Susan Love M D Susan Love M D Breast Cancer Foundation

							  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…..