BREAST CANCER

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BREAST CANCER

• DR. GÖKHAN SÖGÜTLÜ

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• Breast cancer is either noninvasive(in situ) or
  invasive(spreading)
• Ductal carcinoma in situ
• Lobular carcinoma in situ
• LC in situ is a marker for an incresed risk of
  invasive cancer in both breasts ( same breast 18
  and other breast 14 after 20 years)

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• Invasive cancer occurs when cancer cells spread
  beyond the basement mebrane.
• Infiltrating ductal ca
• Infiltrating lobular ca
• They comprises between 70 and 80 10 and 15
  of all breast cancers respectively.
• The typical carcinoma of the breast (80 to 85
  percent) is a scirrhous adenocarcinom with
  prodictive fibrosis that orginates in the
  ductules and invades the parenchyma

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RISK FACTORS

• Age
• More than 80 of breast cancer cases occur in
  women over 50 .
• Cancer in women younger than 30 is very rare,
  accounting for only 1.5 of all breast cancer
  cases.
• A womans chances for breast cancer are 1/8 in
  their whole life.

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• Ethnicity
• North America and Northen Europe people high
  risk (industrial countries), Asian and African
  people low risk (non-industrial countries)
• Genetic factors and family history
• 20-30 of all women with breast cancer have a
  family history (familial)
• 5-10 of all women with breast cancer have
  hereditary
• This often appears in young women under age 50
• In such families, some members may also have
  developed ovarian cancer as well.
  

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HEREDITARY

• Genes are as follows
• -BRCA1 or BRCA2 are now believed to be
  responsible for 30 to 50 of hereditary breast
  cancer, ovarian cancer or both in families with a
  history of these cancers.
• - About 90 of BRCA1 carriers will develop
  breast cancer in whole lifetime.
• -These mutations can be passed down to the
  doughter by either mother or the father.
• -These are present in only about 0.1 of the
  population.

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• Other defective genes that contribute to breast
  cancer including BRCA3, p53,CDKN2A
• A mutation in a gene located on chromosome 10
  called PTEN gene results in a disorder called
  Cowden syndrome, which is associated with a
  higher risk of breast cancer.

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RISK FACTORS(con.)

• Over-exposure to estrogen
• Because growth of breast tissue is highly
  sensitive to estrogens, the more a women is
  exposed to estrogen over her lifetime,the higher
  the risk for breast cancer.

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• For women in whom menopause occurs after the age
  of 45 the risk of developing the disease is twice
  as high as for those whose menopause started
  before age 45.
• Artificially surgical menopause appears to be
  protective for breast cancer. Protection is
  lifelong and removal of endogenous estrogen
  dramatially reduces breast cancer risk.

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• The earlier the surgical menopause (oophorectomy
  at age thirty five or younger), the lower the
  risk.
• Early menarche also increases the risk

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• Pregnanncy and abortion
• Infertility and nulliparity are associated with a
  higher probability.
• With decreasing age at the time of first
  pregnancy,the risk decreases proportionately.
• Women impregnated before 18 who have a full-term
  pregnancy have a breast cancer risk 1/3 that for
  women pregnant after 35.

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• Women,first full-term pregnancy after the age 30,
  have an even greater risk for breast cancer than
  do nullipars.
• Women who have had abortions have risk but this
  is very small.

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• Oral contraception
• New low-dose OCs do not appear to pose this
  risk (more research is needed)
• HRT (hormone replacement theraphy)
• Estrogen use by premenopausal and postmenopausal
  women for HRT may slightly increase the risk of
  breast cancer.

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• The risk is said to be accentuated in women with
  preexisting benign disease of the breast.
• Prolonged use increases the risk
• Interestingly, some studies suggest that in women
  with a history of breast cancer, HRT does not
  increase risk for recurrence

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Risk factors (con.)

• Physical characteristics
• Breast cancer risk is directly correlated with
  relative weight the risk for obese women is 1.5
  to 2 times higher than for nonobese women.
• This relative risk is restricted to
  postmenopausal individuals.

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• There have been conflicting reports of a link
  between increased height and breast cancer risk.
• One study found no association.
• Other studies, however, found that taller adult
  height predicted a greater risk, possibly due to
  the higher estrogen levels associated with
  greater bone growth.

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• Multipl primary neoplasms
• Women with a history of primary breast cancer
  have a risk 3 to 4 times higher for primary
  cancer in the contrlateral breast.
• History of previous ovarian and endometrial
  carcinoma.

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• Environmental factors
• Exposure to estrogen like industrial chemicals
  (xenoestrogens). They are found in pesticides and
  other common industrial products.
• Radiation exposure
• Children receiving high dose radiation
  theraphy face an increased risk for breast cancer
  in adulthood.

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• Mental health
• A 2000 study suggested that women who had a
  history of major depression were four times as
  likely to develop breast cancer.
• Stress was not found as a risk factor.

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• Insulin-like growth factor
• Insulin-like growth factor 1 is an important
  growth hormone during development in the womb and
  childhood. High concentrations have now been
  linked to cancers, including premenapousal breast
  cancer.

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• Alcohol
• Risk is increased 1.5 fold when drunk regularly.
  

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• Benign breast disease
• Hyperplasia without AH 1.5-2 fold
• AH 4-5 fold

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How can the risk of breast cancer be lowered?

• Regular exercise (by modulating estrogen)
• Dietary factors
• Fats
• Although some studies have found an
  association between high-fat intake and breast
  cancer, the most recent data suggest that fat
  from any source plays at most insignificant role
  in incresing the risk for breast cancer.

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• Vitamins and chemicals in fruits and vegetables
• Many fresh fruits and vegetables contain
  chemicals that may be cancer fighter.
• Cabbage, broccoli, cauliflower, turnip, kale
• Apples, onion, green tea (contains polyphenols)
• Tomatos(lycopen)
• Avocado, bananas, fruits, orange juice (folic
  acid)

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• Iron
• High iron stores have been associated with a
  higher risk for breast cancer
• Protein
• Fish may offer some protection

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• Breast feeding
• Evidence on protection from breast feeding is
  weakly positive.

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symptoms

• Hard lump
• 50 of such masses are found in the upper outer
  quarter of the breast.
• The nipple may be retracted or scaly
• Sometimes, the skin of the breast is dimpled like
  the skin of an orange. Skin ulceration may occur.
  
• In some cases there is a bloody or clear
  discharge from the nipple
• Axillary mass

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Diagnosis

• Early detection of breast cancer significantly
  reduces the risk of death
• 20-49 ages physical examination by a
  health professional every 1 to 2 years.
• 50 and over should be examined annualy
• Women should perform self examination every
  month.

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Mammogram

• Mammograms are very effective low-radiation
  screening
• They are not foolproof, however
• In general, they still miss up to 25 of cancers
  (which can sometimes be caught on a physical
  examination)
• Screening mammogram every 12 to 33 months
  significantly reduced mortality, at least in
  women over 55 (a 33 reduction in mortality for
  woman after screening mammogaphy).

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• There are, however, a number of issues as to who
  should screen and when to screen.
• For women between ages 50 and 69. Evidence
  suggest that annual mammograms save lives in this
  age group (per 2 years in our country).
• 40-50 should be tested every 1 to 2 years until
  age 50.

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• Overall, diagnostic mammography has a 90
  sensitivity, 10 false positive rate and 7 false
  negative rate.

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• Ultrasonography
• New ultrasound techniques can detect tumors
  smaller than 1 centimeter.
• However, ultrasound is a time-consuming
  procedure, and remains less efficient than
  mammogram

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Other imaging techniques

• Scintomammography
• Dopler ultrasonography
• Breast MR

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Biopsy

• A definitive diagnosis of breast cancer can be
  made only by a biopsy.
• When a lump can be felt and is suspicious for
  cancer on mammography
• FNAB
• Excisional biopsy
• Incisional biopsy
• Core biopsy
• Radioguided biopsy (for occult lumps)

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• A wire localization biopsy may be performed if
  mammography detects abnormalities but there is no
  lump (microcalcifications)
• A new vacuum-assisted device may be useful for
  some biopsies.

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Prognostic factors

• A number of factors are used to determine
  outlook
• Size and lymh nodes status
• Nuclear grade
• Age
• The location of the tumor and far it has spread
  (tumors that develop toward the outside of the
  breast tend to be less serious than those that
  occur more toward the middle of the breast).

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• Whether the tumor is hormone receptor-positive or
  negative
• Breast cancer cells may contain receptors, or
  binding sites, for hormones like estrogen or
  progesterone.
• Hormone receptor positive cells grow more slowly
  than recptor negative cells.
• Women have a better prognosis if their tumors are
  receptor-positive.

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• The influence of BRCA genes
• The relevance of the BRCA1 or BRCA2 mutations to
  survival is controversial
• Women with these genetic mutations do have a
  greater risk for a new cancer to develop.
• Poor differentiation (for BRCA-1)
• Well differentiation (for BRCA-2)
• High bilateralism
• Early onset of age

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• Tumor markers
• HER-2 is part of the epidermal growth factor
  receptor family and is becoming an important
  marker in breast cancer.
• The precence of HER-2 may suggest agresive
  cancer.
• Angiogenesis factors (such as vascular
  endothelial growth factor)
• P53 gene. P53 is a tumor suppessant gene.
• CA 15-3, c-erb-B-2, cathepsin-D, telomerase,
  b-FGF, Ki-67 are others.

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• Rate of cell division. Mitotic index (MI) is a
  measurement of the rate at which cells divide
  the higher the MI, the more agresive the cancer.

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Staging

• Histopatologic types are as follows
• Carcinoma
• Ductal
• Intraductal (in situ)
• Invasive
• Scirrhous (adenoca. with productive fibrosis)
• Medullary
• Mucinous (colloid)
• Tubuler
• Papillary
• Inflammatory

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• Lobular
• In situ
• Invasive
• Nipple
• Pagets disease
• Sarcoma
• Relaviley rare carcinomas

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Infiltrating ductal carcinoma with prodictive
fibrosis (scirrhous)

• The 80 percent frequency of adenocarcinoma of the
  breast (ductal carcinoma)
• The tumor characteristically possesses a poorly
  defined border, firm, immobile.
• Its cut surfaces show a central stellate
  configuration with white or yellow streaks
  extending into surrounding breast tissues.

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Medullary carcinoma

• 4
• Orginates in large ductus
• Grossly, the tumor is characterised by its soft,
  hemorrhagic bulky presentation
• Commonly, the lesion is positioned deep within
  the breast and mobile.
• Diagnosis of this lesion connotes a better 5-year
  survival than pure invasive ductal or lobular
  carcinoma

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Mucinous (colloid) carc.

• This adenocarcinoma of ductal origin constitutes
  approximately 2 of all breast cancers and
  typically presents as a bulky, mucinous (colloid)
  tumor that is largely confined to the elderly
  population.
• 5- year survival better than ductal and lobular
  carcinomas (5-year survival rates is reported as
  about 73)

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Tubuler carcinoma

• This lesion is a well-differantiated variant of
  breast carcinoma with an incidence of
  approximately 2 percent.
• Most commonly, is diagnosed in the perimenapousal
  or early menopausal population.
• Long term survival is perfect

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Papillary carcinoma

• Papillary cacinoma accounts for less than 2
  percent of all breast carcinomas and generally
  presents in the 7. decade.
• Typically, papillary cancer is small and rarely
  attains sizes greater than 2 to 3 cm in diameter.
• Papillary carcinoma is more indolent, slowly
  progressive disease than the common
  adenocarcinoma
• Best 5 and 10 year survival rates

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Lobular carcinoma

• These carcinomas originate in terminal ductules
  of the lobule and posses characteristic features
  that distinguish them from lesions of the larger,
  lactiferous ducts.
• The noninvasive form is lobular carcinoma in situ
  (LCIS).
• Constitutes approximately 10 percent of breast
  cancers
• At presentation, ILC varies from clinically
  unapparent cancers to those that replace entire
  breast with a poorly defined mass
• These lesions have a high propensity for
  bilaterality, multicentrity and multifocality.

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Pagets disease of the nipple

• Approximately 2
• It is almost always associated with an
  underlaying extensive intraductal (DCIS) or
  invasive carcinoma
• It presents as an encrusted, scaly, hyperemic,
  and enlarged tumor that occupies the surface of
  the nipple-areola complex

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• Symptoms include tenderness, itching, burning,
  and intermittent hemorrhage.
• Intraductal adenocarcinomas often involve the
  epidermis of the nipple and areola by
  intraepithelial dissemination.
• Physical findings in the nipple-areola complex
  precede the identification of a palpabl mass in
  the subareolar area.
• In general, better prognosis than the majority of
  lesions, because the nipp-areol cahanges promote
  early consulatation

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• Differantiation from pagetoid intraepithelial
  melanoma is based on S-100 antigen immunostaining
  in melanoma and CEA immunostaining in Pagets
  disease.
• Surgical theraphy may involve lumpectomy or MRM.
  

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Sarcomas

• Rarely tumours
• These tumors include fibromatosis, fibrosarcoma,
  liposarcoma, leimyosarcoma, angiosarcoma

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Inflammatory carcinoma

• 1.5 to 3
• Clincal features of erythema, peau dorange, and
  skin ridging (at least 50 of whole brast) with
  or without the presence of a palpabl mass are
  evident.
• Typically the skin over the lesion is warm,
  diffusely scaly, and indurated with ridging
• It may present with the charecteristics of a
  cellulits.
• The tumor mass may be diffuse or nondefinable
• Diagnosis is established by biosy of skin,
  subcutaneous tissue, and parenchyma
• This disease progresses rapidly and prognosis is
  poor.

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TNM

• Tx No evidence of primary tumor
• Tis Carcinoma in situ
• T1 Tumor 2cm or lt
• T2 2 to 5 cm
• T3 Tgt 5cm
• T4a extension to chest wall
• T4b edema (including peau dorange), ulceration
  of skin, satellite nodules
• T4c T4a T4b
• T4d Inflammatory carcinoma

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• Peau dorange
• With progressive diffuse skin infiltration in the
  subdermal lymphatic plexus. There is extensive
  edema of the skin, reffered to as peau dorange
• Skin retraction
• Characteristic involvement of Coopers ligaments

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Regional lymh nodes

• N0 no regional lymh node met.
• N1 Movable ipsilateral axillary l.nod.
• N2 Fixed ipsilateral axillary lymph n. or
  Internal mammary lymh nodes
• N3 -Ipsilateral supraclavicular l.n.
• -Fixed ipsilateral axillary lymph n. and
  Internal mammary lymh nodes
• -Ipsilateral infraclavicular l.n.

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Pathologic classification (pN)

• pNX Regional lymph nodes cannot be assessed
  (e.g., not removed for pathologic study or
  previously removed)
• pN0 No regional lymph node metastasis
  histologically, and no additional examination for
  isolated tumor cells (ITC)
•  Note ITCs are defined as single tumor cells
  or small cell clusters not larger than 0.2 mm,
  usually detected only by immunohistochemical
  (IHC) or molecular methods but that may be
  verified on hematoloxylin eosin (HE) stains.
  ITCs do not usually show evidence of malignant
  activity, e.g., proliferation or stromal
  reaction.
• pN0(I-) No regional lymph node metastasis
  histologically, negative IHC
• pN0(I) No regional lymph node metastasis
  histologically, positive IHC, and no IHC cluster
  larger than 0.2 mm
• pN0(mol-) No regional lymph node metastasis
  histologically, and negative molecular findings
  (RT-PCR)
• pN0(mol) No regionally lymph node metastasis
  histologically, and positive molecular findings
  (RT-PCR)
•  Note RT-PCR reverse transcriptase-polymerase
  chain reaction.

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• pN1 Metastasis in 1-3 axillary lymph nodes,
  and/or in internal mammary nodes with microscopic
  disease detected by SLN dissection but not
  clinically apparent
• pN1mi Micrometastasis (larger than 0.2 mm but
  not larger than 2.0 mm)
• pN1a Metastasis in one to three axillary lymph
  nodes
• pN1b Metastasis in internal mammary nodes with
  microscopic disease detected by SLN dissection
  but not clinically apparent
• pN1c Metastasis in one to three axillary lymph
  nodes and in internal mammary lymph nodes with
  microscopic disease detected by SLN dissection
  but not clinically apparent. (If associated
  with more than three positive axillary lymph
  nodes, the internal mammary nodes are classified
  as pN3b to reflect increased tumor burden.)

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• pN2 Metastasis in 4-9 axillary lymph nodes, or
  in clinically apparent internal mammary lymph
  nodes in the absence of axillary lymph node
  metastasis to ipsilateral axillary lymph node(s)
  fixed to each other or to other structures
• pN2a Metastasis in four to nine axillary lymph
  nodes (at least one tumor deposit larger than 2.0
  mm)
• pN2b Metastasis in clinically apparent internal
  mammary lymph nodes in the absence of axillary
  lymph node metastasis

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• pN3 Metastasis in 10 or more axillary lymph
  nodes, or in infraclavicular lymph nodes, or in
  clinically apparent ipsilateral internal mammary
  lymph node(s) in the presence of 1 or more
  positive axillary lymph node(s) or, in more than
  three axillary lymph nodes with clinically
  negative microscopic metastasis in internal
  mammary lymph nodes or, in ipsilateral
  supraclavicular lymph nodes
• pN3a Metastasis in 10 or more axillary lymph
  nodes (at least 1 tumor deposit larger than 2.0
  mm) or, metastasis to the infraclavicular lymph
  nodes
• pN3b Metastasis in clinically apparent
  ipsilateral internal mammary lymph nodes in the
  presence of one or more positive axillary lymph
  node(s) or, in more than three axillary lymph
  nodes and in internal mammary lymph nodes with
  microscopic disease detected by sentinel lymph
  node dissection but not clinically apparent
• pN3c Metastasis in ipsilateral supraclavicular
  lymph nodes

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Distant metastasis

• M0
• M1

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Treatment

• Surgery, radiation or drug theraphy.
• Breast cancer treatment are defined as local or
  systemic
• Local Surgery and radiation.
• Surgery is usually the standart initial treatment
• Systemic Drug treatment

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Stage 0

• Also called noninvasive carcinoma or carcinoma in
  situ.
• Lobular carcinoma in situ
• Careful monitoring with or without preventive use
  of tamoxifen
• In selected cases, consideration of removal of
  both breasts

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• Ductal carcinoma in situ
• Mastectomy (previously was the commonly
  recommended treatment)
• Breast-sparing surgery followed by radiotheraphy
  is reasonable treatment for many women
• Use of tamoxifen or other SERMs after surgery and
  radiation to prevent recurrence in selected
  patients

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Stage I and II

• Breast sparing surgery (lumpectomy,
  quadranectomy) followed by external beam
  radiation theraphy
• Modified radical mastectomy
• Adjuvant theraphy
• Combination chemotheraphy
• Hormonal theraphy

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StageIII

• Mastectomy usually with radiotheraphy and
  systemic treatment (combination chemotheraphy,
  hormonal theraphy or both)
• Neoadjuvat chemotheraphy followed by surgery
  adjuvant chemotheraphy is recommended.

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• Five-year survival rates for individuals with
  breast cancer who receive appropriate treatment
  are approximately
• 100 for stage 0
• 100 for stage I
• 92 for stage IIA
• 81 for stage IIB
• 67 for stage IIIA
• 54 for stage IIIB
• 20 for stage IV