Breast Cancer and Hormones: Still More Questions Than Answers

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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

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Why doesnt ERT/HRT cause more breast cancer?
50-300 pg/ml
100 pg/ml
4-12 pg/ml
Post- menopause
Standard ERT
Pre- menopause
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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

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HRT/ERT in Women with Atypical Hyperplasia
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Tamoxifen in Women with Proliferative Disease

• There was an 88 reduction in risk of breast
  cancer in women with atypical hyperplasia who
  took tamoxifen for four years.

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Tamoxifen plus ERT/HRT for Prevention
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Mortality in breast cancer patients with a
history of previous ERT/HRT
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Mortality in Breast Cancer Patients with previous
ERT/HRT
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Studies of Women with Breast Cancer on ERT/HRT
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OCP and HRT
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Does adding a progestin increase risk of breast
cancer?

• Progestin increases mitotic activity
• PEPI EP causes higher breast density than E
  alone
  
• Two observational studies EP associated with
  greater risk than E alone.

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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.

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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.
  

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Biological Observations

• Safety of low dose
• Systemic versus local hormones
• Other hormones

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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

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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
  

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How does it work?

• Paracrine
• Autocrine
• Stromal
• Intraductal macrophages

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Breast Cancer and the Biosystem
Breast cells
Uterine Life
GONADOSTAT
Hypothalamus
Prenatal Influence
Growth Factors
Maternal and Placental Steroid Hormones
Pituitary
Ovaries
(-)
Target cells Luminal mammary Epithelial cells S
HR (-) and SHR ()
Puberty- Adolescence
Mitogenic and Differentiation Signals
Menstrual Cycle
Mitogenic Microenviroment
Estrogens Progestins Androgens

Pregnancy
Exogenous Sex Hormones
Differentiation
Cell Proliferation

Menopause
Diet-Lifestyle
Accumulation of Genomic Damage
Apoptosis/Atrophy
Cancer
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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
  

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• We must beware of thinking we understand the
  connections between hormones and the breast.
  
• We have only just begun..