# Presentation: 282237

## 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?

- 50-300
- pg/ml

- 4-12
- pg/ml

- ~100
- pg/ml

- Pre-
- menopause

- Post-
- menopause

- Standard
- ERT

## 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 hormones | Ever users | Past users | Current users |
| --- | --- | --- | --- | --- |
| Nurse’s Health Study | 3.4 |  | 3.0 | 2.5 |
| Dupont and Page | 2.87 | 2.53 |  |  |

## Tamoxifen in Women with Proliferative Disease

| NSABP P1 | placebo | Tamoxifen |
| --- | --- | --- |
| # cases of Breast Cancer  | 23 | 3 |

- 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 mortality | Breast cancer mortality |
| --- | --- | --- |
| Gambrell (1984) |  | 0.53 |
| Criqui et al (1988) | 0.22 | 0.73 (0.44-1.22) |
| Berkqvist et al (1989) |  | 0.68 (0.52-0.87) |
| Hunt et al (1990) | 0.70 (0.55-0.85) | 0.76 (0.45-1.06) |
| Henderson et al (1991) | 0.80 | 0.81 |
| Strickland et al (1992) |  | No reduction |

## Mortality in Breast Cancer Patients with previous ERT/HRT 

| Reference | Duration of use | Breast Cancer Mortality |
| --- | --- | --- |
| Colditz (1995) | Past use
  Current use
  < 5 years use
  > 5 years | 0.80 (0.60-1.07)
1.14 (0.85-1.51)
0.99 (0.66-1.48)
1.45 (1.01-2.09) |
| Persson et al (1996) | Overall reduction
< 5 years
5-9 years
>10 years | 0.5 (0.4-.06)
0.2 (0.1-0.3)
0.7 (0.5-0.9)
0.7 (0.5-0.9) |
| Willis et al (1996) | 0.84 (0.75-0.94)
Natural menopause <40
Surgical menopause <40 | 
0.59 (0.40-0.87)
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 (1998) | 64 | 0.67 | 0.28-1.61 |
| Uric-Vrscaj (1999) | 21 | 1.60 | 0.48-5.34 |
| Vassilopoulou-Sellin(1999) | 39 | 0.51 | 0.07-3.79 |

## OCP and HRT

| Ever use | RR | CI |
| --- | --- | --- |
| OCP | 1.1 | (0.9-1.4) |
| HRT | 0.9 | (0.7-1.2) |
| OCP >10 yrs
HRT >3 yrs | 3.2 | (1.4-7.4) |

- 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

## Breast Cancer and the Biosystem

- cells

- Uterine
- Life

- Target cells
- Luminal mammary
- Epithelial cells
- SHR (-) and SHR (+)

- Mitogenic Microenviroment

- Prenatal Influence

- Maternal and Placental Steroid Hormones

- Puberty-
- Adolescence

- Pregnancy

- +

- Menopause

- +

- Differentiation

- Apoptosis/Atrophy

- Cell Proliferation

- Accumulation of Genomic Damage

- Cancer

- Mitogenic and Differentiation Signals

- Growth Factors

- Hypothalamus

- Pituitary

- Ovaries

- Menstrual Cycle

- Estrogens
- Progestins
- Androgens

- Diet-Lifestyle

- Exogenous
- Sex Hormones

- (-)

- GONADOSTAT

**Breast Cancer and the Biosystem**

## 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.....