Susan Love M D Susan Love M D Breast Cancer Foundation
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Breast Cancer and Hormones: Still More Questions Than Answers Susan M Love MD MBA President of the Susan Love MD Breast Cancer Foundation Why doesn’t ERT/HRT cause more breast cancer? 150 50-300 pg/ml 100 ~100 pg/ml 50 4-12 pg/ml 0 Pre- Standard Post- menopause ERT menopause Clinical Paradoxes HRT vs Tamoxifen in women with proliferative disease HRT plus Tamoxifen for prevention Breast cancer in women taking HRT HRT after breast cancer Treatment of metastatic disease HRT/ERT in Women with Atypical Hyperplasia No Ever Past Current hormones users users users Nurse’s 3.4 3.0 2.5 Health Study Dupont 2.87 2.53 and Page Tamoxifen in Women with Proliferative Disease NSABP P1 placebo Tamoxifen # cases of 23 3 Breast Cancer There was an 88% reduction in risk of breast cancer in women with atypical hyperplasia who took tamoxifen for four years. Tamoxifen plus ERT/HRT for Prevention % on ERT/HRT Odds ratio tam versus placebo Marsden 1998 42% No interaction IBIS 2002 40% 0.76 (0.47- 1.23) Italian 1998 19% 0.13 (0.02- 1.02) Mortality in breast cancer patients with a history of previous ERT/HRT Reference Overall Cancer Breast cancer mortality mortality Gambrell (1984) 0.53 Criqui et al 0.22 0.73 (0.44-1.22) (1988) Berkqvist et al 0.68 (0.52-0.87) (1989) Hunt et al (1990) 0.70 (0.55-0.85) 0.76 (0.45-1.06) Henderson et al 0.80 0.81 (1991) Strickland et al No reduction (1992) Mortality in Breast Cancer Patients with previous ERT/HRT Reference Duration of use Breast Cancer Mortality Colditz (1995) Past use 0.80 (0.60-1.07) Current use 1.14 (0.85-1.51) < 5 years use 0.99 (0.66-1.48) > 5 years 1.45 (1.01-2.09) Persson et al Overall reduction 0.5 (0.4-.06) (1996) < 5 years 0.2 (0.1-0.3) 5-9 years 0.7 (0.5-0.9) >10 years 0.7 (0.5-0.9) Willis et al 0.84 (0.75-0.94) (1996) Natural menopause <40 0.59 (0.40-0.87) Surgical menopause <40 0.76 (0.54-1.09) Studies of Women with Breast Cancer on ERT/HRT Reference # RR CI Eden (1995) 90 0.40 0.17-0.93 Beckman 64 0.67 0.28-1.61 (1998) Uric-Vrscaj 21 1.60 0.48-5.34 (1999) Vassilopoulou- 39 0.51 0.07-3.79 Sellin(1999) OCP and HRT Ever use RR CI OCP 1.1 (0.9-1.4) HRT 0.9 (0.7-1.2) OCP >10 yrs 3.2 (1.4-7.4) HRT >3 yrs Brinton Menopause 1998 Does adding a progestin increase risk of breast cancer? Progestin increases mitotic activity PEPI: E+P causes higher breast density than E alone Two observational studies: E+P associated with greater risk than E alone. Or the people who take it? Women who take E plus P all still have their uterus Women on E alone have undergone a hysterectomy usually premenopausally which reduces the risk of breast cancer even when ERT is taken. Treatment of Metastatic Disease: 6 randomized controlled studies comparing DES and Tam 2 comparing ethinyl estradiol to Tam 5 comparing megestrol acetate to Tam 5 comparing medroxyprogesterone acetate to Tam no difference in response rate, duration or survival. Biological Observations Safety of low dose Systemic versus local hormones Other hormones Is low dose really safer? Cell lines exhibit a biphasic response to estrogens: – Low doses increase cell proliferation – High does inhibit cell proliferation Lippman 1976 Prolonged estrogen withdrawal in breast cancer cells results in a hypersensitivity to estrogen Santen 2002 Systemic versus local E2 and E1 concentrations in premenopausal women are 10x and 20x greater in NAF than serum E2 and E1 concentrations in postmenopausal women not on HRT are 50x and 35x greater in NAF than serum. Ernster 1987 Breast tissue has both aromatase and sulfatase necessary to produce its own estrogen Chetrite 2000 Different ducts within the same breast have different levels of estrogen Elia AACR 2002 How does it work? Paracrine Autocrine Stromal Intraductal macrophages Uterine Breast Breast Cancer and the Biosystem Life cells G Hypothalamus Prenatal Influence O Growth N Maternal and Placental Factors A Pituitary Steroid Hormones D O S Ovaries (-) T Target cells A Puberty- Luminal mammary Mitogenic and Adolescence T Menstrual Cycle Epithelial cells Differentiation SHR (-) and SHR (+) Signals Mitogenic Microenviroment Estrogens + Progestins Pregnancy Exogenous Androgens Sex Hormones Differentiation Cell Proliferation + Menopause Accumulation of Genomic Damage Diet-Lifestyle Apoptosis/Atrophy Cancer Research Priorities Beyond formulations and delivery routes Physiology of the non lactating breast What is concentrated and what is absorbed Effect of exogenous hormones on intraductal levels Effects of other hormones, growth factors and inhibitors locally and systemically Physiology of the high risk breast and the breast cancer breast We must beware of thinking we understand the connections between hormones and the breast. We have only just begun…..