BREAST CANCER

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BREAST CANCER

• Basak Oyan-Uluç, MD
• Yeditepe University Hospital
• Department of Medical Oncology

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Epidemiology

• Breast cancer is the most common lethal neoplasm
  in women.
• The incidence varies among different populations.
• 1 out of 8 women will have BC in her life-time.
• The incidence of male breast cancer is about 1
  of all breast cancer cases occur in men.

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2007 Estimated US Breast Cancer incidence and
mortality
INCIDENCE
MORTALITY
Women270,100
Women678,060

• 26 Lung bronchus
• 15 Breast
• 10 Colon rectum
• 6 Pancreas
• 6 Ovary
• 4 Leukemia
• 3 Non-Hodgkin lymphoma
• 3 Uterine corpus
• 2 Brain/ONS
• 2 Liver intrahepatic bile duct
• 23 All other sites

• 26 Breast
• 15 Lung bronchus
• 11 Colon rectum
• 6 Uterine corpus
• 4 Non-Hodgkin lymphoma
• 4 Melanoma of skin
• 4 Thyroid
• 3 Ovary
• 3 Kidney
• 3 Leukemia
• 21 All Other Sites

Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2007.
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Lifetime Probability of Developing Cancer, by
Site, Women, US, 2001-2003
Site
Risk
All sites 1 in 3 Breast 1 in 8 Lung
bronchus 1 in 16 Colon rectum 1 in
19 Uterine corpus 1 in 40 Non-Hodgkin
lymphoma 1 in 55 Ovary 1 in 69 Melanoma
1 in 73 Pancreas 1 in 79 Urinary
bladder 1 in 87 Uterine cervix 1 in 138
All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.
For those free of cancer at beginning of age
interval. Based on cancer cases diagnosed during
2001 to 2003.
Includes invasive and in situ cancer cases
Source DevCan Probability of Developing or
Dying of Cancer Software, Version 6.1.1
Statistical Research and Applications Branch,
NCI, 2006. http//srab.cancer.gov/devcan
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Incidence varies among different
populationsAge-specific incidence (per 100,000)
Adapted from New Horizons in Cancer Management,
SRI International, 1990.
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5-year Relative Survival
1984-1986
1996-2002
Site
1975-1977

• All sites 50 53 66
• Breast (female) 75 79 89
• Colon 51 59 65
• Leukemia 35 42 49
• Lung and bronchus 13 13 16
• Melanoma 82 86 92
• Non-Hodgkin lymphoma 48 53 63
• Ovary 37 40 45
• Pancreas 2 3 5
• Prostate 69 76 100
• Rectum 49 57 66
• Urinary bladder 73 78 82

     

5-year relative survival rates based on follow
up of patients through 2003. Recent changes in
classification of ovarian cancer have affected
1996-2002 survival rates. Source Surveillance,
Epidemiology, and End Results Program, 1975-2003,
Division of Cancer Control and Population
Sciences, National Cancer Institute, 2006.
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Etiology

• Hormones
• Endogenous exposure major risk
• Exogenous exposure e.g. hormone replacement
  therapy
• Genetics
• Majority of BC are diagnosed in women with no
  risk factors
• 10-20 have a family history
• Only 5-10 attributed to a known gene defect
• Other
• Age Radiation
• Breast disease Alcohol
• Parity and lactation Physical activity

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Hormones

• Endogenous exposure
• Early menarche lt12 years
• Late menapouse gt55 years
• Delayed childbirth gt30 years
• Postmnopausal obesity
• Exogenous exposure
• Hormone replacement therapy
• Increased risk if used gt5 years
• Risk increase more with combined
  estrogen-progesterone replacement
• Oral contraceptive
• Not increase risk
• Surgical or medical castration lt37 years
  decrease risk

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Age

• Age risk increases steadily after age 50
• Age Risk
• 25 19.6008
• 55 1/33
• 75 1/11
• 80 1/10
• All 1/8

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Benign breast cancer

• Benign breast disease
• Fibrocystic disease not increase risk
• Hyperplasia with atypia
• Papilloma increased risk
• Sclerosing adenosis
• Lobular carcinoma in situ

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Other risk factors

• Lactation Decrease risk
• Nulliparity
• Diet and lifestyle
• Obesity esp. postmenapousal,
• Excessive alcohol consumption gt1 drink/day
• Physical activity
• Radiation before age 40
• Up to a 30 increased risk
• 20 years after exposure

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How Much Breast and Ovarian Cancer is
Hereditary?
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Causes of Hereditary Susceptibility
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BRCA1-Associated Cancers Lifetime Risk
Possible increased risk of other cancers (e.g.,
prostate, colon)

• BRCA-1
• On chromo. 17
• Tumor supressor gene

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BRCA 2-Associated Cancers Lifetime Risk
Increased risk of prostate, laryngeal, melanoma
and pancreatic cancers (magnitude unknown)

• BRCA-2
• On chromo. 13
• Tumor supressor gene

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Other Gene Defects in Breast Cancer

• P53 gene (tumor supressor gene)
• On chromosome 17
• Associated with Li-Fraumeni syndrome
• Increased risk of breast and rare tmors (sarcoma,
  brain tm, leukemia, tumors of adreanl glands)
• Lifetime risk for breast cancer 50
• PTEN (tumor supressor gene)
• Associated with Cowdens syndrome (multiple
  benign hamartomes and malignant tumors)
• Premenopausal breast cancers, gastrointestinal
  malignancies, and benign and malignant thyroid
  disease

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Indications for genetic testing of BRCA-1 and
BRCA-2

• Multiple cases of early onset breast cancer in
  family history
• Breast and ovarian cancer in the same woman
• Bilateral breast cancer
• Male breast cancer
• Ashkenazi Jewish decent with breast cancer

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Pathology

• Non-invasive carcinoma in situ
• Ductal carcinoma in situ (DCIS)
• Lobular carcinoma in situ (LCIS)
• Invasive carcinoma
• Invasive ductal carcinoma (70-80)
• Invasive lobular carcinoma (10)
• Special types with a good prognosis
• Medullary, mucinous, papillary and tubular
  carcinomas
• Adenocystic carcinoma
• Uncommon tumors
• Inflammatory carcinoma (1)
• Pagets disease

Dollinger M, et al. Everyones Guide to Cancer
Therapy. 1997356-384.
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Normal breast duct
DCIS (Ductal Carcinoma in Situ)
Invasive Cancer
Metastasis to lymph nodes
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Invasive Cancer
Invasive ductal carcinoma Tends to be
unilateral Invasive lobular carcinoma
Increased risk of bilateral breast
cancer Inflammatory carcinoma Poorest
prognosis Breast dermal lymphatics are
infiltrated with tumor
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Inflammatory breast cancer

• Rare, fast-growing type of cancer
• Often causes no distinct lump
• Breast skin may become thick, red, and may look
  pitted -- like an orange peel.
• May also feel warm or tender and have small bumps
  that look like a rash.

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Pagets disease of breast

• Unilateral eczema appearance of the nipple
• Always associated with DCIS in women

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LocationMost are located in upper outer quadrant
Upper inner Nipple Central portion Lower inner
Upper outer Axillary tail Lower outer
RIGHT
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Spread to lymph nodes
Supraclavicular Subclavicular Distal
(upper) axillary Central (middle) axillary Pro
ximal (lower) axillary
Mediastinal Internal mammary Interpectoral (R
otters)
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Sites of distant metastases
Pleura Lung
Brain
Skin Liver Bone
Lymph nodes
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Natural history

• Highly variable in different patients
• Relatively slow growth rate
• Median survival without treatment 2.8 yrs
• Generally present several years by time of
  diagnosis
• Long preclinical period enables early detection

Henderson IC. American Cancer Society Textbook of
Clinical Oncology. 1995198-219.
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Screening and Early Detection
Breast self-examination Clinical breast
Mammographythe examination only
modality shown to decrease mortality
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American Cancer SocietyScreening Recommendations

• Annual mammograms starting at age 40
• 24 reduction in mortality rate
• Clinical breast exams
• every 3 years for women age 20-39
• every year starting at age 40
• Self-breast exams monthly, starting at age 20

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Goals of mammography screening

• Earlier diagnosis in asymptomatic individuals
• Reduction of mortality due to detection at
  earlier stage

PDQ Screening for breast cancer for health
professionals http//Cancernetnci.nih.gov/.
Accessed November 28, 1999.
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Mamography

• Microcalcifications Spicular mass lesion

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Screening in High-risk patients

• Annual mammogram, beginning 5 years before age of
  youngest affected relative at time of diagnosis
• High familial risk
• BRCA 1/2-positive

Tripathy D, Henderson IC. Current Cancer
Therapeutics. 3rd ed. 1999123-129.
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Management of High Risk Patients

• Enhanced Screening
• Starting as early as age 25, shorter screening
  intervals
• Inclusive of screening breast MRI, USG
• Chemoprevention
• Tamoxifen
• Evista (Raloxifene)?
• Surgical risk reduction
• Prophylactic mastectomy
• Reduces risk of breast cancer by gt90
• Prophylactic bilateral salpingo-oophorectomy
• Reduces risk of ovarian cancer by 90
• Reduces risk of breast cancer by 65
• Counseling other family members

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Breast examination
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Breast inspection

• Skin dimpling

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Breast palpation
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Regional node assessment
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Signs and symptoms at presentation

• Mass or painin the axilla
• Palpable mass
• Thickening
• Pain
• Nipple discharge
• Nipple retraction
• Edema or erythemaof the skin

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Presentation

• The majority of carcinoma in situ, T1, or T2
• Painless or slightly tender breast mass or have
  an
• abnormal screening mammogram.
• Patients with more advanced tumors
• breast tenderness, skin changes, bloody nipple
  discharge, or occasionally change in the shape
  and size of the breast.
• Rarely patients may present with axillary
  lymphadenopathy (occasionally painful)
• Distant metastasis.

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Evaluation of a Breast Mass

• Breast mass in women under 30
• USG is preferred
• If mass is solid or suspicious, then mammography
  followed by biopsy
• Cystic mass Simple cyst? observe
• Complex cyst Aspirate
• Breast mass in women over 30
• Diagnostic mammography
• If indeterminate features in mammography, then
  USG
• Biopsy as needed

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Diagnosis

• Radiological tests
• Mammography
• Detects 85 of breast cancers
• USG
• MRI
• In dense breasts
• A mass with normal USG and mammography
• Biopsy
• Fine-needle aspiration biopsy
• Core biopsy
• Excisional biopsy

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Mammography
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Mammography
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Ultrasonography
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Staging procedures

• Complete blood count, liver function tests
• Chest radiograph
• Diagnostic bilateral mammography
• Bone scan
• Radiological evaluation of liver
• Bone marrow aspiration if unexplained cytopenia
  or a leukoerytroblastic blood smear

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Liver metastasis
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MRI scan
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Staging

• Stage 0 -- carcinoma in situ
• Stage I tumor lt 2 cm, no nodes
• Stage II tumor 2 to 5 cm, /- nodes
• Stage III locally advanced disease, fixed or
  matted lymph nodes and variable tumor size
• Stage IV distant metastases (bone, liver, lung,
  brain)

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Prognostic Factors

• Tumor subtype
• Estrogen/progesterone receptors
• (Positive in 2/3 of tumors)
• HER2/neu overexpression
• Number of positive axillary nodes
• Tumor size
• Tumor grade
• Lymphatic and vascular invasion
• Age

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Breast cancer classification

• DNA microarray-based gene expression profiling
• 85 samples
• 78 carcinoma
• 3 benign tumor
• 4 normal breast tissue

Sorlie et al, Proc Natl Acad Sci 1008418, 2003
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Breast cancer Intrinsic subtypes
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Diffreneces between subtypes

• Risk of recurrence
• Sites of metastases
• Response to treatment
• Incidence varies between different populations

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Biyolojik siniflamaImmünhistokimya (IHC)

• Hormone receptor positive
• Luminal A ER /or PR HER2 (), Ki67 low
• Luminal B ER /or PR Ki67 high or HER2
• HER2 ER/PR HER2
• Bazal (triple negatif) ER/PR HER2 (-)
  CK5/6

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HER-2/neu overexpression

• Overexpressed in 25-30 of breast cancer patients
• Significant decrease in 5-year survival for
  patients who overexpress HER-2/neu
• Trastuzumab
• Anti-Her2 Antibody
• Targets Her2

Slamon DJ. Chemotherapy Foundation Symposium.
199946. Abstract 39. Goldenberg MM. Clinical
Therapeutics. 199921(2)309-318.
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Treatment

• Surgery
• Chemotherapy
• Radiation Therapy
• Hormonal Therapy
• Targetted therapy
• Monoclonal antibodies (e.g. Trastuzumab)

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Surgical management

• Breast conservation therapy
• Modified radical mastectomy
• Breast reconstruction

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Treatment

• Stage I-III
• Aim Cure
• Surgery is the mainstay treatment
• Adjuvant therapy as indicated
• Stage IV
• Aim Palliation, prolongation of survival
• Chemotherapy, hormonal therapy, monoclonal
  antibodies

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Principle of Adjuvant Treatment
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Adjuvant Therapy

• Radiation Therapy (local)
• Chemotherapy (systemic)
• Hormonal agents (systemic)
• Each therapy adds to reduction of recurrent
  disease.
• Therapy is individualized

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ErbB Receptor Tyrosine Kinases

• Four receptors
• ErbB-1 (EGFR, HER-1)
• ErbB-2 (HER-2/neu)
• ErbB-3 (HER-3)
• ErbB-4 (HER-4)

ErbB-1 ErbB-2 ErbB-3
ErbB-4
1. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217.
2. Marmor M, et al. Int J Radiat Oncol Biol Phys.
200458903-913.
3. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
4. Vlahovic G, Crawford J. Oncologist.
20038531-538.
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Common Mechanisms of ErbB Activation in Tumors
Receptor Overexpression

• Gene amplification results in overexpression of
  normal receptors
• Receptors spontaneously homodimerize
• Drives tumour growth

1. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217.
2. Holbro T, et al. Exp Cell Res.
2003a28499-110.
3. Marmor M, et al. Int J Radiat Oncol Biol Phys.
200458903-913.
4. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol.
20012127-137.
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Monoclonal Antibodies

• Trastuzumab is humanized monoclonal antibody
  against EC domain of the HER-2 protein
• Mechanism of action
• Inhibit TK activation
• Induce receptor endocytosis and degradation
• Induce immune-mediated cytotoxicity

1. Arteaga C. Breast Cancer Res. 2003b596-100.
2. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217. 3. Rowinsky E. Horizons
in Cancer Therapies From Bench to Bedside.
200123-35. 4. Zwick E, et al. Endocr Relat
Cancer. 20018161-173.
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Endocrine Therapy for Breast Cancer

• Ovarian ablationsurgery, radiation, LHRH
  agonists
• Selective estrogen receptor modulators (SERMs)
  tamoxifen, toremifene, fulvestrant
• Aromatase inhibitorsanastrozole, letrozole,
  exemestane
• Additiveprogestins, estrogens, androgens

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Inhibition ofEstrogen-Dependent Growth
Estrogen biosynthesis
Nucleus
Cancer cell