Hormone therapy (HT) and breast cancer Øjvind Lidegaard Gynaecological Clinic Rigshospitalet Copenhagen University

HT sale DK DDD/1,000 per day Danish Sex Hormone Register Study (DaHORS).

HT sale DK DDD/1,000 per day Danish Sex Hormone Register Study (DaHORS).

Breast cancer incidence rate by age Total: 4,000 per year Lifetime risk: 10% Health statistics, National Board of Health, DK 2003 Incidence per 100,000 80%20%

BC incidence rate in DK Oksbjerg S. Ugeskr Læger 1997; 159: Incidence per 100,000 age standardised Li/07

Family disposition and BC Collaborative group, Lancet 2001; 358:

Age at first birth and risk of BC Vatten LJ. Br J Cancer 2002, 86: Case-control study Norway 373 cases 1,150 controls

Age at first birth Dk Danmarks Statistik Online: 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 day Longnecker. Canc Causes and Control 1994; 5: Beral V et al. Lancet 2002; 87: Tjønneland et al. Canc Causes Control 2003; 14: %/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 combined 3.Length of use 4.Estrogen dose 5.Progestogen type (NETA, MPA, levo) 6.Progestogen dose 7.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. Statistics of Denmark Education, PIN-codes, address, vital status

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, Women previously on HT w BC: 1, Women never on HT with BC: 7, Included with BC: 12,831 Danish Sex Hormone Register Study (DaHoRS): www. dachre.dk

BC risk: Length of systemic HT Stratified by age and duration of use Corrected RR, 95% CI

BC risk according to HT regimen Adjusted HR, 95% CI EstrogenLong cyc Cyc com Cont com Tibolone

BC risk according to route DaHoRS/07 Adjusted HR, 95% CI Oral E Oral comb TD Estrogen TD comb.

The impact of progestagen dose Low = 0.5mg NETA or 2.5mg MPA. High = 1mg NETA or 5mg MPA DaHoRS/07 Adjusted RR, 95% CI All continuous combined regimens

DaHoRS/07 Adjusted HR, 95% CI BC risk acc to progestagen type and estrogen dose. Cyclic combined regimen

DaHoRS/07 Adjusted RR, 95% CI Case-fatality rate 5 yrs after diagnosis Women with BC: 12,831 Dead after diagnosis: 2,347 (18%) Five years follow-up: 1,269

DaHoRS/07 Adjusted RR, 95% CI Risk of BC and subsequent death within five years after diagnosis Women with BC: 12,831 Dead after diagnosis: 2,347 (18%) Five years follow-up: 1,269

HT and BC: Randomised studies Risk after 5.2 and 6.8 years MPA+EE 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: Hulley et al. JAMA 2002; 288: 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 results EPTET Coronary heart disease Stroke Venous thromboembolism2.1* Breast cancer Endometrial cancer0.8hysterect. Colorectal cancer Hip fracture0.70.6NA Vertebral fracture0.70.6NA All cause mortality Rossouw et al. JAMA 2002; 288:

Million women study

Metaanalysis on HT and death Salpeter et al. J Gen Intern Med 2004; 19: OR, 95% CI Aim: HT, deaths, age Meta-analysis on 30 RCT 26,708 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, Lyytinen et al. Int J Cancer 2010; 126: 483-9

BC risk according to HT regimen Adjusted OR, 95% CI Adjusted 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 HT Stratified by age and duration of use Corrected RR, 95% CI

BC risk according to HT regimen DaHoRS/07 Adjusted HR, 95% CI EstrogenLong 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 Ravdin et al. N Engl J Med 2007; 356:

US trend in BC 00-04, yrs Ravdin et al. N Engl J Med 2007; 356: % -14.7%

BC incidence in Norway Cancer Registry, Norway Incidence per 100,000

BC incidence rate Norway 2002 and 2005 Cancer Registry, Norway Incidence per 100, %

BC incidence rate Sweden 2002 and 2005 Cancer Registry, Sweden Incidence per 100, %

Breast cancer: Etiologic fraction of HT 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