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