Update: Breast Cancer Prevention

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					Update: Breast Cancer
    Erin Dunn Snyder, MD
    GIM Noon Conference
       October 16, 2007
TIME October 15, 2007
                        Road Map
   Breast cancer Screening
       Digital Mammography
       Computer aided detection
       MRI
   Primary Prevention of Breast cancer
       Lifestyle changes
         • Diet
         • Exercise
       Medication
         • Selective Estrogen Receptor Modulators
     Breast Cancer Screening
 Guidelines recommend yearly
  mammogram for average risk women,
  beginning at age 40-50
 Other modalities: clinical and self exams,
  ultrasound, digital mammogram, breast
           Digital Mammography
   Allows radiologist to manipulate the image
    AFTER it has been acquired.
       to optimize contrast in certain areas of the breast.
 Potentially allows less radiation dose per study
 Electronic storage
 Easy data transfer
 Substantially more expensive than conventional
  film mammography systems
    Diagnostic Performance of Digital
     versus Film Mammography for
        Breast Cancer Screening
   49,528 asymptomatic women at 33 sites in the US and
   All women underwent digital and film mammography
       Five different digital systems used
   Examinations independently interpreted by 2 radiologists
       Scored both on 7 point malignancy scale, and standard Bi-Rads
   Women returned for follow-up mammogram at one year

                                               Pisano, et al. NEJM 2005;353:1773-83
 Digital vs. Film Mammography
 Positive: cancer verified within 455 days of
  initial mammogram
 Negative: negative follow-up
  mammogram, or negative biopsy
 Subgroup Analysis:
     Age, race, breast density, menopausal status
     Baseline risk of breast cancer
     Type of digital mammogram system
Digital vs. Film Mammography

     Difference in AUC: 0.03
     95% confidence interval -0.02 to 0.08
     P value= 0.18
Digital vs. Film Mammography

Difference in AUC: 0.15   Difference in AUC: 0.11
95% CI: 0.05 to 0.25      95% CI: 0.04 to 0.18
P= 0.002                  P= 0.003
         Digital Mammography
 No difference seen in overall population
 No difference seen in subgroups of:
     Race, Risk of breast cancer, Type of system
 Significant improvement in breast cancer
  detection for:
     Women under age 50
     Women with dense breast tissue
     Pre- or Peri-menopausal women
 Mortality   was not an end point
 Digital vs. Film Mammography
 Four   other studies
     None showed significant differences in the
      whole group screened
     2007 Norwegian study
       • Significant improvement in detection of DCIS

                                Vigeland, E. European J Radiology. 2007
 Digital vs. Film Mammography
 UAB   and TKC do use digital
  mammography for routine screening
 Likely it is as good as conventional film
  mammography, perhaps better in certain
  populations and with certain cancers
 Limited by availability, expense, and
  radiology expertise
    Computer aided detection
 Mammograms     digitized
 Software marks suspicious areas for
  further review
 FDA approval in 1998
      Influence of Computer-Aided
      Detection on Performance of
        Screening Mammography
 43   Facilities, surveyed 1998-2002
     Breast Cancer Surveillance Consortium
      women, 429,345 screening
 222,135
     2351 cases of breast cancer diagnosed within
      one year of screening

                                   Fenton, et al. NEJM 2007;356-1399-409
 Performance of Computer-Aided
 36   facilities did not use CAD
     Patients were older, had denser breasts, less
      likely to have undergone recent
     Radiologists had more experience
7    facilities implemented CAD during study
     No difference in patient or radiologist
      characteristics before and after
  Performance of Computer-Aided
Unadjusted Performance of Screening MMG according to use of CAD

                            Before After          P value
                            CAD    CAD
Specificity                 90.2   87.2           <0.001
Sensitivity                 80.4       84         0.32
PPV                         4.1        3.2        0.01
Recall Rate                 10.1       13.2       <0.001
Breast biopsy per           14.7       17.6       <0.001
1000 MMG
  Performance of Computer-Aided
   Number of cancers detected per 1000 screening mammograms

              Before CAD After CAD P value
All cancers   4.15             4.20           0.9

Invasive      2.98             2.63           0.32
DCIS          1.17             1.57           0.09
Performance of Computer-Aided

     Difference in AUC=0.048
     P= 0.005
  Performance of Computer-Aided
 Significantly decreases specificity and
  positive predictive value
 Significantly decreased accuracy
 Increased recall and biopsy rates
 No change in overall detection of cancer
     Perhaps some increased sensitivity in
      detection of DCIS
                 Breast MRI
 Compared      to mammogram, Breast MRI is:
     More sensitive, less specific
     Detects clinically occult cancers, at earlier
     Associated with higher recall and biopsy rates
     Expensive
                 Breast MRI
 Multiple   studies in young, high risk women
     BRCA Positive patients or family members
     Lifetime risk >25% based on models
     Familial cancer syndromes
    Screening with MRI and MMG of
    UK population at high familial risk
           of breast cancer
   649 women, 35-55 years old with:
       Known BRCA1, BRCA2, TP53 mutation carriers
       First degree relative of carrier
       Strong family history of breast/ovarian cancer
       Family history of Li-Fraumeni syndrome
 Excluded previous breast cancer, expected life
  expectancy <5 years
 Women got annual Mammography and MRI for
  2-7 years
                                         Leach, et al. Lancet. 2005. 365:1769-78
  MRI vs. MMG for high risk women

Modality      Sensitivity   Specificity
MRI           77%           81%

Mammography   40%           93%

P value       0.01          <0.001

Both          94%           77%
                  Breast MRI
 ACS    recommends MRI in addition to MMG
  yearly in High Risk women
 Still not widely available, although it is
  available at UAB
     Need skilled, experienced radiologist
     Need ability to do MRI guided biopsy

                       Saslow, et al. CA Cancer J Clin 2007; 57:75-89
What about prevention?
                     Low Fat Diet
 Women’s         Health Initiative
     Postmenopausal women, age 50-79
     48,835 randomized into Dietary Modification
       • Exclusions:
             Breast or other cancers
             Expected survival <3 years
             Baseline diet with <32% energy intake as fat
             Adherence concerns

                                             WHI investigators. JAMA 2006. 295:629-42
  WHI Diet and Breast Cancer
 Intervention     group:
     18 behavioral modification group sessions in
      first year, quarterly thereafter
     Dietary modification goals:
       • Total fat intake <20% of total energy intake
       • At least 5 servings fruit and vegetables/day
       • At least 6 servings grains/day
 Control    group:
     Dietary guidelines booklet, not asked to make
  WHI Diet and Breast Cancer
 Intake   monitored with questionnaire
     Baseline, year one, year three
 Subgroup     also provided serum yearly for:
     Estradiol, Estrone, Testosterone, SHBG
     Various antioxidant biomarkers, lipids,
      glucose, insulin
 MMG     at baseline and every 2 years
  WHI Diet and Breast Cancer
 Intervention     group had:
     Fewer calories from fat
     More servings fruit and vegetables/ day
     Early weight loss, able to maintain change
      longer than control group
     Minimal changes in blood biomarkers
       • Modest decrease in LDL
       • No change in HDL, triglycerides, insulin, glucose
     Greater reduction in estradiol, increase in
WHI Diet and Breast Cancer
  WHI Diet and Breast Cancer
 9%lower incidence of breast cancer at
 end of study, not significant
    Cancers more likely to be PR negative
    reduction in cancer (CI .64-.95), in
 22%
 women with higher fat intake at baseline
             Physical Activity
 Several  case-control studies show a link
  between breast cancer and physical
 Known to:
     Modify menstrual characteristics
     Increase SHBG levels
     Decrease weight, abdominal adiposity
     Improve insulin sensitivity
 Long Term Recreational Physical
 Activity and Risk of Breast Cancer
   Prospective cohort study
       California Teachers Cohort: 133,479 current and
        retired female participants in CA State Teachers
        Retirement System as of 1995
 Cancer diagnosis determined via CA Cancer
  Registry linkages
 Exclusions:
       Previous history of breast cancer
       >80 yrs at baseline
       Incomplete data

                           Dallal et al. Arch Internal Med 2007; 167:408-15
Recreational Activity and Breast Cancer

         activity self reported via baseline
 Physical
     Moderate vs. strenuous activity
     Hours per week and months per year at
      specific age ranges
     Baseline Breast Cancer risk
       • Age, race, family history, estrogen exposure,
         menopausal status
       • BMI, smoking history, alcohol history
       • MMG and breast biopsy history
Recreational Activity and Breast Cancer

 Differenceonly observed with >5 hrs/week
 of strenuous activity
     Invasive Breast Cancer: RR 0.80 (CI 0.69-
       • ER – cancers: RR 0.45 (CI 0.27-0.76)
     In Situ Breast Cancer: RR 0.69 (CI 0.48-0.98)
 Nodifference seen in ER+ invasive
Selective Estrogen Receptor Modulators

            Tamoxifen       Raloxifene

Bone        Pro-estrogen    Pro-estrogen

Vascular    Pro-estrogen    Pro-estrogen

Uterus      Pro-estrogen    Anti-estrogen

Breast      Anti-estrogen   Anti-estrogen
    Tamoxifen and Breast cancer
   13,388 women randomized to Tamoxifen
    20mg/day or placebo for 5 years
       Inclusion criteria at least one:
         •   >60 years
         •   35-59 with 5 year predicted cancer risk >1.66%
         •   History of LCIS
         •   History of atypical hyperplasia
       MMG within 180 days of randomization without
        evidence of cancer
       No HRT, OCP, androgens within 3 months of
       No history of DVT or PTE
                                        Fisher et al. J National Ca Instit 2005;97:1652-62
Tamoxifen and Breast cancer
  Tamoxifen and Breast cancer
 Unblinded    after 5 years due to positive
 Tamoxifen reduced risk of invasive and
  non invasive breast cancer
     Rate of ER+ cancer significantly less
     Cancers less likely to be node +
 No   difference in breast cancer deaths
      Tamoxifen and Breast cancer
                       Placebo   Tamoxifen RR (CI)
Fractures              5.28      4.29        0.81 (0.63-1.05)

Ischemic heart disease 2.37      2.73        1.15 (0.81-1.64)

Stroke                 0.92      1.45        1.59 (0.93-2.77)

PE                     0.23      0.69        3.01 (1.15-9.27)

DVT                    0.84      1.34        1.60 (0.91-2.86)
Invasive Endometrial   0.91      2.30        2.53 (1.35-4.97)
Cataract               21.72     24.82       1.14 (1.01-1.29)

     Secondary end points: rate of event per 1000 women
      Tamoxifen vs. Raloxifene
 Study   of Tamoxifen and Raloxifene
     19,747 women randomized to Tamoxifen
      20mg/day or Raloxifene 60mg/day x 5years
      • Same risk as tamoxifen trial
      • No stroke, PTE, DVT, uncontrolled A Fib, DM, or
        HTN, current use of warfarin
      • No malignancy within last 5 years

                                  Vogel et al. JAMA 2006; 295: 2727-2751
Tamoxifen vs. Raloxifene
         Tamoxifen vs. Raloxifene
                    Tamoxifen Raloxifene RR (CI)
Fractures           2.73       2.51        0.92 (0.69-1.22)

Ischemic heart      3.00       3.29        1.10 (0.85-1.43)
Stroke              1.39       1.33        0.96 (0.64-1.43)
PE                  1.41       0.91        0.64 (0.41-1.00)
DVT                 2.29       1.69        0.74 (0.53-1.03)
Cataract            12.30      9.72        0.79 (0.68-0.92)

  Secondary end points: rate of event per 1000 women
      Tamoxifen vs. Raloxifene

                    Tamoxifen Raloxifene    RR (CI)
Invasive Cancer     2.00       1.25         0.62
Hyperplasia         4.69       0.76         0.16
Hysterectomy during 13.57      6.04         0.44
follow up                                   (0.35-0.56)

  Secondary end points: rate of event per 1000 women
SERM and Breast cancer

  All trials of Tamoxifen and Raloxifene vs placebo

                                        Cuszick, J et al. Lancet 2003; 361:296-300
SERM and Endometrial cancer

    All trials of Tamoxifen and Raloxifene vs placebo

                                          Cuszick, J et al. Lancet 2003; 361:296-300
SERM and Thromboembolic

  All trials of Tamoxifen and Raloxifene vs placebo

                                        Cuszick, J et al. Lancet 2003; 361:296-300
        SERM and Breast Cancer
   Tamoxifen shown to prevent the development of
    breast cancer
       Increased risk PE, endometrial cancer, cataracts
   Raloxifene as good as Tamoxifen in invasive
    breast cancer prevention
       Less PE, endometrial hyperplasia, cataracts
   Both approved for primary prevention of breast
    cancer in postmenopausal women
       Tamoxifen 20mg qd x 5 years
       Raloxifene 60mg qd x 5 years
   Breast cancer screening
       Digital Mammogram
         • Increased accuracy for younger women, women with dense
           breast tissue
       Computer Aided detection
         • Decreased accuracy due to decreased specificity
         • Significant increase in recall and biopsy rate
       MRI
         • Only studied in high risk women
         • Combination of MRI and MMG more sensitive than either
           modality alone
 Primary    Prevention via lifestyle changes
     Low fat diet might play a role, difficult to study
       • More benefit in women with higher baseline fat
     Recreational activity associated with
      decreased incidence of ER – tumors
       • Had to be strenuous activity, >5 hrs per week over
 Primary    Prevention via SERMs
     Tamoxifen and Raloxifene can prevent
      invasive cancers
       • No difference between the two in cancer incidence
       • Raloxifene with less endometrial hyperplasia but
         not uterine cancers
       • Raloxifene with less PE and cataract
       • Raloxifene known to decrease risk of vertebral

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