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ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

Th is c r oss -t a l k be t ween E R and g r o wt h fact o r rece p t o rs is b i d irecti on al; f o r e x am p le, cons tit u ti ve H E R2 ca n i n crease ER si gn ali ng t o t h e po i n t w h ere it is unr esp ons i ve t o an ti es tr ogen treatme n ts . T h ese fi nd i ng s s ugg est a r o le f o r HE R 2 / I GF- 1R /E G F R ac ti va ti on i n bo t h ac qu ire d a nd d e novo resista n ce to t r eatme n t w it h an ti es tr ogens .

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

Th e E R pa t hway has p r ov e n t o b e a n i nv al u a b le tar g et f o r t h era p e u ti c t r eatme n t s i n b r eas t cance r . A nu m b er o f a g e n ts h a v e b ee n d e v el op e d ov er t h e pr i or decades t ha t can i nhib it t h is p at h wa y by eit h er b i nd i ng t o t h e r ece p t or it se lf ( e.g., se l ec ti ve E R m odu lat o rs s u c h as tam ox ife n, ral ox ife ne, fu l v est ran t) o r by dec r eas i ng t h e p r odu cti on o f e ndog e nou s estr og e n (e .g., a ro matas e i nh i b it o r s, ova ri an ab lati on ) . Rece n t d ata s ugg est t h at a l ong er dur ati on o f t a m ox if en ( 10 yea rs) is s up eri o r t o 5 y ears , a nd 5 y ears o f Aro mat ase I nh i b it o r ( A I) a r e sta nd ar d o f care after a ny du rati on o f tam ox i fen i n pos tm enopausa l w o me n . Alt hough t h ese a g e n ts are h i gh l y e f f ecti ve and have m ade a s i gn ifica n t im p act on b reast ca n cer m o r b i d it y and m or talit y , de novo and acqu ire d resista n ce are als o qu ite c o mm on. Rece nt st ud ies sugges t t ha t t he i nh i b iti on o f g r o wt h fact o r p at h wa y s i n c on j un cti on w it h a n ti es tr ogen t he r apy can ov erc o me resista n ce t o t h ese a g e n ts; f o r e x am p le, t he m a mm a li an t a r g et o f ra p am y ci n (m T OR) i nh i b it o r temsi ro lim us w it h a s t e r o i da l inh i b it o r (e x emesta n e) is a n ew sta nd ar d of ca r e a f ter p r og r ess i on on a non ster o i d al ar o matase i nh i b it o r i n t h e metastati c se tti ng . T he cha lle ng e f o r t h e on c o l ogy c o mm un it y is t o d ef ine op timal b i o m a r ke r s t o p r ed i c t p atie n ts m o st li k el y t o b e n efit fr o m l ong er tam ox i fen o r A I + m T OR t he ra p y . As d escri b e d p re v i ou sl y , t h e O n c o t ype DX assa y , I HC4, and B r eas t Ca n cer I nd e x p r ov i d e i n si gh t i n t o t h e b e h av io r of E R -pos iti ve t u m o r s and he l p i n treatme n t d ecisi on ma k i ng . –

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Growth Factor Receptor Pathways

nan nan

Growth Factor Receptor Pathways

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Growth Factor Receptor Pathways

nan nan

Grow t h f ac t o r r ecep t o r pa t hway s — i n p artic u la r , t y r o si n e- k i n ase rece p t o r s— p la y a n e ssen ti a l r o l e i n i n iti at i ng bo t h p r o liferati v e a nd cell s u r v i v al p at hw a y s i n ti ssues and a r e ti gh tl y re gu late d. I n b reast ca n cer b i o l og y , t he Erb B f amil y has been s t ud i ed m o st e x te n si v el y , bu t a n e xp a nd i ng nu m be r of o t h e r g r ow t h f ac t o r s, such as i n s u li n -li k e g r o wt h fact o r rece p t o rs , h a ve als o b ee n t he sub j ec t o f i n t en se scr u ti ny i n hop es o f i d e n tif y i ng e f fecti v e t h e r a p euti c t a r ge t s T hese g r o wt h fact o r rece p t o r p at h wa y s ca n b e c on stit ut i ve l y ac ti va t ed by a nu m b er o f mec h a n isms , i n cl ud i ng e x cessi ve li g a nd l eve l s, ga i n - o f-f unc ti on m u tati on s , ov ere xp ressi on wit h o r wit hou t

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Growth Factor Receptor Pathways

nan nan

g e n e amplifi ca ti on, and gene rearra ng eme n ts a nd res u lta n t f u si on p r o tei ns w it h oncogen i c po t en ti a l . T h is ca n u ltimatel y lea d t o i n a pp r op riate k i n as e acti v it y and g r ow t h p r o m o ti ng sec ond messe ng er acti v ati on ( .

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Human Epidermal Growth Factor Receptor 2

nan nan

Human Epidermal Growth Factor Receptor 2

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Human Epidermal Growth Factor Receptor 2

nan nan

HE R 2 ( E G F R2 o r Er bB2 ) i s a mem b er o f a famil y o f rece p t o r t y r o si n e k i n ases tha t a l so i nc l udes E G FR (HER 1, Er b B 1 ) , Er b B 3, a nd Er b B 4. L i g a nd b i nd i ng t o t he ex tr acel l u lar do mai n s o f t h e Er b B 1, Er b B 3, o r ErbB 4 r ece p t ors i nduces ho m o - and h eter od imerizati on a nd k i n ase acti v ati on. The

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Human Epidermal Growth Factor Receptor 2

nan nan

HE R 2 p r o t e i n ex i s t s i n a c l os e d c on f o rmati on a nd h as no li g a nd, bu t it is the pr e f e rr e d pa rt ne r f o r d im e ri zat i on wit h HER 1, - 3, a nd - 4. At a m o lec u lar le v el , H ER 2 a m p lifi ca ti on i s ass o ciate d wit h d ere gu lati on o f G 1 /S ph ase cell c y cl e con tr o l v i a t he up r egu lati on o f c y cli n s D 1, E , a nd c dk6, as we ll as p27 d e g r ada ti on. H E R2 a l so i n teracts wit h im po rta n t sec ond messe ng ers , i n cl ud i ng S H2 - do m a i n–con t a i n i ng p r o tei n s (e .g., Src k i n ases) . I m po rt an tl y , H E R2 a m p lificati on o r p r o tei n ov ere xp ressi on (f ound i n 20% of invas i ve b r eas t cance rs) is clearl y ass o ciate d wit h accelerate d cel l grow t h and p r o lif e r a ti on, poo r cli n ical ou tc o me , a nd res pon se t o t h e m ono cl ona l an ti- H E R2 an ti bod y , trast u z u ma b. N u mer ou s ra ndo mize d tri als h a v e s hown t ha t t he add iti on o f trast u z u ma b t o c h em o t h era py im p r ov es s urv i v al i n bo t h m e t as t a ti c and earl y sta g e d isease , lea d i ng t o its i n cl u si on i n t h e sta nda r d o f ca r e f o r a ll p atie n ts wit h HER 2 - po siti v e b reast ca n ce r

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

In a dd iti on, seve r a l o t he r H ER 2 -ta r g ete d a g e n ts h a v e b ee n a pp r ov e d f o r metastati c H E R2 - pos iti ve b r e ast ca n cer a nd are b ei ng e v al u ate d i n t h e e a r ly sta g e se t ti ng. One o f t hese, t h e m ono cl on al a n ti body p ert u z u ma b, w h ic h ta r g ets t he H E R2 - 3 he t e r od imerizati on site , h as rece n tl y b ee n a pp r ov e d f o r u se i n t h e p r eope r a ti ve se tti ng f o r sta g e II a nd III HER 2 - po siti v e b reast ca n ce r . T hese r ap i d advance s i n t h e setti ng o f ta r g ete d t h era py f o r HER 2 - po siti v e d i sease ill us tr a t e t he pr o f ound effect t h at ta r g eti ng a n im po rta n t m o lec u l a r dr i ver can have on cli n ical p ractice . Th e p r ec i se m echan i s m o f acti on o f t h e FDA-a pp r ov e d HER 2 -tar g et ed t h e r a p ies tr as t uzu m ab, pe rt uzu ma b, la p ati n i b, a nd trast u z u ma b emta n si ne (TD M -1 ) a r e no t we ll unde r s t ood , I n p recli n ical st ud ies , t h e first t h re e a pp ea r t o i nh i b it s i gna l tr ansdu cti on t h r ough t h e ca non ical si gn ali ng p at hw a y s f o r t he H E R2 r ecepto r , bu t ma y v ar y i n t h eir d e g ree o f ras-M APK v e r s u s PI 3K - AK T pa t hway i nh i b iti on. T h is ma y lar g el y b e du e t o d i f fer ent d e gr ees o f i nh i b iti on o f t he c orece p t o rs HER 1, 3, a nd 4 t h at h a v e a d i f fer ent pr e d ilec t i on f o r each pa t hwa y . F o r i n sta n ce , la p ati n i b i nh i b its bo t h HER 2 a nd EG F R ( H E R1 ) w it h a g r e ater e f fect on t h e ras-MAPK p at h wa y . Pe r t u z u m ab i n t e rf e r es w it h t h e HER 3 h eter od imer a nd h e n ce h as m o re e f f ect on t he AK T pa t hwa y . T h e n ew ta r g ete d t h era py TDM- 1 is a n a n ti body–d r ug con j uga t e, and its e f fects are m o re c y t o t ox ic t h a n si gn al

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

t r a n s du cti on. A ll t h r ee an ti body t h era p ies are t hough t t o acti v ate n at u ral k ille r cell s i nvo l ved i n an ti body - d e p e nd e n t cell u lar c y t o t ox icit y (ADCC) ; how e v e r , t he r e i s littl e ev i denc e fr o m cli n ical st ud ies t o s uppo rt t h is o r a ny mec h a n ism o f ac ti on. As a r e s u lt , mec h a n isms o f resista n ce are poo rl y und e r st ood ; cu rr en t hypo t hes es i n cl ud e acti v ati on o f alter n ate rece p t o rs ( e .g., IGF - 1R, c -m e t) o r t he AKT p at h wa y v ia a l o ss o f pho s ph atase a nd te n si n ho m o l og (PTE N ) o r P 13 K m u tati on (see ) .

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Ras And Phosphatidylinositol 3-Kinase Pathways

nan nan

Ras And Phosphatidylinositol 3-Kinase Pathways

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Ras And Phosphatidylinositol 3-Kinase Pathways

nan nan

Re dund a nc i es and c r oss -t a l k o f nu mer ou s d i f fere n t si gn ali ng p at h wa y s a r e a c o mm on t he m e. S eve r a l down stream messe ng ers , ho we v e r , b ear s p ecial c on si d e ra ti on due t o t he ir f unc ti on al im po rta n ce a nd t h era p e u tic im p licati ons. Recen t da t a fr om TCGA Breast Ca n cer pub licati on s ugg es t t h at t h e PI 3K / AK T and r as - M AP k i n ase p at h wa y s are p artic u larl y rele vant i n br eas t cance r based on fr equ e n t m u tati on, am p lificati on, a nd / o r acti v a tion of t h ese pa t hways as m easu r e d by g e no mic tec hno l og ies . P 13K - AK T i s a cen tr a l s i g nali ng p at h wa y do w n stream o f ma ny rece pto r

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

c s ubun it o f PI 3K ( PI 3CK A ) ma y b e a n im po rta n t c on tri bu ti ng fact o r t o mammar y t u m o r p r og r ess i on, a nd t h e site o f m u tati on d iffers d e p e nd i ng on t h e br east cance r m o l ecu l a r sub t yp e as no te d p re v i ou sl y . Acti v ati ng m u tati ons o f t he A K T gene f am il y are see n i n 2 % t o 4 % o f b reast ca n cer s, e x cl ud i ng t he basa lli ke sub t yp e , w h ere t h e y are rare . P TEN dephospho r y l a t es— a nd t h eref o re i n acti v ates — t h e p 1 10 catal ytic do mai n o f PI 3K and i s e it he r m u tate d o r und ere xp resse d (e .g., v ia met hy lati on ) i n m any b r eas t c a n cers . Acti v ati on o f t h e PI 3 K p at h wa y , i n t urn, r es u lt s i n t he 3 - phosphoino siti d e –d e p e nd e n t k i n ase-me d iate d acti v atio n o f seve r a l known k i n ases , i n cl ud i ng AKT 1, AKT 2, a nd AKT 3. In te r esti ng l y , ac ti va t ed AK T 1 a pp ears t o b e a n tia pop t o tic bu t als o p la y s an a n ti - i nvas i ve r o l e i n t u m o r f o rmati on. I n a dd iti on t o t h e AK T s , do w n stre am pro li f e ra ti ve e f f ec t o r s o f t he PI 3 K p at h wa y als o i n cl ud e t h e m T OR c o m plex

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Angiogenesis

nan nan

Angiogenesis

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Angiogenesis

nan nan

Ang i ogenes i s i s no rm a ll y a ti gh tl y re gu late d p r o cess o f v essel f o rmati on dur i ng phys i o l og i c even t s, su c h as w ound h eali ng a nd p re gn a n c y . It h as a lso b ee n s hown t o be an im po rt an t p art o f t u m o r g r o wt h a nd s p rea d. I n c on t rast t o phy si o l og i c ang i ogenes i s, t u m o r -ass o ciate d a ng i og e n esis is h i gh l y dy s r e gu l a t ed w it h d i so r gan i zed a nd d ist o rte d v asc u lat u re a nd i n crease d v asc u la r pe rm eab ilit y . T hus, i n rece n t y ears , a ng i og e n esis h as b ec o me a fr e qu e n t t a r ge t f o r t he tr ea tm en t o f ma ny ca n cers . Ce n t ra l t o t h i s p r ocess i s the p r o a ng i og e n ic fact o r , v asc u lar e ndo t h eli al grow t h f ac t o r ( V E G F) , wh i ch t og et h er wit h its rece p t o rs , re gu late e ndo t h e l i a l ce ll g r ow t h and n ew v essel f o rmati on . VEGF rece p t o rs (VEG F R ) , li ke E G F Rs, a r e a ls o t y r o si n e- k i n ase rece p t o rs . VEGF-A b i nds t o bo t h V E G F R1 (Flt- 1 ) and V EGFR 2 (KDR/Fl k1 ) . VEGFR 2 a pp ears t o me d iate m os t o f t he known c ell u lar res pon ses t o VEGFs , w h ereas t h e fun cti on o f V E G F R1 i s l ess well d efi n e d. Be v aciz u ma b, a hu ma n ize d m ono cl ona l an ti body d ir ec t ed a g ai n st VEGF-A , h as b ee n t h e m o st e x te n si ve l y s t ud i ed t hus f a r . T o d ate , t h ree la r g e ra ndo mize d trials h a v e s hown a s t a ti s ti ca ll y s i gn ifi ca nt b e n efit i n p r og ressi on -free s u r v i v al w h e n

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Angiogenesis

nan nan

b e v aciz u m ab was added t o a v ariet y o f d i f fere n t c h em o t h era p ies i n t h e fir st -li n e meta s t a ti c se tti ng. Howev e r , t h e lac k o f s u r v i v al a dv a n ta g e i n a ny st udy h as le d t o t he w it hd r awa l o f b e v aciz u ma b ’ s a pp r ov al , a nd st ud ies i n early sta g e breas t cance r a r e r equ ir ed t o b e po siti v e i n o r d er t o rec on si d er its u s e i n br eas t cance r . Mu ltit a r ge t ed VEGFR t y r o si n e- k i n ase i nh i b it o rs s u c h a s s un iti n i b ( V E G F R, p l a t e l e t- d eri v e d g r o wt h fact o r rece p t o r (PDGFR) , a nd c - k it b l o c kade ) and so r a f en i b ( V EGFR a nd RAF k i n ase b l o c k a d e) h a v e al so b ee n st ud i ed ex t ens i ve l y i n b r e ast a nd o t h er ca n cers . Des p ite t h e s u ccess o f s o me of t hese agen t s, t he i den tificati on o f p re d icti v e fact o rs f o r a n a n tia ng i ogen i c r esponse have t hu s far p r ov e n t o b e el u si v e .

SUMMA R Y

nan nan

SUMMA R Y

SUMMA R Y

nan nan

B r east ca nce r i s a he t e r ogeneou s mali gn a n c y , wit h m u lti p le m o lec u lar s ub t yp es and c li n i ca l p r esen tati on s ra ng i ng fr o m a gg ressi v e t o i ndo le n t , a nd v a ry i ng i n d i s tri bu ti on by age , me nop a u sal stat u s , a nd racial g r oup. Rec ent m o lec u l a r ana l yses have shed li gh t on t h is h eter og e n eit y by ma pp i ng p atte rn s t ha t co rr espond t o c linical ph e no t yp es . T h ese st ud ies i n cl ud e , but a r e no t limit ed t o, t he s t udy o f g erm-li n e v ariati on s i n b reast ca n cer s u sce p ti b ilit y genes, gene exp ressi on, c opy nu m b er a nd s o matic m u tati ons, e p i g e n et ic m od ifi ca ti ons, and alterati on s i n p r o tei n p at h wa y s ass o ciate d w it h t h e m a li gnan t pheno t ype. T h is re v iew attem p ts t o s u mmarize t h e c urr e n t s t a t e o f t he sc i ence w it h a n em ph asis on t h e i n si gh ts p r ov i d e d by t h ese st ud i es on p r ognos i s and p re d icti on f o r t h era py a nd po te n tial n ew t h e r a p euti c t a r ge t s. It i s on l y thr ough ongo i ng researc h t h at t h is d isease will on e d a y be cu r ed.

SUMMA R Y

nan nan

Y ardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibito r . Clin Oncol 2013;31:2128–2135. Lee Y , Ahn C, Han J, et al. The nuclear RNase III Drosha initiates micro-RNA processing. Natu r e 2003;425:415–419. Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Natu r e 2000;403:901–906. Camps C, Bu f fa FM, Colella S, et al. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cance r . Clin Cancer Res 2008;5:1340–1348. Foekens JA, Sieuwerts AM, Smid M, et al. Four miRNAs associated with aggressiveness of lymph node-negative, estrogen recepto r -positive human breast cance r . P r oc Natl Acad Sci U S A 2008;105:13021–13026. Iorio M V , Casalini P , T agliabue E, et al. MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cance r . Eur J Cancer 2008;18:2753–2759. Kovalchuk O, Filkowski J, Meservy J, et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther 2008;7:2152– 2159. Miller TE, Ghoshal K, Ramaswamy B, et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by ta r geting p27Kip1. J Biol Chem 2008;283:29897–29903. Hanahan D, W einbe r g RA. The hallmarks of cance r . Cell 2000;100:57–70. Oesterreich S, Davidson NE. The search for ESR1 mutations in breast cance r . Natu r e Genet 2013;45:1415–1416. Massarweh S, Schi f f R. Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 2007;13:1950–1954. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: A TLAS, a randomised trial. Lancet 2013;9869:805–816. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-recepto r -positive advanced breast cance r . N Engl J Med 2012;366:520–529. Y arden Y , Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137. Hudis CA. T rastuzumab—mechanism of action and use in clinical practice. N Engl J Med 2007;1:39– 51. Jhaveri K, Esteva FJ. Pertuzumab in the treatment of HER2+ breast cance r . J Natl Compr Canc Netw 2014;12:591–598. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activit y . Nat Rev Cancer 2008;8:579–591. Hynes NE, Dey JH. PI3K inhibition overcomes trastuzumab resistance: blockade of ErbB2/ErbB3 is not always enough. Cancer Cell 2009;5:353–355.

SUMMA R Y

Mal i gnant T umors of the B reast

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Mal i gnant T umors of the B reast

AN A T OMY OF THE BR E AST

nan nan

AN A T OMY OF THE BR E AST

AN A T OMY OF THE BR E AST

nan nan

Th e a du lt f e m a l e b r eas t li es b etwee n t h e sec ond a nd si x t h ri b s , a nd b etw een t h e ste rna l edge and t he mi dax illar y li n e . T h e b reast is c o m po se d o f s k i n, s ub c u ta neous ti ssue, and b r ea st tiss u e , wit h t h e b reast tiss u e i n cl ud i ng both e p it h eli a l and s tr o m a l e l e m ent s . E p it h elial eleme n ts ma k e up 10 % t o 15 % of t h e br e as t m ass, w it h t he r e mai nd er b ei ng str o ma . Eac h b reast c on sists o f 15 t o 20 l obes o f g l andu l a r ti s s u e s uppo rte d by fi b r ou s c onn ecti v e tiss u e . Th e s p a ce be t ween l obes i s fille d wit h a d i po se tiss u e , a nd d i f fere n ces i n t he am oun t o f ad i pose ti ssue a r e res pon si b le f o r v ariati on s i n b reast size . T h e b l ood su pp l y o f t he b r eas t i s d eri v e d fr o m t h e i n ter n al mammar y a nd lat e r al t hor acic a rt e ri es. T he b r eas t lym ph atic d rai n a g e o cc u rs t h r ough a s up erfic ial a nd d ee p l y m pha ti c p l exus, and >95 % o f t h e l y m ph atic d rai n a g e o f t h e br east is t h r ough t he ax ill a r y ly m ph nod es , wit h t h e remai nd er v ia t h e i n te rn al m a mm a r y nodes. T h e a x illar y nod es are v aria b le i n nu m b er a nd h a v e t r aditi ona ll y been d i v i ded i n t o t h ree le v els b ase d on t h eir relati on s hip t o t h e pec t o r a li s mi no r m usc l e, as ill u strate d i n . T h e se n ti n el a x illa ry node i s a lm os t a l way s f ound i n t h e le v el 1 a x illar y nod es . T h e i n te rn al m a mm a r y nodes a r e locate d i n t h e first si x i n terc o stal s p aces wi thin 3 cm of t he s t e r na l edge, w it h t h e h i gh est c on ce n trati on o f i n ter n al mammar y nodes i n t he fir s t t h ree i n terc o stal s p aces .

RISK F AC T ORS FOR B REAST CANC E R

nan nan

RISK F AC T ORS FOR B REAST CANC E R

RISK F AC T ORS FOR B REAST CANC E R

Familial Factors

nan nan

Familial Factors

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

Inherited P r edisposition to B r east Cancer

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

M u tati ons i n t he b r eas t cance r s u sce p ti b ilit y g e n es BRCA 1 a nd BRCA 2 a r e ass o ciate d w it h a s i gn ifi can t i n crease i n t h e ris k o f b reast a nd ov aria n ca r ci noma, and accoun t f o r 5 % t o 10 % o f all b reast ca n cers . T h ese m u tati ons a r e i nhe rit ed i n an a u t o s o mal do mi n a n t fas h i on a nd h a v e v ar ying p e n et r an ce. As a r esu lt , t he est imate d lifetime ris k o f b reast ca n cer d e v el opmen t i n m u t a ti on ca rr i ers ra ng es fr o m 26 % t o 85 % , a nd t h e ris k o f

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

ov a r ia n cance r fr o m 16 % t o 63 % a nd 10 % t o 27 % , res p ecti v el y , i n carri e r s of BR C A1 and BR C A 2 I n a m eta-a n al y sis o f 10 i n ter n ati on al st ud ies , t he c u m u lati ve ri sks t o age 70 f o r b reast ca n cer were 57 % f o r BRCA 1 a nd 40 % for BR C A2 ca rri e r s . Mo r e t h a n 700 d i f fere n t m u tati on s o f BRCA 1 a nd 300 d i f f e r e n t m u t a ti ons o f BR C A 2 h a v e b ee n d escri b e d, a nd t h e po siti on o f t he m u tati on w it h i n t he gene has b ee n s ho w n t o i n fl u e n ce t h e ris k o f bo t h b r east a nd ov a r i an cance r s. O t h er cance r s assoc i a t ed wit h BRCA 1 o r BRCA 2 m u tati on s i n cl ud e m ale br east c ance r , f a ll op i an t ube c a n ce r , a nd p r o state ca n ce r . Carriers o f BR CA2 ma y als o have an e l eva t ed ri sk o f mela no ma a nd g astric ca n ce r . Ma n a g em en t s tr a t eg i es ava il ab le f o r ris k re du cti on i n BRCA 1 / 2 m u tati o n ca rr ie r s i nc l ude i n t ens i ve su r v eilla n ce , c h em op re v e n ti on wit h selecti v e est rog e n r ecep t o r m odu l a t o r s (SERM) , a nd p r ophy lactic ( b reast a nd sal p i ngo-ova ri an ) su r ge r y , and t h ese are d isc u sse d i n a later secti on. T h er e is a gr eat i n t e r es t i n t he r o l e o f e nv ir on me n tal a nd lifest y le fact o rs i n t h e m od i f ic a ti on o f cance r ri sk a m ong BRCA 1 o r BRCA 2 carriers; at p rese n t, how e v e r , t he ava il ab l e da t a a re i n c on siste n t . It is w o rt h no ti ng t h at w o m en w it h a sig n ifi can t f a mil y h i s tor y o f b reast ca n cer (i . e ., tw o o r m o re b reast ca n ce r s unde r t he age o f 50 y ears , o r t h ree o r m o re b reast ca n cers at a ny a g e ), bu t who t es t nega ti ve f o r BRCA m u tati on s h a v e a pp r ox imatel y a f ou r - fo l d r is k o f b r eas t cance r I n c on trast , w o me n i n families w h ere a BRC A m u tati on i s p r esen t who t es t n e g ati v e f o r t h e m u tati on are no t at i n creas ed r is k for b r eas t cance r deve l opm e n t i n t h e a b se n ce o f o t h er ris k fact o rs , a nd do no t requ ir e spec i a l su r ve ill an ce . W o m en w it h BR C A 1 m u t a ti on s h a v e a h i gh er i n ci d e n ce o f tri p le- n e g ati v e /basa l-li ke b r eas t canc ers (see t h e f o ll o wi ng ) , a nd ca n cers are m o r e li k el y t o be g r ade 3 t u m o r s an d t o lac k e xp ressi on o f t h e estr og e n rece p t o r (E R ), proges t e r one r ecep t o r (PR) , a nd HER 2 ov ere xp ressi on t h a n s po ra dic ca n ce r s . T he pheno t ype o f BRCA 2 ca n cers do es no t d i f fer fr o m t h at se en i n s por a d i c cance r s. T he p r esen ce o f a BRCA 1 o r BRCA 2 m u tati on ma y be s ugg est ed by t he f a mil y h i s t o r y on eit h er t h e mater n al o r p ater n al si d e of the f amil y . T he f ea t u r es cons i de r ed by t h e 2005 US Pre v e n ti v e Ser v ices T ask F or c a r e li s t ed i n . Less-ri go r ou s criteria f o r referral f o r g e netic

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

c oun seli ng a r e used f o r i nd i v i du als o f As hk e n azi Jewis h a n cestr y , b eca u s e t h e ca rr i e r fr equency o f spec ific BRCA 1 ( 187d elAG , 5385 i n s C) a nd BR C A2 ( 6174de lT) m u t a ti on s i n t h is g r oup is 1 : 40, c o m p are d wit h 1 : 50 0 in t h e g e n e ra l popu l a ti on. T hese gu i d eli n es are p artic u larl y u sef u l f o r i nd i v i du al s no t a f f ec t ed w it h breast ca n ce r . I n t h e p atie n t wit h n ewl y d ia gno se d b r eas t cance r , young a g e at d ia gno sis ( ≤40 y ears) , b ilateral b r east ca n ce r , Ashkenaz i ances tr y , o r a mali gn a n c y c on siste n t wit h t h e BRCA 1 ph e no t ype a ll cons tit u t e r eason s f o r referral t o a g e n etic c oun sel o r , p a r tic u l a rl y i n t he wo m an w it h a small nu m b er o f female relati v es . M odels a r e a v ail ab l e t o es tim a t e t he li k eli hood o f a BRCA 1 o r BRCA 2 m u tati on b ase d on f a mil y h i s t o r y . T he i mp licati on s o f g e n etic testi ng f o r bo t h i nd i v i du al s and t he ir f a mil y mem b ers are c on si d era b le , a nd t h ese iss u es s hou l d b e d i scussed p ri o r t o und erta k i ng g e n etic testi ng. O t h er gene ti c m u t a ti ons hav e b ee n ass o ciate d wit h b reast ca n cer ris k, alt hough w it h a l owe r p r eva l en ce o r p e n etra n ce t h a n BRCA 1 a nd BRCA 2 . T P53 a nd PTE N each accoun t f o r <1 % o f cases , w h ile m u tati on s i n CD H1 a r e ass oc i a t ed w it h an au t oso mal do mi n a n t p re d is po siti on t o d i f f u se g as t r ic ca n ce r a nd l obu l a r b r eas t canc e r Y oung w o me n wit h TP 53 m u tati on s ( Li -

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

F r a u me n i synd r o m e ) see m t o h a v e a g reater p r op e n sit y f o r HER 2 + b reas t ca n ce r s . Mu t a ti ons i n l ow - p e n etra n ce g e n es are t hough t t o acc oun t f o r a si gn i f ic an t nu m be r o f non - BRCA 1 o r - BRCA 2 b reast ca n cers . A s p ecific m u tati on o f t he checkpo i n t k i n ase 2 ( CHEK 2 ) g e n e was f ound i n 1 1.4 % o f f amilies w it h t h r ee o r m o r e c ases o f b reast ca n cer d ia gno se d b ef o re a g e 60, bu t i n a l a r ge s t udy o f 10,860 un selecte d b reast ca n cer p atie n ts fr om f i v e c oun tri es, t he CH E K2 m u tati on was i d e n tifie d i n on l y 1.9 % o f case s

RISK F AC T ORS FOR B REAST CANC E R

Inherited P r edisposition to B r east Cancer

nan nan

RISK F AC T ORS FOR B REAST CANC E R

Hormonal Factors

nan nan

Ag e a t m ena r che and t he e sta b lis h me n t o f re gu lar ovu lat o r y c y cles ar e st rong l y li nked t o b r eas t canc er ris k ; t h e t o tal du rati on o f e xpo s u re t o e ndog e nous es tr ogens see m s i m po rta n t . T h ere a pp ears t o b e a 20 % d ecr ease i n br eas t cance r ri sk f o r each y ear t h at me n arc h e is d ela y e d. Of no te , hor m one l eve l s t h r ough t he re p r odu cti v e y ears i n w o me n w ho e xp erie n c e ea r l y m ena r che m ay be h i gher t h a n i n w o me n w ho und er go a later me n a r ch e Add iti ona ll y , l a t e on set o f me n arc h e res u lts i n a d ela y i n t h e esta b lis h m en t o f r egu l a r ovu lat o r y c y cles , w h ic h ma y c on tri bu te t o pro tecti ve e f f ec t s. Th e r el a ti onsh i p be t ween p re gn a n c y a nd b reast ca n cer ris k a pp ears mo r e c o m p lic a t ed. W o m en whose f i rst f u ll-term p re gn a n c y o cc u rs after a g e 30 h a v e a tw o - t o fi ve -f o l d i nc r ea se i n b reast ca n cer ris k i n c o m p aris on wit h wo me n w ho have a fir s t f u ll-term p re gn a n c y b ef o re a pp r ox imatel y a g e 18. Nu lli pa r ous wo m en a re at g reater ris k f o r t h e d e v el op me n t o f b rea st ca n ce r t han pa r ous wo m en, w it h a RR o f a bou t 1.4. Breast ca n cer ris k i n c r ease s tr ans i en tl y f o r t he 10 y ears after a p re gn a n c y , bu t t h e n d ecli n e s

RISK F AC T ORS FOR B REAST CANC E R

Hormonal Factors

nan nan

RISK F AC T ORS FOR B REAST CANC E R

Hormonal Factors

nan nan

Abor ti on, whe t he r spon t aneo us o r i ndu ce d, do es no t i n crease b reast ca nce r r is k. B reas tf eed i ng, pa rti cu larl y f o r l ong er du rati on, l o wers t h e ris k o f br east c ance r d i agnos i s. T he c o m b i n e d effects o f re p r odu cti v e h ist o r y a nd br east f ee d i ng m ay accoun t f o r s ub sta n tial fracti on s o f t h e d i f fere n ce i n br east c ance r ri sk be t ween dev el op e d a nd d e v el op i ng n ati on s . Th e use o f co m b i ned es tr og e n a nd p r og esti n H R T als o i n creases b rea st ca n ce r risk. I n t he W o m en ’ s Healt h I n itiati v e , u se o f c o m b i n e d estr og e n and prog esti n H R T was assoc i a t ed wit h a h azar d rati o (HR) o f 1.24 ( p <0.001 ) for br ea s t cance r deve l op m en t as c o m p are d t o p lace bo T h e e f fects o f H R T w er e no t ed a ft e r a r e l a ti v el y s ho rt du rati on o f u se . A n e x cess o f a bnor m a l m a mm og r a m s was ob ser v e d after 1 y ear o f H R T u se a nd p e r siste d t h r oughou t t he s t ud y , a nd a n i n crease i n b reast ca n cer i n ci d e n ce w as no t ed a ft e r 2 yea r s. T he ca n cers o cc u rri ng i n H R T u sers were la r g er a nd m ore li ke l y t o have noda l o r d ista n t metastases t h a n t ho se o cc u rri ng in t h e p lace bo g r oup ( 25.4 % ve rs u s 16 %; p = 0.04 ) , alt hough t h e y were o f simila r h i s t o l ogy and g r ade . T h e ob ser v ati on al UK Milli on W o me n Stu dy found t ha t cu rr en t use o f H R T was ass o ciate d wit h a RR o f b reast ca n cer

RISK F AC T ORS FOR B REAST CANC E R

Hormonal Factors

nan nan

d e v el opmen t o f 1.66 ( p <0.001 ) a nd a RR o f b reast ca n cer d eat h o f 1.22 ( p = 0.05).

RISK F AC T ORS FOR B REAST CANC E R

Dietary and Lifestyle Factors

nan nan

Dietary and Lifestyle Factors

RISK F AC T ORS FOR B REAST CANC E R

Dietary and Lifestyle Factors

nan nan

Ob se rv a t i ona l s t ud i es sugges te d t h at h i gh -fat d iets were ass o ciate d wit h h i gh e r r at es o f b r eas t cance r t h a n l o w-fat d iets . H o we v e r , a meta-a n al y si s o f ei gh t prospec ti ve ep i de mi o l og ic st ud ies faile d t o i d e n tif y a n ass o ciati on b et w ee n f a t i n t ake and b r eas t c a n cer ris k i n a du lt w o me n i n d e v el op e d c oun t r ie s. Cons i s t en t w it h t h ese fi nd i ng s , a ra ndo mize d d ietar y m od i f ic a ti on i n 48,835 wo m en i n t h e W o me n ’ s Healt h I n itiati v e st udy d i d no t r es ul t i n a s t a ti s ti ca ll y s i gn ifica n t re du cti on i n b reast ca n cer i n ci d e n c e a f te r 8 yea r s o f f o ll ow - up . Breast ca n cer ris k i n creases li n earl y wit h t he am oun t o f a l coho l consu m ed Decrease d i n ta k e o f nu trie n ts s u c h as v itami n C, f o l a t e, and β- ca r o t en e ma y e nh a n ce t h e ris k relate d t o alc oho l c on s u m p ti on. Ob esit y i s assoc i a t ed w it h bo t h a n i n crease d ris k o f b reast ca n cer d e v el opmen t i n pos tm enopau sal w o me n a nd i n crease d b reast ca n cer m or talit y . W o m en w it h a body mass i nd e x o f ≥31.1 h a v e a 2.5 -f o l d g rea te r r is k of deve l op i ng b r eas t canc er t h a n t ho se wit h a body mass i nd e x o f ≤22.6. W e i gh t and we i gh t ga i n a pp ear t o p la y a n im po rta n t bu t c o m p le x ro le i n breas t cance r ri sk. Du ri ng c h il dhood, ra p i d g r o wt h rates d ecrease the a g e of m ena r che, an es t ab li sh e d ris k fact o r , a nd res u lt i n g reater attai n e d stat ur e , wh i ch has been cons i s te n tl y ass o ciate d wit h i n crease d ris k. D u rin g ea r l y a d ult lif e, obes it y i s asso ciate d wit h a l o wer i n ci d e n ce o f b reast ca nce r b e for e m enopause, bu t no r edu cti on i n b reast m o rtalit y . W ei gh t g ai n afte r a g e 18 is assoc i a t ed w it h a g ra d e d a nd s ub sta n tial i n crease i n po stme nopausa l b r eas t cance r , p artic u larl y i n t h e a b se n ce o f H R T

RISK F AC T ORS FOR B REAST CANC E R

Benign B r east Disease

nan nan

Benign B r east Disease

RISK F AC T ORS FOR B REAST CANC E R

Benign B r east Disease

nan nan

Be n i gn b r eas t l es i ons a r e c l as sifie d as p r o liferati v e o r nonp r o liferati v e . Nonpro l i f e r a ti ve d i sease i s no t ass o ciate d wit h a n i n crease d ris k o f b rea st ca n ce r , whe r eas p r o lif e r a ti ve d isease wit hou t at yp ia res u lts i n a small

RISK F AC T ORS FOR B REAST CANC E R

Envi r onmental Factors

nan nan

Envi r onmental Factors

RISK F AC T ORS FOR B REAST CANC E R

Envi r onmental Factors

nan nan

Expo s ure t o i on i z i ng r ad i a ti on i n creases b reast ca n cer ris k, a nd t h e i n cre ase is p a r ticul a rl y m a r ked f o r expo s u re at a young a g e . T h is p atter n h as b een ob se rv e d i n su r v i vo r s o f t he a t o mic bo m b i ng s , t ho se und e r go i ng m u lti p l e d ia gno st ic X -r ay exa mi na ti on s , a nd i n w o me n recei v i ng t h era p e u tic i rr a d iatio n. A m a r ked l y i nc r ea se d ris k o f b reast ca n cer d e v el op me n t h as b ee n r ep o rt ed i n wo m en who recei v e d ma n tle irra d iati on f o r t h e treatme nt

RISK F AC T ORS FOR B REAST CANC E R

Envi r onmental Factors

nan nan

of Hodgk i n l y m pho m a be f o r e a g e 15 y ears . A dd iti on all y , i n w o me n wi th Hodgk i n l y m pho m a who deve l op un ilateral b reast ca n ce r , t h e ris k o f a c on t r ala te r a l cance r app r ox im a tes t h e le v el o f ris k see n i n BRCA m u tatio n ca rr ie r s . W e ll- conduc t ed s t ud ies do no t s ugg est t h at e xpo s u re t o elect romagne ti c fi e l ds and o r g a no c h l o ri n e p estici d es i n crease b reast ca n c e r r is k. A s u mm a r y o f t he m agni t ud e o f ris k ass o ciate d wit h kno w n b reast ca n ce r risk f ac t o r s i s p r ov i ded i n .

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

MANA GE M E NT OF THE HIGH-RISK PA TIENT

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

Th e r e is no f o rm a l de fi n iti on o f w h at c on stit u tes h i gh risk . W it hou t qu esti on, wo m en who ca rr y m u tati on s i n eit h er BRCA 1 o r BRCA 2 , o r wh o h a v e a fa mil y h i s t o r y cons i s t en t wit h g e n eticall y tra n smitte d b reast ca n c e r , a r e c on si de r ed t o be a t h i ghe r ris k t h a n t ho se i n t h e g e n eral popu lati on. O t h e r h i gh -ri sk g r oups i nc l ud e w o me n w ho h a v e recei v e d ma n tle i rr a d iatio n, usua ll y f o r tr ea tm en t o f H odgk i n l y m pho ma , a nd t ho se wit h l obu la r c a r c i no m a i n s it u (L C IS) o r at yp ical hyp er p lasia . Alt hough a v ar iety of hor m ona l f ac t o r s ( e.g., ea rly me n arc h e , late a g e at first f u ll-term pr e gn a ncy ) a f f ec t b r eas t canc er ris k on a popu lati on b asis , t h ese c ond itio ns h a v e a re l a ti ve l y s m a ll e f f ec t on ris k f o r a ny i nd i v i du al w o ma n. Ma ny wo m en ove r es tim a t e t h eir ris k o f d e v el op i ng b reast ca n ce r , s o prov i d i n g an accu r a t e assess me n t o f b reast ca n cer ris k will o fte n alla y

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

a nx iet y and f ac ilit a t e m anagem e n t d ecisi on s . It ca n b e h el p f u l t o p r ov i d e wo me n w ho a r e conce r ned abou t t h eir b reast ca n cer ris k wit h a nu meric r is k estim a t e. T he Ga il e t a l . mod el , w h ic h calc u lates a w o ma n ’ s ris k o f d e v el oping b r eas t cance r based on a g e at me n arc h e , a g e at first li v e b irt h, nu m b e r o f p r ev i ous b r eas t b io p sies , t h e p rese n ce o r a b se n ce o f at yp ical hyp e rp l as i a, and t he nu m be r o f first- d e g ree female relati v es wit h b reast ca n ce r , has been used i n t he Nati on al S u r g ical A d j uv a n t Breast a nd B o we l P ro ject ( N S AB P) b r eas t cance r p re v e n ti on trials . Eff o rts t o v ali d ate t h e G ail et al . m ode l i n d i f f e r en t se tti ng s h a v e p r odu ce d v aria b le res u lts . It was h i gh l y a ccu r a t e i n t he N S AB P P 1 p re v e n ti on trial , wit h a rati o o f ob ser ved t o pr e d i c t ed cance r s i n s t udy p artici p a n ts o f 1.03. I n g e n eral , t h e Gail et al .

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

m od el i s t hough t t o unde r es ti m ate ris k i n w o me n wit h str ong famil y h ist or ies , a t l eas t i n pa rt becau se it on l y i n c o r po rates a famil y h ist o r y i n f i r st -d e g r ee r e l a ti ves and doe s no t i n cl ud e ov aria n carci no ma . T h e Cla u s et al m ode l t akes i n t o accoun t bo t h first- a nd sec ond - d e g ree relati v es , alt hough it does no t i nc l ude oth er ris k fact o rs , a nd ma y b e m o re u sef u l f o r wo me n at ri sk on t he bas i s o f famil y h ist o r y . Ma nage m en t s tr a t eg i es av aila b le f o r h i gh -ris k w o me n i n cl ud e i n te n si ve s urv eill ance, che m op r even ti o n wit h e ndo cri n e a g e n ts , a nd p r ophy lactic s u r g e r y . S u r ve ill ance, cons i s t ing o f m on t h l y b reast self-e x ami n ati on, a nnual sc r ee n i ng m a mm og r aph y , and cli n ical b reast e x ami n ati on s on ce o r twic e y ea r l y , d i d no t c l ea rl y r esu lt i n earl y d etecti on i n h i gh -ris k w o me n i n t h e p lace bo arm o f t he N S AB P P1 p re v e n ti on trial w h ere 29 % o f t h e w o me n who d e ve l oped b r eas t cance r h a d a x illar y nod e metastases at d ia gno sis .

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

W o me n a t ri sk as a r esu lt o f kno w n o r s u s p ecte d BRCA 1 o r BRCA 2 m u tati ons wa rr an t sc r een i ng wit h ma gn etic res on a n ce ima g i ng (MRI) , wh ic h resu lt s i n ea rli e r de t ec t ion o f b reast ca n cer t h a n c onv e n ti on al s urv eill ance s tr a t eg i es, and h as a h i gh er s p ecificit y a nd se n siti v it y am ong h i gh-r is k wo m en . Because t h e ca n cers d etecte d by MRI are smaller a nd less li k el y t o be assoc i a t ed w it h nod al po siti v it y , it is li k el y t h at a s u r v i val b e n e f it is p r esen t . Howeve r , t h ere is no b e n efit f o r MRI scree n i ng i n w o m en w it h at yp i ca l hype r p l as i a o r L CIS . A n e xp ert p a n el c onv e n e d by t h e A me r ic an Cance r S oc i e t y i n 2007 t o d e v el op gu i d eli n es f o r MRI scree n i ng

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

r ec o mm ended t he use o f MR I i n a dd iti on t o mamm og ra phy f o r a small group of wo m en a t ve r y h i gh ris k o f b reast ca n cer d e v el op me n t , eit h er due t o g e n eti c f ac t o r s o r a h i s t o r y o f p ri o r t ho racic irra d iati on ( ) . It h as b ee n es tim a t ed t ha t on l y 1% o f t h e popu lati on w ou l d b e eli g i b le f o r MR I sc reen i ng us i ng t hese c riteria . F o r w o me n wit h a <15 % ris k o f b r east ca n ce r d e ve l op m en t , t he A m e rica n Ca n cer S o ciet y rec o mme nd e d a g ai n s t t h e u se o f MR I sc r een i ng . I n t h e remai nd e r , t h e y t hough t t h at t h e e v i d en ce w as i n s u f fi c i en t t o r eco mm end f o r o r a g ai n st MRI scree n i ng. C h em opreven ti on i s an op ti on i n a dd iti on t o s u r v eilla n ce strate g ies . T w o S E RMs , t a m ox if en and r a l ox ife n e , h a v e b ee n s ho w n t o re du ce t h e i n ci d e n ce o f E R + b r eas t cance r . F ou r p r o s p ecti v e , ra ndo mize d trials h a ve e x ami n ed t he e f f ec t o f t a m ox ife n on b reast ca n cer i n ci d e n ce (

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

a nd T he r e i s cons i d era b le h eter og e n eit y i n ou tc o me am ong t he t r ials , m uch o f wh i ch can be attri bu te d t o d iffere n ces i n t h e popu lati on s st ud ie d. In an ove r v i ew o f t he f ou r st ud ies , tam ox ife n p r odu ce d a 38 % r e du cti on i n b r eas t cance r i nc i d e n ce ( 95 % c on fi d e n ce i n ter v al [CI] , 8 t o 46; p < 0.001 ) , and a 48 % r educ ti on i n t h e i n ci d e n ce o f E R + b reast ca n cers . No e f f ect on t he i nc i dence o f E R − ca n cers was see n i n a ny o f t h e trials , a nd the ca n ce r s occu rri ng i n wo m en t ak i ng tam ox ife n were no t f ound t o h a v e h a d m or e pos iti ve nodes o r t o be l a r g er i n size t h a n t ho se i n t h e p lace bo arm , prov i d i n g r eassu r ance t ha t t a m ox ife n c h em op re v e n ti on do es no t res u lt i n t h e o cc ur r ence o f b i o l og i ca ll y m o re-a gg ressi v e ca n cers .

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

i n ci d e n ce o f 1 1.7 pe r 1,000 co m p are d wit h 8.1 p er 1,000 i n t h e tam ox ife n group at 6 yea r s ( RR = 1.4 ; p = 0.052 ) . A m o re fa vo ra b le si d e-e f fect p r o f ile w as see n f o r r a l ox if ene, w it h a re du cti on i n t h e nu m b er o f hy sterect o mi es a nd e ndo m e tri a l cance r s i n t he ral ox ife n e g r oup (RR = 0.62 ; 95 % CI = 0.35 t o 1.08), a lt hough t he d i f f e r en ce d i d no t reac h statistical si gn ifica n ce . Si gn i f ica n tl y f ewe r t h r o m boe m bo lic e v e n ts a nd cataracts o cc u rre d wit h r al ox i f en e. Ra l ox if ene i s t hus a v ia b le alter n ati v e t o tam ox ife n f o r t h e c h em opreven ti on o f b r eas t can cer i n po stme nop a u sal w o me n at i n crease d r is k for t he d i sease. I n add iti on, t h e u se o f ral ox ife n e i n w o me n wit h o ste oporos i s has t he po t en ti a l t o l o wer b reast ca n cer i n ci d e n ce i n a g r oup o f wo me n no t cons i de r ed a t h i gh ris k. T r ial s o f a r o m a t ase i nh i b it o rs (AI) f o r b reast ca n cer p re v e n ti on s ugg es t qu alitati ve l y s imil a r r esu lt s as see n wit h SERMs . T h e MA P .3 trial e x am ined t h e u se o f t he A I exe m es t ane i n po stme nop a u sal w o me n wit h a Gail ris k sc or e of 1.66, a t yp i ca l hype r pl asia , LCIS , o r un ilateral du ctal carci no ma in sit u (DC IS) tr ea t ed w it h m as t e ct o m y . After a me d ia n f o ll o w- up o f 3 y ear s, a 65% r e duc ti on i n i nvas i ve b reast ca n cer was see n wit h e x emesta n e ( p = 0.002) T he r educ ti on i n can cer i n ci d e n ce was als o limite d t o E R + ca n cer s. A t pr ese n t , t he r e a r e no che mo p re v e n ti v e a g e n ts t h at h a v e b ee n p r ov e n t o b e e f f ec t i ve i n r educ i ng t he inci d e n ce o f E R − b reast ca n ce r . Th e 2013 A m e ri can S oc i e t y o f Cli n ical O n c o l ogy (ASCO) gu i d eli n e on ph a r ma co l og i c agen t s f o r b r e ast ca n cer ris k re du cti o n rec o mme nd s d isc u ssio n o f t a m ox if en f o r br east ca n cer ris k re du cti on wit h pr eme nopausa l wo m en age 35 a nd o l d er at i n crease d ris k f o r b reast ca n c e r d e v el opmen t , and d i scuss i on o f tam ox ife n, ral ox ife n e , a nd e x emesta n e w ith h i gh-r is k pos tm enopausa l wom e n. Hist o ries o f d ee p v ei n t h r o m bo sis , st rok e , pu lm ona r y e m bo li s m , o r tra n sie n t isc h emic attac k s are c on si d ere d c on t r ai nd i ca ti ons t o t he use o f bo t h tam ox ife n a nd ral ox ife n e . P rop h y l ac ti c su r ge r y , i n t h e f o rm o f b ilateral mastect o m y o r b ilateral sal p i ngo-oopho r ec t o m y , i s ano t h er op ti on f o r b reast ca n cer ris k re du cti on. Th e e f f ic acy o f p r ophy l ac ti c m astect o m y h as n e v er b ee n st ud ie d i n a pro s p ecti ve, r ando mi zed tri a l . I n a retr o s p ecti v e st udy o f 639 w o me n wh o h a d b ilat e r a l p r ophy l ac ti c m a stect o m y du e t o a famil y h ist o r y o f b reast

MANA GE M E NT OF THE HIGH-RISK PA TIENT

nan nan

ca n ce r a 90 % t o 94 % r educ ti on i n b reast ca n cer i n ci d e n ce ( 95 % CI = 71 % t o 99%) and an 81 % t o 100 % re du cti on i n b reast ca n cer m o rtalit y wit h prophy l ac ti c m as t ec t o m y comp are d t o un affecte d sisters o r Gail m od el pr e d icti ons was obse r ved. Pr o s p ecti v e st ud ies i n BRCA m u tati on carrier s ) de m ons tr a t e s im i lar le v els o f ris k re du cti on . P rop h y l ac ti c b il a t e r a l sa l p i ngo - oopho rect o m y is a n alter n ati v e ris k - r e du cti on s tr a t egy i n wo m en at ris k on t h e b asis o f BRCA m u tati on s , w hich h as t h e added bene fit o f r educ i ng t h e ris k o f ov aria n carci no ma , a d iseas e for wh ich e f f ec ti ve sc r een i ng i s no t a v aila b le . I n a p r o s p ecti v e st udy o f t he b e n e f its o f p r ophy l ac ti c sa l p i ngo - oopho rect o m y i n 170 BRCA m u tati on ca rr ie r s , Kau f f e t a l . obse r v e d t h at t h e HR f o r b reast ca n cer was re du ce d to 0.32 (95% C I = 0.08 t o 1.20 ) and t o 0.25 f o r gyn ec o l og ic ca n cer ( 95 % CI = 0.08 t o 0.74 ) a t a m ean f o ll ow - up o f 24 m on t h s . I n a meta-a n al y si o f ri sk - r e du cti on es tim a t es assoc i a t ed wit h ris k -re du ci ng sal p i ngo - oopho rect o m y in BR C A1 o r BR C A 2 m u t a ti on c arriers , statisticall y si gn ifica n t re du cti on s i n br east c ance r ( HR = 0.49 ; 95 % CI = 0.37 t o 0.65 wit h similar ris k r e du cti ons i n BR C A 1 and BRCA 2 m u tati on carriers) a nd i n t h e ris k o f BR C A1 / 2 - assoc i a t ed ova ri an o r fall op ia n t ub e ca n cer (HR = 0.21 ; 95 % CI = 0.12 t o 0.39 ) we r e obse r ved. M o re rece n tl y , rec ogn iti on t h at BRC A -ass o ciate d cance r s a ri se i n t h e fall op ia n t ub e rat h er t h a n t h e ov ar y h as le d s o me t o p r opose b il a t e r a l sa l p i ng ect o m y , wit h ov aria n p reser v ati on, as a r is k-r e d u c i ng s tr a t eg y , bu t t he e f ficac y o f t h is a pp r o ac h is un certai n.

DIAGNO S IS AND BI O PSY

nan nan

Th e pr e sence o r absence o f c arci no ma i n a s u s p ici ou s cli n icall y o r mamm og r aph i ca ll y de t ec t ed abno rmalit y ca n on l y b e relia b l y d etermi n e d

DIAGNO S IS AND BI O PSY

nan nan

by tiss ue b i ops y . An abno rm al MRI do es no t relia b l y i nd icate t h e p rese nce of ca n ce r , and a nonwo rri so me MRI do es no t relia b l y e x cl ud e carci no m a .

DIAGNO S IS AND BI O PSY

nan nan

DIAGNO S IS AND BI O PSY

nan nan

A v aila b l e b i opsy t echn i ques i n cl ud e fi n e n ee d le as p irati on (FNA) , c o re n ee d le biops y , and exc i s i ona l b i op s y . Nee d le b i op s y tec hn i qu es (FNA o r c or e b i opsy ) a r e p r e f e rr ed be ca u se t h e y are m o re c o st-effecti v e t h a n s u r g ical exc i s i on, and becaus e m o st b reast lesi on s are b e n i gn, t h e y a vo i d a s u r g ical sca r and po t en ti a l co smetic d ef o rmit y . F NA i s eas il y pe rf o rm ed, b u t re qu ires a trai n e d c y t op at ho l og ist f o r acc ur ate spec im en i n t e r p r e t a t ion a nd do es no t relia b l y d isti ngu is h i nv asi ve ca n ce r fro m DC IS , a pa rti cu lar d raw b ac k f o r nonp al p a b le a bno rmalities , wh ic h ar e o ft en DC IS . Co r e -c u tti ng n ee d le b i op s y h as ma ny o f t h e a dv a n tag es o f F NA, bu t p r ov i d es a h ist o l og ic s p ecime n s u ita b le f o r i n te rpr etati on by any pa t ho l og ist , a nd facilitates ER , PR , a nd HER 2 testi ng. False -n e ga ti ve r esu lt s fr o m s am p li ng err o r ma y o cc u r wit h bo t h c o re-c u tti ng need l e b i opsy and F N A . W h e n c on c o r d a n ce b etwee n t h e c o re b i op s y or F NA d i agnos i s, and t h e cli n ical a nd ima g i ng fi nd i ng s is no t pr ese n t , add iti ona l ti ssue sho ul d b e ob tai n e d, u s u all y by e x cisi on al b i ops y . C on ce rns abou t t he f a l se - nega ti v e rate o f ima g e- gu i d e d c o re b i op s y h a v e b ee n r es o l ved w it h t he ava il ab ilit y o f lar g e , v ac uu m-assiste d b i op s y d e v i ces t h at i n c rease t he ex t en t o f l es i on sam p li ng, c oup le d wit h t h e d e v el op men t o f clea r l y d e fi ned i nd i ca ti ons f o r f o ll o w- up s u r g ical b i op s y . False- n e g ati v e r ates of co r e b i opsy a r e now relia b l y <1 % . I nd icati on s f o r s u r g ical b i op s y fo ll ow i ng co r e b i opsy a r e li s te d i n Alt hough t h e fi nd i ng o f at yp ical duc t a l hype r p l as i a on a c o re b i op s y is un if o rml y acce p te d as a n i nd icati on f o r open su r g i ca l biop s y , t h e n ee d f o r s u r g ical e x cisi on o f all lesi on s show i ng a t yp i ca l l obul ar hyp er p lasia (ALH) o r LCIS remai n s c on t rove r s i a l ( d i scussed i n t h e secti on “L obu lar Carci no ma i n Sit u ”) . Pa p illa r y ca r c i no m a i n s it u canno t alwa y s b e rea d il y d isti ngu is h e d fr o m b e n i gn pap ill a r y l es i ons on a co re b i op s y , a nd ra d ial scar ma y b e d i f fic u l t to d isti ngu i sh fr o m t ubu l a r ca r c i no ma wit hou t c o m p lete rem ov al o f t h e lesi on.

L OB ULAR CARCIN OM A IN SI T U

nan nan

L OB ULAR CARCIN OM A IN SI T U

L OB ULAR CARCIN OM A IN SI T U

nan nan

In 1941, F oo t e and St ewa r t pub lis h e d t h eir la nd mar k st udy o f LCIS , d esc r i b in g a r e l a ti ve l y unco m mon e n tit y c h aracterize d by a n “alterati on o f l obu la r c y t o l og y .” T hey hypo t h esize d t h at LCIS was a p rec u rs o r lesi on o f i nv asi v e cance r , and, based on t h is , treatme n t wit h mastect o m y was r ec o mm ended. Mo r e r ecen tl y , t h e term ALH h as b ee n i n tr odu ce d t o d esc r i b e m o r pho l og i ca ll y s imila r , bu t less well- d e v el op e d, lesi on s . S o m e ce n te r s use t he t e rm l obu l ar n e op l a si a (LN) t o c ov er bo t h ALH a nd LCI S.

L OB ULAR CARCIN OM A IN SI T U

nan nan

M orpho l og i ca ll y , L N i s de fi n e d as “a p r o liferati on o f g e n erall y small a nd of te n l oose l y cohes i ve ce ll s or i g i n ati ng i n t h e termi n al du ct-l obu lar un it , w it h or wit hou t page t o i d i nvo l v eme n t o f termi n al du cts . ” In t he pas t , L C IS was m ost fre qu e n tl y d ia gno se d i n w o me n a g e d 40 t o 50, a d ec ade ea rli e r t han DC IS , bu t rece n t literat u re i nd icates t h at t h e i n ci d e n ce i n pos tm enopausa l w o me n is i n creasi ng . Determi n i ng t h e tr ue i n ci d e n ce o f L C IS i s d i f fi cu lt , as t h ere are no s p ecific cli n ical o r mamm og r aph i c abno rm a liti e s ass o ciate d wit h t h e lesi on a nd t h e d ia gno si s of L C I S i s o ft en m ade as an i n ci d e n tal , micr o sc op ic fi nd i ng i n a b reast b i op s y p e rf o rm ed f o r o t he r i n dicati on s . T h e p re v ale n ce o f LN i n a n o t h e rw i se ben i gn b r eas t b i opsy h as b ee n re po rte d as b etwee n 0.5 % a nd 4.3% L C IS i s bo t h m u ltif oc al a nd b ilateral i n a lar g e p erce n ta g e o f case s. In a n ana l ys i s o f n i ne s t udi es i n cl ud i ng 172 p atie n ts wit h LCIS w ho w e r e t r eat ed by b i opsy a l one, 15 % d e v el op e d i nv asi v e carci no ma i n t h e i p silate ra l b r eas t and 9.3 % ca rci no ma i n t h e c on tralateral b reast after 10 y ea r s of f o ll ow - up T h i s co rres pond s t o a ris k o f d e v el op me n t o f i nv as ive ca r ci noma o f abou t 1 % t o 2 % p er y ea r , wit h a lifetime ris k o f 30 % t o 40 % . In t h is st udy ( conduc t ed p ri o r t o e f fecti v e b reast ima g i ng ) , 5.7 % o f t h e p atie n ts d eve l oped m e t as t a ti c b reast ca n ce r . I n a m o re rece n t st udy o f 776 wo me n wit h L C IS f o ll owed i n a h i gh -ris k scree n i ng p r og ram at Mem o ri al Sl o a n-K ett e ri ng Cance r Cen te r , Ki ng et al re po rte d t h at 13 % h a d d e v el op e d cance r a t a m ed i an f o ll o w- up o f 58 m on t h s , a rate similar t o t hat see n i n o l de r s t ud i es. Cance r s were d etecte d at a me d ia n size o f 0.8 cm ( 0.1 cm t o 3.5 c m) , and 78 % we r e nod e n e g ati v e . MRI scree n i ng h a d no si gn i f ic an t im pac t on cance r s ta g e at d ia gno sis i n t h is c oho rt . S ub se qu e nt ca n ce r s a r e m o r e o ft en i nvas i v e du ctal carci no ma t h a n i nv asi v e l obu lar ca r ci noma (IL C ) , bu t t he i nc i d e n ce o f s ub se qu e n t ILC is s ub sta n tiall y i n c r ease d co m pa r ed w it h wo me n wit hou t LCIS . Alt hough t h e ris k f o r d e v el opmen t o f b r eas t cance r is b ilateral , s ub se qu e n t i p silateral carci noma is m or e l i ke l y t han con tr a l a t e ral b reast ca n ce r , s uppo rti ng t h e v iew t h at ALH a nd L C IS ac t bo t h as p r e c u rs o r lesi on s a nd as ris k i nd icat o rs . T h e RR for d e v el op m en t o f subsequen t b reast ca n cer is l o wer i n w o me n d ia gno s ed w it h AL H co m pa r ed w it h L CI S . T h eref o re , alt hough LN is a h el p f u l ter m

L OB ULAR CARCIN OM A IN SI T U

nan nan

for c o llecti ve l y desc ri b i ng t h is g r oup o f lesi on s , s p ecific classificati on i nto ALH a nd L C IS i s p r e f e r ab l e i n terms o f ris k assessme n t a nd ma n a g eme nt. L C IS i s t yp i ca ll y pos iti ve f o r ER a nd PR stai n i ng a nd n e g ati v e f o r HER2 / neu s t a i n i ng. L N ( and ILC) c h aracteristicall y lac k s e xp ressi on o f E-ca dh e r in , an ep it he li a l ce ll m e m b ra n e m o lec u le i nvo l v e d i n cell-cell a dh esi on. E- cadhe ri n nega ti v it y ser v es as a fairl y relia b le mea n s o f d isti ngu i sh i ng duc t a l fr o m l obu lar d isease , bo t h i n sit u a nd i nv asi v e . Ple o m orph i c L C IS i s a r e l a ti ve l y un c o mm on v aria n t o f LCIS c h aracteri zed by me d i u m-t o -l a r ge p l eo m o r ph ic cells c on tai n i ng ecce n tric nu clei , pro mi n e n t nuc l eo li , and eos i noph ilic c y t op lasm . As wit h classic LCIS , i t is u s u all y E R + and nega ti ve f o r E-ca dh eri n ; it als o tests po siti v e by imm unoh i s t oche mi s tr y (I HC ) f o r g r o ss c y stic d isease fl u i d p r o tei n - 15. Ple o m orph i c L C IS can be asso ciate d wit h ce n tral n ecr o sis , ma y b e ass o ciate d w it h m a mm og r aphi c micr o calcificati on s , a nd ma y b e d i f fic u l t to d isti ngu i sh fr o m DC IS . A lt hough p le o m o r ph ic LCIS h as a m o re a gg ress ive h ist o l og i c appea r ance t han c lassic LCIS , t h e relati v e rarit y o f t h is lesi on and t h e lac k of un if o rm d i agnos tic criteria ma k e it d iffic u lt t o kno w if p le o m orph i c L C IS has a d i f f er e n t n at u ral h ist o r y t h a n classic LCIS . G e n e t i c changes i n L N hav e b ee n e v al u ate d i n a nu m b er o f st ud ies using c o m p a ra ti ve geno mi c hyb ri d izati on. I n bo t h ALH a nd LCIS , t h ere was l oss at 16q21 - q23.1, an a lt e r ed r eg i on p re v i ou sl y i d e n tifie d i n i nv asi v e ca r ci noma . T h i s geno mi c s i gn at u re , c o mm on t o LN a nd ILC , f u rt h er s ugg ests t ha t L N i s a p r ecu r s or lesi on i n s o me w o me n. Ma nage m en t o f L N m us t a dd ress t h e b ilateral ris k, a nd op ti on s t h ere fo r e i n cl ud e su r ve ill ance, che m opr e v e n ti on, a nd p r ophy lactic b ilateral mastect o m y . S u r ve ill ance i s the strate gy selecte d by m o st p atie n ts . Mamm og r aph i c sc r een i ng i s t h e sta nd ar d b reast ima g i ng tec hn i qu e f o r p atie n ts s e l ec ti ng su r ve ill anc e . Breast MRI h as b ee n u se d, bu t , as no te d pr e v i ous l y , ex i s ti ng ev i dence do es no t s uppo rt its r ou ti n e u se f o r p atie n t s w it h L CIS . Pr ophy l ac ti c m as tect o m y re du ces b reast ca n cer ris k am ong h i gh-r is k wo m en by app r ox imatel y 90 % . C h em op re v e n ti on wit h tam ox i fen i n p atie n t s w it h L C IS has been e v al u ate d as p art o f t h e NSABP P 1 st ud y .

L OB ULAR CARCIN OM A IN SI T U

nan nan

DUC T AL CARCINOMA I N SI T U

nan nan

DUC T AL CARCINOMA I N SI T U

DUC T AL CARCINOMA I N SI T U

nan nan

D C I S is de fi ned as t he p r o lif e rati on o f mali gn a n t-a pp eari ng mammar y du ctal epit he li a l ce ll s w it hou t e v i d e n ce o f i nv asi on b e yond t h e b aseme n t mem br a ne. Pri o r t o t he w i desp rea d u se o f scree n i ng mamm og ra ph y , <5 % o f mammar y cance r s we r e DC IS . At p rese n t , 15 % t o 30 % o f t h e ca n cers d etecte d i n m a mm og r aphy sc ree n i ng p r og rams are DCIS , a nd t h e g reate st i n c r ease i n t he i nc i dence o f DC IS h as b ee n see n i n w o me n a g e d 49 t o 69 y ea r s . DC IS can p r esen t as a p al p a b le o r nonp al p a b le mass , Pa g et d isease o f t h e n i pp l e, an i nc i den t a l fi nd i ng at b i op s y , o r , m o st c o mm on l y , as mamm og r aph i ca ll y de t ec t ed c alcificati on s . A centr a l p r ob l e m i n t he ma n a g eme n t o f DCIS is t h e lac k o f und e r sta nd i ng o f it s na t u r a l h ist o r y a nd t h e i n a b ilit y t o d etermi n e w h ic h

DUC T AL CARCINOMA I N SI T U

nan nan

D C I S w ill p r og r ess t o i nvas i ve carci no ma du ri ng a w o ma n ’ s lifetime . Th e c on c ordance be t ween ri sk f ac t o rs f o r DCIS a nd i nv asi v e carci no ma s ugg ests t ha t t hey a r e pa rt o f t h e same d isease p r o cess . Attem p ts t o b et te r c h a r acteri ze t he na t u r a l h i s t o ry o f DCIS on t h e b asis o f p at ho l og ic feat u r es h a v e not been pa rti cu l a rl y su ccessf u l . T h e tra d iti on al m o r pho l og ic classi f ic a ti on i n t o co m edo, pap illar y , micr op a p illar y , s o li d, a nd cri b rif o r m t yp es is con f ounded by t he ob ser v ati on t h at as ma ny as 30 % t o 60 % o f D C I S le s i ons d i sp l ay m o r e t h a n on e h ist o l og ic p atter n. T o ov erc o me t h i s d i f f ic u lt y , a nu m be r o f c l ass if i cati on s b ase d on nu clear g ra d e a nd t h e pr ese n c e o r absence o f nec r os is h a v e b ee n d e v el op e d. N o si ng le classi f ic a ti on sche m e has been wi d el y a dop te d a nd, m o st im po rta n tl y , none of t h e cl ass ifi ca ti on sys t e m s ha v e b ee n p r o s p ecti v el y d em on strate d t o pr e d ict th e ri sk o f deve l op m en t o f i nv asi v e carci no ma . M o lec u lar p r o fili ng st ud ies i n DC IS have been li m ite d by t h e n ee d f o r h ist o l og ic e x ami n ati on o f t h e e n ti re l es i on t o r e li ab l y ex cl ud e t h e p rese n ce o f i nv asi v e carci no ma . The On c o t ype DX ( Geno mi c Heal t h, Re d w ood Cit y , CA) assa y u si ng p ara f fi n -em b e dd e d ti ssue was m od ifi ed f o r DCIS , a nd a n i n itial st udy s ugg este d u se fu l n e ss i n p r ed i c ti ng t he ri sk o f i nv asi v e i n - b reast rec u rre n ce . T h is f i nd i ng has no t been va li da t ed i n o t h er popu lati on s , no r h as t h is test b ee n s hown t o p r ed i c t t he bene fit of ra d i o t h era py ( R T) T h e a v aila b le d ata i nd icate t ha t DC IS l es i ons sh are ma ny o f t h e g e n etic alterati on s o f i nv as ive ca r ci noma, bu t p r ed i c t o r s o f p r og ressi on t o i nv asi on remai n t o b e i d e n tif ied.

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

Ca n ce r - s pec ifi c su r v i va l f o r t h e w o ma n d ia gno se d wit h DCIS e x cee d s 95 % , r e g a rd le ss o f t he t ype o f l oca l t h era py em p l oy e d . Mastect o m y , e x cisio n a nd R T , and exc i s i on a l one h a v e all b ee n p r opo se d as ma n a g eme n t st r ate g ie s f o r DC IS . T he app r op riate t h era py f o r t h e w o ma n wit h DCIS d e p e nd s on t he ex t en t o f t he DCIS lesi on, t h e ris k o f l o cal rec u rre n ce (L R ) w it h eac h f o rm o f tr ea tm en t , a nd t h e p atie n t ’ s attit ud e t o war d t h e ris k s a nd b e n e f its o f a pa rti cu l a r t he r ap y .

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

Th is s ugges t s t ha t even i n l ow -ris k DCIS , R T ca n l o wer t h e ris k o f i n - b r east r ec urr e nce. L R r a t es a ft e r exci si on a nd R T h a v e d ecrease d ov er time du e to im prov e men t s i n im ag i ng and p at ho l og ic a n al y sis . I n a retr o s p ecti v e re view of 246 c onsecu ti ve pa ti en t s tr e ate d at Da n a-Far b er Ca n cer I n stit u te a nd

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

B r i gh am and W o m en ’ s Hosp ital fr o m 2001 t o 2007, t h ere were no LRs w ith a me d ian f o ll ow - up tim e o f 5 8 m on t h s D es p it e t he c l ea r bene fit o f R T see n i n t h ese fi v e trials , t h ere was c on si d e rab l e i n t e r es t i n i den tif y i ng p atie n ts w ho c ou l d b e s p are d R T f o r D C I S . The Dana -F a r be r/ Ha r va r d Ca n cer Ce n ter c ondu cte d a si ng le-arm , pro s p ecti ve tri a l o f w i de exc i s i on al on e fr o m 1995 t o 2002 am ong 158 p atie n ts . E n tr y c rit e ri a i nc l u de d DCIS o f p re do mi n a n t g ra d e 1 o r 2 with a mamm og r aph i c ex t en t o f no g reater t h a n 2.5 cm a nd fi n al mar g i n wi d t h of at least 1 c m . T a m ox if en was no t p ermitte d. T h e st udy was cl o se d t o f u r the r acc ru al because t he nu m be r o f LRs ( n = 13 ) met t h e p re d efi n e d st opp i ng ru les . The m ed i an pa ti en t age was 51 y ears , a nd 94 % h a d mamm og r aph i ca ll y de t ec t ed D CIS . T h e me d ia n f o ll o w- up was 1 1 y ears , a nd 143 pa ti en t s we r e f o ll owed f o r >8 y ears . Ni n etee n p atie n ts d e v el op e d a n L R . F ou rt een r ecu rr ences were i n t h e same qu a d ra n t as t h e i n itial DCI S, a nd f i v e we r e e l sewhe r e i n t he i p silateral b reast . A t o tal o f 32 % rec u rre d w it h i nvas i ve d i sease. No pa tie n t d e v el op e d d ista n t metastasis . T h e 10 - yea r c u m u lati ve i nc i dence o f L R w as 15.6 % . Simi la r r esu lt s we r e seen i n t h e Easter n C oop erati v e O n c o l ogy Gr oup si ng le - a r m tri a l o f exc i s i on a lo n e f o r DCIS . Eli g i b ilit y criteria f o r t h is st udy i n cl ud e d DC IS a t l eas t 3 mm in size , e x cise d wit h a ma r g i n wi d t h o f ≥3 mm as d ete r mi ned by sequen ti a l s ecti on i ng, a nd c o m p lete em b e dd i ng. T h e st udy e nro lle d pa ti en t s w it h l ow - o r i n terme d iate- g ra d e DCIS ≤2.5 cm i n size and h i gh-gr a de DC IS ( de fi ned as nu clear g ra d e 3 wit h n ecr o sis) up t o 1 cm i n size . A pos t exc i s i on m a mm o gram was re qu ire d f o r all p atie n ts . At a me dian fo ll ow-up o f 8.8 yea r s, t he 10-y ear LR rate was 19.0 % f o r p atie n ts wit h h i gh-gr a de DC IS , and 14.6 % fo r t ho se wit h l o w- o r i n terme d iate- g ra d e D C I S T aken t oge t he r , t hese p r o s p ecti v e st ud ies i nd icate t h at e v e n p ati ents w it h small l ow - t o imm ed i a t e - g ra d e DCIS treate d wit h e x cisi on t o wi d el y n e g ati v e m a r g i ns o f r esec ti on h a v e a bou t a 15 % 10 - y ear ris k o f a LR i n t he a b se n ce o f R T . No r educ ti on i n rec u rre n ce was ob ser v e d f o r p atie n ts e x cise d t o m a r g i ns o f ≥1 c m c o m p are d t o t ho se wit h ma r g i n s o f 3 t o 9 mm. Th e 2016 Na ti ona l Co m p r eh e n si v e Ca n cer Netw o r k (NCCN) Gu i d eli ne s ® endo r se l u m pec t o m y a nd w ho le b reast ra d iati on t h era py o r

DUC T AL CARCINOMA I N SI T U

T r eatment of the B r east

nan nan

t o tal ma s t ec t o m y as ca t ego r y 1 rec o mme nd ati on s , a nd l u m p ect o m y wit hout R T as a ca t ego r y 2B r eco mme nd ati on . Clearl y , p atie n ts s hou l d b e i n cl uded i n t h e t rea tm en t dec i s i on m ak i ng t o lear n w h at ma gn it ud e o f ris k re du cti on is mea n in g f u l t o t he m . A de t ai le d d isc u ssi on o f t h e p r o s a nd c on s o f t h e v a r i ou s tr ea tm en t op ti ons i s ne e d e d t o all o w eac h w o ma n wit h DCIS t o ma k e a n i n f o rm ed tr ea tm en t c ho ice .

DUC T AL CARCINOMA I N SI T U

T r eatment of the Axilla

nan nan

In sit u car c i no m a by de fi n iti on do es no t metastasize , s o t h e o reticall y , a x illa ry s t ag i ng shou l d be unn ecessar y f o r DCIS . St ud ies o f a x illar y d issecti on ( A L ND ) i n DC IS ha v e d em on strate d a x illar y nod al metastase s in on l y 1% t o 2 % o f pa ti en t s, p r e s u ma b l y du e t o un rec ogn ize d micr o i nv asi on. D ata fro m t he N S AB P B - 17 a nd B- 24 st ud ies c on firm t h at t h e ris k o f is o late d a x ill a r y r ecu rr ence wi t h no a x illar y s u r g er y is <0.1 % , re g ar d les s o f wh et h e r R T and t a m ox if en a re a d mi n istere d . T h ese l o w rates o f a x illar y r ec urr e nce a r gue aga i ns t r ou ti n e u se o f se n ti n el l y m ph nod e b i op s y i n D C I S . Sel ec ti ve use o f sen ti n el nod e b i op s y i n p atie n ts wit h DCIS w ho a r e at si gn i f i can t ri sk o f hav i ng co e x iste n t i nv asi v e carci no ma is a pp r op riate . Approx i ma t e l y 15 % o f pa ti en ts d ia gno se d as h a v i ng DCIS wit h lar g e v ac uu m -ass i s t ed b i opsy dev i c es are f ound t o h a v e i nv asi v e ca n cer after c o m p let e exc i s i on o f t he l es i on. T h e d ia gno sis o f DCIS i n a p al p a b le b re ast mass a n d pa t ho l og i c i n t e r p r e tati on o f a c o re b i op s y s p ecime n as s u s p icio us, bu t no t d i agnos ti c, o f mi c r o i nv asi on are circ u msta n ces i n w h ic h i nv asi v e ca n ce r i s fr equen tl y f ound when t h e lesi on is c o m p letel y e x ami n e d a nd so se n ti n el n ode b i opsy shou l d b e c on si d ere d. Beca use pa ti en t s unde r go i ng mastect o m y f o rfeit t h e oppo rt un it y f o r se n ti n el n ode b i opsy if no t pe rf o rme d c on c u rre n tl y , p atie n ts recei v i ng mastect o m y f o r DC IS shou l d und e r go se n ti n el nod e b i op s y .

DUC T AL CARCINOMA I N SI T U

Endocrine Therapy

nan nan

Th e E R i s p r esen t i n abou t 80% o f DCIS lesi on s a nd is m o re fre qu e n t i n non c o m edo t han co m edo DCI S E ndo cri n e t h era py mi gh t re du ce LR af te r

DUC T AL CARCINOMA I N SI T U

Endocrine Therapy

nan nan

br east - c onse r v i ng t he r apy ( B CT) a nd p re v e n t d e v el op me n t o f n ew p rim a r y br east c ance r s i n t he con tr a l a teral b reast . T w o trials h a v e e x ami n e d t h e use of tam ox if en i n wo m en w it h D CIS . I n t h e NSABP B- 24 trial , p atie n ts with D C I S we r e tr ea t ed w it h exc i sion a nd R T a nd ra ndo mize d t o tam ox ife n 20 m g d ail y o r a p l acebo f o r 5 ye ars . Patie n ts i n t h e tam ox ife n arm h a d a 3 2% r e du cti on i n t he ri sk o f an i nva si v e LR ( p = 0.025 ) , a 16 % re du cti on i n t he r is k of a DC IS L R ( p = 0.33 ) , a nd a 32 % re du cti on i n c on tralateral b reast ca n ce r ( p = 0.023 ) co m pa r ed to t h e p atie n ts i n t h e p lace bo arm . I n t h e s ub set o f wo m en w it h E R + DC IS , tam ox ife n re du ce d t h e ris k o f a ny b re ast ca n ce r e ven t by 51 % ( RR = 0.41 ; 95 % CI = 0.25 t o 0.65 ; p = 0.0002 ); t he r e w as no bene fit seen if t he DC IS lesi on was E R − T h e U n ite d K i ngdo m/ Aus tr a li a New Z ea la nd tria t h at ra ndo mize d w o me n t o tam ox i fen o r t o no t a m ox if en a nd wit h a me d ia n f o ll o w- up o f 12.7 y ears found t ha t t a m ox if en r educed i p silateral e v e n ts (HR = 0.78 ; 95 % CI = 0.62 t o 0.99), bu t m o r e s i gn ifi can tl y , re du ce d c on tralateral e v e n ts (HR = 0.44; 95% C I = 0.25 t o 0.77 ) (I n a s ub set a n al y sis , t h e b e n efit o f tam ox ife n a pp ea r e d r es tri c t ed t o pa ti en ts w ho d i d no t recei v e R T . ) T a k e n t og et h e r , t h ese t r i a l s sugges t t ha t t a m ox ife n m od estl y re du ces i p silateral e v e n ts w ith or w it hou t R T , and subs t an ti a ll y re du ce c on tralateral e v e n ts . T h e a dd iti on o f tam ox i fen t o R T i s pa rti cu l a rl y attracti v e i n young p atie n ts wit h E R + DCI S, i n who m t he ri sk o f L R i s h i gh er a nd t h e t ox icit y o f tam ox ife n is less t han i n o l d e r pa ti en t s. Ev i dence t ha t t he A I s r educ e t h e i n ci d e n ce o f c on tralateral b reast ca nce r t o a gr e a t e r ex t en t t han t a m oxi fe n h as le d t o i n terest i n t h eir u se i n DCIS . Ongo i ng tri a l s ( N S AB P B53 and IBIS II) are c o m p ari ng tam ox ife n wit h an AI ; howeve r , a t p r esen t , t he r e are no d ata f o r u se o f AIs i n ma n a g eme n t . In s u mm a r y , pa ti en t s w it h l o calize d DCIS h a v e treatme n t op ti on s r a ng i ng fr o m s im p l e exc i s i on t o mastect o m y , all o f w h ic h h a v e h i gh s urv i v al r a t es bu t d i f f e r en t ri s ks o f LR . Patie n t p refere n ce p la y s a maj o r r ole i n t r eatm en t se l ec ti on, bu t av aila b le e v i d e n ce i nd icates t h at p atie n ts h a ve limite d unde r s t and i ng o f t he n at u re o f DCIS . I n on e st ud y , w o me n wit h D C I S es t im a t ed t he ir ri sk o f breast ca n cer d eat h t o b e 39 % . Per h a p s r elate d t o t h i s, Ka t z e t a l . f ound t h at alt hough p atie n ts re po rte d t h at t h e i r

DUC T AL CARCINOMA I N SI T U

Endocrine Therapy

nan nan

s u r g e on i n fr equen tl y r eco mme nd e d mastect o m y f o r DCIS , g reater i nvo l v em en t o f pa ti en t s i n t he d ecisi on -ma k i ng p r o cess was ass o ciate d with h i gh e r r at es o f m as t ec t o m y .

S T AGING

nan nan

Th e stagi ng sys t e m f o r b r eas t ca n cer was last upd ate d i n 2010 . T h e A me r ic an Jo i n t Co mmitt ee o n Ca n cer (AJCC) s y stem is bo t h a cli n ical and p at ho l og i c s t ag i ng sys t e m , and is b ase d on t h e TNM s y stem i n w h ic h “T ” r e f e r s t o t u m o r , “N” t o nodes, a nd “M” t o metastasis . T h e c u rre n t v ersi on is t h e se v e n t h ed iti on o f t he sys tem a nd is p r ov i d e d i n t h e f o ll o wi ng Th e m a j o r changes i n t h i s ed iti on were t h e i n cl u si on o f a n ew classi f ic a ti on sys t e m f o r pa ti en ts after n e o a d j uv a n t t h era py a nd t h e creat ion of a n e w M0 (i + ) ca t ego r y f o r p atie n ts f ound t o h a v e circ u lati ng t u m o r c ells, t u m or in t he bone m a rr o w , o r i n ci d e n tall y d etecte d t u m o r d e po sits i n o t h er tiss u es n o t exceed i ng 0.2 mm i n size . Patie n ts i n t h is cate go r y are sta g e d acc ord in g t o T and N, and a r e no t classifie d as sta g e I V . Th e AJCC s t ag i ng sys t e m p r ov i d es a strate gy f o r g r oup i ng p atie n ts with r es p ect t o p r ognos i s. Howeve r , TNM sta g i ng, w h ile still im po rta n t , h as b ee n s upe r seded by r ap i d l y e v o l v i ng m o lec u lar c h aracterizati on s o f b reas t ca n ce r s , wh i ch m o r e p r ec i se ly d efi n e s ubg r oup s wit h d iffere n t ou tc o mes , bo t h i n term s o f p r ognos i s and res pon se t o s p ecific treatme n ts . I n creasi ngl y , m u lti g e ne d i agnos ti c t es t s, such as O n c o t yp e DX a nd MammaPri n t (Ag e nd i a I nc. U S A, Ir v i ne, C A) , are em p l oy e d as p art o f treatme n t d ecis ion ma k i ng f o r i nvas i ve b r eas t can ce r .

S T AGING

T umo r , Node, and Metastases Definitions

nan nan

T umo r , Node, and Metastases Definitions

S T AGING

T umo r , Node, and Metastases Definitions

nan nan

D e f i n itio ns f o r c l ass if y i ng t h e p rimar y t u m o r (T) are t h e same f o r cli n ic al a nd for pa t ho l og i c c l ass ifi ca ti on. If t h e meas u reme n t is ma d e by phy sica l e x ami n a t i on, t he exa mi ne r w ill u se t h e maj o r h ea d i ng s (T 1, T 2, o r T 3 ) . I f o t h e r m easu r e m en t s a r e used, s u c h as mamm og ra ph ic o r p at ho l og ic meas ur em en t s, t he subse t s o f T 1 ca n b e u se d. T u m o rs s hou l d b e meas u re d

S T AGING

T umo r , Node, and Metastases Definitions

nan nan

t o t h e nea r es t 0.1 c m i nc r e m e nt . T h e AJCC TNM sta g i ng s y stem is ill u st r at ed i n . St ag e IIIC b reast ca n cer i n cl ud es p atie n ts wit h any T sta g e w ho have pN3 d i seas e . Patie n ts wit h p N 3 a a nd p N 3b d isease are c on si d e red ope r ab l e and a r e ma n a g e d as d escri b e d i n t h e secti on on sta ge I , II, IIIA, a nd ope r ab l e III C b r e ast ca n ce r . Patie n ts wit h p N 3 c d isease , i n wh ic h t he i ps il a t e r a l sup r ac l av ic u lar nod es are affecte d by ca n ce r , are c on si d e red i nope r ab l e and a re ma n a g e d as d escri b e d i n t h e secti on on i nop e r a b l e s t age III B o r III C o r i n flammat o r y b reast ca n cer (IBC) .

PA THOL OG Y OF BREAST CANCER

nan nan

PA THOL OG Y OF BREAST CANCER

PA THOL OG Y OF BREAST CANCER

nan nan

H ist or ic a ll y , c l ass ifi ca ti on o f i nv asi v e b reast ca n cers h as b ee n b ase d on t he m orpho lo g i c appea r ance o f t h e ca n cer as see n by li gh t micr o sc op y . T he m o st w i de l y used such c l ass ificati on is t h at o f t h e W o rl d Healt h O r g a n izati on ( second ed iti on ) , b ase d on t h e g r o wt h p atter n a nd c y t o l ogic f eat ur es o f t he i nvas i ve t u m o r cells . Alt hough t h e classificati on s y stem r ec ogn i zes i nvas i ve “duc t a l ” a nd “l obu lar” carci no mas , t h is is no t mea n t to i nd icate t ha t t he f o rm e r o ri g i n ates i n t h e du cts a nd t h e latter i n t h e l obu l es of t h e br e as t . Mos t i nvas i ve b reast ca n cers arise i n t h e termi n al du ct l obula r un it , r e g ar d l ess o f h i s t o l og i c t yp e . Th e m os t co mm on h i s t o l og ic t yp e o f b reast ca n cer is i nv asi v e ( i nf ilt r ati ng ) duc t a l ca r c i no ma , c o m p risi ng 70 % t o 80 % o f cases . T h e d ia gno sis o f i nvas i ve duc t a l c arci no ma is a d ia gno sis by e x cl u si on (i . e ., this t u m or ty pe i s de fi ned as a t ype o f ca n cer no t classifie d i n t o a ny o f t h e o t he r s p ecial ca t ego ri es o f i nvas i ve mammar y carci no ma , s u c h as i nv asi v e l obu la r , t ubu l a r , m uc i nous, me du llar y , a nd o t h er s p ecial t yp es) . T o

PA THOL OG Y OF BREAST CANCER

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ov e r all h i s t o l og i c g r ade. T u m o rs wit h a s u m o f t h e sc o res o f 3 t o 5 are d esi gn at ed g r ade 1 ( we ll d i f f er e n tiate d ) , t ho se wit h s u ms o f 6 a nd 7 are d esi gn at ed g r ade 2 (m ode r a t e l y d i f fere n tiate d ) , a nd t ho se wit h s u ms o f 8 a nd 9 a re des i gna t ed g r ade 3 ( poo rl y d i f fere n tiate d ) . Hist o l og ic g ra d i ng, p a r tic u l a rl y t he d i s ti nc ti on bet wee n g ra d es 1 a nd 3, h as p r ogno stic si gn i f ic ance as d i scussed i n t h e secti on “Pr ogno stic a nd Pre d icti v e Fact o r s i n B r east Cance r .” I n add iti on, b reast ca n cers wit h pu re t ubu la r , m u ci nous, p a p illa r y , o r c ri b rif o rm f ea t u r e s are rec ogn ize d t o h a v e a m o re fa vo ra b le ou tc o m e t han t he m o r e co mm on t yp es o f b reast ca n ce r Micr op a p illar y t u m or s a r e a r ecen tl y r ecogn ize d e n tit y wit h a h i gh i n ci d e n ce o f l y m ph ati c a nd v as cu l a r i nvas i on, and sy stemic rec u rre n ce .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

nan nan

L O CAL MANA GEME NT OF IN V ASIVE CANCER

L O CAL MANA GEME NT OF IN V ASIVE CANCER

nan nan

Th e e v a lua ti on o f t he pa ti en t n ewl y d ia gno se d wit h b reast ca n cer b e g i n s w it h a de t e rmi na ti on o f ope r ab ilit y . T h e p rese n ce o f d ista n t metastases a t d ia gno sis has tr ad iti ona ll y be e n c on si d ere d a c on trai nd icati on t o s u r g er y . S o me r etr ospec ti ve s t ud i es ha ve s ugg este d a s u r v i v al b e n efit f o r s u r g er y o f t h e pr im a r y t u m o r i n t he pa tie n t p rese n ti ng wit h metastatic d isease , but s y stemi c t he r apy r e m a i ns t he i n itial t h era p e u tic a pp r o ac h. E x te n si v e e v al u atio ns t o l ook f o r m e t as t a tic d isease are no t warra n te d i n as y m p t oma ti c pa ti en t s w it h s t ag e I a nd II ca n cer b eca u se o f t h e l o w li k eli hood o f i den tif y i ng m e tastatic d isease . I n p atie n ts wit h sta g e III d isease , occu lt m e t as t ases a r e m o re fre qu e n t , o fte n estimate d at 20 % o f cases , a nd s t ag i ng s t ud i es a r e r ec o mme nd e d . Patie n t s w it h T 4 t u m o r s and t ho se wit h N 2 o r N 3 nod al d isease are al so no t ca nd i da t es f o r su r ge r y as t h e first t h era p e u tic a pp r o ac h a nd s hou l d be t r eate d w it h sys t e mi c t he r apy i n itiall y ( d isc u sse d i n t h e secti on “L o call y Adv a n ce d B r eas t Cance r and I n flammat o r y Breast Ca n cer” on p a g e 477 ) . I n t h e p ati en t w it h c li n i ca l s t age I , II , a nd T 3 N 1 d isease , t h e i n itial ma n a g e men t i s usua ll y su r g i c al . I n t h ese p atie n ts , t h e e v al u ati on c on sist s o f

L O CAL MANA GEME NT OF IN V ASIVE CANCER

nan nan

a d ete r mi na ti on o f t he ir su it ab ilit y f o r BCT a nd a d isc u ssi on o f t h e op ti ons of maste c t o m y w it h and w it hou t rec on str u cti on. I n itial s y stemic t h era py ma y b e used t o sh ri nk t he p rimar y t u m o r t o all o w BCT i n a w o ma n w ho wou l d o t he r w i se r equ ir e m as tect o m y , bu t is no t ma nd at o r y , as it is f o r wo me n wit h l oca ll y advanced a nd i n flammat o r y carci no ma . T h e c u rre n t stat u s of m anage m en t app r oa c h es f o r p rimar y op era b le b reast ca n cer is d isc u sse d i n de t a il i n t he f o ll o wi ng secti on s .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

B r east-Conserving Therapy

nan nan

B r east-Conserving Therapy

L O CAL MANA GEME NT OF IN V ASIVE CANCER

B r east-Conserving Therapy

nan nan

L O CAL MANA GEME NT OF IN V ASIVE CANCER

B r east-Conserving Therapy

nan nan

In t h e 1,459 wo m en i n who m BCT was attem p te d, c onv ersi on t o mastect o m y occu rr ed i n 12 % , a nd re-e x cisi on was no t attem p te d i n t h e maj or it y . T hus, t he ava il ab l e d ata i nd icate t h at a mi no rit y o f p atie n ts h a ve c on t r ai nd i ca ti ons t o BC T , and t h ese are rea d il y i d e n tifie d wit h sta nd ar d cli n ical too l s. P a ti en t pa rti c i p ati on i n t h e s u r g ical d ecisi on -ma k i ng p r o ce ss is a n im po rt an t f ac t o r i n m as tect o m y u se . I n a popu lati on - b ase d st udy o f p atie n ts di agnosed w it h b r eas t ca n cer i n 2002 i n tw o lar g e metr opo lita n a r eas (Los Ange l es and De tr o it) , m o re p atie n t i nvo l v eme n t i n d ecisi on ma k i ng was assoc i a t ed w it h a g r e a ter li k eli hood o f und e r go i ng

L O CAL MANA GEME NT OF IN V ASIVE CANCER

B r east-Conserving Therapy

nan nan

mastect o m y . T he i nc i dence o f LR after BCT h as d ecli n e d ov er time , fro m 10 - yea r r a t es o f 8 % t o 19 % see n i n retr o s p ecti v e st ud ies a nd t h e i nitial r a ndo mi zed tri a l s o f BC T , t o 2 % t o 7 % i n p atie n ts e x cise d t o n e g ati v e ma r g i n s i n m o r e r ecen t s t ud i es. s ho ws t h e 10 - y ear rates o f LR i n nod e -nega ti ve N S AB P tri al s . T h is d ecrease i n LR rates is t h e res u lt o f a c o m b i na ti on o f im p r oved m a mm og ra ph ic a nd p at ho l og ic e v al u ati on, a nd t h e m or e fr equen t use o f ad j u va n t s y stemic t h era py ( d isc u sse d i n d etail i n t h e secti on “R i sk F ac t o r s f o r Lo cal Rec u rre n ce F o ll o wi ng C on ser v ati v e S u r g e ry and Rad i a ti on T he r a p y ” on p a g e 459 ) . I n c on trast , rates o f LR af te r mastect o m y have r e m a i ned s t ab le ov er t h e same time p eri od. Rec u rr ences i n t he b r eas t are t yp icall y classifie d by t h eir l o cati on i n r elati on t o t he o ri g i na l t u m o r . Rec u rre n ces at o r n ear t h e p rimar y site (pr es u m ab l y r ep r esen ti ng a r e c u rre n ce o f t h e o ri g i n al t u m o r) are classifi ed as eit h e r a t rue r ecur r ence ( w it h i n t h e boo ste d re g i on ) , a m a r g i na l miss ( a d jace n t t o t he boos t ed r eg i on ) , o r elsew h e r e i n t h e b reast ( o cc u rri ng at a d ista n ce fr o m t he o ri g i na l t umo r a nd p res u ma b l y re p rese n ti ng a n ew pr ima ry). T he tim e cou r se t o L R i n t h e p atie n t und er go i ng BCT is

L O CAL MANA GEME NT OF IN V ASIVE CANCER

B r east-Conserving Therapy

nan nan

pro l onged. I n one s t ud y , t he annu al i n ci d e n ce rate f o r a tr u e r ec urr e nce /m a r g i na l mi ss r ec urre n ce was b etwee n 1.3 % a nd 1.8 % f o r y e a r s 2 t hrough 7 a ft e r tr ea tm en t an d t h e n d ecrease d t o 0.4 % by 10 y ears after t r eatme n t . T he annua l i nc i den ce rate f o r rec u rre n ce elsew h ere i n t h e b re ast i n c r ease d s l ow l y t o a r a t e o f a p p r ox imatel y 0.7 % p er y ear at 8 y ears a nd r emai n ed s t ab l e. It a l so appea rs t h at j u st as t h e time t o d e v el op me n t o f d ista n t me t as t ases i s m o r e r apid i n p atie n ts wit h E R − o r HER 2 + ca n cers t han i n t ho se wit h E R + and P R + can cers , t h e time t o LR als o v aries wit h rece p t o r stat u s . (These r esu lt s have been c on traste d t o t ho se see n after mastect om y , i n wh ic h m os t L Rs occu r i n t h e first 3 t o 5 y ears after s u r g er y . ) I n t h e M ilan I t r ial , a f t e r 20 yea r s o f f o ll ow - up, t h e ris k o f a ny t yp e o f rec u rre n ce i n t he t r eate d b r eas t was 0.63 pe r 100 w o ma n - y ears c o m p are d wit h a ris k o f 0.66 p e r 100 wo m an - yea r s f o r con tralateral ca n ce r T h is s ugg ests t h at alt hough who le -b r eas t irr ad i a ti on ( WB I) is e f fecti v e at era d icati ng s ub cli n ical m u ltice n tri c f oc i o f b r eas t ca rci no ma p rese n t at t h e time o f d ia gno sis , it do es no t p r even t t he subsequen t d e v el op me n t o f n ew ca n cers . T hu s , p atie n ts w ho e l ec t BC T r equ i r e lifel ong f o ll o w- up t o scree n f o r t h e d e v el opmen t o f new cance r s i n bo t h t h e treate d a nd t h e c on tralateral b re ast.

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

Patient Risk Factors

nan nan

Th e m o st im po rt an t pa ti en t ris k fact o rs f o r LR rec u rre n ce are a g e a nd i nh e r ite d suscep ti b ilit y . A ge ( <35 o r 40 ) is ass o ciate d wit h a n i n crease d r isk of L R a f t e r BC T . Y oung pa ti e nt a g e is ass o ciate d wit h a n i n crease d fr e qu e ncy o f va ri ous adve r se p at ho l og ic feat u res , s u c h as l y m ph atic v ess el i nv asi on, g r ade 3 h i s t o l og y , ab se n ce o f ER/ p rese n ce o f HER 2 , a nd t h e pr ese n c e o f an ex t ens i ve i n tr adu ctal c o m pon e n t (EIC) . H o we v e r , e v e n when c orr ecti on i s done f o r t he d i f feri ng i n ci d e n ce o f t h e p at ho l og ic feat u res o f

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

Patient Risk Factors

nan nan

t h e pr im a r y t u m o r be t ween t h e a g e g r oup s , young a g e is still ass o ciate d w it h a n i nc r eased li ke li hood o f rec u rre n ce i n t h e b reast H o we v e r , young a g e is al so a ri sk f ac t o r f o r L R after mastect o m y a nd s hou l d no t b e c on si d e red a con tr a i nd i ca ti on t o BC T . An i nher it ed suscep ti b ilit y t o b reast a nd ov aria n ca n ce r , a nd o t h er ca n ce r s has been m a i n l y li nk e d t o g ermli n e m u tati on s i n BRCA 1 a nd BR C A2 . P a ti en t s w it h b r eas t ca n cer wit h a m u tati on h a v e a s ub sta n tial ris k of c on t r al a t e r a l and l a t e i ps il at eral b reast ca n cers . I n a retr o s p ecti v e st ud y , ou tc o m e f o ll ow i ng C S and R T was c o m p are d f o r 302 sta g e I-III p atie n ts w it h br e as t cance r w it h ge rmli n e BRCA 1 o r BRCA 2 m u tati on s a nd 353 sta g e I-I II pa ti en t s tr ea t ed w ith mastect o m y . W it h a f o ll o w- up time o f 8.2 a nd 8.9 yea r s f o r BC T and mastect o m y p atie n ts , res p ecti v el y , LR was si gn i f ic an tl y m o r e li ke l y i n t ho se treate d wit h BCT c o m p are d t o mastect o m y , w it h a cu m u l a ti v e estimate d ris k o f 23.5 % v ers u s 5.5 % , r es p ecti ve l y , a t 15 yea r s ( p <0.0001 ); t h e 15 - y ear estimate i n carriers tre ated w it h BC T and che m o t he r apy was 1 1.9 % ( p = 0.08 w h e n c o m p are d t o mastect o m y ) . Mos t L R even ts a pp eare d t o b e sec ond p rimar y ca n cers . T he r is k of c on tr a l a t e r a l b r eas t can cer was h i gh i n all g r oup s , e x cee d i ng 40 % . I t is im por t an t t o cons i de r gene tic testi ng i n a p atie n t wit h n ewl y d ia gno se d br east c ance r w it h a pe r sona l and famil y h ist o r y s ugg esti v e o f a BRCA 1 o r BR C A2 ge rmli ne m u t a ti on. I n p atie n ts wit h a m u tati on, t h e op ti on o f b ilate r al m as t ec t o m y shou l d b e str ong l y c on si d ere d t o a vo i d t h e l ong -ter m r is k of a second b r eas t cance r i n eit h er b reast . Patie n ts wit h b reast ca n cer m o st li ke l y t o bene fit fr o m b ilateral mastect o m y are t ho se w ho are youn g a nd h a v e ea rl y - s t age d i sease. G i v e n t h e h i gh ris k o f a c on tralateral b reas t ca n ce r , un il a t e r a l m as t ec t o m y is g e n erall y no t p erf o rme d i n a p atie n t w ho is a ca nd i d at e f o r BC T .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

T umo r -Based Risk Factors

nan nan

c on j un c t i on w it h t he ope r a ti ve fi nd i ng s . A cl o se d ee p mar g i n is no t si gn i f ic an t if t he b r eas t r esec t ion was carrie d do w n t o t h e p ect o ral fascia ; t h e sam e i s tr ue f o r a c l ose ant eri o r mar g i n if t h e resecti on e x te nd e d t o t he d ee p d erm a l su rf ace. P a ti en t s wit h n e g ati v e mar g i n s o f e x cisi on h a v e l o w r ates of L R a ft e r tr ea tm en t w it h CS a nd R T . T h e im p act o f cl o se ma r g i ns o f r esecti on on L R has been m o re c on tr ov ersial , res u lti ng i n t h e fre qu e n t u s e of r e - e xc i s i on t o ob t a i n m a r g i n s m o re wi d el y clear t h a n no i nk on t u m o r . A 2013 m u lti d i sc i p li na r y conse ns u s p a n el c on si d ere d a meta-a n al y sis o f ma r g i n w i d t h and I B T R fr o m a s y stematic re v iew o f 33 st ud ies i n cl ud i ng 28,162 pa ti en t s. T he r esu lt s o f ra ndo mize d trials , re p r odu ci b ilit y o f ma r gin assessme n t , and cu rr en t pa tt e r n s o f m u ltim od alit y care were als o c on si d e red. T he pane l conc l ud e d t h at po siti v e mar g i n s (i nk on i nv asi v e ca r ci noma o r DC IS) we r e asso ciate d wit h a tw o -f o l d i n crease i n t h e ris k o f I B T R c o m pa r ed t o nega ti ve ma r g i n s . T h is i n crease d ris k was no t miti g a ted by f a vorab l e b i o l og y , endoc ri n e t h era p y , o r a ra d iati on boo st . T h e p a n el also c on cl ud e d t ha t m o r e w i de l y c lear mar g i n s b e yond “ no i nk on t u m o r” do not si gn i f ic an tl y dec r ease t he r a t e o f IBTR . T h ere is no e v i d e n ce t h at m o re w i d el y c l ea r m a r g i ns r educe IBTR f o r young p atie n ts , un fa vo ra b le b i o l og y , l obu la r c ance r s, o r cance r s w i th a n EIC . (W h e n a n EIC is p rese n t , young a g e a nd m u lti p l e c l ose m a r g i n s are ass o ciate d wit h a n i n crease d ris k o f I B T R a nd can be used t o se l e ct p atie n ts w ho mi gh t b e n efit fr o m re-e x cisi on ) . T he r e f o r e, t he use o f no i nk on t u m o r as t h e sta nd ar d f o r a n a d e qu ate m a r g i n i n i nvas i ve c a n cer i n t h e era o f m u lti d isci p li n ar y t h era py is ass o ciate d w it h l ow r a t es o f IBTR a nd h as t h e po te n tial t o d ecrease re-e x cisi on r a t es, im p r ove cos m e tic ou tc o mes , a nd d ecrease h ealt h -care c o sts . Th e unde rl y i ng m o l ecu l a r s ub t yp e o f t h e t u m o r is t h e m o st si gn ifica nt d ete r mi nan t o f t he li ke li hood o f LR after BCT (a nd mastect o m y ) , p a r tic u l a rl y a m ong t hose tr eat e d i n t h e m od er n era wit h s u r g er y t o ac h ie ve n e g ati v e m a r g i ns – H i ghe r ris k s o f LR are ob ser v e d i n p atie n ts wit h t r i p le -n eg a ti ve b r eas t cance r t h a n i n t ho se wit h o t h er s ub t yp es , re g ar d les s o f wh et h e r t hey a r e tr ea t ed w it h BCT o r mastect o m y .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

T umo r -Based Risk Factors

nan nan

Th e r e i s i n t e r es t i n i den tifyi ng m o lec u lar p re d ict o rs o f t h e ris k o f LR . Th e 21-gene r ecu rr ence sco r e (O n c o t yp e DX) p re d icts l o cal-re g i on al r ec urr e nce (L RR ) i n node - neg ati v e , E R + b reast ca n ce r , re g ar d less o f t ype o f s u r g e r y . T he 10 - yea r L R r at e was 4.3 % f o r p atie n ts wit h a l o w rec u rre nce sc or e ( < 18 ) , 7.2 % w it h an i n terme d iate rec u rre n ce sc o re ( 18 t o 30 ) , a nd 15.8% w it h a h i gh r ecu rr ence sc o re ( >30 ) .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

T reatment-Based Risk Factors

nan nan

O t h e r im po rt an t t r ea t men t r i sk f a ct o rs are t h e u se o f a boo st a nd t h e u se o f a d j uv a nt sys t e mi c t he r ap y . A boo st o r s upp leme n tar y irra d iati on t o t h e a rea of t h e pri m a r y s it e i s gene r a ll y u se d. It is sta nd ar d i n R T after l u m p ect omy for p atient s t o r ece i ve 45 t o 50 G y o f WBI f o ll o we d by a 10 t o 16 G y boost t o t h e r e g i on o f t he t u m o r bed ( . T h e u se o f a boo st is s uppo rte d by t h e l a r ge E u r opean O r gan isati on f o r Researc h a nd T reatme n t o f Ca n cer (EO R TC ) tri a l i n wh i ch 5,318 p atie n ts wit h n e g ati v e mar g i n s were r a ndo mi zed t o a boos t o f 16 G y o r no boo st f o ll o wi ng 50 G y t o t h e w ho l e br east W it h a m ed i an f o ll o w- up o f 10.8 y ears , t h e c u m u lati v e i n ci d e nce of i p silat e r a l b r eas t r ecu rr enc e was 10.2 % wit hou t a boo st a nd 6.2 % wit h a boo st ( p <0.0001 ) . T h i s 41 % p r opo rti on al re du cti on i n LR was similar in all a g e groups ; howeve r , t he abso l u te b e n efit o f t h e boo st was g reatest i n y o ung p atie n ts a ged 40 yea r s o r l ess ( 24 % d ecrease d t o 14 %) a nd was smallest in p atie n ts o ve r age 60 ( 7 % dec rease d t o 4 %) . Se v ere fi b r o sis was i n crease d fro m 2 % t o 4 % w it h t he boost. S u r v i v al at 10 y ears was t h e same i n bo t h a r ms . A c li n i copa t ho l og i c s t u d y was p erf o rme d on 1,616 p atie n ts i n t h e EO R T C tri a l . I n m u lti va ri a t e a n al y sis , h i gh - g ra d e i nv asi v e du ctal carci n o ma w as ass oc i a t ed w it h an i nc r ea se d ris k o f LR (HR = 1.67 ; p = 0.026 ) , a nd the boo st w a s e f f ec ti ve i n r educ i ng LR i n t h is s ubg r oup .

L O CAL MANA GEME NT OF IN V ASIVE CANCER

Risk Factors for Local Recur r ence Following Conservative Surgery and Radiation Therapy

T reatment-Based Risk Factors

nan nan

w as 13.4 % w it hou t che m o t he ra py a nd on l y 2.6 % wit h c h em o t h era py g i ven c on c urren tl y w it h t he R T . T h e n et res u lt o f t h e b e n efit o f s y stemic t h er apy on l o cal con tr o l i s t ha t be t ween 1990 a nd 20 1 1, LRR d ecrease d fr o m 30 % t o 15% o f a ll r ecu rr ences seen i n a popu lati on o f 86,598 w o me n e n r o lle d in 53 r a ndo mi zed phase 3 tri a l s . Th e s t anda r d app r oach i s t o u se se qu e n tial c h em o t h era py a nd R T . Gi ven t h e pr im a r y im po rt ance o f p re v e n ti ng s y stemic rela p se , it h as b ee n t h e sta nd a rd t o use i n iti a l che m o t h era py f o ll o we d by R T . Alt hough c on cer ns h a v e b e en exp r essed abou t an i n crease d rate o f LR wit h t h is a pp r o ac h, t he r es u lts of c li n i ca l tri a l s i n pa tie n ts wit h n e g ati v e ma r g i n s h a v e no t s ho w n t h is t o be a p r ob l e m even f o ll o wi ng 6 m on t h s o f c h em o t h era py as wit h f ou r c y cles o f doxo r ub i c i n and cyc l opho s ph ami d e f o ll o we d by f ou r c y cles o f ta xo l , bo t h g i ven eve r y 3 week s .