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Breast cancerBreast cancer
Cancer from breastCancer from breast
From duct and lobuleFrom duct and lobule– Invasive ductal carcinoma(IDC)Invasive ductal carcinoma(IDC)– Invasive lobular carcinomaInvasive lobular carcinoma
OthersOthers– From stroma: sarcoma(Phyllodes)From stroma: sarcoma(Phyllodes)– Squamous cell carcinomaSquamous cell carcinoma– LymphomaLymphoma
Normal BreastNormal Breast
A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs
A. Cells lining duct A. Cells lining duct B. Basement membrane B. Basement membrane C. Open central duct C. Open central duct
Invasive ductal carcinoma(IDC)Invasive ductal carcinoma(IDC) A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs
A. Cells lining duct A. Cells lining duct B. Cancer cells, breaking B. Cancer cells, breaking
through the basement through the basement membrane membrane
C. Basement membrane C. Basement membrane
Ductal carcinoma in situ(DCIS)Ductal carcinoma in situ(DCIS) A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs
A. Cells lining duct A. Cells lining duct B. Extra cancer like cells, but B. Extra cancer like cells, but
aaacontained within duct aaacontained within duct C. Intact basement membranC. Intact basement membran
e e D. Open central duct D. Open central duct
Invasive lobular carcinoma(ILC)Invasive lobular carcinoma(ILC) A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs
A. Cells lining lobule A. Cells lining lobule B. Cancer cells, breaking B. Cancer cells, breaking
through the basement through the basement membrane. membrane.
C. Basement membrane C. Basement membrane
Lobular carcinoma in situ(LCIS)Lobular carcinoma in situ(LCIS)
A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs
A. Cells lining lobule A. Cells lining lobule B. Cancer cells, but all B. Cancer cells, but all
contained within the contained within the lobules lobules
C. Basement membrane C. Basement membrane
DCIS and LCISDCIS and LCIS
DCISDCIS– Premalignant changePremalignant change– Turn out to be cancer in ongoing yearsTurn out to be cancer in ongoing years
LCISLCIS– Not a premalignent changeNot a premalignent change– A sign, which indicate risk of breast caA sign, which indicate risk of breast ca
SymptomsSymptoms
In early breast caIn early breast ca– Easily self palpatedEasily self palpated– Nipple dischargeNipple discharge– May accompanied with axillary LNMay accompanied with axillary LN
Late breast caLate breast ca– Local usually symptomaticLocal usually symptomatic– Depends on metastatic sitesDepends on metastatic sites
Diagnosis toolDiagnosis tool
Breast sonographyBreast sonography– Superior in dense breast, young ageSuperior in dense breast, young age
MammographyMammography– Superior in loose(fatty) breast, elderSuperior in loose(fatty) breast, elder
CytologyCytology– Fine-needle aspiration (FNA)Fine-needle aspiration (FNA)
BiopsyBiopsy– IncisionIncision– ExcisionExcision
How to describe a breast caHow to describe a breast ca
TNM stageTNM stage
Tumor morphologyTumor morphology– Grade Grade – VLIVLI– PNIPNI
Special receptorSpecial receptor– Hormone receptor: ER and PRHormone receptor: ER and PR– Her2/NeuHer2/Neu
TNMTNM
T1: tumor<2cmT1: tumor<2cm– T1mic: <0.1cmT1mic: <0.1cm– T1a:0.1-0.5cm, T1b:0.5-1cmT1a:0.1-0.5cm, T1b:0.5-1cm– T1c:1-2cmT1c:1-2cm
T2: 2-5cmT2: 2-5cm T3: >5cmT3: >5cm T4: chest wall, skin invasion, or T4: chest wall, skin invasion, or
inflammatory breast cancerinflammatory breast cancer
Inflammatory breast cancerInflammatory breast cancer
TNMTNM
NN– N0: no axilla LAPsN0: no axilla LAPs– N1:1-3N1:1-3– N2:4-9N2:4-9– N3>10N3>10
M: M0 or M1M: M0 or M1
II T1N0T1N0
IIAIIAT1N1T1N1
T2N0T2N0
IIBIIBT2N1T2N1
T3N0T3N0
IIIAIIIA
T1N2T1N2
T2N2T2N2
T3N1T3N1
T3N2T3N2
IIIBIIIBT4N0T4N0
T4N1T4N1
T4N2T4N2
IIICIIIC N3N3
Tumor morphologyTumor morphology
GradeGrade– Tubule FormationTubule Formation– Nuclear PleomorphismNuclear Pleomorphism– Mitotic CountMitotic Count
Vascular lymphatic invasion(VLI)Vascular lymphatic invasion(VLI) Perineural invasion(PNI)Perineural invasion(PNI)
– Both indicate aggressive behaviorBoth indicate aggressive behavior
VLIVLI A. Veins in breast A. Veins in breast B. Lymph channels in breast B. Lymph channels in breast
A. Cells lining duct A. Cells lining duct B. Cancer cells, breaking B. Cancer cells, breaking
through the basement through the basement membrane. membrane.
C. Broken basement C. Broken basement membrane membrane
D. Cancer entering a lymph D. Cancer entering a lymph channel. channel.
E. Cancer entering a vein. E. Cancer entering a vein. F. Normal breast tissue.F. Normal breast tissue.
Receptor statusReceptor status
Hormone receptorHormone receptor– Estrogen receptor (%)Estrogen receptor (%)– Progesterone receptor (%)Progesterone receptor (%)>10% predict response to hormone tx>10% predict response to hormone tx
Her2/neuHer2/neu– Associate with invasion, metastasis…Associate with invasion, metastasis…– Predict poor prognosisPredict poor prognosis– IHC stain, FISHIHC stain, FISH
The EGFR (erbB) family
Membrane
Extracellular
Intracellular
Receptor domain
K
EGFTGF-
Amphiregulin
Tyrosine kinasedomain
erbB4HER4
erbB3HER3
erbB1HER1EGFR
erbB2HER2neu
Ligands
K
No specific ligands Heregulins
K
NRG2NRG3
Heregulins
Current assay of HER2/neu Immunohistochemistry
‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)
Fluorescence in situ hybridization (FISH)
HER2 gene no amplification FISH negative
HER2 gene amplification FISH positive
TreatmentTreatment
Localized breast cancerLocalized breast cancer– Surgery is mainstaySurgery is mainstay– Halsted, 1882, radical mastectomyHalsted, 1882, radical mastectomy
John HopkinsJohn Hopkins
Metastatic breast cancerMetastatic breast cancer– Systemic treatmentSystemic treatment
Radical mastectomyRadical mastectomy
A. Entire breast and a chA. Entire breast and a chest wall muscle is removest wall muscle is removed. ed.
LNs in the level 1 (B) and LNs in the level 1 (B) and level 2 (C ), and even solevel 2 (C ), and even sometimes more distant lymetimes more distant lymph node groups (D, E amph node groups (D, E and F) were also removed.nd F) were also removed.
Modified radical mastectomy Modified radical mastectomy (MRM)(MRM)
A. Entire breast is reA. Entire breast is removed moved
Classically some lymClassically some lymph nodes in the level ph nodes in the level 1 (B) and level 2 (C ) 1 (B) and level 2 (C ) were removed, callewere removed, called an axillary lymph nd an axillary lymph node dissection. ode dissection.
MRM = simple mastectomy + ALND
Breast conserving surgeryBreast conserving surgery
Also called Also called lumpectomylumpectomy
RT should be RT should be followedfollowed
Surgical evolutionSurgical evolution
Radical mastectomyRadical mastectomy– 1885 ~ 1960s1885 ~ 1960s
Modified radical mastectomy: 1970sModified radical mastectomy: 1970s
Lumpectomy + RT, 1970sLumpectomy + RT, 1970s– NSABP B-06, NEJM 1985NSABP B-06, NEJM 1985
Lumpectomy vs. MRMLumpectomy vs. MRM
– Milan Cancer Institute, NEJM 1977Milan Cancer Institute, NEJM 1977 Lumpectomy vs. RMLumpectomy vs. RM
Impact of surgical evolutionImpact of surgical evolution
Local control: no survival benefitLocal control: no survival benefit– Local control: RM>MRM>BCT+RT>BCTLocal control: RM>MRM>BCT+RT>BCT– Survival no differentSurvival no different
Why? distant metastasis is the main cause Why? distant metastasis is the main cause
Distant “micrometastasis” Distant “micrometastasis” – Not from local residual dzNot from local residual dz– Does exist at diagnosisDoes exist at diagnosis
Adjuvant systemic treatmentAdjuvant systemic treatment
Adjuvant systemic treatmentAdjuvant systemic treatment
Hypothesis: Hypothesis: – Eradicate micrometastasisEradicate micrometastasis– From effective tx for overt(macro) metastasiFrom effective tx for overt(macro) metastasi
s s
ChemotherapyChemotherapy Hormone therapyHormone therapy
Adjuvant chemotherapyAdjuvant chemotherapy
CMF, first generation, 1970sCMF, first generation, 1970s– CyclophosphamideCyclophosphamide– MethotrexateMethotrexate– 5-FU5-FU
– Benefit in Benefit in Distant recurrence Distant recurrence Survival Survival
Adjuvant chemotherapyAdjuvant chemotherapy
CAF or CEF, 2nd generation, 1980sCAF or CEF, 2nd generation, 1980s– CyclophophamideCyclophophamide– Adramycin(or Epirubicin)Adramycin(or Epirubicin)– 5-FU5-FU
– More toxic than CMFMore toxic than CMF– CAF better than CMF in high-risk groupCAF better than CMF in high-risk group
Axilla LN+Axilla LN+LN-, but tumor large or other risk factorLN-, but tumor large or other risk factor
Adjuvant chemotherapyAdjuvant chemotherapy
Incorporate TaxaneIncorporate Taxane TAC, 3rd generation, mid-1990sTAC, 3rd generation, mid-1990s
– TaxotereTaxotere– AdriamycinAdriamycin– CyclophosphamideCyclophosphamide
– More toxic than CAFMore toxic than CAF– Better than CAF in high-risk groupBetter than CAF in high-risk group
Need more time to observeNeed more time to observe
Adjuvant HerceptinAdjuvant Herceptin
Effective in Her2+ ptsEffective in Her2+ pts– ICH3+ICH3+– FISH+FISH+
Herceptin + adjuvant chemotherapyHerceptin + adjuvant chemotherapy– Optimal role to be definedOptimal role to be defined
Concurrent or sequential?Concurrent or sequential?Maintenance ? Duration ?Maintenance ? Duration ?
Adjuvant hormone therapyAdjuvant hormone therapy
In premenopausal womanIn premenopausal woman– Oophorectomy could control metastatic disOophorectomy could control metastatic dis
ease ease
TamoxifenTamoxifen– Selective estrogen receptor antagonistSelective estrogen receptor antagonist– Effective in pre- and post-menopausalEffective in pre- and post-menopausal– Effective in adjuvant settingEffective in adjuvant setting
Adjuvant hormone therapyAdjuvant hormone therapy
Aromatase inhibitorAromatase inhibitor– Effective in post-menopausal stateEffective in post-menopausal state– Aromatase, in fat tissue, Aromatase, in fat tissue,
Convert androgen to estrogenConvert androgen to estrogenMain estrogen source in post-menopausalMain estrogen source in post-menopausal
– Exemestane : AromasinExemestane : Aromasin– Letrozole: FemaraLetrozole: Femara– Anastrozole: Arimidex Anastrozole: Arimidex
More effective than TamoxifenMore effective than Tamoxifen
Adjuvant ovarian suppressionAdjuvant ovarian suppression
Effective in pre-menopausal stateEffective in pre-menopausal state Type Type
– Surgical ablationSurgical ablation– RT ablationRT ablation– GnRH analogue: Goserelin, LeuprideGnRH analogue: Goserelin, Leupride
Exact role to be definedExact role to be defined– Combination with chemotherapy?Combination with chemotherapy?– Combination with AI or TAM?Combination with AI or TAM?
Treatment of metastatic dzTreatment of metastatic dz
Usual sites: bone, lung, liver, brainUsual sites: bone, lung, liver, brain Incurable Incurable
– Goal: live with dz for longest timeGoal: live with dz for longest time
Systemic treatment is mainstaySystemic treatment is mainstay– ChemotherapyChemotherapy– Hormone therapyHormone therapy
Palliative local therapyPalliative local therapy– Radiotherapy Radiotherapy – Palliative surgeryPalliative surgery
Treatment strategyTreatment strategy
Principle: Principle: – Save your bulletSave your bullet– Right time, right treatmentRight time, right treatment
Why?Why?– Treatment effectiveness only in limited Treatment effectiveness only in limited
durationduration– To avoid unnecessary toxicityTo avoid unnecessary toxicity– Ultimately incurableUltimately incurable
Chemotherapy Chemotherapy
In general, chemotherapyIn general, chemotherapy– Single agent: RR: 20-30%Single agent: RR: 20-30%– Combination: doublet: 40-60%Combination: doublet: 40-60%
triplet: 70-80% triplet: 70-80%
Hormone therapyHormone therapy– Tamoxifen: RR 15-20%Tamoxifen: RR 15-20%– Aromatase inhibitor: RR 30-35%Aromatase inhibitor: RR 30-35%
Chemotherapeutic agentsChemotherapeutic agents
Single agents:Single agents:– Doxorubicin/EpirubucinDoxorubicin/Epirubucin– CyclophosphamideCyclophosphamide– MTXMTX– 5-FU5-FU– Taxane(Paclitaxel, Docetaxel)Taxane(Paclitaxel, Docetaxel)– NavelbineNavelbine– GemcitabineGemcitabine– BCNUBCNU
Chemotherapy regimensChemotherapy regimens
Combination:Combination:– Navelbine-HDFLNavelbine-HDFL– Paclitaxel-CisplatinPaclitaxel-Cisplatin– Doxorubicin-CyclophosphamideDoxorubicin-Cyclophosphamide– Gemcitabine-PaclitaxelGemcitabine-Paclitaxel
Combination C/T provide better RR, but Combination C/T provide better RR, but overall survival not differentoverall survival not different
Example - 1Example - 1
– 55y/o woman, ER/PR +/+, 55y/o woman, ER/PR +/+, – Dz recurred 5yrs after surgeryDz recurred 5yrs after surgery– Only neck and mediastinum LNsOnly neck and mediastinum LNs– Slowly progressed clinically(!)Slowly progressed clinically(!)
Hormone therapyHormone therapy
May do RT for symptomatic siteMay do RT for symptomatic site
Example - 2Example - 2
– 45 y/o woman, ER/PR -/-45 y/o woman, ER/PR -/-– Dz recurred 3 yrs after operationDz recurred 3 yrs after operation– Only right supraclavicle LNsOnly right supraclavicle LNs– Slowly progressed Slowly progressed
RT alone
Observation
Example - 3Example - 3
– 50 y/o woman, ER/PR +/+50 y/o woman, ER/PR +/+– Back, shoulder, hips pain, 3m, progressBack, shoulder, hips pain, 3m, progress– Massive bone mets over spine, pelvis, shoulMassive bone mets over spine, pelvis, shoul
der, and ribsder, and ribs
Systemic chemotherapy, combination
RT for symptomatic sites
Bisphosphonate: Aredia or Zometa
Example - 4Example - 4
– 55 y/o woman, ER/PR +/+55 y/o woman, ER/PR +/+– Dyspnea progressivelyDyspnea progressively– Lung mets bilaterallyLung mets bilaterally
Systemic chemotherapy, combination
Treatment principleTreatment principle
For visceral organ crisisFor visceral organ crisis– Combination chemotherapyCombination chemotherapy– Failure is not allowedFailure is not allowed
(high RR necessary)(high RR necessary)
For isolated LN or bone metsFor isolated LN or bone mets– Hormone tx (more chance to try)Hormone tx (more chance to try)– RT alone in hormone unresponderRT alone in hormone unresponder