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Underwriting Breast Cancer Steven E. Zimmerman M.D. Vice President

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40,930 estimated deaths from breast cancer in 2008 ... Annual Incidence of Female Breast Cancer (1975-2004) ... Breast Cancer Incidence, Hormone Receptor ... – PowerPoint PPT presentation

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Title: Underwriting Breast Cancer Steven E. Zimmerman M.D. Vice President


1
Underwriting Breast Cancer Steven E. Zimmerman
M.D. Vice President Chief Medical Director
2
(No Transcript)
3
Breast Cancer Statistics 2008
  • The most common cancer in females
  • 250,230 new cases estimated
  • 182,460 invasive breast cancers
  • 67,770 in situ breast cancers
  • Second only to lung cancer in mortality for
    females
  • 40,930 estimated deaths from breast cancer in
    2008
  • Leading cause of death for American females
    between ages 40-55
  • Lifetime risk is 1 in 7

4
Annual Incidence of Female Breast Cancer
(1975-2004)
Ravdin P et al. N Engl J Med 20073561670-1674
5
Risk Factors for Breast Cancer
  • Age
  • Familial (5 to 10 of all cases ½ BRCA 1/2)
  • 1ST degree relative 1.5 to 3x increased risk
  • BRCA 1/2 mutation 26 to 85 lifetime risk
  • Hormonal factors
  • Estrogen exposure (HRT, serum estrogen levels)
  • Reproductive history
  • Early menarche
  • Late menopause
  • Nulliparity

6
Risk Factors for Breast Cancer
  • Benign breast disease
  • Atypical hyperplasia
  • Dietary and lifestyle factors
  • Alcohol consumption
  • Dietary fat intake
  • Environmental factors
  • Radiation exposure
  • Greatest when exposure occurs at young age
  • Risk is greatest in young women treated for
    Hodgkins Lymphoma with mantle radiation

7
Breast Cancer Trends Incidence by Age
8
Absolute Risk of Breast Cancer and Age
9
Breast Cancer Incidence, Hormone Receptor Status
and Hormone Replacement Therapy
Ravdin P et al. N Engl J Med 20073561670-1674
10
How Much Breast Cancer Is Hereditary?
11
Cancer Arises From DNA Mutations in Cells
12
BRCA Mutations
  • Highest prevalence in Ashkenazi Jewish population
  • Tumor suppressor genes
  • BRCA1
  • Associated with 45 of inherited breast cancer
    over 80 of inherited breast and ovarian cancer
  • Location chromosome 17
  • BRCA2
  • Associated with male breast cancer, prostate
    cancer, and GI malignancies as well
  • Location chromosome 13

13
Causes of Hereditary Susceptibility
Contribution to Hereditary Breast Cancer 20 -
40 10 - 30 Gene BRCA1 BRCA2 TP53 PTEN Undiscovered genes
14
Genes Associated with a Hereditary Predisposition
to Breast Cancer
Robson M and Offit K. N Engl J Med
2007357154-162
15
Magnitude of Relative Risk
16
Detecting Diagnosing Breast Cancer
  • Breast self examination (BSE)
  • Physical examination
  • Mammography
  • Ultrasonography
  • Magnetic resonance mammography (MRM)

17
U.S Preventive Services Task Force
Nelson, H. D. et. al. Ann Intern Med
2005143362-379
18
Mammography
  • Detection of calcifications
  • Microcalcifications
  • Common sign of cancer, e.g. DCIS
  • Macrocalcifications
  • More typical of benign disease
  • Mass with or without calcification
  • Issues with
  • Dense breasts
  • Implants

19
Mammographic Findings
20
Mammographic Findings
21
Breast Ultrasonography
  • Not used for screening
  • Used to evaluate suspicious lesions palpated
    and/or seen on mammography
  • Differentiates cystic from solid lesions
  • Distinguish tumor from lymph nodes

22
Breast Ultrasonography
23
Breast Ultrasonography
24
Breast MRI
  • More sensitive than mammography
  • Advantages
  • Dense breasts
  • Implants
  • Young women
  • Hereditary risks
  • Prior lumpectomy
  • Disadvantages
  • Less specific more false positives
  • More expensive

25
Breast MRI
  • Fibroadenoma before contrast
  • Invasive Lobular Ca before contrast

26
Breast MRI
  • Fibroadenoma 5 minutes after contrast
  • Invasive Lobular Ca 5 minutes after contrast

27
Breast MRI
  • Fibroadenoma subtracted image
  • Invasive Lobular Ca subtracted image

28
Impact of Screening
29
Anatomy of the Breast
30
Normal Breast Tissue
31
Benign Breast Disease
  • Fibroadenoma
  • Fibrocystic disease
  • Atypical hyperplasia
  • Other

32
Benign Breast Disease - Fibroadenoma
  • Usually in women under age 30
  • Rounded, easily movable mass
  • About 10 will disappear per year
  • Small long term risk for developing cancer

33
Benign Breast Disease Fibrocystic disease
  • Gross cyst
  • Usually in 40s
  • Needle aspiration or ultrasound for diagnosis
  • Non-bloody fluid obtained, then lump disappears

34
Benign Breast Disease Fibrocystic disease
  • Fibroadenosis Micro cysts
  • Found in 30s 40s
  • Disappears after menopause
  • Usually diffuse and ill-defined
  • Usually cyclic with menses
  • Painful and prominent before resolves after

35
Benign Breast Disease Atypical hyperplasia
  • Marked proliferation and atypia of epithelium
  • Found in 3 of benign breast biopsies
  • Associated with 13 subsequent development of
    breast cancer 4x risk factor
  • Diagnosed by same criteria as DCIS, but doesnt
    have all the characteristics
  • Some may be under-diagnosed DCIS

36
Benign Breast Disease Other
  • Phylloides tumor
  • Unpredictable behavior
  • About 10 metastasize from either malignant or
    benign phylloides tumors
  • Mammary duct ectasia
  • Breast inflammation and abscess formation
  • Presents as periareolar inflammation
  • When chronic, most frequent cause of nipple
    discharge in premenopausal women

37
Benign Breast Disease Other
  • Papillomas
  • Small (
  • Frequently have nipple discharge
  • May be solitary or multiple
  • Frequently develop more papillomas or cancer
  • Single without atypia 3-fold risk
  • With atypical hyperplasia 4-fold risk
  • Multiple often associated with carcinoma

38
Presenting Symptoms of Breast Cancer
  • Painless breast mass 66
  • Painful breast mass 11
  • Nipple discharge 9

39
Breast Cancer
  • Lobules and Ducts are structures within the
    breast
  • Cancer seen only in the ducts ductal
  • Cancer seen only in the lobules lobular
  • Tumor confined to the ducts or lobules in situ
  • Cancer extending beyond the ducts or lobules to
    adjacent tissue invasive or infiltrating

40
Breast Cancer Non-infiltrating (in situ)
  • Lobular carcinoma in situ not a cancer?
  • Usually an incidental finding
  • Low risk of developing invasive breast cancer
  • More common in premenopausal women
  • Treatment is usually observation
  • Breast examination every 6-12 months
  • Mammogram every 1-2 years
  • Ductal carcinoma in situ (DCIS)
  • Diagnosed with increased frequency due to
    mammography
  • Subtypes
  • solid, cribiform, papillary, comedo
  • High grade and comedo type (usually) can travel
    extensively but undetected throughout the breast

41
Lobular Carcinoma in situ
42
Ductal Carcinoma in situ
43
DCIS - Subtypes
44
Normal Breast Tissue
45
Pathology DCIS
46
Breast Cancer - Infiltrating
  • Infiltrating ductal carcinoma
  • Most common form 70-80
  • Invades breast structures and may spread to lymph
    nodes and to other organs
  • Same subtypes as DCIS
  • Infiltrating lobular carcinoma
  • Less common 10-15
  • Most common in 45-55 year age group
  • Sometimes bilateral often without a lump

47
Breast Cancer - Infiltrating
  • Pagets disease of the breast
  • Uncommon 1-2
  • Red, scaly rash involving the nipple
  • Nipple may be inverted
  • May be a discharge
  • About 50 with underlying lump
  • If no lump, 60 will be in situ cancers

48
Infiltrating Ductal Carcinoma
49
Infiltrating Lobular Carcinoma
50
Vascular and Lymphatic Invasion
51
Normal Breast Tissue
52
Pathology Infiltrating Tumor
53
Grading of Tumors Nottingham
  • Tubule Formation
  • Majority of Tumor (75) 1
  • Moderate Degree (10-75) 2
  • Little or None (
  • Mitotic Count
  • 0-9 Mitosis/10 hpf 1
  • 10-19 Mitosis/10 hpf 2
  • 20 or Mitosis/10 hpf 3

54
Grading of Tumors Nottingham
  • Nuclear Pleomorphism
  • Small Regular Uniform Cells 1
  • Moderate Nuclear Size and 2 Variation
  • Marked Nuclear Variation 3

55
Grading of Tumors Nottingham
  • Combined Histologic Grade
  • Low Grade (I) 3-5
  • Intermediate Grade (II) 6-7
  • High Grade (III) 8-9

56
Pathology Infiltrating Tumor
57
Pathology Sentinel Lymph Node
58
Pathology Sentinel Lymph Node
59
Staging
  • The American Joint Committee on Cancer stages
    adenocarcinoma of the breast using the TNM system
  • Tumor, Node, Metastasis
  • Local growth primary tumor T
  • Regional growth lymph nodes N
  • Distant growth distant metastasis M

60
Breast Cancer Staging TNM
  • Tumor (T)
  • Tis Carcinoma in situ
  • T1 Tumor 2.0 cm or less in greatest dimension
  • T1a 0.5 cm or less
  • T1b more then 0.5cm but not more than 1.0 cm
  • T1c more than 1.0 cm but not more than 2.0 cm
  • T2 Tumor more than 2.0 cm but not more than 5.0
    cm
  • T3 Tumor more than 5.0 cm
  • T4 Tumor of any size with direct extension to
    chest wall or skin

61
Breast Cancer Staging TNM (cont.)
  • Regional Lymph Nodes(N)
  • N0 No regional lymph node metastasis
  • N1 Mobile ipsilateral axillary lymph node
    metastasis
  • N2 Ipsilateral axillary lymph node metastasis
    fixed to one another or other structures
  • N3 Ipsilateral internal mammary lymph node
    metastasis
  • Metastatic Sites (M)
  • M0 No distant metastasis
  • M1 Distant metastasis present

62
Breast Cancer Staging
  • Stage 0 Tis, N0, M0
  • Stage I T1, N0, M0
  • Stage IIA T0, N1, M0 T1, N1 ,M0 T2, N0,
    M0
  • Stage IIB T2, N1, M0 T3, N0, M0

63
Breast Cancer Staging (cont.)
  • Stage IIIA T0, N2, M0 T1, N2, M0 T2, N2,
    M0 T3, N1, M0 T3, N2, M0
  • Stage IIIB T4, any N, M0 or any T, N3, M0
  • Stage IV Any T, any N, M1

64
Survival by Stage
65
Survival by Stage
66
Additional Prognostic Factors
  • Estrogen/progesterone receptors
  • Proliferative markers
  • Ploidy analysis
  • S-phase fraction
  • Mitotic index
  • Genetic markers
  • HER2/neu

67
Estrogen/Progesterone Receptor Status
  • Estrogen receptor-positive tumors have a better
    response to hormonal therapy
  • Longer time to recurrence
  • Weak predictor of mortality
  • Long-term survival outcomes are similar

68
Proliferative Markers
  • DNA Histogram (flow cytometry)

69
Proliferative Markers
  • Ploidy refers to the amount of DNA contained in
    tumor cells compared to normal ones
  • Diploid
  • Cells contain a normal amount of DNA (1.0)
  • Aneuploid
  • Cells contain abnormal amounts of DNA
  • Aneuploidy has 8.3 times greater relative risk
    for death compared to diploid cancers

70
Proliferative Markers
  • S-Phase Fraction
  • Cell proliferative activity (S phase index or
    SPI)
  • Measure of the proliferative capacity of tumor
    cells
  • Correlated high SPI with more aggressive tumor
    behavior and greater propensity for recurrence or
    metastatic disease
  • A low SPI characterizes a tumor with a slower
    proliferative rate, significantly longer
    relapse-free and overall survival
  • Mitotic index

71
HER-2/neu
  • Human epidermal growth factor receptor 2
  • Proto-oncogene that acts as a key component in
    regulating cellular growth
  • Located on chromosome 17
  • High levels associated with poor prognosis and
    shorter survival
  • Predicts response to trastuzumab (Herceptin)
  • Significant reduction in recurrence in HER2/neu
    positive tumors

72
Treatment of Breast Cancer
  • Surgery
  • Mastectomy
  • Lumpectomy
  • Radiation Therapy
  • Chemotherapy
  • Bone Marrow Transplant
  • Hormonal Therapy
  • Adjuvant Therapy

73
Underwriting Evaluation of Breast Cancer
  • Date Diagnosed
  • Risk Factors
  • Tumor Pathology
  • Stage
  • Hormone Receptor Status
  • Ploidy and S-Phase Index
  • Treatment
  • Follow-up

74
Factors Associated with Poor Prognosis
  • "Garden variety" invasive ductal cancer
  • Presence of lymph node metastases
  • 2cm in diameter tumor
  • High grade
  • Lack of estrogen progesterone receptors
  • Aneuploidy
  • High proliferation index
  • HER-2/neu oncogene over expression

75
(No Transcript)
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