MENOPAUSAL HORMONAL MENOPAUSAL HORMONAL TREATMENT AND BREAST TREATMENT AND BREAST

CANCER RISKCANCER RISK

PROF DR H DEPYPEREPROF DR H DEPYPERE

Gynaecologische oncologie en borstkliniek, Gynaecologische oncologie en borstkliniek, Universitair Ziekenhuis, GentUniversitair Ziekenhuis, Gent

Sixty procent of women have vasomotor complaints

Cochrane data base of randomised trials indicates hormonal replacement is the most effective treatment to treat vasomotor symptoms

A small increase in breast cancer will deter women from taking HRT

cardiovascular disease

7%don't know

16%

other problems 16%

cancer27%

breast cancer34%

Women’s perceptions of their greatest health problems

Mosca L et al Arch Fam Med 2000;9:506-515

Age No alive atbeginning ofinterval

No incidentbreastcancers

No deathfrom breastcancer

No incidentbreast cancersper 5 years per1000

No incidentbreast cancersper year per1000

0 1000 0 0 0 025-29 990 0 0 0 030-34 988 1 0 1.0 0.235-39 986 3 0 3.1 0.640-44 983 5 1 5.1 1.045-49 977 8 2 8.2 1.650-54 968 11 3 11.4 2.355-59 952 12 3 12.6 2.560-64 929 12 3 12.9 2.665-69 892 14 4 15.7 3.170-74 836 13 5 15.6 3.175-79 752 11 6 14.6 2.980-84 624 9 6 14.4 2.8>85 434 5 7 11.5 2.3

Age at menarche 3 menarche before 11

age at menopause 2 menopause after 54

age at first full pregnancy 3 first child in early 40s

family history >2 first degree when young

previous benign disease 4-5 atypical hyperplasia

cancer in other breast >4

diet 1.5 high sat fat intake

BMI premenopausal 0.7 BMI>35

postmenopausal 2 BMI>35

alcohol 1.3

hrt 1.35 hers, NHS, WHI

Estrogen only

Safer progestogens

Serm : MORE trial

STAR trial

CORE trial

Estrogens are not associated with an increase in breast cancer incidence (WHI : JAMA 2002;288:321-333; Olsson et al, Cancer, 2003, 97;1387-1392). Latest results of WHI suggest a significant reduction.

Million Women Study does suggest an increase in breast cancer in estrogen only treatment (Lancet 2003;362:419-427). This is also observed in E3N study Int J Cancer 2005;114:448-454). Dahors study indicates a very small increase.

INFLUENCE OF ET ON BREAST CANCER INCIDENCE

Estrogen only WHI RR 0.77

NHS - duration ? 28 835 women with hysterectomy

BMI <25 BMI>25

never 78 1.00 148 1.00

<5 y 45 1.03 (0.69-1.52) 54 0.96 (0.96-1.33)

5-9.9 78 1.17 (0.84-1.62) 66 0.74 (0.55-1.00)

10-14.9 94 1.18 (0.86-1.62) 94 0.97 (0.74-1.28)

15-19.9 66 1.36 (0.97-1.92) 63 1.11 (0.82-1.51)

>20 80 1.77 (1.26-2.48) 65 1.25 (0.91-1.71)

Estrogen only

Safer progestogens

Serm : MORE trial

STAR trial

CORE trial

Hers I study (RR : 1.38 (0.82-2.31; p =0.22))

WHI (RR :1.26 (1.00-1.59))

conform : Nurses’ health study and Lancet ‘97 meta analysis (RR :1.35 (1.21-1.49))

This is also observed in E3N study for synthetic progestogens and not for natural progesterone.

In WHI only significant increase in breast cancer after more than 5 years of intake of EPT

INFLUENCE OF EPT ON BREAST CANCER INCIDENCE

Prospective studyProspective study 54.584 postmenopausal women54.584 postmenopausal women 5,8 years follow-up5,8 years follow-up 29.420 HRT users (54%)29.420 HRT users (54%) 12% E2 alone12% E2 alone 88% EP combined88% EP combined 948 invasive breast cancer948 invasive breast cancer

Oral estrogens

+ Synthetic progestogen

+ micronized progesteron

+ micronized progesteron

+ Synthetic progestogen

RR = 1.3(1.1-1.5)

RR = 0.9 (0.7-1.2)

RR = 1.4(1.2-1.7)

RR = 1.5 (1.1-1.9)

Cutan. estrogens

estrogens + progestatogen

•To small number to compare

1,4

1,0

1,3

1,8

-0,5 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 5,5

Estrogens alone (57)<2 years (26)2-4 years (17)4-6 years (4)6+ years (9)Estrogens + progesterone (109)<2 years (45)2-4 years (29)4-6 years (19)6+ years (16)Estrogens + retroprogesterone (97)

<2 years (34)2-4 years (29)4-6 years (15)6+ years (18)Estrogens + other synthetic progestins (468)<2 years (174)2-4 years (123)4-6 years (87)6+ years (81)

0

0,5

1

1,5

2

2,5

3

51-54 55-59 60-64 65-69

2mg E2, 1 mgNETA4mg E2, 1 mgNETA

Breast cancer risk according to progestogen type and estrogen dose

1 mg NETA 51-54 RR 1.3; 55-59 RR 2.2; 60-64 RR 2.7; 65-69 RR 3.00.5 mg NETA no significant increase in any age group;

Dahors : Danish Sex Hormones Dahors : Danish Sex Hormones register Studyregister Study

4 242 334 women years4 242 334 women years12 831 breast cancers12 831 breast cancersdeaths per 100 women yearsdeaths per 100 women years

never usersnever users :: 5.95.9ever users :ever users : 4.54.5current users :current users : 2.92.9

Estrogen only

Safer progestogens

Serm : MORE trial

STAR trial

CORE trial

Cauley J, et al. Breast Cancer Res Treatment. 2001;65:125-134

Years

0.0

2.0

0 1 2 3 4 5

Raloxifene1.9 per 1000woman-years

Placebo5.3 per 1000woman-years

% o

f Ran

dom

ize

d P

atie

nts

RR = 0.38 (95% CI = 0.24-0.58)*

Effect of Raloxifene on Breast Cancer Effect of Raloxifene on Breast Cancer IncidenceIncidence

MORE Trial - 48 MonthsMORE Trial - 48 Months

Total Cases = 77*P<.001

1.0

7705 postmenopausal women

10.5 per 1000 women in control arm.

Reduction by 76 % with raloxifen. This implicates a reduction of 2.52 breast cancers per 1000 women.

Only ER rec positive tumors are prevented.

Raloxifen

3510 women receiving raloxifene 60 mg/d vs 1703 women receiving placebo from more that continue in core.

ER positive invasive breast cancers reduced 66 % (RR 0.34 CI : 0.18-0.66). No difference in ER negative cancers. Absolute numbers 1.4 cancers per 1000 women per year vs 4.2 cancers.

CORE - Continuing Outcomes Relevant to Evista

Mammografie voor en na Mammografie voor en na behandeling met Livialbehandeling met Livial®®

Vrouwen onderVrouwen onderCEE/MPACEE/MPA

Dezelfde vrouwen na 1 jaarbehandeling met Livial

Valdivia & Ortega 2000 Clin Drug Invest 20:101-107

Practical guidelinesA small increase in breast cancer will deter women from taking HRT.

Small increase in breast cancer with EPT formulations. Importance of progestogen.

Increase with ET after 20 years. The combination with mirena is an interesting option.

Serm concept is an interesting field of new development.

Tibolone data from liberate will be disclosed next year.