Medical risk reducing strategies for breast cancer

Transcription

1 Medical risk reducing strategies for breast cancer PROF. DR. H. DEPYPERE Menopause Clinic, University Hospital, Ghent, Belgium

2 Life expectancy in Belgium 46,6 y in 1880 and 83,8 y in Women Men

3 Aantal gevallen per per jaar Leeftijdspecifieke incidentie invasief borstcarcinoom (SEER , National Cancer Institute) >79 Leeftijdscategorie

4 ETIOPATHOGENESIS BREASTCANCER 4

5 DUCTLOBULAR UNIT 5

6 6 Mareel en Bracke

7 Occult breast cancer reservoir Santen model (200 days doubling time, 1.16 cm detection, 7 % prevalence) How can we prolong dormancy of subclinical tumours? Santen R et al. Horm canc, 2013; Santen R J of steroid biochemistry and molecular biology 2013.

8 Different breast cancer subtypes per age in the US (similar in Europe) 8

9 biomedische les hormonen en kanker Prof Depypere - 9

10 Risk factors : Endogenous estradiol Box and whiskers plots of the concentration of 17β-estradiol in breast epithelial cells of women taking aromatase inhibitors (AI, n=6), premenopausal women taking oral contraceptives (EE2, n=12), postmenopausal controls (CTL post, n=16), premenopausal controls (CTL pre, n=24), premenopausal women taking tamoxifen (TAM pre, n=6), and postmenopausal women taking tamoxifen (TAM post, n=4). (Depypere et al. Maturitas May;81(1):42-5).

11 Central adiposity is associated with insulin resistance. Besides increased circulating levels of insulin, glucose and insulin-like growth factor (IGF), insulin resistance presents with increased levels of bio-available estrogen because the high-abundant insulin outcompetes estrogen binding to sexhormone binding globulin (SHBG).

12 pmol/mlorg estrogen levels in cancer Premenopausal Postmenopausal L bloodvessel Peripheral estrogen production Estrogen synthesis in the breast F Tumour 0 O = Ovulatory L = Luteal F = Follicular Peripheral estrogen Estrogen concentration in the breast Peripheral estrogen Estrogen concentration in the breast Miller W et al.

13 Risk factors: BMI, more specific insulin levels. Apple shape Metabolic syndroom

14 The women s health initiative (WHI, initiated in 1991 by the U.S. NIH) revealed hyperinsulinemia as an independent risk factor for postmenopausal breast cancer. Insulin is in fact a known mitogen and has been shown to stimulate cell proliferation in normal breast tissue and cancer progression in human breast cancer cell lines. While the association between obesity and estrogen receptor (ER)-negative breast cancer is lower than between obesity and ER-positive breast cancer, this association indeed indicates a connection between obesity and breast cancer independent of estrogen.

15 Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women (Gunter et al. J Natl Cancer Inst 2009;101:48-60) Case cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, P trend <.001). Obesity (BMI 30 kg/m 2 ) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI 30 kg/m 2 vs 18.5 to <25 kg/m 2 = 2.12, 95% CI = 1.26 to 3.58, P trend =.003); however, this association was attenuated by adjustment for insulin (P trend =.40). These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity breast cancer relationship.

16 biomedische les hormonen en kanker Prof Depypere -Prof Bracke 16

17 Van de Voorde J, Depypere H. Inflamm res 1999, 48,

18 Proliferatie en cel cel adhesie 18 SLOW AGGREGATION ASSAY

19 Estrogen only WHI RR 0.77 NHS - duration? women with hysterectomy 19 BMI <25 BMI>25 never <5 y ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) > ( ) ( )

20 Balans between insulin, estrogen, endogenous production of hormones by breast cells. Which system is dominant?

21 Risk factors: Alcohol 7 % increase per consumption per day.

22 More en core studie Total Cases = 77 *P<.001 RR = 0.38 (95% CI = )* Placebo 5.3 per 1000 woman-years 0.0 Raloxifene 1.9 per 1000 woman-years

23 Percentage of women reporting one or more days of breast tenderness at week 12. BZA/CE (both doses), BZA, and placebo demonstrated similar incidences of breast tenderness. CE/MPA showed a significantly higher rates (P < versus all other... Review Mirkin S, Pickar J Intern women health

24 Total isoflavones concentration is higher in the breast glandular tissue compared to the adipose tissue 60/40. Aglycone equivalents in the breast are pmol/g. The β- estradiol equivalents towards the estrogen β receptor were times higher for the isoflavones than for 17β estradiol. Further gen expression profiles will clarify is phyto estrogens may be usefull in a preventative setting.

25 Risk factors 6: NULLIPARITY

26 birth Two years puberty pregnancy Proliferation Proliferation Proliferation Differentiation

27 Proliferation decreases mutation repair Carcinogen Time for DNA damage repair before DNA duplication Low Proliferation Cancer Gene cancer gene In een cel DNA High Proliferation Time for DNA damage repair before DNA duplication Normal Normal cancer gene Cancer in daughter Gene cell In elke dochter cel Permanently mutated Mutated gene Cancer in daughter Genecell

28 Parous woman % type 3 lobules Nulliparous woman has % type 1 lobules Puberty Development of the breast Pregnancy Lactation but formation Lobule Type 1 Proliferation Lobule Type Lobule Type 3 Lobule Type 4

29 Cells at Risk Cells at Risk Cells at Risk Carcinogens

30 Current running study Nulligravida BRCA1/2 women breast biopsy (gene profile) Ovitrelle 12 weeks breast biopsy (gene profile) breast biopsy (6 months)

31 conclusion Insulin levels, glycemia, IGF-1 play an important role in the growth of subclinical tumors. Weight loss through diet improve insulin resistance. Serm s have a proven benefit. Further gen expression profiles will clarify is phyto estrogens may be usefull in a preventative setting. Stop smoking. Start moving. In patients with breast cancer, a short overnight fast of less than 13 hours was associated with a statistically significant, 36 percent higher risk of breast cancer recurrence and a non-significant, 21 percent higher probability of death from the disease compared to patients who fasted 13 or more hours per night, report University of California, San Diego School of Medicine researchers WHEL study