underwriting breast cancer steven e zimmerman m d vice president chief medical director l.
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Underwriting Breast Cancer Steven E. Zimmerman M.D. Vice President & Chief Medical Director 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

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breast cancer statistics 2008
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
annual incidence of female breast cancer 1975 2004
Annual Incidence of Female Breast Cancer (1975-2004)

Ravdin P et al. N Engl J Med 2007;356:1670-1674

risk factors for breast cancer
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
risk factors for breast cancer6
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 Hodgkin’s Lymphoma with mantle radiation
breast cancer incidence hormone receptor status and hormone replacement therapy
Breast Cancer Incidence, Hormone Receptor Status and Hormone Replacement Therapy

Ravdin P et al. N Engl J Med 2007;356:1670-1674

how much breast cancer is hereditary




Family clusters


How Much Breast Cancer Is Hereditary?
cancer arises from dna mutations in cells
Cancer Arises From DNA Mutations in Cells

Normal cell

DNA mutations

Uncontrolled proliferation

Last DNA mutation from:

• heredityor

• radiation or chemicalsor

• spontaneous errorsduring DNA duplication

brca mutations
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
causes of hereditary susceptibility
Causes of Hereditary Susceptibility

Contribution to Hereditary Breast Cancer

20% - 40%

10% - 30%



30% - 70%






Undiscovered genes

genes associated with a hereditary predisposition to breast cancer
Genes Associated with a Hereditary Predisposition to Breast Cancer

Robson M and Offit K. N Engl J Med 2007;357:154-162

detecting diagnosing breast cancer
Detecting & Diagnosing Breast Cancer
  • Breast self examination (BSE)
  • Physical examination
  • Mammography
  • Ultrasonography
  • Magnetic resonance mammography (MRM)
u s preventive services task force
U.S Preventive Services Task Force

Nelson, H. D. et. al. Ann Intern Med 2005;143:362-379

  • 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
breast ultrasonography
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
breast mri
Breast MRI
  • More sensitive than mammography
  • Advantages
    • Dense breasts
    • Implants
    • Young women
    • Hereditary risks
    • Prior lumpectomy
  • Disadvantages
    • Less specific – more false positives
    • More expensive
breast mri25
Breast MRI

Fibroadenoma – before contrast

Invasive Lobular Ca – before contrast

breast mri26
Breast MRI

Fibroadenoma – 5 minutes after contrast

Invasive Lobular Ca – 5 minutes after contrast

breast mri27
Breast MRI

Fibroadenoma – subtracted image

Invasive Lobular Ca – subtracted image

impact of screening
Impact of Screening

Age-standardized incidence of and mortality from female breast cancer, England and Wales, Rate per 100,000

benign breast disease
Benign Breast Disease
  • Fibroadenoma
  • Fibrocystic disease
  • Atypical hyperplasia
  • Other
benign breast disease fibroadenoma
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
benign breast disease fibrocystic disease
Benign Breast Disease – Fibrocystic disease
  • Gross cyst
    • Usually in 40’s
    • Needle aspiration or ultrasound for diagnosis
    • Non-bloody fluid obtained, then lump disappears
benign breast disease fibrocystic disease34
Benign Breast Disease – Fibrocystic disease
  • Fibroadenosis & Micro cysts
    • Found in 30’s & 40’s
    • Disappears after menopause
    • Usually diffuse and ill-defined
    • Usually cyclic with menses
      • Painful and prominent before; resolves after
benign breast disease atypical hyperplasia
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 doesn’t have all the characteristics
  • Some may be under-diagnosed DCIS
benign breast disease other
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
benign breast disease other37
Benign Breast Disease – Other
  • Papillomas
    • Small (< 1cm) intraductal growths
    • 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
presenting symptoms of breast cancer
Presenting Symptoms of Breast Cancer
  • Painless breast mass 66%
  • Painful breast mass 11%
  • Nipple discharge 9%
breast cancer
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
breast cancer non infiltrating in situ
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
lobular carcinoma in situ

A – Normal cells

B – Lobular cancer cells

C – Basement membrane

Lobular Carcinoma in situ
ductal carcinoma in situ

A – Normal cells

B – Ductal cancer cells

C – Basement membrane

Ductal Carcinoma in situ
dcis subtypes





DCIS - Subtypes
breast cancer infiltrating
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
breast cancer infiltrating47
Breast Cancer - Infiltrating
  • Paget’s 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
infiltrating ductal carcinoma

A – Normal cells

B – Invading ductal cancer cells

C – Basement membrane

Infiltrating Ductal Carcinoma
infiltrating lobular carcinoma

A – Normal cells

B – Invading lobular cancer cells

C – Basement membrane

Infiltrating Lobular Carcinoma
vascular and lymphatic invasion
Vascular and Lymphatic Invasion

Lymphatic channel

Blood vessels

grading of tumors nottingham
Grading of Tumors – Nottingham
  • Tubule Formation
    • Majority of Tumor (>75%) 1
    • Moderate Degree (10-75%) 2
    • Little or None (<10%) 3
  • Mitotic Count
    • 0-9 Mitosis/10 hpf 1
    • 10-19 Mitosis/10 hpf 2
    • 20 or > Mitosis/10 hpf 3
grading of tumors nottingham54
Grading of Tumors – Nottingham
  • Nuclear Pleomorphism
    • Small Regular Uniform Cells 1
    • Moderate Nuclear Size and 2Variation
    • Marked Nuclear Variation 3
grading of tumors nottingham55
Grading of Tumors – Nottingham
  • Combined Histologic Grade
    • Low Grade (I) 3-5
    • Intermediate Grade (II) 6-7
    • High Grade (III) 8-9
pathology infiltrating tumor56
Pathology – Infiltrating Tumor



  • 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
breast cancer staging tnm
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
breast cancer staging tnm cont
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
breast cancer staging
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
breast cancer staging cont
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
additional prognostic factors
Additional Prognostic Factors
  • Estrogen/progesterone receptors
  • Proliferative markers
    • Ploidy analysis
    • S-phase fraction
    • Mitotic index
  • Genetic markers
    • HER2/neu
estrogen progesterone receptor status
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
proliferative markers
Proliferative Markers
  • DNA Histogram (flow cytometry)
proliferative markers69
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
proliferative markers70
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
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
treatment of breast cancer
Treatment of Breast Cancer
  • Surgery
    • Mastectomy
    • Lumpectomy
  • Radiation Therapy
  • Chemotherapy
    • Bone Marrow Transplant
  • Hormonal Therapy
  • Adjuvant Therapy
underwriting evaluation of breast cancer
Underwriting Evaluation of Breast Cancer
  • Date Diagnosed
  • Risk Factors
  • Tumor Pathology
  • Stage
  • Hormone Receptor Status
  • Ploidy and S-Phase Index
  • Treatment
  • Follow-up
factors associated with poor prognosis
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