short note by S.Wichien (SNG KKU)

Embryology Anatomy 5th,6th wk -15-20 lobes -2 ventral bands of ectoderm -Cooper suspensory lig ament (mammary ridge/milk line) -2nd/3rd rib--6th/7th rib (axilla to inguinal area) -lateral sternum--ant axillary line Polymastia -retromammary bursa -accessory breast -axillary tail of Spence Polythelia -upper outer--greater volume -accessory -lactiferous sinus--stratified sq.epi -<1% of infant major duct--2 cuboidal cell -asso urinary/CVT abnormality minor duct--single columnar/cuboid Inverted nipple Nipple-areola complex -failure of pit to elevate above skin -pigment -4% infant -puberty--darker,elevate configuration Witch milk -sebaseous gl,sweat gl,accessory gl -maternal H.via placenta -smooth m--cir/long--erection -arrest milk line develop Alveolar epithelium -- 2 products Poland synd 1.prot.component of milk -hypoplasia/absence of breast -merocrine secretion -rib/costal cartilage defect -in endoplasmic reticulum -hypoplasia of subcu of chest wall 2.lipid component of milk -brachysyndactyly -apocrine secretion Symmastia -in cytoplasm -rare anomaly colostrum -webbing between breast across -first few day midline -low lipid--hi Ab(lympho,plasma cell) Supernumerary breast -along milkline Blood supply -common btw nipple and symphysis Artery -accessory axilla breast -perforating br of int mam.a. -lateral br of post ICS a. -br from axillary a. :highest thoracic :lateral thoracic :pectoral br of thoraco-acroomial a Vein -perforating br of int mam.v. -perforating br of post ICS v. -tributaries of axillary v. °Batson vertebral v.plexus :root of bone metas Nerve -3-6 ICS n. -cervical plexus--ant br of supraclavi n -intercostobrachial n--lat.br of 2 ICS n

Breast short note by S.Wichien (SNG KKU)

Lymph node Investigation Internal mammary node 25% MMG Axillary node 75% -detect early breast ca Level 1 -true positive 90% -axillary v.gr -screen at 40 yr -ext.mammary gr--ant -scapular gr--post Ultrasound Level 2 -in equivocal MMG finding ,cystic mass -central gr -uls guide bx -interpectoral gr--rotter Level 3 Ductogram -subclavicular gr--apical gr -nipple discharge -duct dilator-->small canular Skip metastasis -0.1-0.2 ml contrast is injected -25-29%--level 2,3 -filling defect-->intraductal papilloma -3%--level 3 **SLNB can miss 3% MRI -hi-sen, low spec than MRM Node metastasis 1.tumor cluster 1.ALN+ve, unknown 1° -isolated tumor cell <0.2cm 2.promblematic MMG 2.micrometas 3.rupture silicone -0.2-2 cm 3.macrometas ->2cm Nonpalpable lesion Bx -u/s localization--have mass Physiology -stereotactic technic --no mass Estrogen--duct development Progesterone--lobular development Palpable lesion Bx Prolactin--lactogenesis -FNA bx Pregnancy -CNB -inc ovarian/placental E&P -duct&lobular epi proliferate Indice of -prominent Montgomery gland Poliferation PCNA Milk production&relaese Apoptosis Bcl2 protein -stimulate nerve ending (NAC) bax:bcl2 ratio -prolactin secretion (dec ratio-poor prog) -oxytocin--contract myoepithelium Angiogenesis VGEF GF EGF ,HER2/neu Steroid H.R EP ,PR

Dx study Hx,PE ca stage 1-4 CBC,LFT CXR,MMG ER,PR HER-2/neu

Bone scan ca stage 2-4 U/s or CT abdo

Breast short note by S.Wichien (SNG KKU)

Gynecomastia ANDI -Male breast enlarge,elongate,inc epi Abberrant of Normal Development -often unilateral and Involution -12-15 yr -at least 2 cm in diameter Early reproductive yr (15-25yr) -usually not predispose ca Normal 1.lobular development Physiologic 2.stromal development 1.neonate 3.nipple eversion 2.adolescent Disorder 3.senescence--dec T,relative inc E 1.fibroadenoma (<3cm) 2.adolescent hypertrophy Klinefelter synd (XXY) 3.nipple inversion -hypoandrogenic state Disease -inc risk of ca breast 1.giant fibroadenoma (>3cm) 2.gigantomastia Classification 3.subareolar absecss gr1-mild enlarge,wo skin redundancy Mammary duct fistula gr2a-mod enlarge,wo skin redundancy gr2b-mod enlarge,w skin redundancy Later reproductive yr (25-40yr) gr3-mark enlarge,as female breast Normal 1.cyclic change of menstruation Cause 2.epi hyperplasia of preg Estrogen excess Disorder 1.testicular tumor 1.cyclic mastalgia and nodularity -germ cell tumor--seminoma 2.bloody nipple discharge -gonodal tumor--leydig,sertoli cell Disease 2.non testicular tumor 1.incapacitating mastalgia -adrenal cortical tumor 2.- -lung ca -hepatoma Involution 3.non alc/alc cirrhosis Normal 1.lobular involution Androgen deficiency 2.duct involution--dilatation/sclerosis 1.senescene 3.epi turnover 2.hypogonadism Disorder 1°testicular failure--klinefelter synd 1.macrocyst/sclerosing lesion 2°testicular failure 2.duct ectasia/nipple retraction :trauma,orchitis,cryptorchidism,XRT 3.epi hyperplasia Tx Disease -add testosterone 1.- 2.periductal mastitis Drugs 3.epi hyperplasia w atypia reserpine,theophylline verapamil TCA,furosemide Tx -stop drugs

Idiopathic -tamoxifen 40 mg/d 1-4 m

Breast short note by S.Wichien (SNG KKU)

Benign Benign breast Tx 1.Non-proiferative disorder cyst ¤no inc risk ca -cyst aspiration -fibrocystic disease (cyst & apocrine metaplasia) Fibrocystic dz -duct ectasia -reassure/symp Tx -mild ductal epi hyperplasia -danazol,nsaid,tamoxifen,bromocrip -calcification -fibroadenoma and related lesion fibroadenoma giant fibroadenoma >5cm 2.proliferative disorder wo atypia -should r/o phyllodes tumor ¤no inc risk ca Sx I/C -sclerosing adenosis ->40yr -radial & complex sclerosing lesion -rapid growth>20% -ductal epi hyperplasia ->5cm -intraductal papilloma sclerosing disorder 3.atypical proliferative lesion -excision bx are needed to r/o ca ¤inc risk ca 4x -stereotactic guide bx -atypical lobular hyperplasia -atypical ductal hyperplasia periductal mastitis -ATB--metro+cloxa -abscess--drainage Recurrent abscess w fistula Fistulectomy Total d excision -small abscess large>50%areolar -same lesion different lesion -no N.inversion mark N.inversion -young pt old pt -no d/c pus d/c -no fistulec recur after fistulec

nipple inversion -shortening subareolar duct -sx correction--cosmetic reason -c/p--nipple sensation/necrosis, fibrosis-->nipple retraction

intraductal papilloma -microdochectomy

Breast short note by S.Wichien (SNG KKU)

Infection LCIS & DCIS 1.bact infection -Staph--localized,deep abscess LCIS DCIS Strep--diffuse superficial involve 1. age 44-47 54-58 yr -breast feeding 2.i ncidence 2-5 5-10% -subareolar,periduct,retromam space 3.c linical no mass,pain,dc Tx 4.MMG no microcalci -local w care--warm comp 5.p remen o 2/3 1/3 -iv ATB 6.s ynchro 5 2-46% -I&D--should Bx abscess cavity 7. multicentric 60-90 40-80% 8. bilat 50-70 10-20% Zuska disease 9. axilla metas 1 1-2% (recurrent periductal mastitis) 10.male - 5% -recurrent retroarolar infect/abscess 11. subsequent ca Tx interval to dx 15-20 5-10 yr -ATB+I&D histo ductal ductal incidence 25-35% 25-70% 2.mycotic infection laterality bilat ipsilat -blastomycosis or sporotrichosis -intra oral fungi--sucking infant LCIS -abscess close to NAC -only in female breast Tx -Terminal Duct Lobular Unit-- TDLU -antifungal agent -distort/distend TDLU -+/-drainage -maintain normal N:C ratio -calcify in adjacent tissue 3.hiradenitis supparativa -incidental finding -axilla--sebaceous gl NAC--Montgoney gl DCIS -mimic chronic inflam,paget,ca -can seen in male breast ca -proliferation of epi in duct 4.mondor s dz -papillary growth -variant of thrombophlebritis -intraductal ca -superficial v of ant chest wall 1.cribiform pattern -lateral thoracic v,thoracoepigastric v 2.solid growth pattern superficial epigastric v 3.comedo growth pattern -tender,cord like structure -benign, self limited dz--4-6 wk Classification of DCIS Tx Histo nu.gr necrosis DCIS grade -anti-inflam comedo hi extensive high -warm compression IM IM focal/no IM -restrict of motion of ipsilat ext noncomedo low absent low -braissiere support -not improve-->excision ¤IM--intermediate

Breast short note by S.Wichien (SNG KKU)

Ca breast 2.invasive ductal ca 1.sporadic 65-75% 2.1 adenoca c productive fibrosis 2.familial 20-30% (scirrhous,simple,NST)--80% 3.hereditary 5-10% -60% axillary LN metas BRCA1 45% -perimenopausal,menopause BRCA2 35% -poor margin p53(Li fraumeni) 1% -solitary,firm mass STK11/LKB1(Peutz J egh ) <1% -cut surface--stellate,chalky white or PTEN(cowden) <1% yellow streak into surrounding tissue 2.2 medullary ca--4% BRCA1 BRCA2 -special type 1.chro 17q21 13q12 -BRCA-1 hereditary breast ca 2.fxn Tumor suppression -soft,hemorhage DNA damage repair -often deep in breast 3.risk ca 60-80% -50%asso DCIS 4.age young 50 yr -5yr better than NST,invasive lobular 5.fam hx 52% 32% Microscopic 6.ovary ca 80% 20% -dense lymphoreticular infiltrate 7.male <20% 76% lymp/plasma cell predominate 8.ca prostate,colon,pancreas -poorly diff,active mitosis 9.diff poorly diff well diff -sheet like growth pattern 10.HR -ve +ve 2.3 mucinous (colloid)--2% 11.bilat yes yes -elderly -bulky tumor Hereditary risk of ca breast -extracellular pool of mucin ->=2 fam hx of ca breast/ovary -glistening and gelatinous -ca breast < 50yr -firm consistency -ca breast+ovary in same pt -5yr--73%, 10yr--59% -male breast 2.4 papillary--2% -small Cancer prevention for BRCA mutation -fibrovascular stalk 1.prophylactic mastectomy & recons -multilayer epithelium 2.prophylactic oophorectomy & HRT -prognosis as mucinous 3.intensive survei for ca breast&ovary 2.5 tubular--2% 4.chemoprevention -perimenopausal,menopause Screening recommendation -tubular arranged -early screen at 25 yr -long term survival approach 100% -clinical breast exam q 6 m -MMG q 12 m 3.invasive lobular ca--10% -TVS, ca-125 q 1yr -histo--small cell c round nuclei, scant cytoplasm Invasive breast ca -special stain--intracytoplasmic mucin, 1.paget dz of nipple displace nucleus(signet-ring cell) -chronic,eczema of nipple -poorly defined mass -weeping lesion,ulcer -multifocal,multicentric and bilat -extensive of DCIS -insidious growth--difficult to detect -pagetoid feature -pathognomonic=paget cell in epi 4.rare ca -DDx-superficial spreading melanoma -adenoid cystic :S-100 immunostaining--melanoma -squamous cell :CEA immunostaining--paget dz -apocrine

Breast short note by S.Wichien (SNG KKU)

Ca breast staging Sentinel LN bx -palpate axillary LN -- ccuracy only 33% -T1,2,3 , No -axillary LN dissect >=10 node C/I -tumor size correlate c axillary metas -palpable lymphadenopathy -single most predictor of survival is -prior sx,CMT,XRT number of axillary LN involve -multifocal breast ca -supraclavicular LN metas--stage4 agent T 1.radioactive colloid T0-no evidence -intraop gamma probe Tis-ca in situ -radioactivity count T1-tumor < =2cm T2-tumor 2-5cm 2.isosulfan blue dyle (Lymphazurin) T3-tumor >5cm -->intraop visualization T4-any size c extend chest wall,skin T4a--chest wall, not pectoralis m. *combine 1+2=more accurate T4b--edema,peau d orange,ulcer T4c--both a+b Procedure T4d--inflam ca -4ml of isosulfan blue dye is inject -1ml inject between ca site and skin N -nonpalpate--u/s guide,wire localize N0-no -3-4 cm incision curved transverse N1 +ve1-3,mobile -lower axilla just below hairline N2+ve4-9,fix or matted -identify lateral of pectoralis m N3+ve>10 or IMLN/SCLN/IFLN -divided clavipectoral fascia M -exposed axilla content M0-no M1-distant metas Tx -false+ve--3% (3% skip to level 3) N0 N1 N2 N3 T1 I IIa IIIa IIIc Macrometas(pN1) T2 IIa IIb IIIa IIIc ->2mm T3 IIb IIIa IIIa IIIc Tx--must ALND T4 IIIb IIIb IIIb IIIc Micrometas(pN1mic) Early breast ca--T1-2, N0-1 -0.2-2mm Locally advance--T3-4, N2-3 Tx--should ALND Stage 4,recurrent--M1 Isolated tumor cell or tumor cruster (pN0) -<0.2mm Tx--ALND=controversy

Breast short note by S.Wichien (SNG KKU)

Ca breast Tx 3.locally advanced (stage 3a,3b) 1.in situ -metastasis w/u 1.1 LCIS --risk ca 15-20 yr -induction cmt--anthracyclin 4 cycle A.close f/u A.65%--reduce size--sx -CBE q 6-12mo -BCT vs MRM -mammogram,US q 1yr -then PO RT, CT+/-ET B.tamoxifen B.not reduce size C.prophylactic bilat.mastectomy -change anthracyclin--taxane -in BRCA1 +ve -RT -not ALND -if HER2+ve--Herceptin 1.2 DCIS --premalignant A.local excision 4.stage 4/recurrent -size<0.5 cm -local control--sx,RT -low grade -all--systemic tx B.local excision + RT Local recurrent ->0.5 cm A.prior BCT C/I as BCT -total mastectomy +CT+/-ET -prior RT -not RT -can't free margin B.prior MRM :multicentric/diffuse calcify -wide local excision +/- RT or :persist +ve margin >=2 -RT alone then CT +/- ET C.simple mastectomy Tx for metastasis -can't b Bone D.chemoprevention -bone pain--RT -not tamoxifen except -patho.fx--ORIF -DCIS in premenopause -biphosphonate--all bone metas E.SLNB -ER+ve--ET -not done--risk +ve <1% -ER-ve--CT up 1 grade Brain ¤Van nuy prognostic index -localize--sx -multiple,can't sx--steroid+/-RT 2.Early breast ca (stage1,2a,2b) SC compression -BCT-- Tx of choice -can sx--laminectomy -MRM+/-reconstruction--alternative -unresectable--steroid+/-RT -SLN,RT,systemic tx--if have I/C Liver -can sx--sx -CT up 1 grade Lungs -isolated should sx > RT

Breast short note by S.Wichien (SNG KKU)

Breast Sx Mastectomy 1.BCT Simple mastectomy -wide local excision -all breast tissue -margin 1cm -nipple-areolar complex -label margin 3,6,9,12 o clock -1cm of skin around excised scar Absolute C/I Extend simple mastectomy -multicentric, >1quadrant -above + level 1 node -persistence +ve margin (2 time) Modified radical mastectomy -prior RT -above + level 1,2 node -1st trimester pregnancy -if palpate level 3--remove Relative C/I The Halstead radical mastectomy -multifocal but in same quadrant -above + pectoralis major/minor -large and pendulum breast + level 1,2,3 nodes -large tumor to breast ratio Nipple sparing mastectomy -medial quadrant lesion ->nipple 2cm+frozen -CNT except RA Skin sparing mastectomy -BRCA1,2 mutation -early ca, preserve native skin -nipple areola complex excision Axillary node dissection -for staging, control regional ds 2.MRM -10-15 node 1,2 level -dissect breast, nipple -ALND (at least10) level 1,2

3.SLNB -if -ve ---not ALND indication -clinical -ve node -T<5cm -no prior systemic tx C/I -palpable node -T>5cm---often metas -T1---rare to +ve -inflam ca -metastasis -previous sx -previous neoadjuvant CMT -multifocal

Breast short note by S.Wichien (SNG KKU)

MRM MRM C/p -preserve pectoralis m. 1.wound infection -removed axillary LN level 1,2 -staph -preserve medial pectoral n. 2.flap necrosis :penetrate pectoralis minor -minor <2cm2--conservative :supply pectoralis major -major--graft/flap -skin flap 7-8 mm 3.hematoma -fascia of pec.major m.and overlying 4.pneumothorax breast tissue are elevated off -Halsted sx -->complete removal of breast 5.seroma Boundary -most common c/p lateral--ant margin of latissimus dorsi -off when<20 ml ¤2d medial--midline of sternum 6.lymphedema seperior--subclavius -ALND--25-30% inferior--2-3cm inf to inframam.fold -ALND+RT--50-60% Axillary LN dissection -SLNB--2-4% Preserve 7.lymphagiosarcoma -thoracodorsal n -Stewart Treves synd -long thoracic n--wing scapular -chronic lymphedema If palpate LN at apex of axilla -s/p MRM >10yr -divided pectoral minor -poor prognosis :near insertion--coracoid process -WLE or RT+CMT -dissect axilla v.medial to 8.nerve inj costoclavicular (Halsted) ligament -long thorasic n--wing scapula Seroma -thoracodorsal n--int rotate,abduct -30%of case -med pectoral n--m atrophy -use closed system suction drainage -intercostobrachial n--sensory -until <30ml/d 9.chronic pain synd Infection -s/p intercostobrachial inj -2nd to skin flap necrosis -neuroma -debridement,ATB 10.axillary v/A inj Lymphedema 11.frozen shoulder -10% 12.c/p asso SLNBx Predisposing f. -allergic rxn/shock -extensive axillary LN dissection -not use in pregnancy -obesity -radiation therapy -presence of pathologic LN Rx -fitted compressive sleeves -intermittent compressive device

**Patey modification -remove pectoralis minor -complete dissect level 3 nodes

Breast short note by S.Wichien (SNG KKU)

Breast reconstruction Endocrine Tx -defect can't cover c skin graft -all in HR+ve -->myocutaneous flap -premense--tamoxifen > AI Immediate after sx :20mg/d *5yr -after mastectomy for early inva ca :stop if AUB,thromboembolic Delayed 6mo after complete adju T x -postmense--AI > Tamoxifen -for advanced breast ca :upfront--tamoxifen 5yr -ensure locoregional control of ds :switching--tamoxifen 2yr--AI 3yr Myocutaneous flap :extended AI--tamoxifen 5yr--AI 3yr 1.latissimus dorsi flap Determining menopause -skin paddle--latissimus dorsi m. -prior bilat oophorectomy -thoracodorsal a.--from post ICS a ->=60yr, <=60yr+no mens >=12mo 2.rectus abdominis flap Drugs -Transverse Rectus Abdominis 1.antiestrogen Myocutaneous flap (TRAM) -tamoxifen,toremifene,fulvestrant -skin paddle--rectus abdominis m. Tamoxifen s/e -inf epigastric a -DVT,pulmo.emboli -free TRAM--microvascu.anastomosis -endometrial ca Chest wall defect -hot flush--most common -ca involved chest wall -thrombocytopenia,leukopenia -1,2 rib -- ok 2.AI ->2 rib--Marlex mesh -anastrozol--arimidex -then cove by flap -letrozole--femara AI s/e -osteoporosis Breast RT 3.LHRH I/C -goserelin,leuprolide,buserelin -BCT--aftet sx 2-3 wk, not>6 wk -T3,4 Chemotherapy -inflam breast I/C -skin,fascia,pectoralis involve -T>1cm -lymphovascular invasion -all in node +ve -close margin,free margin <1mm -ER,PR -ve -axilla LN status -lymphovascular invasion :+ve>4node -hi nuclear grade :>2cm -HER2/neu overexpression :matted node>3 nodes 3 groups :gross extracapsular invasion 1.non-anthracyclin based regimen-- CMF -palliative tx for stage 4/recurrent -low risk of recurrent 2.anthracycline based regimen -FAC*6, CAF*6 -<35yr, node+ve, HER2+ve 3.taxane based regimen -pacitaxel,docetaxel -failure from 2 -hi risk of recurrent :<35yr, poorly diff tumor, HR-ve, HER2+ve

3.Target tx -HER2/neu overexpression + metas -early case--trial -Herceptin(Trastuzumab) iv q3wk--1yr

Breast short note by S.Wichien (SNG KKU)

Other Ca 5.inflam breast ca 1.axillary LN metas + unknown 1° -stage 3b -1% presentimg sign of ca breast -<3% of ca breast -HR suggest ca breast but not dx -75%--LN metas -thyroid--breast--pelvis/rectum 25%--distant metas -breast--MMG/us/MRI -dermal lymph vv invasion -indurate,erythema,raise edge, 2.ca breast during pregnancy edema(peau d orange) -bigger breast --delay in dx Tx -MRM>BCT -neoadjuvant w doxorubicin -should not SLNB -MRM remove residual ca -if need RT--after delivery :if must--2nd,3rd trimester 6.Bilateral breast ca -CMT/HT--2nd,3rtrimester -breast ca---risk 5x -not tamoxifen,metrotrexate -metachronous(>3mo) > synchronous -abortion,suppress lactation Hi-risk :not improve prognosis -<45yr -familial,hereditary ¤Benign breast in pregnancy -LCIS,invasive lobular ca :galactocele,lobular hyperplasia Rx lactating adenoma,abscess Synchronous -tx higher stage tumor 3.male breast ca Metachronous -<1% ca breast -tx as recurrent ca -rare in young -peak incidence--60yr 7.rare ca -20% is preceded by gynecomastia Squamous (epidermoid) cell -asso RTX,estrogen Tx -rare, from metaplasia in duct Klinefelter,testicular feminize synd Adenoid cystic ca -same staging -rare -poor prog than women -indistinguish from adenoid cystic ca (advance stage when dx) arising in salivary gland Tx -rare node metas -as female Apocrine ca -advance--orchidectomy -well diff ca -round vesicular nuclei, 4.phyllodes tumor prominent nucleoli -cut surface--classical leaf like appear -low mitotic rate -stromal cell--always monoclonal Sarcoma -need CNBx (FNA--not adequate) -fibrosarcoma,MFH,liposarcoma 1.benign leiomyosarcoma,rhabdomyosarc -mitotic <2/10 chrondosarc,malig schwannoma 2.low gr malignant -large,painless mass,rapid growth -mitotic 2-5/10, stromal invade Tx 3.hi gr malignant -wide local excision -mitotic >5/10, stromal invade -may need mastectomy Tx -ALND not indicate, unless palpable -wide excision 1cm free margin Angiosarcoma -not ALND (lymphangiosarcoma I/C mastectomy -post mastec lymphedema /post XRT -large size to breast ratio -p/o 10.5 yr -skin ulceration Tx--Forequarter ampu in palliative Tx

Breast short note by S.Wichien (SNG KKU)

St gallen Van Nuy prognostic index (DCIS) Low risk 1 2 3 -node -ve and all of size <=15 16-40 >=41 -T<2cm margin >=10 1-9 <=1 -gr1 patho -no perivascular invasion -hi gr no no yes -ER,PR +ve -necrosis no yes y/n -HER2 -ve -nuclear gr 1,2 1,2 3 ->35yr age >60 40-60 <40

Intermediate risk 4-6=excision/lumpectomy only Node -ve and at least one of 7-9=add XRT -T>2cm 10 -12=mastectomy -gr2,3 -per ivascular invasion BIRADs -ER,PR -ve Breast Imaging Reporting And Data S. -HER2 +ve 0=incomplete-- additional imaging -<35yr 1=neg--routine screening 2=benign--routine screening Node +ve (1-3) and 3=probably benign-->98% -ER,PR +ve :microcalcify-- f/u 6 m o -HER2 -ve :mass--f/u 4 mo 4=suspicious abnormality --5-95%-- bx High risk 4a=low probability Node +ve (1-3) and 4b=intermediate probability -ER,PR -ve 4c=intermediate but not typical -HER2 +ve 5=highly suspicious -->=95%--bx/sx 6=known bx proven malignancy Node +ve (>4)

E.rxn E.uncertain E.nonrxn low ET ET - Inter ET CT-->ET CT or (antra) (antra/tax) CT-->ET (CMF/antra) high CT-->ET CT-->ET CT (antra) (antra) (tax)

E.responsive--ER/PR+ve E.uncertain--ER/PR+ve but <10% E.non-responsive--ER/PR-ve