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Seehusen Patient centered Breast CA lecture USAFP minimizer

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					Patient-centered Strategies for Breast
Cancer Screening and Prevention


Dean A. Seehusen, MD, MPH, FAAFP


Department of Family and Community Medicine
Eisenhower Army Medical Center
Fort Gordon, GA 30905
Overview

   Introduction
   Case based scenarios
    – Risk calculation
    – BRCA testing
    – Screening strategies for high risk women
    – Chemoprophylaxis
   Question and answer session
Incidence and Prevalence

   About 1 in 8 women will develop
   Almost 180,000 cases annually in US
   1 in 4 of all female cancers
   Over 40,000 deaths annually in US
   2.5 million American women with a
    history of breast cancer


                           Breast Cancer Facts and Figures 2007-8. ACS
Trends

   Increasing incidence from 1980 to
    2001
   Decreasing incidence since 2001
   Mortality decreasing since 1990




                            Breast Cancer Facts and Figures 2007-8. ACS
Risk Factors

   RR > 4.0
    – Age 65+
    – BRCA gene mutations
    – 2+ first degree relatives
    – Personal history of breast cancer
    – Increased breast tissue density
    – Atypical hyperplasia on breast biopsy


                                Breast Cancer Facts and Figures 2007-8. ACS
Risk Factors continued

   RR = 2.1 – 4.0
    – One first degree relative
    – High dose radiation to chest
    – High bone density if postmenopausal




                              Breast Cancer Facts and Figures 2007-8. ACS
Risk Factors continued
   RR = 1.1- 2.0
    – First full-term pregnancy after age 30
    – Menarche before age 12
    – Menopause after age 55
    – No full-term pregnancies
    – Never breastfed a child
    – Recent OCP use (within 10 years)
    – Recent and long term HRT
    – Obesity (postmenopausal only)
                                Breast Cancer Facts and Figures 2007-8. ACS
Risk Factors continued

   Other risk factors
    – Personal history of endometrial, ovarian
      or colon cancer
    – Alcohol consumption
    – Height
    – High socioeconomic status
    – Jewish


                                Breast Cancer Facts and Figures 2007-8. ACS
Mrs. Lee

A 39-year-old white woman, comes in
  for her annual well woman visit.

She tells you that since her last visit, her
  44-year-old sister has been diagnosed
  with breast cancer. She would like to
  know what her risk is.
Further History

   No significant past medical history
   Never smoked, social alcohol
   Menarche at age 12
   Term deliveries at ages 21 and 23
   One benign breast biopsy
   Mother with breast cancer at age 62
   BMI = 28
   Normal mammogram last year
Clinical Question


How can you estimate Mrs. Lee’s risk for
 breast cancer?
Risk Modeling

   Many models available
   The Gail Model the most widely used
    – Never been validated for population
      based screening
    – Would dramatically underestimate risk in
      women with BRCA 1 or 2
   NCI website very user friendly and
    based on the Gail Model
Breast Tissue Density

   Recent area in interest
   Women with dense tissue in 50% or
    greater total breast area are at 3-5
    fold greater risk than those with
    <25%
   Several newer risk models incorporate



                                  Tice et al. Ann Int Med 2008
Mrs. Lee continued

At the end of the well woman visit, you
  enter an order for a mammogram.
  Mrs. Lee wants to know if there is any
  other screening that she should have
  done given her risk.
Clinical Question


What additional screening options exist
 for women with a high risk of breast
 cancer?
Mammography

   Utility varies depending upon age, risk
    factors, breast density, frequency
   Conflicting results from meta-analyses
   Quality has changed considerably
   Mortality rate has dropped about 25%
    during since widespread screening
Current Guidelines

   USPSTF recommendations a
    mammogram every 1-2 years for
    average risk women beginning at 40
   Evidence for benefit is greatest for
    women aged 50-69
   No clear upper age limit can be given



                                   USPSTF Ann Int Med 2002
Additional Considerations

   Women with a first degree relative
    should begin 10 years prior to age of
    diagnosis
   Mammograms should never begin
    prior to age 25
Additional Screening Tools

   Breast self-examination
   Clinical breast examination
   Digital mammography
   US
   MRI
Breast Self-Examination

   No proven benefit
   2003 Cochrane Review found a possible
    increase in biopsy rate
   USPSTF found insufficient evidence to
    recommend for or against
   AAFP, ACOG, AMA, ACS all support BSE


                                Knutson and Steiner AFP 2007
                                USPSTF Ann Int Med 2002
Clinical Breast Examination

   Has mostly been studied in
    conjunction with mammography
   Highly dependent upon technique and
    time spent performing exam
   USPSTF found insufficient evidence to
    recommend for or against


                                 Knutson and Steiner AFP 2007
                                 USPSTF Ann Int Med 2002
Digital Mammography

   Overall accuracy similar to film
   More accurate in women under 50
   More accurate for dense breasts
   Recent cost-effectiveness model
    – Exclusive use = $331,000 per QALY gained
    – Targeted use = $26,500 per QALY gained


                                 Pisano et al. NEJM 2005
                                 Tosteson et al. Ann Intern Med 2008
Breast Ultrasound

   In theory would be most useful for
    younger women and in dense breasts
   Berg et al. in 2008 showed a 55%
    increase in sensitivity when added to
    mammography in high risk women
   Found mostly small, node (-) tumors
   No mortality benefit proven to date

                                     Berg et al. JAMA 2008
Breast MRI

   Gadolinium contrast study
   Fat subtraction images
   Used as an adjunct to mammography
    in high risk patients
   High sensitivity, low specificity
   Higher rates of recall and biopsy
   Expensive

                                 Saslow et al. CA 2007
2007 ACS Guidelines
Annual MRI Adjunct to Mammogram

   Based on evidence
    – Known BRCA mutation
    – Untested 1 degree relative of BRCA carrier
    – Lifetime risk of 20-25% or greater
   Based on consensus opinion
    – Chest radiation between ages 10 and 30
    – Li-Fraumeni, Cowden, Bannayan-Riley-
      Ruvalcaba syndromes and first degree
      relatives
                                         Saslow et al. CA 2007
2007 ACS Guidelines
Annual MRI adjunct to mammogram

   Insufficient Evidence
    – Lifetime risk of 15-20%
    – Lobular carcinoma in situ or atypical
      lobular hyperplasia
    – Atypical ductal hyperplasia
    – Mammographically dense breast tissue
   Recommend against MRI
    – Less than 15% lifetime risk

                                        Saslow et al. CA 2007
Mrs. Lee continued

A month later, Mrs. Lee calls you and
  says that her other sister has been
  diagnosed with ovarian cancer. She
  wants to know if perhaps she should
  be tested for “those genes” that cause
  breast cancer.
Clinical Question


Who should be tested for genetic
 mutations that put them at increased
 risk for breast cancer?
BRCA1 and BRCA2

   Autosomal dominant mutations
   1/500 to 1/1000 in general population
   1/50 in Jewish populations
   Responsible for 1-2% of breast cancers
   Lifetime breast cancer risk 50 – 85%
   More aggressive tumors at younger ages
   Other increased cancer risks

                                   Saslow et al. CA 2007
Family History

   Know BRCA mutations
   Multiple close relatives with breast or
    ovarian cancer
   Breast cancer before the age of 50
   Both breast and ovarian cancer
   Close relatives with multiple cancers
   Male breast cancer

                                       Saslow et al. CA 2007
Genetic Testing

   Many risk alleles have been identified
   Tests for most of these genes are not
    widely available
   Individual genetic risk determination
    may be possible in the future




                                    Pharoah et al. NEJM 2008
BRCA Testing
   BRCA risk models
    – BRCAPRO, BOADICEA, MYRIAD II, others
    – All with unique characteristics
   Using multiple models has advantages
   Threshold of ~10% suggested
   American Society of Clinical Oncology in
    2003 recommended using clinical
    judgment instead of numerical cutoff

                               Berliner and Fay J Genet Counsel 2007
BRCA and USPSTF

   Grade D for general public
   Grade B for women with increased risk
    of breast or ovarian cancer associated
    with BRCA1 or BRCA2
    – Threshold risk cannot be determined
    – Testing should be preceded by genetic
      counseling done by a trained provider


                                     USPSTF Ann Intern Med 2005
Genetics Counseling

   Done prior to testing
   Should be done be trained individual
   Guidelines available from the NSGC
   2007 Cochrane review of counseling:
    – short term improvement in psychological
      wellbeing
    – decreased level of worry
    – improved accuracy of risk perception
    – increased knowledge
                                  Sivell et al. Cochrane Database 2007
Mrs. Lee continued

After counseling, Mrs. Lee decides she
  does not want to be tested for BRCA
  but does wants to know if there any
  medications she can take to reduce
  her risk of breast cancer.
Clinical Question


How can Mrs. Lee reduce her risk of
 breast cancer?

Is chemoprophylaxis an option?
Lifestyle Modification

   Regular exercise
   Decreasing alcohol intake
   Maintaining a healthy BMI
   Eating a low fat diet showed a 9%,
    statistically non-significant, reduction




                                         Afonso JABFM 2009
Tamoxifen Studies

   National Surgical Adjunct Breast and
    Bowel Project (NSABP) P-1 Study
    – 13,338 women
    – Randomized controlled trial
    – 20 mg/d tamoxifen vs. placebo
    – 5 years of therapy




                                  Fisher et al. J Natl Caner Inst 1998
P-1 Eligibility Criteria

   > 60 years of age
   History of LCIS
   5 year risk ≥ 1.66% by Gail Model
   Excluded if history of DVT or PE




                               Fisher et al. J Natl Caner Inst 1998
P-1 Results

   About 20% drop out rate in both arms
   49% reduction in breast cancer rate
   50% reduction in invasive disease
   Estrogen receptor positive only
   No survival difference at 4 years



                               Fisher et al. J Natl Caner Inst 1998
P-1 Adverse Reactions

   Tamoxifen group had higher rates of:
    – Endometrial cancer
    – PE
    – Newly diagnosed cataracts
   Women over age 50 at greatest risk of
    vascular events



                                  Fisher et al. J Natl Caner Inst 1998
Other Tamoxifen Studies

   Italian Tamoxifen Prevention Study
    – 5,408 subjects
    – RR = 0.92 (95% CI not available)
   Royal Marsden Hospital Tamoxifen
    Randomised Chemoprevention Trial
    – 2,471 subjects
    – RR = 0.94 (95% CI = 0.7 – 1.7)


                                         Levine et al. CMAJ 2001
Raloxifen Studies

   Multiple Outcomes of Raloxifen (MORE)
   7,705 subjects
   Randomized controlled trial
   60 mg/d vs. 120 mg/d vs. placebo
   90% reduction in ER+ breast cancer
   Increased DVT/PE risk (RR = 3.1)


                                  Levine et al. CMAJ 2001
Aromatase Inhibitors

   Last enzyme in estrogen synthesis
   3rd generation: anastrozole (arimidex),
    letrozole (Femara), vorozole
   Often used in breast cancer therapy
   Early evidence suggests effects better
    than SERMs with less side effects
   Large trials underway

                               Smith and Dowsett NEJM 2003
                               Cuzick Recent Results Cancer Res 2003
Individualized Approach
   Must weigh several factors
    – Individualized risk
    – Age less than or greater than 50
    – Risk of VTE disease
   USPSTF recommends discussing
    chemoprophylaxis with high risk women
   CTFPHC supports consideration if 5 year
    risk ≥ 1.66%
   American Society of Clinical Oncology and
    ACOG have similar positions
                                         USPSTF Ann Intern Med 2002
                                         Levine et al. CMAJ 2001
Prophylaxis Mastectomy

   Decreases breast cancer risk by 95%
   Consider only after significant
    counseling
   ASSO guidelines:
    – BRCA or other genetic mutations
    – Strong family history
    – ADH, ALH, LCIS on biopsy
    – Difficult surveillance such as excessively
      dense breasts
                                             Afonso JABFM 2009
Salpingo-oophorectomy

   Considered in known BRCA 1 or 2
   80-95% reduction in ovarian cancer
   50% reduction in breast cancer
   Negative effects
    – Menopausal symptoms
    – Increase cardiovascular risk
    – Accelerated bone loss
    – Decreased quality of life measures
                                           Afonso JABFM 2009
Conclusion

   Determining individual risk is the key
    to patient-centered care
   Women at highest risk should undergo
    additional screening examinations
   Genetic testing can be offered to
    selected women after counseling
   Chemoprophylaxis decisions need to
    be based on a risk-benefit analysis
Questions ?

				
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