• Dramatic increase in BMI

These factors fully explain the increase

Lidegaard & Kroman. Eur Clinics Obstet Gynaecol 2005; 1: 24-8

Message 1

• Breast cancer is a multifactorial disease.

• Risk factors are identified and quantified

• We can explain the increase.

HT and breast cancer (BC)Seven different axes

1. Hormone regimen (estrogen vs combined)2. Cyclic combined vs continuous combined3. Length of use4. Estrogen dose5. Progestogen type (NETA, MPA, levo)6. Progestogen dose7. Route of administration; oral, transdermal,

vaginal, intrauterine,

HT and breast cancer (BC)Seven different axes

To discriminate between these seven different

axes at the samt time, demands • Large-scale studies • Precise exposure history• High follow-up rate

Danish sex Hormone Register StudyDaHoRS

Hormone therapy and breast cancer Øjvind Lidegaard

Ellen Løkkegaard

Lisbeth Møller

Carsten Agger

Anne Helms Andreasen

HT and breast cancer: Methods

National Registry of Patients (NRP)

BC diagnoses,Previous CaVD/canc.Pregnancies

National Registry of Medicinal products (NRM): HT, OC, Medication against BP , DM, Hyperchol.

Statistics of DenmarkEducation, PIN-codes,

address, vital status

1995 2005

HT and breast cancer: Results

• Cohort: Included women 50-69: 785,397• Exposed women (current+prev): 234,955• Control women (never users): 550,442• Women currently on HT with BC: 3,010 2.5• Women previously on HT w BC: 1,957 1.7• Women never on HT with BC: 7,864 1.4• Included with BC: 12,831

Danish Sex Hormone Register Study (DaHoRS): www. dachre.dk

BC risk: Length of systemic HTStratified by age and duration of use

1,0 1,0 1,0 1,00,9

1,21,4

1,7

1,4

1,7

2,1

1,61,7

2,2

1,1 1,1

0,5

1,0

1,5

2,0

2,5

Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4

Corrected RR, 95% CI

51-54 55-59 60-64 65-69

BC risk according to HT regimen

0,0

1,0

2,0

3,0

4,0

0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65

Adjusted HR, 95% CI

Estrogen Long cyc Cyc com Cont com Tibolone

BC risk according to route

0

1

2

3

0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65

DaHoRS/07

Adjusted HR, 95% CI

Oral E Oral comb TD Estrogen TD comb.

The impact of progestagen doseLow = 0.5mg NETA or 2.5mg MPA. High = 1mg NETA or 5mg MPA

0,41

1,040,91

1,4

2,3

2,9

1,77

3,0

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Never Low p High p Low p High p Low p High p Low p High p

DaHoRS/07

Adjusted RR, 95% CI

51-54 55-59 60-64 65-69

All continuous combined regimens

1,0

1,4

2,0 2,0

1,2

1,9

2,5 2,4

1,01,2

2,2

1,4

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

51-54 55-59 60-64 65-69 51-54 55-59 60-64 65-69

2mg E2, 1mg NETA

4mg E2, 1mg NETA

1.5mg E2, 10mg MPA

DaHoRS/07

Adjusted HR, 95% CI

BC risk acc to progestagen type and estrogen dose.

Cyclic combined regimen

1

0,40,3

0,4

0,70,5 0,5

0

1

2

Never Estrogen Longcycle

Cyclcomb

Contcomb

Tibolone All

DaHoRS/07

Adjusted RR, 95% CI

Case-fatality rate 5 yrs after diagnosis

Women with BC: 12,831Dead after diagnosis: 2,347 (18%)Five years follow-up: 1,269

1

0,81

0,5

1,0

1,5

Never Ever HT

DaHoRS/07

Adjusted RR, 95% CI

Risk of BC and subsequent death within five years after diagnosis

Women with BC: 12,831Dead after diagnosis: 2,347 (18%)Five years follow-up: 1,269

HT and BC: Randomised studiesRisk after 5.2 and 6.8 years MPA+EE

1,26 1,27

0

0,5

1

1,5

2

2,5

WHI HERS

WHI study: Cohort: 8,506 EE+MPA, 8,102 placebo. Follow up: 5.2 yrs. Endpoints: 166 exposed, 124 non-exposed

Rossouw et al. JAMA 2002; 288: 321-33.Hulley et al. JAMA 2002; 288: 58-66

HERS: 5,100 women with AMI randomised for EE+ MPA 2,5mg. Follow up 6.8 years. Endpoints: 49 exposed, 39 non-exposed women with BC

WHI resultsEPT ET 50-59

• Coronary heart disease 1.3 0.9 0.6

• Stroke 1.4 1.4 1.1

• Venous thromboembolism 2.1* 1.3 1.2

• Breast cancer 1.3 0.8 0.7

• Endometrial cancer 0.8 hysterect.

• Colorectal cancer 0.6 1.1 0.6

• Hip fracture 0.7 0.6 NA

• Vertebral fracture 0.7 0.6 NA

• All cause mortality 1.0 1.0 0.7

Rossouw et al. JAMA 2002; 288: 321-33.

Million women study

1

1,3

2

1,45

1,22

0,9

1,1

1,3

1,5

1,7

1,9

2,1

Never Est only Est + Prog Tibolone Death

Metaanalysis on HT and death

0,68

1,11

0,69

1,07

0,44

0,680,61

1,03

0

0,2

0,4

0,6

0,8

1

1,2

1,4

CVD Cancer Other Total CVD Cancer Other Total

<60 >60

Salpeter et al. J Gen Intern Med 2004; 19: 791-804

OR, 95% CI

Aim: HT, deaths, ageMeta-analysis on 30 RCT26,708 participants

The reduced case-fatality rate and low risk of lethal BC may be due to

• Earlier detection of BC in hormone users

• Less pathological histology

• More receptor positive tumors

• Withdrawal of hormones after detection

• More intensive screening of women on hormones with detection of tumours which would never have manifested as clinical BC

Danish Sex Hormone Register Study (DaHoRS): www. dachre.dk

HT and breast cancer – new study

Finnish Cancer Registry (cases)

BC diagnoses: 9,956

Previous canc.

National medical Reimbursement Registry. HT

Population reg of Finland 3 controls per case

N = 29,868

1995 2007

Lyytinen et al. Int J Cancer 2010; 126: 483-9

BC risk according to HT regimen

0,0

1,0

2,0

3,0

4,0

0 E2 <3 3-<5 >5 <3 3-<5 >5 <3 3-<5 >5 <3 3-<5 >5

Adjusted OR, 95% CIAdjusted for age, parity, age at first birth, district

Estrogen Long cyc Cyc com Cont com IUD+E2

Lyytinen et al. Int J Cancer 2010; 126: 483-9

BC risk: Length of systemic HTStratified by age and duration of use

1,0 1,0 1,0 1,00,9

1,21,4

1,7

1,4

1,7

2,1

1,61,7

2,2

1,1 1,1

0,5

1,0

1,5

2,0

2,5

Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4

Corrected RR, 95% CI

51-54 55-59 60-64 65-69

BC risk according to HT regimen

0,0

1,0

2,0

3,0

4,0

0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65

DaHoRS/07

Adjusted HR, 95% CI

Estrogen Long cyc Cyc com Cont com Tibolone

Message 2

• HT for less than five years plays a little quantitative role for the risk of getting BC

• Estrogen only confer less risk than combined regimens, and cyclic combined less risk than continuous combined therapy

• Dose seems more important than length of use according to Danish data, opposite according to data from Finland

• The risk of lethal breast cancer is not increased in users of hormones

HT in US 2000-2004

Ravdin et al. N Engl J Med 2007; 356: 1670-4.

US trend in BC 00-04, 50-69 yrs

Ravdin et al. N Engl J Med 2007; 356: 1670-4.

-11.8%

-14.7%

BC incidence in Norway 1996-2005

23522403 2416 2409

2527

26222696 2723

2786 2780

2000

2200

2400

2600

2800

3000

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

Cancer Registry, Norway

Incidence per 100,000

BC incidence rate Norway 2002 and 2005

0 0 0

104

236

307330

312

0 0 1

96

226

270305

272

3 1350

164

267235

202

321

6 2155

179

323

252

212

332

0

50

100

150

200

250

300

350

400

<15

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

485

+

Cancer Registry, Norway

Incidence per 100,000

-5.1%

BC incidence rate Sweden 2002 and 2005

0 0 1

282317

0 0 0

234

282

364

297

98

5 2043

190

363

294318

374364372

107

9 2148

201

380

323349

398

0

50

100

150

200

250

300

350

400

<15

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

485

+

Cancer Registry, Sweden

Incidence per 100,000

-4.7%

Breast cancer: Etiologic fraction of HT

0

50

100

150

200

250

300

350

400

<15 15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

Li/07

Etiological fraction:All: 3%All >50 years: 4%

Health Statistics, National Board of Health, Denmark

Incidence per 100,000

Message 3

• Hormone IUD + systemic oestrogen is apparently not more safe than combined oral regimens

• The overall risk of death is not increased in users of hormones

Message 3

• Hormone IUD + systemic oestrogen is apparently not more safe than combined oral regimens

• The overall risk of death is not increased in users of hormones

Thank you.Presentation on www.Lidegaard.dk