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Breast Cancer Epidemiology and Hormone Replacement Therapy
Mindy Goldman, MD

A. Breast Cancer Epidemiology
192,200 new cases per year
Breast Ca accounts for 30% of all cancers among women
2 million women in US with history of Breast Ca
Lifetime risk 1 in 8
80% women diagnosed alive at 5 yrs
Risk of death from Breast Ca 1 in 28
41,000 deaths per year
Second leading cause of cancer deaths after Lung Ca
Leading cause of death for women 40-55

B. Hormone Replacement Therapy and Breast Cancer
a. Does HRT cause Breast Cancer?
b. Can women who have had Breast Cancer take HRT?
c. Does OCP use cause Breast Cancer?
d. Can women who have Had Breast Cancer take OCP's?

1. Hormone Replacement Therapy and Breast Cancer
More than 50 Epidemiologic studies
At least 6 Meta-analyses
a. Problems:
Many of studies are Observational
Lack of data from RCT
Meta-analysis of observational data may exaggerate inherent biases

Collaborative Group on Hormonal Factors in Breast Ca reanalyzed data in 90% of studies looking at HRT and Breast Ca 1997:
Increased risk of breast cancer RR 1.35 associated with HRT use 5 yrs or more.
Increased risk with longer duration of use
Increased risks were greater for thinner women
No difference with ERT vs. HRT but limited data only 12% on combination HRT
Increased risk disappears by 5 yrs after stopping HRT
Cancers in HRT users were less advanced than nonusers

Bush et al, 2001: assessed 45 articles assessing association or ERT and Breast Ca - no consistent results for any association or with duration of use, observational data

Breast Cancer Risk - Is There a Difference Between HRT and ERT?

Conflicting Data:

a. NCI Breast Cancer Detection Demonstration Project, 2000: RR HRT 1.4 vs 1.2 for ERT
Controversies - Absolute risks small, current ERT use only assoc with increased risk in lean women, HRT risks only for small number pts with increased BMD

b. Case control study in LA, 2000:
OR 1.06 ERT
OR 1.24 HRT
OR 1.38 sequential HRT
OR 1.09 continuous HRT

Controversies - No increased risks for estrogen alone, risks for continuous HRT no different than nonusers, no difference between current and past users
c. Case control study in Washington, 2000:
HRT increased risk of lobular carcinoma (only 5-10% breast ca and more favorable prognosis) OR 2.6, no increased risk for ductal carcinoma with current users of HRT or ERT

d. Nurses Health Study cohort, 2000: mathematical estimates of risks, 10 yrs ERT increased risk 23% by age 70 vs 67% HRT. Controversies - benign breast dz had 57% increased risk, small numbers of women had reached 70 or used HRT for >10 yrs, model of risk estimates may exaggerate small effects

e. Bush et al 2001: No consistent results for HRT and Breast Ca. Only 4 statistically significant, 2 with increased risk, 2 decreased. What about ovarian status? Oophorectomy protective for ER+ Breast Ca, women on ERT alone more likely to have had ovaries out

f.  Chen et al. JAMA 2/2002:

Current and long term HRT and ERT assoc. with increased risk Breast Ca
Long term HRT/ ERT and current HRT assoc with increased risk of Lobular Breast Ca
Long term HRT/ERT assoc with increased risk of nonlobular Breast Ca

Breast Cancer Mortality and Hormone Replacement Therapy
Consistent findings of lower mortality in women diagnosed with Breast Ca on HRT/ERT vs. none
Some studies show reduction in mortality remains up to 12 yrs after diagnosis

a. Breast Cancer Mortality and Hormone Replacement Therapy
Why is hormone use associated with lower mortality?
1.Surveillance vs Biologic Effect of HRT
Surveillance bias due to increased use of mammography by HRT users.
Earlier diagnosis
Healthy estrogen user bias
Most studies show Breast Ca on HRT has more favorable histology or associated with DCIS
Recent reports of tumors among HRT users have lower proliferation rates measured by S-phase fraction
ER + tumors tend to be less aggressive
Hypothesis that HRT may stimulate preexisting tumor, develops faster, diagnosed in earlier stage

C. Is HRT safe to use after Breast Cancer?
Life Expectancy for women 80 yrs
5 year survival rates for localized breast ca 97% and 77% for regional spread
More women may be interested in HRT for QOL
No current data from RCT
7 case control/cohort studies show do not show adverse affects on recurrence rates and some suggestion of improved survival

a. Largest study: O'Meary et al 2001
matched women in large HMO diagnosed with breast ca then identified pharmacy data for HRT after diagnosis, matched to 4 controls
RR .50 for recurrence in HRT
RR .48 for mortality For ER + Tumors:
RR .31 for recurrence in HRT
RR .30 for mortality
RR 1.33 for contralateral ca in HRT

Observational data
Symptomatic patients may have lower circulating estrogen levels
Users post breast ca more likely to have used HRT prior with screening bias/earlier diagnosis
Users of HRT post breast cancer may be screened more
Healthy selection bias, patients with more favorable prognosis more likely to get HRT

b. Until data available from RCT:
Consider HRT to reduce menopausal symptoms if if histology favorable, long disease free interval
Use lowest dose , consider short term use 6 mos or less
Discuss alternatives - SSRI's, herbs, vitamins

D. Oral Contraceptives and Breast Cancer
Complex Biologic Effects:
Cause anovulation
May stimulate mitotic activity within the breast

Oral Contraceptives and Breast Cancer
Many epidemiologic studies suggest no increased risk with OCP use
Meta-analysis of available literature by Collaborative Group on Hormonal Factors in Breast CA, 1996
Current users RR 1.24
Long term users >10 yrs RR 1.16
Initiation of OC use < age 20 RR 1.22
After 10 yrs discontinuation RR 1.01
Cancers diagnosed in users less advanced than in non users
No difference in rates with respect to family history

Oral Contraceptives and Breast Cancer
Gabrick et al, 2000 evaluated risk in women with family history of breast ca
RR 3.3 for first degree relative
RR 4.6 for 3 family members with breast or ovarian ca
RR 11.4 for 5 family members with breast or ovarian ca
Only seen for OC's used prior to 1975 RR 3.3

Oral Contraceptives and Breast Cancer
Small studies suggest increased risks when looking at BRCA1/2 mutations
Unclear whether current low dose preparations of OCP's have effects on breast ca

Oral Contraceptives and Breast Cancer
No data on the use of oral contraceptives after prior Breast Cancer

E. Hormones and Breast Cancer - Conclusions
Most studies suggest that current users > 5 yrs have slight increased risk of Breast Cancer, although still controversial
Increased risks are mainly in thin women
Insufficient data to determine whether combined HRT has greater risks than ERT alone
Need for RCT - Women's Health Initiative
Data that exists suggests that hormone therapy after breast cancer does not increase risk of recurrence
Older preparations of OCP's have an increased risk of breast ca in current users, long term users and those starting at an early age
Unclear if any increased risks for low dose preparations used today
Women with BrCA1 and BrCA2 mutations may have increased risks of breast ca with OCP use
No data exists on safety of any hormonal form of birth control after breast cancer

Mindy Goldman, MD
Associate Clinical Professor Department of OB/Gyn and Reproductive Sciences
Director, Follow Up Program, Carol Franc Buck Breast Care Center
University of California, San Francisco,CA

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