is postmenopause hormone therapy acceptable in view of breast

EndocrinologistEndocrinologist

Ass. Professor of Gynecological EndocrinologyAss. Professor of Gynecological Endocrinology

University of Athens, GreeceUniversity of Athens, Greece

Irene LambrinoudakiIrene Lambrinoudaki

Is postmenopausal hormone therapy Is postmenopausal hormone therapy acceptable in view of breast cancer risk?acceptable in view of breast cancer risk?

National Institutes of Health, http://seer.cancer.gov,

accessed April 2010

• The most frequent cancer in women

• Incidence: 124 cases / 100,000 women/years

• Lifetime risk: 12.1%

• Risk between 50 and 60 years: 2.4%

Breast cancer

Breast cancer has a favorable prognosis

10-year survival rate:

80%

National Institutes of Health, http://seer.cancer.gov,

accessed April 2010

Breast cancer:High incidence + favorable prognosis = high prevalence

National Institutes of Health, http://seer.cancer.gov, accessed April 2010

Meta-analysisMeta-analysis (51 (51 studiesstudies) ) 1.351.35 11

NHS EPT 1.32 NHS EPT 1.32 22

WHI EPT 1.26 WHI EPT 1.26 33

WHI EPT 1.24WHI EPT 1.24 4 4

MWS EPT/ET 1.66MWS EPT/ET 1.66 5 5

11 . Lancet 1997;350:1047 . Lancet 1997;350:1047

2 . Chen WY et al, Ann Intern Med 2 . Chen WY et al, Ann Intern Med 2002;137:7982002;137:798

3. Writing Group for WHI, JAMA 3. Writing Group for WHI, JAMA 2002;288:3212002;288:321

Study RRStudy RR

Hormone therapy is associated with a small but significant risk of breast cancer

4. Chlebowski et al, JAMA 4. Chlebowski et al, JAMA 2003;289:32432003;289:3243

5. Beral V, Lancet 2003;362:419-275. Beral V, Lancet 2003;362:419-27

Characteristics of HT regimen and breast cancer risk

A. Characteristics of HT regimen

B. Real impact of risk (attributable risk)

1. Estrogen monotherapy versus combined EPT

2. Duration of use

3. Mode (sequential versus continuous)

4. Route (oral versus transdermal)

5. Dose

6. Type of estrogen

7. Type of progestin

1. Estrogen monotherapy is associated with lower risk compared to combined EPT therapy

Shah NR, Wong TExpert Opin

Pharmacother. 2006;7(18):2455-63.

E

EPT

1. Estrogen monotherapy versus combined EPT therapy1. Estrogen monotherapy versus combined EPT therapy

•EPIC study: prospective observational study

• 10 European countries

• 134,000 women

•Mean follow-up: 8.6 years

Bakken K et al, Int J Cancer 2010

2. Breast cancer risk increases with duration of HT use

EPIC Study, Bakken K et al, Int J Cancer 2010

WHI Study: women with no prior exposure to HT had no increased risk of breast cancer

Anderson GL, Maturitas 2006;55:103

1,21,31,41,51,61,71,81,9

2

sequential HT fixed continuous

RR

3. Continuous regimens may be associated with higher risk compared to sequential regimens

EPIC Study, Bakken K et al, Int J Cancer 2010

The cumulative exposure to progestin is lower with the

sequential regimensLyytinen H et al, Int J Cancer 2010

• Finnish case-control study

• 10,000 cases and 30,000 controls

aged 50-62

4. The route of HT does not modify the risk of breast cancer

Oral HT

Transdermal HT

Lyytinen H et al, Int J Cancer 2010

RR

RR

Cases controls

Cases controls


EPIC study: oral versus transdermal RR 1.13 (NS)

5. Dose of estrogen in HT and breast cancer risk

• No RCT on the effect of different HT doses on

breast cancer risk

• Lower estrogen doses have less impact on breast

density1

• Breast density is a surrogate marker of breast

cancer

Martin LJ et al, Maturitas 2009;64:20-26

Stuedal A Climacteric 2009;12:248-58

Grady D Menopause 2007;14:391-6

Identical HT regimens differing only in E2 dose are associated with different increases in breast density

Christodoulakos G, Lambrinoudaki I, Vourtsi A et al, Maturitas 2006;54:78

% of subjects with breast density increase

0

5

10

15

20

25

30

35

CEE/MPA low E2/NETA E2/NETA

p=0.6

p=0.04 p=0.04

6. The type of estrogen in HT does not influence breast cancer risk

•No RCT directly comparing CEE to E2

•EPIC study:compound RR of breast cancer

estradiol 1.08 – 1.61

CEE 1.16 – 2.18

RR CEE versus E2: 1.15 NS


•E3N Study (French component of EPIC)• 80,391 postmenopausal teachers in France•Mean follow-up: 8.1 years

Fournier A et al, J Clin Oncol 2008;26:1260

7. The type of progestin may modify breast cancer risk

7. The type of progestin may modify breast cancer risk

• All Finnish women > 50 years (221,551 women)• Follow – up 1994 – 2005• 6,211 incident cases of breast cancer

Lyytinen H et al, Obstet Gynecol 2009;113:65

B. HT and absolute risk of breast cancerB. HT and absolute risk of breast cancer

Among 50-year old women not on HT, 11 out of 1000

will develop breast cancer until the age of 55

http://seer.cancer.gov

B. HT and absolute risk of breast cancerB. HT and absolute risk of breast cancer

• Baseline 5-year absolute risk: 1.1%

• HT related RR: 1.26 (WHI)

5-year risk of breast cancer attributable to HT: 3 women in 1000

Among 50-year old women who use HT (CEE/MPA)

for 5 years, 14 out of 1000 will develop breast cancer

until the age of 55

Risk factors of breast cancer: comparative assessmentRisk factors of breast cancer: comparative assessment

Risk factorsRisk factors

• ΒΜΙ (>29,7 Kg/m2) 1.26-2.521.26-2.52

• alcohol (2020gg / /dayday xx 5 5 yearsyears) 1.28

• Hormone Therapy Hormone Therapy ((EPT / WHI) EPT / WHI) 1. 1.2626

• 11stst delivery delivery > 30 > 30 years years 1.1.55

• Family history of breast cancer Family history of breast cancer 1. 1.55

• Benign breast disease - breast biopsy 1.6-2.8Benign breast disease - breast biopsy 1.6-2.8

• Increased breast density 2.0-4.0Increased breast density 2.0-4.0

RRRR

Shah NR, Exp Opin Pharmacotherapy 2006;7(18):2455-63

Pichard C et al, Maturitas 2008;60:19-30

Mammographic patterns according to BI-RADS system

I II III IV

< 25% dense > 75% dense51-75% dense25-50% dense

RR 1.0 2.03 2.95 4.03

Cummings SR, J Natl Cancer Institute 2009;101:384-389

Bluming AZ et al, Cancer J 2009;15:93-104

Is postmenopausal hormone Is postmenopausal hormone therapy acceptable in view of therapy acceptable in view of

breast cancer risk?breast cancer risk?

expectationsOsteoporosis prevention

Cardiovascular disease prevention

WHI

• Osteoporosis prevention

• Increase of stroke risk

• Increase of CHD risk in older women

• Increase of VTE risk

• Increase of breast cancer risk

Pre-WHI era: HT to every postmenopausal woman

Post -WHI era…

• Patient selection

• Timing of initiation

• Duration of use

• Regimen selection

• Maximal efficacy

• No clinically relevant risks

Quality of life, osteoporosis prevention, CHD prevention

Breast cancer, stroke, VTE

• Estrogen dose• Progestin type•Mode of delivery• Route of delivery

Patient classification

1. Premature ovarian failure (<40), early menopause (<45)

2. Symptomatic women, normal age at menopause

3. Asymptomatic women, normal age at menopause


• CVD prevention

• Gynecologic cancer prevention

Premature ovarian dysfunction is associated with high bone turnover before the establishment of amenorrhea

Pal, Lubna et al, Menopause 2008; 15(6):1086-1094.

Premature ovarian failure and osteoporosis risk

Luborsky JL et al, Hum Reprod 2002

0,6 0,6

2,0

3,6

2,2

3,64,0

6,5

0

1

2

3

4

5

6

7

<40 40-44 45-49 50-54

Premenopausal

Postmenopausal

Premature ovarian failure is a strong risk factor for ischemic heart disease

Inci

den

ce

(p

er

1,0

00 w

om

en

)

Age (years)

Kannel W, et al. Ann Intern Med. 1976;85:447-52.

Premature ovarian failure

Early menopause

HT is indicated as “replacement” therapy

• CVD prevention


• Quality of life

• Breast cancer

• Stroke, VTE

• Low incidence in ages< 45

• WHI results NOT extendable to this age group

Panay N et al, Best Pract Res Clin Obstet Gynaecol 2008

Nelson L, N Engl J Med 2009

Symptomatic women at their fifties

Climacteric symptomatology

• Vasomotor

• Psychosomatic

• Sexual / urogenital

• Hot flashes

• Night sweats

• Vaginal dryness

• Painful intercourse

• Loss of libido

• Recurrent urogenital infections

• Sleep disturbances

• Fatigue, diminshed well-being

• Loss of interest in life

• Mood swings, irritability

• Headaches, arthralgias

Duration of vasomotor symptoms in middle-aged women: a longitudinal study.Col, Nananda et al, Menopause 2009; 16(3):453-457.

Hot flashes last longer than we thought…

• 50% of women have hot flashes > 4 years• 23% of women still have hot flashes after 13 years

• Quality of life

• prevention of urogenital atrophy

• Prevention of osteoporosis

• Prevention of CHD

• Breast cancer

• VTE / Stroke

• CHD??

Individual benefit / risk ratio

HT in the symptomatic postmenopausal woman

risk

benefit

•Symptom severity

•Osteoporosis risk

•Cardiovascular risk

•Breast cancer risk

• BMD

• personal of family history of Fx

• BMI

• corticosteroid use

• Smoking

• Calcium intake, exercise

Martin KA, Manson J, JCEM Dec 2008; 93:4576

Assessing the individual risk / benefit ratio

• Age• Years since menopause• BMI, WHI• Smoking• Hypertension• Diabetes• Personal or fam. history of VTE

Kanis JA et al, Osteoporosis Int 2008; 19:399

Individual breast cancer risk assessment

• Age, age at menarche and menopause

• BMI, adult weight gain

• Family history of breast cancer (1st degree relative)

• Benign breast disease requiring FNA or biopsy

• Previous hormone therapy

• Nulliparity / 1st delivery > 30years

• Daily alcohol intake

• Breast density

Vogel VG et al, Menopause 2008; 15(4 Suppl):782

Santen RJ et al, Endocr Relat Cancer. 2007 Jun;14(2):169-87

Risk factor patient

age 52

menarche 12

1st delivery 27

1st degree relative with breast cancer NO

Breast biopsy NO

Race white


US National Institutes of Health, www.cancer.gov accessed April 2010

Patient 5-year risk: 1.2%

Average 5-year risk: 1.4%

National Cancer Institute breast cancer risk assessment tool

• Breast density: BI-RADS II• BMI: 27•Menopause: 51

• Quality of life

• Urogenital atrophy prevention


• CHD prevention

• Breast cancer

benefit

risk

•Lowest effective E dose•Progestin selection•Follow-up: assess need of HT annually

Risk factor patient

age 52

menarche 12

1st delivery 34

1st degree relative with breast cancer YES

Breast biopsy YES

No of biopsies 1

Atypical hyperplasia NO

Race white


US National Institutes of Health, www.cancer.gov accessed April 2010

Patient 5-year risk: 2.5%

Average 5-year risk: 1.4%

US National Cancer Institute breast cancer risk assessment tool

• Breast density: BI-RADS III• BMI: 27•Menopause: 51

• Quality of life

• prevention of urogenital atrophy

• Prevention of osteoporosis

• Prevention of CHD• Breast cancer ??risk

benefit

Summary

• Hormone therapy is associated with a small, but statistically significant increase in breast cancer risk• The risk is more apparent with continuous

combined HT regimens• The risk increases with duration of use• The risk may differ by the progestin in the HT

regimen• The absolute risk is small and in most cases has

minor clinical relevance

• HT is acceptable, provided a thorough assessment of individual risk is performed in each woman

…. see you in Athens in 2012

is postmenopause hormone therapy acceptable in view of breast

Health & Medicine