Breast cancer screening and prevention in the highrisk patient

1
Breast cancer screening and prevention in the
high-risk patient

• Kirsten Stoesser, MD
• August 2008

2
Objectives

• Based on history
• Categorize a patient as average risk or high-risk
  for breast cancer
• Based on risk level
• Know appropriate breast cancer screening
  recommendations
• Know when to offer genetic counseling and testing
• Know when to offer chemoprophylaxis for primary
  prevention
• Know when to offer surgical consult for
  prophylactic mastectomy or oophorectomy

3
Case 1

• A 38 yo female patient presents for her annual
  physical exam. On her history, she has a
  maternal grandmother, and two paternal aunts who
  had breast cancer, all after age 50.
• Does she have a high-risk family history?
• Does she need referral to a genetic counselor?
• Does she need BRCA gene mutation testing?
• How often does she need mammograms?
• Does she need yearly breast MRI?

4
Case 2

• A 25 yo patient presents the same day for her
  annual physical. On family history, her mother
  died at age 35 from breast cancer. BRCA status
  of her mother is unknown. The patient has
  already seen a genetic counselor, has tested
  negative for BRCA gene mutations, and informs you
  that she needs yearly breast mammograms and MRIs.
• Does she really need yearly MRIs?
• Should she be offered chemoprophylaxis?
• Should she be offered surgical prophylaxis?

5
Breast cancer-- estimated new invasive cancer
cases and deaths in the US for 2007

• Estimated new cases
• Women 178,480
• Men 2,030 (1 of all breast cancers)
• Total 180,510
• Estimated deaths
• Women 40,460
• Men 450
• Total 40,910

6
Female breast cancer incidence and mortality
rate, Utah, 2000-2004

• Breast cancer incidence
• 117.5/100,000
• Mortality
• 23.2/100,000

7
Breast cancer-- death rates

• Only lung cancer causes more cancer deaths in
  women
• From 1990-2004 national breast cancer death rates
  have decreased 2-3 annually
• The decline in mortality since 1990 is attributed
  to improvements in early detection and treatment

8
Breast cancer-- precursor lesions

• Majority of breast cancers start in ductal cells
  or lobules
• Atypical ductal hyperplasia --gt ductal carcinoma
  in situ (DCIS) --gt invasive cancer
• Atypical lobular hyperplasia --gt lobular
  carcinoma in situ (LCIS) --gt invasive cancer
• Both atypical ductal hyperplasia and LCIS have a
  similar risk for progressing to breast cancer

9
Probability of developing invasive breast cancer
during selected age intervals
10
Risk factors for breast cancer

• Genetics
• Family history of breast cancer
• BRCA1 or BRCA2 gene mutation carriers
• Increased lifetime estrogen exposure
• Early menarche, late menopause
• Nulliparity or older age at first birth
• Absence of breastfeeding
• Increasing age
• HRT
• Personal breast history
• Mammographically dense breasts
• Prior breast biopsies
• Prior atypical ductal hyperplasia or LCIS on
  biopsy
• Prior breast cancer
• Miscellaneous
• Radiation exposure
• Alcohol
• Obesity
• Sedentary lifestyle

11
Risk stratification

• Patients can be stratified into the following
  categories based on their risk factors
• Average risk
• High-risk
• Recommendations differ dependent on risk for
• Screening
• Risk-reduction strategies

12
Approach to stratify risk of breast cancer

• Get a thorough history!
• Family history
• Clinical history
• Genetic testing
• If indicated by family history

13
Approach to the high-risk patient

• Increased surveillance
• Recommended for all patients
• Referral to genetic counseling if high-risk due
  to family history
• BRCA testing
• Prevention
• Prophylactic medication (chemoprevention)
• Selective estrogen receptor modulators (SERMs)
• Tamoxifen
• Raloxifene
• Aromatase inhibitors
• Prophylactic surgery
• Bilateral mastectomy
• Bilateral oophorectomy

14
Highest risk factor for breast cancer-- BRCA
mutation

• The highest risk factor for breast cancer is
  having a gene mutation in either BRCA1 or BRCA2
• Both are autosomal dominant, high-penetrance
  genes
• Normally function as a tumor suppressor
• Over 30 known mutations
• 35 to 85 lifetime risk of breast cancer
• 10 to 50 lifetime risk of ovarian cancer

15
Family history suggestive of a BRCA1 or BRCA2
mutation

• Two first degree relatives with breast cancer,
  one of whom received the diagnosis ltage 50
• Three or more first or second degree relatives
  with breast cancer at any age
• Both breast and ovarian cancer among first and
  second degree relatives
• First degree relative with bilateral breast
  cancer
• 2 or more first or second degree relatives with
  ovarian cancer regardless of age
• First or second degree relative with both breast
  and ovarian cancer
• A male relative with breast cancer

16
Family history suggestive of a BRCA1 or BRCA2
mutation

• Women of Ashkenazi Jewish descent
• Any first degree relative with breast or ovarian
  cancer
• Two second degree relatives with breast or
  ovarian cancer

17

• What percentage of patients have a family history
  that is suggestive of a BRCA1 or BRCA2 mutation?
• 0.01
• 0.1
• 1
• 10

18

• What percentage of patients have a family
  history that is suggestive of a BRCA1 or BRCA2
  mutation?
• 0.01
• 0.1
• 1 (to 2 )
• 10

ACS 2007
19

• In those patients who have a family history
  suggestive of an inherited mutation, what percent
  of families will actually carry this mutation?
• 5
• 10
• 25
• 50

20

• In those patients who have a family history
  suggestive of an inherited mutation, what percent
  of families will actually carry this mutation?
• 5
• 10
• 25
• 50

ACS 2007
21
Genetic counseling and BRCA testing

• Women with a FH at increased risk for BRCA1 or
  BRCA2 mutations should be referred for genetic
  counseling and evaluation for BRCA testing (level
  B recommendation)

USPSTF 2007
22
Genetic testing results

• If a woman from a family with a known BRCA
  mutation tests negative, then her family history
  does not factor in to her breast cancer risk
• In women from high-risk families by history,
  failure to find a mutation in an affected
  individual does not decrease risk

23

• Of those women who develop breast cancer
• 85 have no prior family history

24
High-risk factors for breast cancerrelative risk
Willey et al. Screening and follow-up of the
patient at high risk for breast cancer. Obstet
Gynecol 20071101404-16.
25
Risk assessment tools

• Gail model
• Uses predominantly clinical history
• Estimates 5-yr and lifetime breast cancer risk
• www.breastcancerprevention.org
• National Surgical Adjuvant Breast and Bowel
  Project
• www.cancer.gov/bcrisktool
• National Cancer Institute
• Claus model
• Uses family history only
• Tyrer-Cuzick model
• BRCAPRO

26
Risk assessment tools-- Gail model

• Most commonly used by clinicians
• Least accurate
• Based on
• National Surgical Adjuvant Breast and Bowel
  Project
• Breast Cancer Detection and Demonstration Project
• Looks at
• Current age, age at menarche, age at first live
  birth, number of prior breast biopsies, biopsy
  results, of first degree relatives with breast
  cancer, and race
• Limitations
• Does not account for extended family history,
  history of chest radiation, breast density
• A calculated 5-year risk of breast cancer of
  1.67 is high-risk
• Women age 35 or older with a 5-yr breast cancer
  risk of 1.67 or more were included in the first
  breast cancer chemoprevention trial

27
Sample Gail model calculation

• Hx of breast cancer, DCIS, or LCIS No
• Womans age 36
• Age of menarche 12 to 13
• Age at first birth of child gt30
• First-degree relatives with breast cancer 0
• Hx of breast biopsy No
• Race White
• 5 year risk
• This patient 0.5
• Average patient 0.3
• Lifetime risk
• This patient 13.8
• Average patient 12.5

28
Risk assessment tools-- Claus model

• Includes
• Number of maternal and paternal first and
  second-degree relatives with breast cancer
• Their age at diagnosis

29
Sample Claus model calculation

• Number of first degree relatives with breast
  cancer 0
• Number of second degree relatives with breast
  cancer 1
• Age at diagnosis 55
• Risk of breast cancer
• By age 39 --gt 0.2
• By age 49 --gt 1.3
• By age 59 --gt 3.4
• By age 69 --gt 6.3
• By age 79 --gt 9.0

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31
Breast cancer screening

• Screening has significantly contributed to a
  23.5 decline in breast cancer mortality from
  1990 to 2000

National Cancer Institute 2007
32
Breast cancer screening-- harms and benefits

• Potential benefits
• Earlier diagnosis
• Decreased mortality
• Potential harms
• False-positive results
• Unnecessary biopsies
• Increased anxiety
• Increased cost
• Inconvenience
• Overtreatment
• Overdiagnosis occurs mostly with DCIS
• Less than 50 of DCIS becomes invasive, but
  everyone gets treated

33
Breast cancer screening--methods

• Self breast exam (SBE)
• Clinical breast exam (CBE)
• Standard mammography
• MRI

34
Breast cancer screening in the average risk
patient--SBE

• Most women do not regularly perform
• If they do perform, most do it incorrectly
• The practice of regular breast self-exam by
  trained women does not reduce breast cancer
  mortality
• Evidence from 2 large RCTs
• Randomized trial of breast self-examination in
  Shanghai final results. J Natl Cancer Inst 2002.
• Breast self-examination and death from breast
  cancer a meta-analysis. Br J Cancer 2003.

35
Breast cancer screening in the average risk
patient--SBE

• Cochrane review 2003
• Conclusions
• SBE has no beneficial effect
• Increases the number of biopsies
• Evidence of harm
• Recommendation
• Women should NOT perform SBE

36
Breast cancer screening in the average risk
patient-- SBE

• USPSTF 2007
• Insufficient evidence to recommend for or against
  breast self-examination
• ACS 2007
• Monthly breast self-examination optional at any
  age 20 or older

37
Breast cancer screening in the average risk
patient-- SBE

• If women choose to perform breast
  self-examination after being informed of the lack
  of benefit and potential harms, the physician
  should train the patient in appropriate
  technique, timing, and follow-up.
• Knutson D, Steiner E. Screening for breast
  cancer current recommendations and future
  directions. Am Fam Phys 200751660-6.

38
Breast cancer screening in the average risk
patient--SBE

• Self breast-exam at any age
• Not supported by the evidence
• Physicians should discourage, or at least not
  encourage
• If patients want to perform, should be taught the
  appropriate way to perform the exam

Harris, R. Screening for breast cancer what to
do with the evidence. Am Fam Phys 200751623-4.
39
Breast cancer screening in the average risk
patient-- CBE

• Sensitivity 50 at best
• 5 to 10 of breast cancers detected only by CBE
• (not detected by mammogram)
• USPSTF 2007
• Insufficient evidence to recommend for or against
  CBE
• ACS 2007
• CBE every 3 yrs ages 20 to 39
• CBE annually age 40 and older

40
Breast cancer screening in the average risk
patient--CBE

• Age 20 to 39
• Even necessary?
• Every 3 years?
• Age 40 to 49
• Benefits and harms approximately equal
• May discuss, but do not need to actively
  encourage
• Every 1 to 2 years, if at all
• Age 50 to 70
• Encourage every year
• Every 2 years acceptable
• After age 70
• Balance of benefits and harms uncertain, take
  patients general health and life expectancy into
  consideration

Harris, R. Screening for breast cancer what to
do with the evidence. Am Fam Phys 200751623-4.
41
Breast cancer screening in the average risk
patient-- standard mammography

• Sensitivity to detect breast cancer is between
  60 to 90
• Less sensitive
• in younger women (ltage 40)
• in women with dense breasts
• in tumors associated with BRCA1 or 2
• Positive predictive value is higher in women who
  are high-risk

42
Breast cancer screening in the average risk
patient-- standard mammography

• Women age 40 to 49
• reduces breast cancer mortality 15
• Number needed to screen to prevent one breast
  cancer death after 14 years 1,792
• Women age 50 to 69
• reduces breast cancer mortality 22
• Number needed to screen to prevent one breast
  cancer death after 14 years 838
• Humphrey et al. Breast cancer screening a
  summary of the evidence from the USPSTF. Ann
  Intern Med 2002137347-60.

43
Breast cancer screening in the average risk
patient-- standard mammography

• Cochrane review (2001)
• Meta-analysis concluded that screening for breast
  cancer with mammography is unjustified
• USPSTF (2007)
• Meta-analysis using many of the same trials
• For women of average risk, recommended screening
  mammography (B recommendation)
• Every one to two years for women ages 40 to 49
• Every year for women age 50 and older
• Little evidence to suggest this is better than
  every 2 yrs
• ACS (2007)
• Every year for women age 40 and older

44
Breast cancer screening in the average risk
patient-- mammogram

• Age 40 to 49
• Benefits and harms approximately equal
• May discuss, but do not need to actively
  encourage
• Every 1 to 2 years, if at all
• Age 50 to 70
• Encourage
• Every 2 years acceptable
• After age 70
• Balance of benefits and harms uncertain, take
  patients general health and life expectancy into
  consideration

Harris, R. Screening for breast cancer what to
do with the evidence. Am Fam Phys 200751623-4.
45
Breast cancer screening-- MRI

• Not recommended for average risk patients
• Too expensive for screening all patients
• Availability issues
• More sensitive (but less specific) than
  mammography in high-risk women
• Sensitivity of 71 to 100 vs 16 to 40 for
  mammogram in high-risk women
• Particularly more sensitive with dense breasts
• Tumors found are smaller and earlier
• Combination of mammography and MRI is better than
  either alone for detection
• No data yet on mortality reduction

46
ACS indications for annual breast cancer
screening with MRI

• Women age 30 or older with any of the following
  should be screened yearly
• Patient with BRCA1 or BRCA2 mutation
• First degree relative with BRCA1 or BRCA2
  mutation
• If the patient has not yet been tested
• History of therapeutic chest radiation between
  the ages of 10 to 30 years
• Lifetime risk of breast cancer of 20 or greater,
  based on a risk assessment calculation tool that
  depends largely on family history

47
ACS indications for annual breast cancer
screening with MRI

• Of note what is NOT included
• Insufficient evidence to recommend for or against
  MRI screening with other risk factors
• Lifetime risk of breast cancer 15-20
• Hx of atypia/CIS/breast cancer
• Dense breasts
• These above items should be discussed
  individually
• MRI screening may be recommended by expert
  opinion, but not endorsed by ACS

48
Breast cancer screening in the high-risk patient

• SBE?
• CBE
• Annually or every 6 months?
• Mammogram
• Yearly
• ? Age to start
• ?Once determined they are high-risk
• If high-risk due to family history, start 10
  years earlier than youngest affected first-degree
  relative
• If BRCA 1 or 2 mutation in patient (or in family
  and patient not tested), start age 25
• MRI
• Yearly, starting at age 30, if meet ACS criteria
• (And consider screening if other high-risk
  factors present that dont yet meet criteria,
  such as dense breasts)

49
Chemoprophylaxis of breast cancer

• Clinicians should discuss chemoprevention with
  women at high risk for breast cancer and at low
  risk for adverse effects of chemoprevention. (B
  recommendation)
• Clinicians should inform patients of the
  potential benefits and harms of chemoprevention
  (B recommendation)

USPSTF 2007
50

• It isnow considered standard of care to
  evaluate breast cancer risk factor information in
  women and to counsel high-risk women about the
  options of chemoprevention
• Newman et al. Breast Cancer Risk Assessment and
  Risk Reduction. Surg Clin N Am 87 (2007) 307-316.

51
Tamoxifen

• Selective Estrogen Receptor Modulator (SERM)
• Competes with estrogen for estrogen receptors on
  breast cancer cells
• Blocks estrogen uptake
• Prevents cell growth
• FDA-labeled for breast cancer prophylaxis in
  high-risk patients
• gt35 yo with a Gail model 5-yr risk of 1.67
• Dose 20 mg orally daily for 5 years

52
Tamoxifen

• Only acts on estrogen receptor positive tumors
  (ER)
• BRCA2 gene mutation carriers can have estrogen
  receptor positive or negative tumors
• Tamoxifen is effective only in the subset of
  patients who are ER
• BRCA1 gene mutation carriers are usually estrogen
  receptor negative
• Tamoxifen is ineffective for most of these
  patients

53
Tamoxifen Prophylaxis

• Women using tamoxifen to treat established breast
  cancer found to have a 47 lower risk of a second
  primary breast cancer compared to patients not on
  tamoxifen
• Prompted the first large chemoprevention trial in
  the US, the NSABP P-1 study in 1998
• Prospective, randomized
• Tamoxifen vs placebo for 5 yrs
• gt13,000 high-risk women enrolled
• Inclusion criteria
• Age 60 or greater,
• Or age 35-59 with a Gail model 5-yr risk of
  breast cancer of 1.67
• Or personal history of LCIS

54
Tamoxifen prophylaxis

• Tamoxifen lowered invasive breast cancer risk by
  50
• For ER cancers
• No reduction in ER- cancers
• Statistically significant
• (95 CI 0.39-0.66)
• The trial was unblinded early

55
Tamoxifen

• Increased risks of
• Uterine cancer
• Stroke
• Myocardial infarction
• Thromboemboli (DVT, PE)
• Cataracts
• Decreased risks of
• Osteoporosis
• Hyperlipidemia
• Side effects
• Hot flashes, night sweats, irregular menses

56
Predicted benefits vs harms for 5 years of
tamoxifen per 1000 women
57
Chemoprophylaxis of breast cancer

• Best for
• Women in their 40s who are at increased risk for
  breast cancer and have no predisposition to
  thromboembolism
• Women in their 50s who are at increased risk for
  breast cancer, have no predisposition to
  thromboembolism, and do not have a uterus.
• Less beneficial for
• Women in their 30s (less risk of breast cancer)
• Women gt age 60 (increased risk of thromboembolism)

58
Raloxifene

• SERM
• FDA approved in Sept 2007 for breast cancer
  prophylaxis in postmenopausal women at high risk
• Dose 60 mg orally daily optimal duration unknown
• Risks similar to tamoxifen
• Less uterine cancer and cataract risk

59
Tamoxifen vs Raloxifene

• Study of Tamoxifen and Raloxifene (STAR)
• 2006 JAMA
• 19,000 high-risk postmenopausal women
• Similar enrollment criteria as NSABP P-1
• Randomized to receive either tamoxifen or
  raloxifene for 5 yrs
• Comparable efficacy to prevent invasive breast
  cancer
• Raloxifene also reduced the risk of invasive
  breast cancer by 50
• Raloxifene had fewer thromboembolic events,
  cataracts, and trend for less uterine cancer
• Similar risk of MI, stroke, and osteoporotic
  fractures

60
Aromatase inhibitors

• Block the peripheral conversion of
  androstenedione to estrone and testosterone to
  estradiol
• Not yet approved for prophylaxis
• Anastrazole, Tamoxifen, Alone or in Combination
  (ATAC) trial (Lancet 2002)
• Multicenter, international, double-blind, RCT
• 9,366 postmenopausal women with early stage
  breast cancer
• After 33 months statistically significant gt50
  reduction in contralateral primary invasive
  breast cancers in the anastrazole alone group

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62
Prophylactic oophorectomy

• In women who have a known BRCA mutation,
  prophylactic oophorectomy can decrease breast
  cancer incidence by 50
• Rebbeck et al. Breast cancer risk after
  bilateral prophylactic oophorectomy in BRCA1
  mutation carriers, J Natl cancer Inst
  199991(17)1475-9.
• Insufficient evidence regarding mortality benefit
• Adverse effects
• Premature menopause
• Increased risks of osteoporosis, cardiovascular
  disease

63
Prophylactic mastectomy

• Retrospective review of Mayo Clinic database
• 214 prophylactic mastectomy patients with
  high-risk family history
• Controls were 403 sisters of these patients
• Median f/u of 14 yrs
• 90 reduction in breast cancer incidence and
  mortality
• Hartman et al. Efficacy of bilateral
  prophylactic mastectomy in women with a family
  history of breast cancer. N Engl J Med
  1999340(2)77-84.
• Further analysis performed when BRCA testing
  available
• Similar risk reduction in subset of patients with
  BRCA mutation
• Hartman et al. Efficacy of bilateral
  prophylactic mastectomy in BRCA1 and BRCA2 gene
  mutation carriers. J Natl Cancer Inst
  200193(21)1633-7.
• Insufficient evidence regarding mortality benefit

64
Case 1

• A 38 yo female patient presents for her annual
  physical exam. On her history, she has a
  maternal grandmother, and two paternal aunts who
  had breast cancer, all after age 50.
• Does she have a high-risk family history?
• Does she need referral to a genetic counselor?
• Does she need BRCA gene mutation testing?
• How often does she need mammograms?
• Does she need yearly breast MRI?

65
Case 2

• A 25 yo patient presents the same day for her
  annual physical. On family history, her mother
  died at age 35 from breast cancer. BRCA status
  of her mother is unknown. The patient has
  already seen a genetic counselor, has tested
  negative for BRCA gene mutations, and informs you
  that she needs yearly breast mammograms and MRIs.
• Does she really need yearly MRIs?
• Should she be offered chemoprophylaxis?
• Should she be offered surgical prophylaxis?

66
Identifying high-risk patients in clinic

• Any FH of breast or ovarian cancer?
• Any 1º or 2º relative with both breast and
  ovarian cancer?
• Any male relatives with breast cancer?
• Any 1º relative with cancer in both breasts?
• Two or more 1º relatives?
• Three or more 1º or 2º relatives?
• Both breast and ovarian cancer in 1º or 2º
  relatives?
• Two or more 1º or 2º relatives with ovarian
  cancer?
• Has a relative tested positive for a BRCA gene
  mutation?
• Has the patient tested positive for a BRCA gene
  mutation?
• Gail model 5-yr risk 1.67?
• Lifetime risk 20
• Therapeutic chest radiation ages 10-30?
• HRT 10 yrs?
• Dense breast tissue?
• Atypical hyperplasia, LCIS, or prior breast
  cancer?

67
Summary--Management options for high-risk women

• Surveillance
• SBE?
• CBE yearly (? or q 6 mos)
• Annual mammogram (? age to start)
• Once determined high-risk
• 10 years younger than age of youngest affected
  first degree relative
• Age 25 if BRCA mutation carrier
• Annual MRI
• Starting at age 30 if they meet the ACS criteria
• Known BRCA mutation
• 1º relative with a BRCA mutation, and patient
  untested
• 20 or greater lifetime risk of breast cancer
• Chest radiation exposure between ages 10 and 30
  yrs
• And consider even if they dont meet ACS
  criteria
• Lifetme breast cancer risk 15-20
• Mammographically dense breasts
• Personal history of atypia, LCIS, breast cancer

68
Summary--Management options for high-risk women

• Genetic testing
• If high-risk based on family history
• To help guide surveillance and prophylaxis
• Chemoprophylaxis
• If BRCA mutation carrier
• If Gail 5-yr risk 1.67
• Use of tamoxifen or raloxifene
• Surgical prophylaxis
• If BRCA mutation carrier
• Mastectomy and/or oophorectomy

69
References

• ACS Recommendations on MRI and mammography for
  breast cancer screening. Am Fam Phys
  200751715-6.
• Breast cancer facts and figures. ACS 2007-2008.
• Guide to Clinical Preventive Services. USPSTF
  2007.
• Harris, R. Screening for breast cancer what to
  do with the evidence. Am Fam Phys 200751623-4.
• Kutson D, Steiner E. Screening for breast
  cancer Current Recommendations and Future
  Directions. Am Fam Phys 200751660-6.
• Newman LA, Vogel VG. Breast Cancer Risk
  Assessment and Risk Reduction. Surg Clin N Am 87
  (2007) 307-316.
• Saslow D et al. American Cancer Society
  Guideline for Breast Screening with MRI as an
  adjunt to mammography. CA Cancer J Clin 2007
  5775-89.
• Update on Breast Cancer Risk Reduction. Cedars
  Sinai Medical Center. 2006.
• Willey S, Costanza C. Screening and follow-up of
  the patient at high-risk for breast cancer.
  Obstet gynecol 20071101404-16.