Hormone therapy (HT)
and breast cancer
Øjvind Lidegaard
Gynaecological Clinic
Rigshospitalet
Copenhagen University
HT sale DK 2002. DDD/1,000 per day
250
www.dachre.dk
Local
Mirena
Comb cont
Comb cycl
Progestagen
Oestrogen
200
150
100
50
0
15-39
40-44
45-49
50-54
55-59
60-64
65-69
Danish Sex Hormone Register Study (DaHORS).
70+
HT sale DK 2004. DDD/1,000 per day
250
www.dachre.dk
Local
Mirena
Comb cont
Comb cycl
Progestagen
Oestrogen
200
150
100
50
0
15-39
40-44
45-49
50-54
55-59
60-64
65-69
Danish Sex Hormone Register Study (DaHORS).
70+
Breast cancer incidence rate by age
400
350
300
Incidence per 100,000
352
Total: 4,000 per year
Lifetime risk: 10%
368
326
338 342
324
271
250
244
200
189
150
127
100
50
0
0
2
3
<1
5
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
4
85
+
0
22
50 20% 80%
Health statistics, National Board of Health, DK 2003
BC incidence rate in DK 1945-2000
120
Incidence per 100,000 age standardised
119
110
112
100
105
98
90
92
86
80
78
70
72
60
61
62
63
45
50
55
66
50
60
65
70
75
80
85
Oksbjerg S. Ugeskr Læger 1997; 159: 7134-40.
90
95
20
Li/07
Family disposition and BC
4
3,9
Risk of BC
(95% CL)
3,5
3
2,9
2,5
2
1,8
1,5
1
1
0
1
2
Collaborative group, Lancet 2001; 358: 1389-99
3+
Age at first birth and risk of BC
1,8
1,6
1,4
Risk of BC
(95% CL)
1,7
Case-control study
Norway
373 cases
1,150 controls
1,5
1,2
1,1
1
1
<20
20-24
25-29
Vatten LJ. Br J Cancer 2002, 86: 89-91
30+
Age at first birth Dk 1965-2008
30
28,9
29
28
28,1
27,5
Increase: 1 year/6 years
26,4
27
25,5
26
24,6
25
23,7
24
23
29
24
22,7
Childless at 49 years 1995: 7.9%
Childless at 49 years 2005: 12.7%
22
1965
1970
1975
1980
1985
1990
1995
2000
Danmarks Statistik Online: www.dst.dk
2005
2008
Li/09
Alcohol intake and risk of breast cancer
1,5
1,4
Risk of BC
(95% CL)
10%/drink
1,3
13%/drink
1,2
7.1%/drink
1,1
drinks
per day
1
0
1
2
3
4
Longnecker. Canc Causes and Control 1994; 5: 73-82
Beral V et al. Lancet 2002; 87: 234-45.
Tjønneland et al. Canc Causes Control 2003; 14: 277-84
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.
2.
3.
4.
5.
6.
7.
Hormone regimen (estrogen vs combined)
Cyclic combined vs continuous combined
Length of use
Estrogen dose
Progestogen type (NETA, MPA, levo)
Progestogen dose
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 Study
DaHoRS
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.
1995
2005
Statistics of Denmark
Education, PIN-codes,
address, vital status
HT and breast cancer: Results
•
•
•
•
•
•
•
Cohort: Included women 50-69:
Exposed women (current+prev):
Control women (never users):
Women currently on HT with BC:
Women previously on HT w BC:
Women never on HT with BC:
Included with BC:
785,397
234,955
550,442
3,010 2.5
1,957 1.7
7,864 1.4
12,831
Danish Sex Hormone Register Study (DaHoRS): www. dachre.dk
BC risk: Length of systemic HT
Stratified by age and duration of use
2,5
Corrected RR, 95% CI
2,2
2,1
2,0
1,7
1,7
1,5
1,0
1,4
1,4
1,1 1,1
1,0
1,6
1,7
1,2
1,0
1,0
1,0
0,9
51-54
55-59
60-64
65-69
0,5
Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4
BC risk according to HT regimen
4,0
Adjusted HR, 95% CI
3,0
2,0
1,0
Estrogen Long cyc Cyc com
Cont com Tibolone
0,0
0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65
BC risk according to route
3
Adjusted HR, 95% CI
2
1
Oral E
0
0
Oral comb
TD Estrogen TD comb.
50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65
DaHoRS/07
The impact of progestagen dose
Low = 0.5mg NETA or 2.5mg MPA. High = 1mg NETA or 5mg MPA
3,5
3,0
Adjusted RR, 95% CI
All continuous combined regimens
3,0
2,9
2,5
2,3
2,0
1,77
1,5
1,4
1,04
1,0
51-54
0,5
55-59
0,91
60-64
65-69
0,41
0,0
Never Low p High p Low p High p Low p High p Low p High p
DaHoRS/07
BC risk acc to progestagen type
and estrogen dose.
Cyclic combined regimen
4,0
2mg E2, 1mg NETA
Adjusted HR, 95% CI
3,5
4mg E2, 1mg NETA
3,0
1.5mg E2, 10mg MPA
2,5
2,5
2,0
1,9
1,5
1,0
1,2
1,0
2,0
2,4
2,2
2,0
1,4
1,4
1,0
1,2
0,5
51-54
55-59
60-64
65-69
51-54
55-59
60-64
65-69
DaHoRS/07
Case-fatality rate 5 yrs after diagnosis
2
1
Adjusted RR, 95% CI
Women with BC:
12,831
Dead after diagnosis: 2,347 (18%)
Five years follow-up: 1,269
1
0,7
0,4
0,5
0,5
0,4
0,3
0
Never
Estrogen
Long
cycle
Cycl
comb
Cont
comb
Tibolone
All
DaHoRS/07
Risk of BC and subsequent death
within five years after diagnosis
1,5
Adjusted RR, 95% CI
Women with BC:
12,831
Dead after diagnosis: 2,347 (18%)
Five years follow-up: 1,269
1,0
1
0,81
0,5
Never
Ever HT
DaHoRS/07
HT and BC: Randomised studies
Risk after 5.2 and 6.8 years MPA+EE
2,5
2
1,5
1
0,5
0
WHI study: Cohort: 8,506
EE+MPA, 8,102 placebo.
Follow up: 5.2 yrs.
Endpoints: 166 exposed,
124 non-exposed
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
1,26
WHI
Rossouw et al. JAMA 2002; 288: 321-33.
Hulley et al. JAMA 2002; 288: 58-66
1,27
HERS
WHI results
• Coronary heart disease
• Stroke
• Venous thromboembolism
• Breast cancer
• Endometrial cancer
• Colorectal cancer
• Hip fracture
• Vertebral fracture
• All cause mortality
EPT
1.3
1.4
2.1*
1.3
0.8
0.6
0.7
0.7
1.0
ET 50-59
0.9 0.6
1.4 1.1
1.3 1.2
0.8 0.7
hysterect.
1.1 0.6
0.6 NA
0.6 NA
1.0 0.7
Rossouw et al. JAMA 2002; 288: 321-33.
Million women study
2,1
2
1,9
1,7
1,5
1,45
1,3
1,3
1,22
1,1
1
0,9
Never
Est only
Est + Prog
Tibolone
Death
Metaanalysis on HT and death
1,4
OR, 95% CI
<60
>60
1,2
1,11
1
1,03
1,07
0,8
0,68
0,69
0,68
0,61
0,6
0,44
0,4
Aim: HT, deaths, age
Meta-analysis on 30 RCT
26,708 participants
0,2
0
CVD
Cancer
Other
Total
CVD
Cancer
Other
Salpeter et al. J Gen Intern Med 2004; 19: 791-804
Total
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
1995
2007
Population reg of Finland
3 controls per case
N = 29,868
Lyytinen et al. Int J Cancer 2010; 126: 483-9
BC risk according to HT regimen
4,0
3,0
Adjusted OR, 95% CI
Adjusted for age, parity,
age at first birth, district
2,0
1,0
Estrogen Long cyc Cyc com
Cont com
IUD+E2
0
<3 3-<5 >5
<3 3-<5 >5
0,0
E2
<3 3-<5 >5
<3 3-<5 >5
Lyytinen et al. Int J Cancer 2010; 126: 483-9
BC risk: Length of systemic HT
Stratified by age and duration of use
2,5
Corrected RR, 95% CI
2,2
2,1
2,0
1,7
1,7
1,5
1,0
1,4
1,4
1,1 1,1
1,0
1,6
1,7
1,2
1,0
1,0
1,0
0,9
51-54
55-59
60-64
65-69
0,5
Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4 Ne <1 1-4 >4
BC risk according to HT regimen
4,0
Adjusted HR, 95% CI
3,0
2,0
1,0
Estrogen Long cyc Cyc com
Cont com Tibolone
0,0
0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65
DaHoRS/07
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
-11.8%
-14.7%
Ravdin et al. N Engl J Med 2007; 356: 1670-4.
BC incidence in Norway 1996-2005
3000 Incidence per 100,000
2800
2696 2723
2786 2780
2622
2527
2600
2400
2352
2403 2416 2409
2200
Cancer Registry, Norway
20
05
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
2000
BC incidence rate Norway 2002 and 2005
400
Incidence per 100,000
350
307
321
305
300
236
250
270
200
179 226
150
323 312
252
267 272
212
235
202
104 164
-5.1%
100
50
330 332
0
0
0
0
0
1
<1
5
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
4
85
+
0
55 96
21 50
6
3 13
Cancer Registry, Norway
BC incidence rate Sweden 2002 and 2005
400
Incidence per 100,000
350
282
300
318
282
250
201
200
294
297
234
190
150
107
100
50
380
372 398
364
349
317 364374
323 363
-4.7%
48 98
0
0
1
0
0
0
<1
5
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
4
85
+
0
9 21 43
5 20
Cancer Registry, Sweden
Breast cancer: Etiologic fraction of HT
400
350
300
Incidence per 100,000
Etiological fraction:
All: 3%
All >50 years: 4%
250
200
150
100
50
0
<15 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85+
19 24 29 34 39 44 49 54 59 64 69 74 79 84
Health Statistics, National Board of Health, Denmark
Li/07
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