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. 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