Fifth Dimension Table of Contents

Breast Cancer 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

THE BIG QUESTIONS

• 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?

• Epidemiology:
  • 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
      • Criticisms:
        • 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

1. Complex Biologic Effects:
   • Cause anovulation
   • May stimulate mitotic activity within the breast
     
     
2. 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
     
     
3. 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
     
     
4. 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
     
     
5. 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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