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