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COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Options for Surveillance, Risk Reduction, and T ailo r ed T r eatment

nan nan

W o m en who ca rr y BR C A 1 / 2 m u tati on s are als o at i n crease d ris k t o d e v el op ova ri an, f a ll op i an t ub e , a nd p rimar y p erit on eal ca n ce r , e v e n if no on e i n t he ir f a mil y has deve l o pe d t h ese ca n cers . S u r v eilla n ce f o r ov aria n ca n ce r i nc l udes tr ansvag i na l u ltras ound s a nd CA- 125 testi ng ; ho we v e r , t he e f f ecti veness o f such su r ve illa n ce i n d etecti ng ov aria n ca n cers at earl y , m or e t r eat ab l e s t ages has no t b ee n p r ov e n i n a ny popu lati on. Oral c on t r ace p ti ves r educe t he ri sk o f ov aria n ca n cer i n all w o me n, i n cl ud i ng BR C A c a rri e r s . Recen t da t a i nd icate t h at t h e im p act o f t h is i n ter v e n ti on on i n c r easi ng b r eas t cance r ri sk, i f a n y , is l o w . Gi v e n t h e d i f fic u lties i n sc r ee n i ng and i n t he tr ea tm en t o f ov aria n ca n ce r , t h e ris k / b e n efit a n al y si s li k el y f a vo r s t he use o f o r a l c o n trace p ti v es i n young carriers o f BRCA 1 / 2 m u tati on s who a r e no t ye t rea dy t o h a v e t h eir ov aries rem ov e d. P rophy la c ti c b il a t e r a l sa l p i ngo - oopho rect o m y (BSO) is c u rre n tl y t h e m o s t e f f ecti ve m eans t o r educe t he ris k o f ov aria n ca n cer a nd is rec o mme nd e d to BR C A1 / 2 ca rri e r s by t he age o f 35 t o 40 o r w h e n c h il db eari ng is c o m p le te .

COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Options for Surveillance, Risk Reduction, and T ailo r ed T r eatment

nan nan

COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Options for Surveillance, Risk Reduction, and T ailo r ed T r eatment

nan nan

S p eci f ic ope r a ti ve and pa t ho lo g ic p r o t o c o ls h a v e b ee n d e v el op e d f o r t h i s prophy l ac ti c su r ge r y . I n BRCA 1 / 2 carriers w ho se p at ho l og ies c o me b a ck nor mal , th i s su r ge r y i s h i gh l y e f fecti v e at re du ci ng t h e s ub se qu e n t ris k o f ov a r ia n cance r . A dec i s i on a nal y sis , c o m p ari ng v ari ou s s u r v eilla n ce a nd r is k-r e d u c i ng op ti ons ava il ab le t o BRCA carriers , h as s ho w n a n i n crease in li f e e xpec t ancy if B S O i s pu r su e d by a g e 40 . Eme r g i ng d ata i nd icate t hat m o st ova ri an cance r s beg i n i n t h e fall op ia n t ub e , a nd t h at sal p i ng ect o m y ma y s omeday be su f fi c i en t i n re du ci ng ov aria n ca n cer ris k i n young wo me n ; howeve r , m o r e da t a are n ee d e d b ef o re t h is op ti on is o f fere d t o p atie n ts o u t s i de o f c li n i ca l tri a ls . A relati v el y small p erce n ta g e o f w o m en who pur s ue B S O m ay deve l op p rimar y p erit on eal carci no ma . T h ere h as b ee n s o m e deba t e abou t whe t h er BRC A 1 / 2 carriers s hou l d als o op t f o r t otal a bdo mi na l hys t e r ec t o m y ( T AH ) du e t o t h e fact t h at small st u m p s o f t h e f all op ia n t ubes r e m a i n a ft e r BS O al on e . T h e qu esti on o f w h et h er BRCA ca rr ie r s a r e a t i nc r eased ri sk f o r u teri n e ser ou s p a p illar y carci no ma (US P C) h as als o been r a i sed . If a relati on s h i p do es e x ist b etwee n BRCA m u tati ons and u t e ri ne cance r , t h e ris k a pp ears t o b e l o w a nd no t ele v ate d ov e r t h at o f t he gene r a l popu l a ti on . Rem ov i ng t h e u ter u s ma y ma k e it

COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Options for Surveillance, Risk Reduction, and T ailo r ed T r eatment

nan nan

po ssi b le f o r a BR C A ca rri e r to ta k e unoppo se d estr og e n o r tam ox ife n i n the fu t ur e wi t hou t t he ri sk o f u t e ri n e ca n ce r , bu t t h is s u r g er y is ass o ciate d w ith a l ong e r r ecove r y tim e and ha s m o re si d e e f fects t h a n do es BSO al on e . Each p atie n t sh ou l d be counse l ed abou t t h e p r o s a nd c on s o f eac h p r o ce du re a nd t h e r is k s assoc i a t ed w it h p r e mat u re me nop a u se b ef o re h a v i ng s u r g er y A se conda r y , bu t im po rt an t , reas on f o r female BRCA carriers t o c on s ide r prophy l ac ti c oopho r ec t o m y i s t h at it als o si gn ifica n tl y re du ces t h e ris k o f a s ub se quen t b r eas t cance r , pa r t ic u larl y if t h e y h a v e t h is s u r g er y b ef o re me nop a use . T he r educ ti on i n b reast ca n cer ris k remai n s e v e n if a h ea lthy pr eme nopausa l ca rri e r e l ec t s to ta k e l o w- do se ho rm on e-re p laceme n t t h e r a py ( H R T) a ft e r t h i s su r g er y Earl y d ata s ugg est t h at tam ox ife n, i n a dd iti on t o p r e m enopausa l oo p ho rect o m y , i n BRCA carriers ma y h a v e li ttle a dd iti ona l bene fit i n t e rm s o f b reast ca n cer ris k re du cti on . Researc h is n ee d e d in ba l anc i ng qua lit y o f life iss u es sec ond ar y t o estr og e n d e p ri v at ion w it h can ce r ri sk r educ ti on i n th ese young female BRCA 1 / 2 carriers . N e w deve l op m en t s a r e a l so eme r g i ng i n t h e treatme n t a nd, po ssi b l y , the pr e v e n ti on o f BR C A -r e l a t ed c a n cers . Earl y d ata re v eale d t h at b reast a nd ov a r ia n cance r s i n BR C A ca rriers were p artic u larl y se n siti v e t o treatme nt w it h po l y adenos i ne d i phosph ate (ADP)-ri bo se po l y merases ( P ARP) i nh i b it ors i n co m b i na ti on w ith c h em o t h era p y , New trials are f o c u si ng on wh ic h c he m o t he r apeu ti c r eg i m e n s are m o st effecti v e i n m u tati on carriers . M or e d a ta a r e needed on l a r g er c oho rts o f p atie n ts a nd are c u rre n tl y b ei ng st ud ies i n m u lti p l e c li n i ca l trials . G e n e t i c counse li ng and t e sti ng is als o a v aila b le f o r do ze n s o f ca n cer s yndro m es, i nc l ud i ng L ynch synd r o me , von Hi pp el-Li nd a u s ynd r o me , m u lti p le endoc ri ne neop l as i as, a nd familial a d e no mat ou s po l ypo sis . S urv eilla nce and ri sk r educ tio n f o r p atie n ts w ho are kno w n m u tati on ca rr ie r s f o r such cond iti ons ma y d ecrease t h e ass o ciate d m o r b i d it y a nd m or talit y o f t hese synd r o m es.

COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Follow-up

nan nan

Follow-up

COMPON E NTS O F TH E CANCER GE NETIC COUNSEL I NG SESSI O N

Follow-up

nan nan

A fo ll o w- up l e tt e r t o t he pa ti en t is a c on crete mea n s o f do c u me n ti ng t h e i nfor ma t i on conveyed i n t he se ssi on s s o t h at t h e p atie n t a nd h is/ h er fami ly mem b e rs can r ev i ew it ove r ti m e . T h is letter s hou l d b e se n t t o t h e p atie n t a nd h eal th - ca r e p r o f ess i ona l s to w ho m t h e p atie n t h as g ra n te d access t o this i nfor ma t i on. A f o ll ow - up phon e call a nd / o r c oun seli ng sessi on ma y als o be h el pfu l , pa rti cu l a rl y i n t he ca se o f a po siti v e test res u lt . S o me p r og rams prov i d e pa ti en t s w it h an annu al o r b ia nnu al n ewsletter upd ati ng t h em on n e w i nfo rm a ti on i n t he fi e l d o f ca n cer g e n etics o r p atie n t s uppo rt g r oup s . I t is now reco mm ended t ha t pa tie n ts ret u r n f o r f o ll o w- up c oun seli ng sessi ons m on t h s , o r even yea r s, a ft e r t h eir i n itial c on s u lt t o d isc u ss a dv a n ces i n g e n etic tes ti ng and changes i n s u r v eilla n ce a nd ris k re du cti on op ti on s . T his ca n b e bene fi c i a l f o r i nd i v i du als w ho h a v e b ee n f ound t o carr y a h ere d it a r y pr e d is pos iti on, f o r t hose i n w h o m a s ynd r o me/m u tati on is s u s p ecte d bu t yet un i d e n tifi ed, and f o r t hose who are rea dy t o m ov e f o rwar d wit h g e n etic testi ng. Fo ll ow - up counse li ng is als o rec o mme nd e d f o r p atie n ts w ho se lif e ci r c u ms tances have changed ( e .g., p rec on ce p ti on, after c h il db eari ng is c o m p let e ) , who a r e p r epa ri ng f o r p r ophy lactic s u r g er y , o r w ho are rea dy to d isc u ss the f a mil y gene ti cs wi t h t h eir c h il d re n.

ISSU E S IN CANCER GE NET I C C O UNSELING

nan nan

ISSU E S IN CANCER GE NET I C C O UNSELING

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

Th e p s y c hosoc i a l im pac t o f c a n cer g e n etic c oun seli ng ca nno t b e und e r est i m a t ed. Jus t t he p r oce ss o f sc h e du li ng a ca n cer ris k c oun seli ng sessi on may be qu it e d i f fi cu lt f o r s o me i nd i v i du als wit h a famil y h ist o r y who a r e no t on l y fri gh t ened a b ou t t h eir o w n ca n cer ris k, bu t als o are r eli v i ng pa i n f u l expe ri ences as s o ciate d wit h t h e ca n cer o f t h eir l ov e d on e s .

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

C oun sel ees m ay be f aced w it h a n on sla ugh t o f em o ti on s , i n cl ud i ng a ng e r , f ea r of deve l op i ng cance r , f ea r o f d isfi gu reme n t a nd dy i ng, g rief , lac k o f c on t ro l , nega ti ve body im age, a nd a se n se o f is o lati on . S o me c oun sele es wr estle wit h t he f ea r t ha t i nsu ra n ce c o m p a n ies , em p l oy ers , famil y mem be r s, a nd e v e n f u t u r e pa rt ne r s w ill r eact n e g ati v el y t o t h eir ca n cer ris k s . F o r

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

ma n y , it i s a doub l e - edged swo r d as t h e y b ala n ce t h eir fears a nd a ppr e h en s i ons abou t d r edg i n g up t h ese iss u es wit h t h e po ssi b ilit y o f ob tai n i ng r eassu ri ng news an d m u c h n ee d e d i n f o rmati on. A p er son ’ s pe r ce i ved canc er ris k is o fte n d e p e nd e n t on ma ny “ non me d i ca l ” va ri ab l es. T hey ma y estimate t h at t h eir ris k is h i gh er if t hey l ook li k e an a f f ec t ed i nd i v i du al , o r s h are s o me o f t h eir p ers on alit y traits

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

ISSU E S IN CANCER GE NET I C C O UNSELING

Psychosocial Issues

nan nan

Th ei r p e rce i ved ri sks w ill va r y d e p e nd i ng on if t h eir relati v es were ca n c e r s urv i vors o r d i ed pa i n f u l dea t h s fr o m t h e d isease . Ma ny p e op le w ond er not if t h e y a re go i ng t o ge t cance r , bu t w h e n . Th e counse li ng sess i on i s an oppo rt un it y f o r i nd i v i du als t o e xp ress w hy t h e y b eli eve t hey have deve l op e d ca n ce r , o r w hy t h eir famil y mem b ers h ave ca n ce r . S o m e exp l ana ti ons m ay re vo l v e ar ound famil y f o l k l o re , a nd it is im por ta n t t o li s t en t o and add ress t h ese e xp la n ati on s rat h er t h a n d ismiss t h em . I n do i ng t h i s, t he coun sel o r will all o w t h e clie n ts t o alle v iate t h eir gr eatest f ea r s and t o g i ve m o r e cre d i b ilit y t o t h e me d ical t h e o r y . Und e r st and i ng a pa ti en t ’ s pe rcei v e d ca n cer ris k is im po rta n t , b eca u se t hat f ea r ma y dec r ease su r ve ill anc e a nd p re v e n ti v e h ealt h -care b e h a v i o rs . Fo r p atie n ts a nd f a mili es who a r e m ov i ng f o rwar d wit h DNA testi ng, a referr al t o a me n t a l hea lt h - ca r e p r o f ess i on al is o fte n v er y h el p f u l . Ge n etic testi n g h as a n im pac t no t on l y on t he p atie n t , bu t als o on h is/ h er c h il d re n, si b li ngs, p a r e n ts , a nd ex t ended r e l a ti ve s . T h is ca n b e ov erw h elmi ng f o r a n i nd i v i dual a nd t h e fa mil y , and shou l d be d isc u sse d i n d etail p ri o r t o testi ng. T o da t e, s t ud i es conduc t ed i n t h e setti ng o f p re- a nd po st- g e n etic c oun seli ng have r evea l ed t ha t, at least i n t h e s ho rt term , m o st p atie n ts do no t e xpe ri ence adve r se psycho l og ical ou tc o mes after recei v i ng t h eir test r es u lts . I n f ac t , p r e limi na r y d ata h a v e re v eale d t h at i nd i v i du als i n f amilies w it h known m u t a ti o ns w ho see k testi ng seem t o fare b etter p s y c ho l og i ca ll y a t 6 m on t hs t h a n t ho se w ho a vo i d testi ng Am ong i nd i v i du al s who l ea r n t hey a re BRCA m u tati on carriers , a nx iet y a nd d istr ess le v els ap pea r t o i nc r ease s li gh tl y after recei v i ng t h eir test res u lts bu t r et urn e d t o p r e t es t l eve l s i n s e v eral wee k s . Alt hough t h ese d ata are r eass ur i ng, it i s im po rt an t t o r e c ogn ize t h at g e n etic testi ng is a n i nd i v i dual d ecisi on and w ill no t be ri gh t f o r e v er y p atie n t o r e v er y famil y .

ISSU E S IN CANCER GE NET I C C O UNSELING

P r esymptomatic T esting in Child r en

nan nan

P r esymptomatic T esting in Child r en

ISSU E S IN CANCER GE NET I C C O UNSELING

P r esymptomatic T esting in Child r en

nan nan

P r es y m p t o m a ti c t es ti ng i n ch il d re n h as b ee n wi d el y d isc u sse d, a nd m o st c on c ur t ha t it i s app r op ri a t e on l y w h e n t h e on set o f t h e c ond iti on re gu lar ly o cc ur s i n ch il dhood o r if t he r e are u sef u l i n ter v e n ti on s t h at ca n b e a pp lie d .

ISSU E S IN CANCER GE NET I C C O UNSELING

P r esymptomatic T esting in Child r en

nan nan

ISSU E S IN CANCER GE NET I C C O UNSELING

P r esymptomatic T esting in Child r en

nan nan

F or e x am p l e, gene ti c t es ti ng f o r m u tati on s i n t h e BRCA g e n es a nd o t h er a du lt -on s e t d i seases i s gene r a ll y limite d t o i nd i v i du als w ho are >18 y ear s o f a g e . The A m e ri can Co ll ege of Me d ical Ge n etics states t h at if t h e “me d i cal or p s y c hosoc i a l bene fit s o f a g e n etic test will no t accr u e un til a du lt hood . . . g e n etic tes ti ng gene r a ll y should b e d eferre d. ” I n c on trast , t h e DNA- b a sed d ia gno sis o f ch il d r en and you n g a du lts at ris k f o r h ere d itar y me du llar y t hyro i d ca r c i no m a ( M T C ) i s app r op riate a nd h as im p r ov e d t h e ma n a g e ment of t h ese pa ti en t s . DNA - based testi ng f o r MTC is v irt u all y 100 % acc u r ate a nd all ows a t-ri sk f a mil y m e m b ers t o ma k e i n f o rme d d ecisi on s a bou t prophy l ac ti c t hy r o i dec t o m y . F AP is a d is o r d er t h at o cc u rs i n c h il dhood a nd i n wh ic h m o rt a lit y can be r edu ce d if d etecti on is p res y m p t o matic . T est ing is clea r l y i nd i ca t ed i n t hese i ns ta n ces . Qu esti ons have been r a i sed a bou t t h e p are n ts’ ri gh t t o d ema nd testi ng f o r a du lt -on s e t d i seases, and t h i s is no w h a pp e n i ng re gu larl y wit h d irect-t o -c on s u mer t es t s and who l e exo me testi ng o f c h il d re n . T h e ris k s o f s u c h testi ng t o t he ch il d, and t he ch il d ’ s ri gh t no t t o b e teste d m u st b e c on si d er ed. Wh e n e ve r ch il dhood t es ti ng i s no t me d icall y i nd icate d, it is p refera b le th at testi ng dec i s i ons a r e pos t pon e d un til t h e c h il d re n are a du lts a nd ca n d eci de for t h e mse l ves whe t he r t o be teste d.

ISSU E S IN CANCER GE NET I C C O UNSELING

Confidentiality

nan nan

Confidentiality

ISSU E S IN CANCER GE NET I C C O UNSELING

Confidentiality

nan nan

Th e le ve l o f con fi den ti a lit y s urr ound i ng ca n cer g e n etic testi ng is p aram ount du e t o c once r ns o f gene ti c d i s crimi n ati on. Caref u l c on si d erati on s hou l d be g i v e n t o t he con fi den ti a ll y o f famil y h ist o r y i n f o rmati on, p e d i g rees , g e netic test r es u lt s, pa t ho l ogy r epo rt s, a nd t h e carrier stat u s o f o t h er famil y mem b e rs as m os t hosp it a l s and cli n icia n s tra n siti on t o electr on ic me d ica l r ec ord s s ys t e m s. T he goa l o f electr on ic rec o r d s is t o s h are i n f o rmati on

ISSU E S IN CANCER GE NET I C C O UNSELING

Insurance and Discrimination Issues

nan nan

Wh e n g e ne ti c t es ti ng f o r canc er p re d is po siti on first b ecame wi d el y a v aila b le , t he f ea r o f hea lt h i n s u ra n ce d iscrimi n ati on by bo t h p atie n ts a nd prov i d e r s was one o f t he m os t c o mm on c on cer n s . It a pp ears t h at t h e r is k s of hea lt h i nsu r ance d i sc rimi n ati on were ov erstate d a nd t h at alm o st no d isc r imi na ti on by hea lt h i nsu rers h as b ee n re po rte d HI P AA b a nn e d t he u se of gene ti c i n f o rm a ti on as a p ree x isti ng c ond iti on . I n Ma y o f 2008, C ongr es s passed t he Gene ti c I n f o rmati on N ond iscrimi n ati on Act (GINA , H R 493), wh i ch p r ov i des b r o a d p r o tecti on o f a n i nd i v i du al ’ s g e n etic

ISSU E S IN CANCER GE NET I C C O UNSELING

Rep r oductive Issues

nan nan

Rep r oductive Issues

RECE N T AD V ANCES AND FUTU R E DIRECTIONS

nan nan

RECE N T AD V ANCES AND FUTU R E DIRECTIONS

RECE N T AD V ANCES AND FUTU R E DIRECTIONS

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Ca n ce r gene ti c counse li ng and testi ng were t h r u st i n t o t h e n ati on al s po tl ight i n t h e s pr i ng o f 2013 when H oll y w ood ic on A ng eli n a J o lie pub licall y d iscl o se d t ha t she was a BR C A 1 carrie r . O n e m on t h later t h e S up reme C ou r t un a n im ous l y r u l ed aga i ns t gen e p ate n ts . Referrals f o r g e n etic testi ng s p i ked ac ro ss t he coun tr y and have n ot ret u r n e d t o b aseli n e le v els at m o st ce n ter s. W it h i n h ou r s o f t he r u li ng, o t h er la b s b e g a n o f feri ng less e xp e n si v e a nd m or e c o m p r ehens i ve BR C A testi ng, d ramaticall y c h a ng i ng t h e mar k et p la ce of g e n eti c t es ti ng f o r he r ed it a r y b reast ca n ce r . A ll la bo r a t o ri es t ha t have e n tere d t h e BRCA mar k et p lace h a v e don e s o by i n cl ud i ng BR C A 1 and BRCA 2 i n g e n e p a n els . T h ese p a n els sim u lta neous l y ana l yze g r oups o f g e n es t h at c on tri bu te t o i n crease d ris k f o r br east , c o l on, ova ri an, u t e ri ne , a nd o t h er ca n cers . T h e c o st o f t h is tec hno l ogy con ti nues t o dec r e ase wit h s o me m u lti g e n e p a n els c o sti ng j u s t a f e w hund r ed do ll a r s l ess t han tra d iti on al BRCA testi ng (~ $4,000 ) . S o me p a n els i nc l ude on l y we ll- known g e n es (e .g., p53, APC , MLH 1 ) , alt houg h ma ny i nc l ude l esse r known gen es (e .g., BRIP 1 , NBN , MRE 1 1 A ) f o r w h i ch ca n ce r risks a r e ill de fi ned and me d ical ma n a g eme n t op ti on s are unknown. Beca u se t es ti ng f o r t hese gene s is n ew t o t h e cli n ical setti ng, it is e xp ect ed t o ta k e s eve r a l yea r s t o co m p ile acc u rate ca n cer ris k estimates a nd a ppropr iat e r eco mm enda ti ons f o r s u r v eilla n ce a nd ris k re du cti on. F ur t h e rmo r e, t he r a t e o f var i an ts o f un cert a i n si gn ific an ce will li k el y b e m or e c o mm on i n t he l esse r kno w n g e n es . T h ese c h a ng es h a v e i n crease d the c o m p le x it y o f gene ti c t es ti ng expon e n tiall y . I n res pon se , se v eral state a nd on e n ati ona l i nsu r ance co m pany h a v e ma nd ate d g e n etic c oun seli ng by ce r ti f ie d p r ov i de r s be f o r e t hey will c ov er ca n cer g e n etic testi ng. I n a s urpr isi ng r esponse, t he A m e rica n S o ciet y o f Cli n ical O n c o l ogy (ASCO) oppo se d t h i s i nsu r e r ’ s dec i s i on, d es p ite m o re t h a n a d eca d e ’ s w o rt h o f data d em on st ra ti ng t ha t t he m a j o rit y o f phy sicia n s do no t h a v e t h e time o r e xp e r tis e t o o f f e r gene ti c coun seli ng a nd testi ng ( . T h e AMA wil l d eci d e w he t he r t o back t he A SCO res o l u ti on i n J un e 2014. S o m e co m pan i es a r e now o f feri ng d irect-t o -c on s u mer (DTC) g e n etic testi ng v i a webs it es. T he accu rac y o f s o me o f t h ese DTC g e n etic tests ar e in

RECE N T AD V ANCES AND FUTU R E DIRECTIONS

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qu esti on, and t he l ead i ng co m p a n y , 23 a nd Me , h as rece n tl y c o me und er f i r e by t h e U. S . F ood and D r ug Ad mi n istrati on . Mai nta i n i ng h i gh s t anda r d s f o r t ho r ough g e n etic c oun seli ng, i n f o rme d c on se n t , and accu r a t e r esu lt i n ter p retati on will b e p aram oun t i n re du ci ng po te n tial ri sks and m ax imi z i ng t h e b e n efits o f g e n etic tec hno l ogy i n t h e n e x t ce ntu r y .

RECE N T AD V ANCES AND FUTU R E DIRECTIONS

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Peters J. Breast cancer genetics: relevance to oncology practice. Cancer Cont r ol 1995;2:195–208. Brierley KL, Campfield D, Ducaine W , et al. Errors in delivery of cancer genetics services: implications for practice. Conn Med 2010;74:413–423. Brierley KL, Blouch E, Cogswell W , et al. Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications. Cancer J 2012;18:303–309. American College of Su r geons, Commission on Cancer: Cancer Program Standards 2012: Ensuring Patient-Centered Care. Accessed on December 3, 2012. Y ale Cancer Genetic Counseling Program. Mammography techs ordering their own genetic testing? It appears our suspicion was correct. yalecancergeneticcounseling.blogspot.com October 2, 2013. Lubin IM, Caggana M, Constantin C, et al. Ordering molecular genetic tests and reporting results: practices in laboratory and clinical settings. J Mol Diagn 2008;10:459–468. W eeks WB, W allace AE. T ime and money: a retrospective evaluation of the inputs, outputs, e f ficienc y , and incomes of physicians. A r ch Intern Med 2003;163(8):944–948. Doksum T , Bernhardt BA, Holtzman NA. Does knowledge about the genetics of breast cancer di f fer between nongeneticist physicians who do or do not discuss or order BRCA testing? Genet Med 2003;5:99–105. Rosenthal E T . Shortage of genetics counselors may be anecdotal, but need is real. Oncology T imes 2007;29:34–36. Informed Medical Decisions. Adult Genetics: Genetic counseling for your health concerns. A vailable at: Accessed August 24, 2009. Informed Medical Decisions. News: Aetna Press Release: Aetna to o f fer access to confidential telephonic cancer genetic counseling to health plan members. A vailable at: . Accessed August 24, 2009. Schneide r , ME. Cigna to require counseling for some genetic tests. Internal Medicine News Digital Claus E, Schildkraut J, Thompson W , et al. The genetic attributable risks of breast and ovarian cance r . Cancer 1996;77:2318–2324.

IN T RODUCTION

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I t h as b e en sa i d t ha t cance r i s a g e n etic d isease a nd ca n b e b est und erst ood by st ud yi ng t he DNA a lt e r a ti on s t h at lea d t o t h e d e v el op me n t o f ca n ce r . How e v e r , a deepe r unde r s t and i ng o f carci nog e n esis re qu ires i n si gh t i n t o how t h e se gene ti c changes a lter cell u lar p r og rams t h at lea d t o g r o wt h, i nv asi on, and m e t as t as i s. T h i s c h a p ter is p rese n te d f o ll o wi ng t h e l og ical progr ess ion o f DNA t o RNA t o p r o tei n, a nd it d escri b es , at eac h ste p, t he lesi on s t ha t con tri bu t e t o b r ea st ca n cer carci nog e n esis . T h e c h a p ter als o i n t rodu ce s concep t s i n ep i gen etics , micr o RNAs , a nd g e n e e xp ressi on a n al y ses t ha t ill us tr a t e how n ew b i o l og ic d isc ov eries a nd nov el tec hno l ogies h a v e pro f ound l y a f f ec t ed ou r und ersta nd i ng o f b reast ca n cer p at hog e n esi s a nd i nf l uenced t he tr ea tm en t o f p atie n ts .

G E NETICS O F B REAST C A NC E R

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G E NETICS O F B REAST C A NC E R

G E NETICS O F B REAST C A NC E R

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B r east ca nce r i s a he t e r ogeneou s d isease f und ame n tall y ca u se d by t h e progr ess ive accu m u l a ti on o f g e n etic a b errati on s , i n cl ud i ng po i n t m u tati ons, c hro m oso m a l a m p lifi ca ti ons, d eleti on s , rearra ng eme n ts , tra n sl o cati on s , a nd dup licati ons Ge rm-li ne m u tati on s acc oun t f o r on l y a bou t 10 % o f all br east c ance r s, whe r eas t he va st maj o rit y o f b reast ca n cers a pp ear t o o cc u r s por a d ic a ll y and a r e a ttri bu t ed t o s o matic g e n etic alterati on s ( )

H E REDI T A R Y B REAST CANC E R

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On e of t he m os t im po rt an t ri sk fact o rs f o r b reast ca n cer is famil y h ist o r y . A lt hough f a mili a l f o rm s co m p rise n earl y 20 % o f all b reast ca n cers , m o st o f t h e g e n es r espons i b l e f o r f a m i lial b reast ca n cer h a v e y et t o b e i d e n tifie d. B r east ca nce r suscep ti b ilit y gen es ca n b e cate go rize d i n t o t h ree classes acc ord in g t o t he ir fr equency and le v el o f ris k t h e y c on fer: rare h i gh - p e n et r an ce genes, r a r e i n t e rm ed iate- p e n etra n ce g e n es , a nd c o mm on l o w- p e n et r an ce genes and l oc i )

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

BRCA1 and BRCA2

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BRCA1 and BRCA2

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

BRCA1 and BRCA2

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BR C A1 and BR C A 2 m u t a ti on s acc oun t f o r a pp r ox imatel y h alf o f all do mi n a n tl y i nhe rit ed he r ed it ary b reast ca n cers . T h ese m u tati on s c on fer a r elati v e ri sk o f b r eas t cance r 10 t o 30 times t h at o f w o me n i n t h e g e n eral popu lati on, r esu lti ng i n a nea rl y 85 % lifetime ris k o f b reast ca n cer

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

BRCA1 and BRCA2

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BR C A1 -r e l a t ed b r eas t can cers are c h aracterize d by feat u res t h at d isti ngu i sh t he m fr o m bo t h BRCA 2 -relate d a nd s po ra d ic b reast ca n cers .

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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BR C A1 -re l a t ed t u m o r s t yp i cal l y o cc u r i n young er w o me n a nd h a v e m o re a ggr essi ve f ea t u r es, w it h h i gh h ist o l og ic g ra d e , h i gh p r o liferati v e rate , a n e up l oid y , and absence o f es tr og e n a nd p r og ester on e rece p t o rs a nd human e p i d e r m a l g r ow t h f ac t o r r ece pt o r 2 (HER 2 ) . T h is tri p le- n e ga tive ph e no t ype of BR C A1 -r e l a t ed b r eas t canc ers is f u rt h er c h aracterize d by a ba s a llike gene e xpr essi on p r o fil e o f cy t oke rati n s 5 / 6, 14, a nd 17, e p i d ermal g r o wt h fact o r ,

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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a nd P - c adhe ri n A lt hough BRCA 1 a nd BRCA 2 g e n es e n c od e la r g e p r o te ins w it h m u lti p l e f unc ti ons, t hey p rimaril y act as classic t u m o r s upp ress o r g e n es t ha t f unc ti on t o m a i n t a i n g e no mic sta b ilit y by facilitati ng doub le-st r a nd DNA r epa ir t h r ough ho m o l ogou s rec o m b i n ati on . W h e n l o ss o f h ete ro zy gos it y (L OH ) occu r s v ia l o ss , m u tati on, o r sile n ci ng o f t h e wil d- t yp e BRC A 1 o r BR C A 2 a ll e l e, t h e res u lta n t d efecti v e DNA re p air lea d s t o r a p i d acq u i s iti on o f add iti onal m u tati on s , p artic u larl y du ri ng DNA r e p licati on, and u ltim a t e l y se t s t h e sta g e f o r ca n cer d e v el op me n t . Th e i n t eg r a l r o l e o f BR C A 1 a nd BRCA 2 i n doub le-stra nd DNA re p air ho l d s p ot en ti a l as a t he r apeu ti c tar g et f o r BRCA -relate d b reast ca n cers . F o r e x am p le, p l a ti nu m agen t s caus e i n terstra nd cr o ss-li nk s , t h ere by b l o c k i ng DNA r e p li ca ti on and l ead i ng to stalle d re p licati on f o r k s . P o l y (a d e no si ne d i pho s p h a t e [ AD P]-ri bose ) po l y merase- 1 ( P ARP 1 ) i nh i b it o rs a dd iti on all y s how pro mi se as spec ifi c t he ra py f o r BRC A -relate d t u m o rs . P ARP 1 is a cell u la r enzy m e t ha t f unc ti on s i n si ng le-stra nd DNA re p air t h r ough b ase e x cisi on and r ep r esen t s a m a j o r alter n ati v e DNA re p air p at h wa y i n t h e cell . When P AR P i nh i b iti on is a pp lie d t o a b ac kg r ound d eficie n t i n doub le -s tr and DNA r epa i r , as is t h e case i n BRC A -relate d t u m o r cells , t he cells a r e l e ft w it hou t adequa te DNA re p air mec h a n isms a nd u ltimatel y und e r go ce ll cyc l e a rr es t , ch r o m o s o me i n sta b ilit y , a nd cell d eat h Gi v e n t h ei r ph e no t yp i c s imil a riti es t o BRCA 1 -relate d b reast ca n cers , s po ra d ic b asalli k e b r eas t t u m o r s m ay d is p la y se n siti v it y t o P ARP i nh i b iti on as we ll .

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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P h ase II s t ud i es a r e cu rr en tl y und er wa y t o e xp l o re t h e u se o f P ARP i nh i b it ors i n bo t h BR C A - and b asalli k e , non – BRC A -relate d b reast t u m o r s. Th e r e is m uch t ha t r e m a i ns t o b e und erst ood a bou t t h e op timal u se o f P A R P i nh i b it ors. Cu rr en t cha ll enges i n cl ud e , bu t are no t limite d t o, i d e n tif y i ng robu st p r ed i c ti ve b i o m a r ke r s of res pon se t h at ca n gu i d e p atie n t selecti on a nd unde r s t and i ng va ri a ti ons am ong P ARP i nh i b it o rs i n cli n ical d e v el opmen t . D i f f e r ences i n po te n c y a nd t h e mec h a n ism o f acti on h a v e b ee n w ell e l uc i da t ed i n r ecen t p recli n ical st ud ies , – a nd t h e res u lts o f ongo i ng c li n i ca l tri a l s w ill ne e d t o b e i n ter p rete d i n t h is c on te x t . Add iti ona ll y , r ecen t s t ud i es h a v e als o i d e n tifie d mec h a n isms o f resista nce t o P A R P i nh i b it o r s. One o f t h ese im po rta n t mec h a n isms i n cl ud es sec onda r y

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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m u tati ons i n t he BR C A 1 / 2 gen e t h at ca n rest o re t h e op e n rea d i ng frame , and t h e r e fore, DNA r epa ir f unc ti on al acti v it y , w h ic h re nd ers t u m o rs r esista n t t o P AR P i nh i b it o r s. Sec ond l y , l o ss o f t u m o r p r o tei n p53 b i nd i ng pro tei n 1 (TP 53B P 1 ) i n BR C A 1 - d eficie n t cells ca n rest o re DNA re p air acti v it y and t h i s m ay con fer resista n ce .

H E REDI T A R Y B REAST CANC E R

High-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

Other High-Penetrance Genes

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A small n u m be r o f o t he r h i gh- ris k, l o w-fre qu e n c y b reast ca n cer s u sce p ti b ilit y genes ex i s t , and t h e y i n cl ud e TP 53, PTEN , S TK 1 1 / LKB 1 , and C DH1 . T hese h i gh - pene tr an ce g e n es c on fer a n ei gh t- t o te n f o l d i n crea se i n t h e r i sk o f b r eas t cance r as co m p are d t o non carriers , bu t t h e y c o llecti vely acc oun t f o r l ess t han 1 % o f br east ca n cer cases . Li k e BRCA 1 a nd BRCA 2 , t h ese g e nes 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 f un cti on as t u m or s upp r esso r s. T he he r ed itar y ca n cer s ynd r o mes ass o ciate d wit h ea ch g e n e a r e usua ll y cha r ac t e ri ze d by m u lti p le ca n cers i n a dd iti on t o b reast ca n ce r , as su mm a ri zed i n .

H E REDI T A R Y B REAST CANC E R

Moderate-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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Moderate-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

H E REDI T A R Y B REAST CANC E R

Moderate-Penetrance, Low-F r equency B r east Cancer P r edisposition Genes

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F our g e nes have been i den tifie d t h at c on fer a n ele v ate d bu t m od erate risk o f d e v el oping b r eas t cance r , nam el y CHEK 2 , A TM , BRIP 1 , a nd P ALB 2 (se e . E ach o f t hese ge nes c on fers a pp r ox imatel y a tw o - t o t h reef old r elati v e ri sk o f b r eas t cance r i n m u tati on carriers , alt hough t h is ris k ma y be h i gh e r i n se l ec t c li n i ca l se tti ng s . M u tati on fre qu e n cies i n t h e g e n eral popu lati on a r e r a r e, on t he o r d er o f 0.1 % t o 1 % , alt hough s o me f ound er m u tati ons have been i den tifi ed. T og et h e r , t h ese g e n es acc oun t f o r a pprox im a t e l y 2.3 % o f i nhe rite d b reast ca n ce r . T h e m od erate relati v e ris k of br eas t cance r o f t hese gene s i n c on j un cti on wit h t h e l o w popu lati on fr e qu e ncy r ende r s t h i s c l ass o f g e n es v er y d i f fic u lt t o d etect wit h t yp ical ass o ciat ion s t ud i es. Howeve r , t h ese g e n es were s p ecificall y selecte d f o r st udy as cand i da t e b r eas t can cer g e n es b ase d on t h eir kno w n r o les i n si gnal t r a n s du cti on and DNA r epa ir i n cl o se ass o ciati on wit h BRCA 1 a nd BRC A 2

H E REDI T A R Y B REAST CANC E R

Low-Penetrance, High-F r equency B r east Cancer P r edisposition Genes and Loci

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Low-Penetrance, High-F r equency B r east Cancer P r edisposition Genes and Loci

H E REDI T A R Y B REAST CANC E R

Low-Penetrance, High-F r equency B r east Cancer P r edisposition Genes and Loci

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B o t h ca nd i da t e gene and gen ome-wi d e ass o ciati on st ud ies (G W AS) h a v e i d e n ti f ie d a l ow -ri sk pane l o f app r ox imatel y 10 d iffere n t alleles a nd l o ci in 15% t o 40 % o f wo m en w it h breast ca n cer (see . Des p ite t h eir fr e qu e nc y , t he r e l a ti ve ri sk o f b reast ca n cer c on ferre d by a ny on e o f t h es e g e n etic v a ri an t s a l one i s mi n imal , on t h e o r d er o f less t h a n 1.5 .

H E REDI T A R Y B REAST CANC E R

Low-Penetrance, High-F r equency B r east Cancer P r edisposition Genes and Loci

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H E REDI T A R Y B REAST CANC E R

Low-Penetrance, High-F r equency B r east Cancer P r edisposition Genes and Loci

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N e v e r t he l ess, t hese a ll e l es and l o ci ma y b ec o me cli n icall y rele v a n t i n t h e i r s ugg esti on o f i n t e r ac ti ons w it h o t h er h i gh - , m od erate- , a nd l o w-ris k g e nes; t h ese a dd iti ve o r m u lti p li ca ti v e relati on s h i p s c ou l d acc oun t f o r a meas u r able fr acti on of popu l a ti on ri sk. For e x am p le , ass o ciati on st ud ies o f fi b r ob las t grow t h f ac t o r r ecep t o r 2 (F G FR 2 ) a nd mit og e n -acti v ate d p r o tei n k i n ase k i n ase k i nase 1 ( MA P 3K1 ) wi t h i n BRCA families s ho we d t h at t h ese SN Ps c onf e rr e d an i nc r eased ri sk i n t h e p rese n ce o f BRCA 2 m u tati on s .

H E REDI T A R Y B REAST CANC E R

Mic r osatellite Instability in B r east Cancer

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Mic r osatellite Instability in B r east Cancer

H E REDI T A R Y B REAST CANC E R

Mic r osatellite Instability in B r east Cancer

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Th e r e is e m e r g i ng da t a t ha t L yn c h s ynd r o me , a n a u t o s o mal- do mi n a n t i nh e r ite d d i so r de r o f cance r su sce p ti b ilit y ca u se d by g erm-li n e m u tati ons in t h e DNA mi s m a t ch r epa ir ( MM R) g e n es i n cl ud i ng, MLH 1, M S H 2, M S H 5 , a nd PMS2, m ay i nc r ease t he r i s k o f b reast ca n ce r M u tati on carriers ar e at i n c r ease d ri sk o f co l o r ec t a l and o t h er ca n cers , bu t its ass o ciati on wit h b r east ca n ce r risk has been con tr over sial . A p r o s p ecti v e c oho rt st udy u si ng t h e C o l on Ca nce r F a mil y Reg i s tr y e v al u ate d ca n cer ris k s am ong un a f fecte d ca rr ie r s and nonca rri e r s w it h a p at hog e n ic MMR g e n e m u tati on ; no ta b l y , br east c ance r ri sk was es tim a te d t o b e f ou rf o l d am ong m u tati on carriers c o m p a red t o t he gene r a l popu lati on . A s y stematic re v iew o f b reast ca nce r r is k st ud i es f o r L ynch synd r o me m u tati on carriers s ho we d mi x e d res u lts ; 13 st ud ies d i d no t obse r ve an i nc rease d ris k, w h ereas 8 st ud ies ob ser v e d a n i n c r ease d ri sk o f b r eas t cance r ra ng i ng fr o m 2 - t o 18 -f o l d c o m p are d t o t he g e n e r al p opu l a ti on . F u rt he r st ud ies are n ee d e d t o d etermi n e m o re p reci se estimate s o f b r eas t cance r ri s k i n L yn c h s ynd r o me carriers wit h l ong er

H E REDI T A R Y B REAST CANC E R

Mic r osatellite Instability in B r east Cancer

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fo ll ow-ups. T hese s t ud i es m ay als o gu i d e f u t u re b reast ca n cer scree n i ng gu i d eli nes f o r t h i s popu l a ti on.

H E REDI T A R Y B REAST CANC E R

Mic r oRNA and Cancer Susceptibility

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Mic r oRNA and Cancer Susceptibility

H E REDI T A R Y B REAST CANC E R

Mic r oRNA and Cancer Susceptibility

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Rece n t s t ud i es sugges t t ha t micr o RNA (miRNA) SNPs ma y als o c on tri bute t o br eas t cance r suscep ti b ilit y , a nd miRNAs a pp ear t o re gu late ma ny t umo r s uppr es so r genes and oncogen es v ia d e g ra d ati on o f ta r g et miRNAs o r r e pr essi on o f t he ir tr ans l a ti on. T hu s , g e n etic v ariati on s i n miRNA g e n es o r miR NA b i nd i ng s it es cou l d a f fect t h e e xp ressi on o f t u m o r s upp ress o r g en es or on c ogenes and, t he r eb y , a f fect ca n cer ris k. F o r e x am p le , s p ecific SN Ps l o cate d wit h i n p r e - m i r - 27a and mi r - 196a - 2 g e n es h a v e b ee n ass o ciate d with r e du ce d b r eas t cance r ri sk, wh ic h h as b ee n c on firme d i n a rece n t meta-a n al y sis

SOM A TIC CHANGES IN B REAST CANC E R

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SOM A TIC CHANGES IN B REAST CANC E R

SOM A TIC CHANGES IN B REAST CANC E R

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Wh e n s pec ifi c d ri ve r m u t a ti on s are catal og e d am ong se v eral d i f fere n t b re ast t u m or s , a b im oda l cance r geno mic l and sc ap e a pp ears , c o m p risi ng a sma ll nu m b e r o f co mm on l y m u t a t ed g e n e m oun t a i n s am ong hund re d s o f i nfr e qu e n tl y m u t a t ed gene h ills Ge n e m oun tai n s c o rres pond t o t h e m ost fr e qu e n tl y m u t a t ed genes f ound wit h i n b reast t u m o rs , s u c h as TP 53 , CD H1 , pho s ph ati dy li nos it o l 3 - k i nase ( PI 3 K ) , c y cli n D , PTEN , a nd AK T . Eac h i nd i v i du al gene h ill , on t he o t h er h a nd, is t yp icall y f ound i n less t h a n 5 % o f br east tum o r s . T h i s subs t an tial h eter og e n eit y o f DNA m u tati on s am ong br east tum o r s m ay exp l a i n t he wi d e v ariati on s i n ph e no t yp es , bo t h i n ter ms of t u m o r behav i o r as we ll as r e s pon si v e n ess t o t h era p y . H ist o ri ca ll y , t he f ocus o f gen etic researc h h as b ee n on t h e g e n e m oun tai ns, i n pa rt because t h e y were t h e on l y m u tati on s t h at a v aila b le tec hno l ogy cou l d i den tif y . How e v e r , eme r g i ng d ata s ugg est t h at it is act u all y t he gene h ill s t ha t p la y a m u c h m o re p i vo tal r o le i n b reast ca n ce r , wh ic h is cons i s t en t w it h t he idea t h at h a v i ng a lar g e nu m b er o f m u tati ons, eac h ass oc i a t ed w it h a s m a ll s u r v i v al a dv a n ta g e , d ri v es t u m o r p r og ressio n. Rece n t s t ud i es have shown t h at a s ub sta n tial nu m b er o f t h ese i n fre qu e n t s o matic mu t a ti ons so rt ou t a m ong a m u c h smaller nu m b er o f b i o l og ic group s and ce ll s i gna li ng pa t h wa y s t h at are kno w n t o b e p at hog e n ic i n br east c ance r , t he r eby vas tl y re du ci ng t h e c o m p le x it y o f t h e g e no mic la nd sca pe. E xa m p l es o f such p at h wa y s i n cl ud e i n terfer on si gn ali ng, cell c y cle c heckpo i n t , BR C A 1 / 2 -r e late d DNA re p ai r , p53, AK T , tra n sf o rmi ng grow t h f ac t o r β (T G F-β) s i gn ali ng, N o tc h, e p i d ermal g r o wt h fact o r rece pto r (EG FR ), F G F , E RBB2, RA S , a nd PI 3 K . I n s ho rt , it a pp ears t h at c o mm on p at hw a y s , r a t he r t han i nd i v i du al g e n e m u tati on s , gov er n t h e c ou rse o f br east c ance r deve l op m en t . A lt hough r ecu rr en t po i n t m u tati on s are less c o mm on i n b reast ca n cer t h a n o t he r so li d t u m o r s, e m e r g i ng d ata s ho w t h at p artic u lar re g i on s o f t he g e no me a r e co mm on l y a m p li f ie d, a nd t h ese re g i on s c on tai n g e n es t h at d r ive ca n ce r prog r ess i on. T he bes t e x am p le o f a n im po rta n t am p lifie d re g i on i s t h e 17q12 a m p li con t ha t ha r bo rs t h e HER 2 on c og e n e . T h is am p lic on lea ds t o a m or e agg r ess i ve t u m o r ph e no t yp e , no w t h e tar g et o f a h i gh l y s u cces s f ul a n ti body t he r ap y , tr as t uzu m ab (Herce p ti n ) . It h as b ee n ob ser v e d t h at RN A -

SOM A TIC CHANGES IN B REAST CANC E R

nan nan

me d iated i n t e rf e r ence ( RNA i) kno c kdo w n o f c o am p lifie d g e n es wit h i n t he 17q12 am p li con r esu lt s i n de crease d cell p r o liferati on a nd i n crease d a pop t o sis T hus, t he 17q12 a m p lic on a pp ears t o e n c od e a c on certe d g e n etic pr og r a m t ha t con tri but es t o t h e on c og e n esis . Th e r e a r e seve r a l o t he r a mplic on s , i n a dd iti on t o 17q12 ( HER 2 ) , t h at seem t o d ri ve t he cance r phen ot yp e a nd h a v e p r ogno stic si gn ifica n ce i n br east c ance r s, f o r exa m p l e, 1 1q13 ( CCDN 1 ) a nd 8q24 ( MYC ) , 20q13.

SOM A TIC CHANGES IN B REAST CANC E R

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SOM A TIC CHANGES IN B REAST CANC E R

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Th ese reg i ons con t a i n gene se ts t h at are im po rta n t i n DNA meta bo lism a nd i n t h e m a i n t enance o f ch r o m o s o mal i n te g rit y , s ugg esti ng t h at a res pon se to DNA d a mag i ng agen t s used a s a n tica n cer t h era py mi gh t b e m odu late d by t h e pr ese nce o f pa rti cu l a r a m p lic on s . I nd ee d, t h ese c o am p lic on s are fr e qu e n t i n H ER 2 - a m p lifi ed t u m o rs a nd ma y m od if y t u m o r b e h a v i o r a nd p atie n t ou t co m e . T he con tri bu ti on o f t h ese g e no mic alterati on s t o fun cti on al consequences m ay lie no t i n t h e ov ere xp ressi on o f i nd i v i du al g e n es , bu t o f gene casse tt es on t h e am p lic on. D i r e c t c li n i ca l tr ans l a ti on of t h e g r o wi ng catal og o f s o matic alterati ons i n br eas t cance r has ye t t o evo l v e . H o we v e r , wit h a dv a n ci ng tec hno l ogy and fur t h e r i den tifi ca ti on and ca t ego rizati on o f g e n etic m u tati on s , n ew oppor t un iti es f o r i nd i v i dua li zed d ia gno sis a nd treatme n t op ti on s are li k el y t o eme r ge.

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

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TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

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Th e cell u l a r p r og r a m s t ha t a r e e n c od e d by DNA are e n acte d by t r a n sc r i p ti on i n t o m essenge r RNA (mRNA) a nd tra n slate d i n t o p r o tei n. Not s urpr isi ng l y , t he DNA a lt e r a tio n s d escri b e d p re v i ou sl y lea d t o eit h er unde r- or ov e r e xp r ess i on o f t he ir asso ciate d mRNAs; c on se qu e n tl y , a bno rmal gene e xpr essi on pa tt e r ns a r e a co m mon fi nd i ng i n b reast t u m o rs . Ge n e e xpr essi on p r o fili ng has been i n tr odu ce d i n t o t h e cli n ical literat u re du ri ng t h e p ast decade because r esea rc h s ugg ests t h at assessi ng t h e e xp ressi on o f m u lti p le genes i n a t u m o r samp le ma y reflect p r og rams t u r n e d on by D NA

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

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alte rn ati ons and p r ed i c t t u m o r b e h a v i o r . S o -calle d m o lec u lar si gn at u res ho l d pro mi se f o r im p r ov i ng t h e d ia gno sis , t h e p re d icti on o f rec u rre n ce , a nd t h e sele c ti on o f t he r ap i es f o r i nd i v i du al p atie n ts . Se v e ra l t echno l og i es have b ee n d e v el op e d t o g e n erate m o lec u lar si gn at ures, i nc l ud i ng cDNA and o li gonu cle o ti d e arra y s a nd m u lti p le x po l y me r a se cha i n r eac ti on (PCR) tec hno l og ies . T h ese tec hno l og ies a nd n e w l y deve l oped s t a ti s ti ca l met hodo l og ies no w all o w f o r e v al u ati on s o f hundr e ds and even t housands o f mRNAs sim u lta n e ou sl y wit h g r oup i ng s o f sam p les based on coexp r essedg e n es .

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

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Molecular Classification of B r east Cancer

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

nan nan

Th e se m i na l wo r k by P e r ou e t al . a nd S o rlie et al . s ugg ests a classi f ic a ti on o f b r eas t cance r s ub t yp es b ase d on g e n e e xp ressi on p attern s t h e y te r m ed mo l ecu l ar por t rai ts o f b reast ca n ce r . Am ong t h e cate go ries t h e y d e f i ned we r e t he l u mi na l A a nd B t u m o r t yp es (t yp icall y estr og e n - r ece p t or [E R ] o r p r oges t e r on e-rece p t o r [PR] po siti v e) , HER 2 g e n e-am p li f ie d t u m o r s, and a c l ass t erme d ba s a l-like du e t o t h e e xp ressi on o f b asal k er a ti ns. Recen t l a r ge sc ale e f f o rts by T h e Ca n cer Ge no me Atlas N et work (T CGA and t he Mo lec u lar T a xono m y o f Breast Ca n cer In te rn atio na l Conso rti u m ( ME T ABRIC g r oup s h a v e c on firme d t h ese ea r lie r f i nd i ngs i n add iti on t o p r ov i d i ng m o re d etaile d m o lec u lar po rtrait s.

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

Luminal Subtypes

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Luminal Subtypes

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

Luminal Subtypes

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Th e l u mi na l sub t ypes co m p rise t h e maj o rit y o f b reast ca n cers a nd are c h a r acteri zed by t he exp r ess i on o f g e n es t h at are no rmall y e xp resse d i n t he l u mi n al ep it he li a l o f t he b r east s u c h as c y t ok erati n s 8 a nd 18 a nd t h e l u mi n al exp r ess i on s i gna t u r e ( E S R 1, G A T A 3, FOXA 1, XPB 1, a nd MYB ) . Lu mi n al sub t ypes co m p ri se t h e maj o rit y o f cli n ical ER- po siti v e b reast ca n ce r s and can be d i v i ded i nto tw o s ubg r oup s: l u mi n al A a nd l u mi n al B . Lu mi n al A t u m o r s a r e m o r e co mm on a nd are c h aracterize d by h i gh e xpr essi on l eve l s o f E R -r e l a te d g e n es a nd l o w e xp ressi on o f t h e HER 2 cl u ste r a nd p r o lif e r a ti on - asso ciate d g e n es . I n c on trast , l u mi n al B t u m o rs a r e

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

Luminal Subtypes

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c h a r acteri zed by l owe r exp r e ssi on le v els o f ER-relate d g e n es , v aria b le e xpr essi on o f t he H E R2 c l us t e r , a nd h i gh er le v els o f p r o liferati on -ass o ciate d genes. L u mi na l A t u m o rs h a v e a n ov erall b etter p r ogno sis t h a n l u mi n al B t u m o r s.

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

HER2-Enriched Subtype

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HER2-Enriched Subtype

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

HER2-Enriched Subtype

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Th e HER2 - en ri ched sub t ype c o m p rises a pp r ox imatel y 10 % t o 15 % o f al l br east c ance r s and ove r exp r e sses bo t h HER 2 a nd p r o liferati on -ass o ciate d g e n es a nd has l owe r exp r ess io n o f ER-relate d g e n es . I n teresti ng l y , m o re r ece n t wo r k by t he T CGA de m on strates t h at no t all ca n cers t h at are cli n ically H E R2 - pos iti ve as d efi n e d by a n imm unoh ist o c h emical (IHC) a n al y sis and / o r fl uo r escen t i n sit u hyb ri d izati on (FISH) fall i n t o t h e HER 2 -e nr ic h ed m o l ecu l a r sub t ype and v ice v ersa . T h e maj o rit y o f cli n icall y HE R 2-pos iti ve b r eas t cance r s t h at are no t c on si d ere d p art o f t h e HER 2 -e nr ic h ed subg r oup by gene exp ressi on p r o fili ng fall i n t o t h e l u mi n al i n t r i n sic sub t ype w it h ove r exp ressi on o f HER 2.

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

Estrogen Receptor–Negative Subtypes

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Estrogen Receptor–Negative Subtypes

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

Estrogen Receptor–Negative Subtypes

nan nan

Th e E R- nega ti ve sub t ypes co m p rise a h eter og e n e ou s g r oup o f t u m o rs t h a t cli n ically a r e t e rm ed tri p l e ne gati v e b reast ca n cer (TNBC) b eca u se t h e y t yp icall y l ack E R, P R, and HE R 2 , a nd are o fte n referre d t o as tri p le n e ga tiv e , a lt hough no t a ll bas alli k e t u m o rs are tri p le n e g ati v e a nd v isa v e r sa . The basa lli ke ca t ego r y o f t h e ER- n e g ati v e s ub sets were first i d e n ti f ie d w it h fir s t- gene r a ti o n micr o arra y tec hno l ogy a nd s ho w a h i gh e xpr essi on o f p r o lif e r a ti on gen es a nd b asal c y t ok erati n s a nd a l o ss o f g e n es as soc i a t ed w it h ce ll cy cle c on tr o l , w h ic h c on fer a n ov erall poo r progno si s. T hough basa lli ke t u m o rs are t h e m o st c o mm on o f t h e ER- n e g ati v e sub t ypes ( 50 % t o 75 % o f all ER- n e g ati v e t u m o rs) a nd c o m p ris e 15% t o 20 % o f a ll t ypes o f b reast ca n ce r , o t h er ER- n e g ati v e s ub t yp es al so e x ist , w hi ch i nc l ude t he r ecen tl y d escri b e d cla ud i n -l o w g r oup, as well a s i n te rf e r o n -ri ch, and r ogen r ec e p t o r , no rmalli k e g r oup s . T hough t h e cla ud i n -l ow s ubg r oup has so m e s imilarities t o b asalli k e b reast ca n ce r , it is d isti nct

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

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TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Molecular Classification of B r east Cancer

nan nan

Maj or cl us t e r s i nc l uded t wo b asalli k e , a n imm uno m odu lat o r y , a mese n c hy m a l , a m esenchy m al stem – li k e , a nd a l u mi n al a nd r og e n rece p t o r s ub t yp e . O f f u rt he r s i gn ifi can ce , t h is g r oup p r ov i d e d p recli n ical e v i d e n c e t h at t h ese m o l ecu l a r sub t ypes were se n siti v e t o d iffere n t t h era p ies . T h i s h as d i r e c t tr ans l a ti ona l r e l evan ce a nd s hou l d b e v ali d ate d f u rt h e r . A lt hough t he exac t de fi n iti on o f m o lec u lar s ub t yp es is a n area o f acti ve d e b ate , i t i s c l ea r t ha t t hese sub t yp es are re p r odu ci b le i n m u lti p le , un rela ted d ata set s, and t he ir p r ognos ti c im p act h as b ee n v ali d ate d i n t h ese setti ng s . As a r esu lt , c li n ical trials are no w b ei ng d esi gn e d t o s ubd i v i de pa ti en t s by E R /P R a nd HER 2 stat u s t o v ali d ate claims t h at t h e r a p euti c app r oaches shou l d a dd ress t h ese g r oup s rat h er t h a n t h e popu lati on o f b r eas t cance r pa tie n ts as a w ho le . I n 20 1 1, t h e St . Galle n In te rn atio na l B r eas t Cance r Con fere n ce rec ogn ize d t h at b reast ca n cer s hou l d n o t be tr ea t ed as a s i ng le d isease a nd rec o mme nd e d d efi n i ng d ise ase by m o le cu l a r sub t ype us i ng g e n etic arra y testi ng o r a pp r ox imate d by E R/PR/ H E R2 s t a t us i n con j un cti on wit h mar k ers o f p r o liferati on, s u c h a s K i -67. T he pane l r ea f firm ed this po siti on a g ai n i n 2013 .

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Genetic Changes in B r east Cancer by Molecular Subtype

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Genetic Changes in B r east Cancer by Molecular Subtype

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Genetic Changes in B r east Cancer by Molecular Subtype

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M u tati ona l p r o fili ng o f a ll t yp es o f b reast ca n cer h as d em on strate d t h e ma rk e d he t e r ogene it y t ha t ex i s ts acr o ss t h e e n tire s p ectr u m o f t u m o rs . D ata fro m t he T CGA h i gh li gh t s t h e fact t h at s o matic m u tati on s i n j u st t h ree g e n es ( TP 53, PI K3 A , and G A T A 3 ) o cc u rre d at a n i n ci d e n ce o f g reater t han 10% Howeve r , when t he m u tati on p r o file o f b reast ca n cers is a n al y zed by i n t r i n sic subg r oup, ce rt a i n pa t t er n s c on ti nu e t o emer g e . Alt hough t h e rat e o f si gn i f ic an tl y m u t a t ed genes i s t h e l o west i n t h e l u mi n al s ubg r oup, it is als o

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

Genetic Changes in B r east Cancer by Molecular Subtype

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t h e m o s t he t e r ogeneous g r oup i n terms o f m u tati on al s p ectr u m . T h e m o s t fr e qu e n t m u t a ti on i n l u mi na l A t u m o rs was i n PIK 3 CA ( 45 %) f o ll o we d by MAP3 K 1, G A T A 3, TP 53, CD H 1 , a nd MAP 2 K 4. Li k e l u mi n al A ca n cers , l u mi n al B cance r s a l so showe d a wi d e ra ng e , wit h t h e m o st fre qu e n tl y m u tati on genes be i ng TP 53 and PIK 3 CA ( bo t h 29 %) . H o we v e r , t h e TP 53 p at hw a y appea r s t o be d i f f e r en tiall y i n acti v ate d wit h l o wer TP 53 m u tatio ns i n l u mi n al A ( 12 %) and h i gh er m u tati on s i n l u mi n al B ( 29 %) . Alt hough the HE R 2- e n ri ched subg r oup a l so s ho ws a h i gh fre qu e n c y o f m u tati on s i n T P53 (7 2%) and PI K3C A ( 39 %) , un li k e t h e l u mi n al s ub t yp es , HER 2 -e nr ic h ed t u m o r s appea r t o hav e a m u c h l o wer fre qu e n c y o f o t h er si gn i f ic an tl y m u t a t ed genes. Basalli k e t u m o rs c o mm on l y h ar bo r m u tati ons i n T P53 ( 80 %) , and t he r e see ms t o b e little ov erla p wit h t h e m u tati on s s een i n t h e l u mi na l sub t ypes. I n add iti on, t h e TP 53 m u tati on s p rese n t i n t h e b asalli k e g r oup we r e m os tl y non se n se a nd frames h ift – t yp e m u tati on s as oppo se d t o m o r e mi ssense m u tati on s see n i n t h e l u mi n al g r oup. I n fact , t he m u tati ons seen i n t he basa lli ke g r oup s ho we d si gn ifica n t similarities t o se rou s ca nce r s o f t he ova r y

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

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P r ognostic and P r edictive Genomic Signatu r es

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Prognostic Signatures

nan nan

Prognostic Signatures

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Prognostic Signatures

nan nan

G e n e e xp r ess i on m o l ecu l a r s i gn at u res are c u rre n tl y i n cli n ical u se f o r bo t h d e f i n i ng p r ognos i s and f o r det ermi n i ng t h e b e n efit o f s y stemic t h era p ies , i n cl ud i ng che m o t he r apy and endo cri n e treatme n t , f o r b reast ca n ce r . V a n ’ t V ee r et al and van de V ij ve r et al were t h e first t o a pp l y g e n e e xp res sion a n al y sis t o de fi ne a subg r oup o f b reast ca n cer p atie n ts wit h a n i n crease d li k eli hood o f m e t as t as i s. T he estimate d h azar d rati o f o r d ista n t metastas es in t h e group w it h a poo r p r ogno sis si gn at u re , as c o m p are d t o t h e g r oup wit h t h e good p r ognos i s s i gna t u r e, was 5.1 ( 95 % c on fi d e n ce i n ter v al [CI] , 2.9 to 9.0 ; p < 0.001 ) . T he E u r opean O r g a n isati on f o r Researc h a nd T reatme n t o f Ca n ce r (E O R T C ) and t he B r e ast I n ter n ati on al Gr oup (BIG) are c u rre n tl y c ondu ct ing a p r ospec ti ve c li n ical trial t o v ali d ate t h e u tilit y o f t h is assa y f o r

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Prognostic Signatures

nan nan

s p a r i ng pa ti en t s fr o m sys t e mic c h em o t h era py (t h e MINDACT st udy ) . I n a pr elimi n ar y ana l ys i s, t he 70 - gen e p r o file si gn at u re was str ong l y p r ogno s tic, ou t p e rfor mi ng c l ass i c p r ogno stic criteria s u c h as t ho se u se d by t h e St . G alle n c onsensus pane ; ho we v e r , t h e ma gn it ud e o f e f fect was m u c h les s t h a n pr e v i ous l y r epo rt ed, w ith h azar d rati o s f o r time t o d ista n t metastase s o f 1.85 (1. 1 4 t o 3.0 ) and f o r ove rall s u r v i v al o f 2.5 ( 1.4 t o 4.5 ) . T h e 70 - g e ne si gn at ure i s now co mm e r c i a lize d as t h e MammaPri n t a nd h as recei v e d clea r a n c e by t he U. S . F ood a n d Dr ug A d mi n istrati on (FDA) as a class 2, 510(k) pr oduc t . O t h er g r oups have deve l op e d p r ogno stic g e n e e xp ressi on si gn at u res , i n cl ud i ng t he 76 - gene Ro tt e r d am si gn at u re , w h ic h i d e n tifies a h i gh -ris k group of node - nega ti ve pa ti e nts , a nd t h e Ge no mic Gra d e I nd e x (GGI) , wh ic h dis ti ngu i shes poo r and good p r ogno sis g r oup s i n b reast t u m o rs o f i n te r me d i a t e h i s t o l og i c g r ade . T h e po te n tial v al u e o f t h ese si gn at u res has y et t o be c l ea rl y de fi ned, bu t it em ph asizes t h e r o le o f g e n e e xp ressi on prof ili ng a t d i s ti ngu i sh i ng p r ogno stic g r oup s no t o t h erwise rec ogn iza b le by sta nd a rd h i s t o l og i c o r c li n i ca l p arameters .

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

Predictive Signatures

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

S eve r a l g r oup s h a v e a pp lie d a g e n e e xp ressi on prof ili ng ana l ys i s t o be tt e r de fi n e t h e li k eli hood o f b e n efit fr o m t h era p y . S u c h pred i c ti ve s i gna t u r es ma y h a v e p artic u lar v al u e as t h e y h el p on c o l og i s t s counse l pa ti en t s abou t a pp r op riate c ho ices f o r treatme n t . G e no mic s Hea lt h I nc. ( Redwood Cit y , Calif o r n ia) d e v el op e d t h e O n c o t ype DX assay as a p r ed i c t o r o f ben efit fr o m a n tiestr og e n t h era py u si ng m u lti ple r eal - time r eve r se tr ansc ri p t as e po l y merase c h ai n reacti on ( R T -PCR) assa ys i n for m a li n -fi xed pa r a f fi n - e m b e dd e d tiss u e . T h e assa y was d e v el op e d fr om 250 ca nd i da t e genes se l ec t ed fr o m pub lis h e d literat u re , g e no mic d ata b as es, a nd i n-house expe rim en t s pe rf o rme d on fr o ze n tiss u e . Fr o m t h ese d ata , a p a n el of 16 cance r -r e l a t ed gen es a nd 5 refere n ce g e n es were u se d t o d e v el op an a l go rit h m t o co m pu te a rec u rre n ce sc o re , ra ng i ng fr o m 0 t o 100, t h at ca n b e used t o es tim a t e t h e odd s o f rec u rre n ce ov er 10 y ears fr o m th e d ia gno sis P a i k e t a l r epo rte d a n a n al y sis o f tw o ra ndo mize d c on tr o ll ed

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

t r ials: t he Na ti ona l S u r g i ca l Ad j uv a n t Breast a nd B o wel Pr o ject NSABP-B 14, i n wh i ch node - nega ti ve p atie n ts wit h ER- po siti v e t u m o rs were r a ndo ml y ass i gned t o t a m ox ife n o r n il; a nd NSABP-B 20, i n w h ic h nod e- n e g ati v e pa ti en t s w it h E R - po siti v e t u m o rs were ra ndo ml y assi gn e d t o tam ox i fen a l one o r w it h cyc l opho s ph ami d e , met ho tre x ate , a nd fl uo r ou ra cil ( CM F) che m o t he r ap y . Us i ng th e tiss u e sam p les fr o m NSABP-B 20, p ati ents w e r e cat ego ri zed i n t o t h r ee r ecu rre n ce sc o re g r oup s: l o w ris k (rec u rre n c e sc or e le ss t han 18 ) , i n t e rm ed iate ris k (rec u rre n ce sc o re 18 t o 30 ) , a nd h i gh r is k (r ec u rr ence sco r e 31 t o 100 ) . Sam p les fr o m NSABP-B 14 were t h e n a n al y ze d and f ound t o be 6.8 % ( 4.0 % t o 9.6 %) , 14.3 % ( 8.3 % t o 20.3 %) , a nd 30.5 % ( 23.6 % t o 37.4 %) . Pai k et al . f u rt h er a n al y ze d t h e p erf o rma nce of t h e Onco t ype DX assay t o i n cl ud e p atie n ts i n t h e o t h er arms o f NSAB P -B 14 a nd N S AB P- B20 and f ound t h at t h e O n c o t yp e DX assa y was a str ong pr e d ict o r o f bene fit fr o m CMF i n NSABP-B 20, wit h little o r no b e n efit fro m c h em o t he r apy f o r pa ti en ts wit h l o w o r i n terme d iate rec u rre n ce sc ores bu t s ub st an ti a l bene fit f o r t ho se wit h h i gh rec u rre n ce sc o res . C onv ersel y , in N S A B P - B14, t he bene fit fr o m tam ox ife n v ers u s ob ser v ati on was c on fi ned t o t h e l ow and i n t e rm ed i a t e ris k cate go ries ( p v al u e f o r i n teracti on o f 0.001). These da t a sugges t t ha t i n p atie n ts w ho h a v e a n a pp are n t fa vo ra ble progno si s based on c li n i ca l f e at u res ( n e g ati v e nod es , po siti v e ER) , t h e On c o t ype DX assay he l ps de termi n e t ho se m o st li k el y t o b e n efit fr o m tam ox i fen on l y (l ow r ecu rr en ce sc o res) v ers u s t ho se m o st li k el y no t t o b e n e f it f r o m t a m ox if en bu t li k el y t o b e n efit fr o m c h em o t h era py ( h i gh r ec urr e nce sco r es ) . T he bene f i ts o f c h em o t h era py i n t h e 25 % o f p atie n ts who h a ve i n t e rm ed i a t e r ecu rre n ce sc o res remai n s un certai n a nd are t h e b asis of an ongo i ng p r ospec ti v e ra ndo mize d trial ( T ail o r R x ) w h ere t ho s e w it h h i gh r ecu rr ence sco r es w ill recei v e e ndo cri n e t h era py a nd c h em o t he r ap y , t hose w it h l ow rec u rre n ce sc o res will recei v e e ndo cri n e t h e r a py a l one, and t hose w it h i n terme d iate rec u rre n ce sc o res are ra ndo m ly assi gn ed t o endoc ri ne t he r apy v ers u s e ndo cri n e a nd c h em o t h era p y . A st udy by A l b ai n e t a l . sugges t ed t h at a l o w rec u rre n ce sc o re p re d icts a lac k o f b e n e f it o f fl uo r ou r ac il ( 5 -F U ) , a d riam y ci n ( doxo r ub ici n ) , a nd c y cl ophospha mi de ( F AC ) che m o t h era py i n nod e- po siti v e b reast ca n cer

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

p atie n ts t r ea t ed on S ou t hwes t O n c o l ogy Gr oup SWOG- 8814. Alt hough t h ese provoca ti ve da t a sugges t a similar u tilit y f o r O n c o t yp e DX i n nod e- po siti v e pa ti en t s, t hey r equ ir e a dd iti on al v ali d ati on wit h m od er n - d a y r e g ime ns. T he va l ue o f t he O nc o t yp e DX assa y i n p re d icti ng a b e n efit fr om hor m ona l t he r apy i n pa ti en t s treate d wit h ar o matase i nh i b it o r t h era py h a s r ece n tl y been pub li shed, de m on strati ng t h at t h e assa y p erf o rms e qu all y with bo t h tam ox if en and anas tr ozo le bu t do es no t d isti ngu is h a b e n efit o f on e ov e r t h e o t he r . G i ven t he i nd e p e nd e n t p r ogno stic u tilit y o f bo t h t h e On c o t ype DX r ecu rr ence scor e a nd t h e cli n ic op at ho l og ic fact o rs , s u c h a s t u m or siz e and g r ade, a r ecen t st udy f o rmall y i n te g rate d eac h o f t h ese meas ur e s t o de t e rmi ne whe t h er p r ogno stic a nd p re d icti v e v al u e is im p r o v ed ov e r u si ng a s i ng l e m easu r e . T h e u se o f a n i n te g rate d sc o re , rec u rre n ce sc or e -p a tho l ogy - c li n i ca l ( R SPC) , am ong ER- po siti v e , nod e- n e g ati v e p atie n ts pr ov i ded a m o r e s i gni fica n t p r ogno stic v al u e f o r d ista n t rec u rre nce wh e n c ompa r ed t o t he r ecu rr en ce sc o re al on e . T h is sc o re als o res u lte d i n b ette r r is k s tr a tifi ca ti on and r edu ce d t h e nu m b er o f p atie n ts classifie d as i n te r me d i a t e ri sk. Howeve r , t h e a dd iti on o f cli n ic op at ho l og ic fact o rs t o t he r ec urr e nce sco r e d i d no t im p r ov e its p re d icti v e v al u e f o r c h em o t h era py b e n e f it Se v e ra l o t he r add iti ona l p r ed ict o rs f o r ER- po siti v e b reast ca n cer i n cl ude t h e B r ea s t Cance r I ndex ( A var iaD x I n c ., Carls b a d, Calif o r n ia) , a qu a n titati ve R T -P CR–based as sa y t h at meas u res t h e rati o o f t h e HOXB 6 and IL17BR genes, and i nc l udes a p r o liferati on sc o re . It was s ho w n t o b e a ma rk e r o f r ecu rr ence ri sk i n un treate d ER- po siti v e/ nod e- n e g ati v e p atie n t s i n t wo s t ud i es o f lym ph nod e –n e g ati v e , ER- po siti v e , tam ox if en -t r eate d pa ti en t s w it h b r eas t can cer a nd was m o re rece n tl y f ound t o p re d i ct late r ec u rr ence a ft e r ad j uvan t e ndo cri n e t h era p y . T h e b reast ca n cer i ndex ( BC I) was co m pa r ed w it h On ct oyp e DX rec u rre n ce sc o re , a nd IHC 4, a sc or e b a sed on f ou r p r o t e i n mar k ers d etecte d by imm unoh ist o c h emistr y . I n E R -po siti ve, node - pos iti ve b r e ast ca n cer p atie n ts g i v e n eit h er tam ox ife n o r a n ast ro z o l e i n t he A rimi dex, T am ox ife n, o r Al on e o r i n C o m b i n ati on ( A T A C ) tri a l , t he BC I i ndex was t h e on l y p r ogno stic i nd e x t h at i d e n tifie d popu lati ons a t ri sk o f bo t h ear l y a nd late rec u rre n ces . T h is ma y b e o f

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

cli n ical v a l ue i n pos tm enopau sal p atie n ts , w ho h a v e und e r gon e 5 y ears o f e ndo c r i ne t he r apy because t h e test was d efi n e d i n t h is popu lati on.

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

Predictive Signatures

nan nan

De fi n i ng p r edi ct o rs o f res pon se t o c h em o t h era py a nd ta r g ete d t he r ap i es has been m o re c h alle ng i ng. A y ers et al fr o m t h e M .D. And e r s on Cance r Cen t e r we re t h e first t o re po rt t h at a m u lti g e n e a n al y si s o f f i n e n eedl e asp ir a ti on spec im en s p re d icts a res pon se t o n e o a d j uv a n t T a xol, 5-f l uourac il , Ad ri a m yc i n, and c y cl opho s ph ami d e (T F AC) c h em o t h era p y

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

nan nan

TRANSCRI P TI O NAL P ROFILING OF BREA S T CANC E R

P r ognostic and P r edictive Genomic Signatu r es

nan nan

V ali d ati on o f gene s i gna t u r es is o f u tm o st im po rta n ce i n t h e f u t u re t o d ete r mi ne t he va l ue o f t hese e xp ressi on p r o files at p re d icti ng treatme n t r es pon s e and c li n i ca l ou t co m e i n b reast ca n cer p atie n ts . Nati on al o r g a n izati ons such as t he A m e rica n S o ciet y o f Cli n ical O n c o l og y , t h e N ati on a l Co m p r ehens i ve Canc er Netw o r k, a nd t h e C o lle g e o f America n Pat ho l og i s t s have ongo i ng e f f o rts t o i n ter p ret t h e d ata fr o m t h e bu r g e on i ng f iel d of mu lti gene b i o m a r ke r t ests t o h el p t h e p ractici ng cli n icia n i n ter p re t t h ei r cli n i ca l u tilit y .

E P IG E NETICS O F B REAST CANC E R

nan nan

E P IG E NETICS O F B REAST CANC E R

E P IG E NETICS O F B REAST CANC E R

nan nan

Cells m a i n t a i n t he ir s t ab l e i den tit y a nd ph e no t yp e ov er ma ny g e n erati on s w it hou t ex t e r na l s tim u li o r s ig n ali ng e v e n ts . T h is cell u lar mem o r y is e n c od e d i n t he ep i geno m e, a c o llecti on o f h erita b le i n f o rmati on t h at e x is ts al ong si d e t he geno mi c sequen ce . DNA met hy lati on a nd c h r o mati n m od i f ic a ti on a r e m a j o r ep i gen etic mec h a n isms i n h i gh er e uk ar yo tes a nd a r e ti gh tl y c oup l ed t o bas i c gene t i c p r o cesses , s u c h as DNA re p licati on, t r a n sc r i p ti on, and r epa i r . It i s well do c u me n te d t h at ca n cers , i n cl ud i ng br east c ance r , have a lt e r ed pa tter n s o f DNA met hy lati on a nd h ist on e acet y lati on, l ead i ng t o a lt e r a ti on s i n tra n scri p ti on t h at a pp ear t o b e on c og e nic . Recen t wo r k fr o m TCGA d em on strates d i f fere n t p atter n s o f met hy lati on by b r eas t cance r s ub t yp es as d efi n e d by g e n e e xp ressi on prof ili ng. A m ong t hese sub t yp es , l u mi n al B s ub t yp e h a d a hyp ermet hy l ated ph e no t ype, whe r eas basa lli ke s ub t yp e h a d a hypo met hy late d ph e no t yp e .

E P IG E NETICS O F B REAST CANC E R

nan nan

E P IG E NETICS O F B REAST CANC E R

nan nan

Ongo i ng i n iti a ti ves, i nc l ud i ng t h e E p i g e no me Pr o ject , a nd f u rt h er a n al yses

E P IG E NETICS O F B REAST CANC E R

nan nan

of t h e T C GA da t a w ill li ke l y e nh a n ce ou r und ersta nd i ng o f e p i g e n etics i n br east c ance r . Maj or ep i gene ti c cance r drug s i n cl ud e DNA met hy ltra n sferase (DNM T ) a nd h ist one deace t y l ase ( HDA C) i nh i b it o rs . Precli n ical st ud ies s ho w pro mise t ha t HDAC i nh i b it o r s ma y h a v e acti v it y i n b reast ca n cer cells , and ma ny cli n i ca l phase I and II stud ies are i n p r og ress .

E P IG E NETICS O F B REAST CANC E R

Mic r oRNAs

nan nan

Mic r oRNAs

E P IG E NETICS O F B REAST CANC E R

Mic r oRNAs

nan nan

miR NAs a r e s m a ll noncod i ng RNAs t h at b el ong t o a nov el class o f r e gu lat o r y m o l ecu l es t ha t con tr o l t h e e xp ressi on o f hund re d s o f tar g et mR NA tr ansc ri p t s i n t wo w a y s . First , miRNAs t h at b i nd t o p r o tei n -c oding mR NA sequences t ha t a r e ex actl y c o m p leme n tar y t o t h e miRNA i ndu ce the R NA i pa t hwa y . Messenge r R NA ta r g ets are t h e n clea v e d by ri bonu cleas es i n t h e RN A -i nduced s il enc i ng c o m p le x (RISC) . Sec ond, miRNAs b i nd t o im p e rf ect co m p l e m en t a r y s it es wit h i n t h e 3 ′ un tra n slate d re g i on s ( 3 ′UTR) of t h ei r ta r ge t p r o t e i n - cod i ng mRNAs a nd re p ress t h e e xp ressi on o f t h ese g e n es at t he l eve l o f tr ans l a ti on . miR NAs a r e known t o be ass o ciate d wit h b reast ca n cer i n bo t h cell li nes a nd cli n i ca l sa m p l es. F o r exa m p le , miR- 21 , miR- 15 5 , miR- 7 , a nd miR- 210 a r e ov e r e xp r essed i n agg r ess ive hu ma n b reast ca n cers , w h ereas let- 7 and m i R-125a have been shown t o b e do w n re gu late d i n b reast ca n cers . It has als o b ee n shown t ha t m iR- 125a ma y f un cti on as a t u m o r s upp ress o r by i nh i b iti n g E RBB2 and E RBB3. M o re rece n tl y , t h e TCGA i d e n tifie d se ven s ub t yp es by mi c r oRNA exp r e ssi on p r o fili ng. Am ong all o f t h ese mic ro R NA c l us t e r s, on l y t wo o f t h em h a d a po siti v e c o rrelati on wit h TP 53 m u tati on and ove rl ap w it h t h e b asalli k e s ub t yp e . N o a dd iti on al c o rrelati on w it h m u t a ti on s t a t us o r m RN A- d efi n e d b reast ca n cer s ub t yp es was i d e n ti f ie d

E P IG E NETICS O F B REAST CANC E R

Mic r oRNAs

MicroRNAs and Response to Cancer T reatment

nan nan

miR NA mi sexp r ess i on pa tt e r n s were f ound t o b e ass o ciate d wit h ca n cer ou tc o m e and r esponse t o tr ea t m e n t , i n cl ud i ng ra d iati on a nd c h em o t h era p y .

E P IG E NETICS O F B REAST CANC E R

Mic r oRNAs

MicroRNAs and Response to Cancer T reatment

nan nan

Ce r tai n m i RNAs assoc i a t ed w it h hypox ia , s u c h as miR- 210 , h a v e b ee n s hown t o be b i o m a r ke r s o f poo r ou tc o me i n b reast ca n ce r . F u rt h erm o re , in v it ro d at a show t ha t ce rt a i n miRNAs are ass o ciate d wit h resista n ce t o doxorubic i o r t a m ox if en . I n p atie n t sam p les , a n ass o ciati on o f miRN A ’ s t u m or s ub t ypes have spec ifi c m iRNA p atter n s a nd t h is is ass o ciate d wit h a poor ou tc o m e. De fi n i ng t he role o f miRNAs as b i o mar k ers f o r p r ogno si s a nd pr e d i c ti on, as we ll as t he i r po te n tial as tar g ete d t h era p ies , is a n acti ve a r ea of resea r ch i n b r eas t can ce r .

PROTEIN/ P A T H W A Y A L TER A TI O NS

nan nan

PROTEIN/ P A T H W A Y A L TER A TI O NS

PROTEIN/ P A T H W A Y A L TER A TI O NS

nan nan

Th e m o le cu l a r m echan i s m s that lea d t o ca n cer h a v e b ee n c h aracterize d as t h e h allm a r ks o f cance r , as p r opo se d by Ha n a h a n a nd W ei nb e r g a nd re v i sed i n 20 1 1 T hey i nc l ude sus t a ine d p r o liferati v e si gn ali ng, e v a d i ng g r o wt h s uppr es so r s, r es i s ti ng ce ll dea t h, re p licati v e imm o rtalit y t h r ough tel o mer ase i nh i b iti o n , ang i ogenes i s, i nva si on a nd metastasis , g e no mic i n sta b ilit y , d e r e gu l a t ed m e t abo li s m , and avo i d i ng imm un e d estr u cti on. T h e e f fect o r s o f g e n etic a nd ep i gene ti c abno rmalities are , i n m o st cases , reflecte d i n t h e a bnor m a l l eve l s, f unc ti ons, and i n teracti on s o f p r o tei n s a nd si gn ali ng p at hw a y s . Recen t s t ud i es o f the g e no me h a v e g e n erate d n ew i n si gh ts i n t o t h e pro t eo m e assoc i a t ed w it h sp ecific b reast ca n cer s ub t yp es a nd s ugg es t im por ta n t t a r ge t s f o r t he r ap y , i n a dd iti on t o t ho se ca non ical d ri v ers ER a nd HE R 2. Undoub t ed l y , nu m e ro u s alterati on s c oo r d i n ate t o res u lt i n t h e mali gn a n t pheno t ype ; howeve r , a nu m b er o f k e y p r o tei n s a nd t h eir p at hw a y s have e m e r ged as c r i tical d ri v ers o f b reast ca n cer d e v el op me n t and grow t h as we ll as po t en ti a l t h era p e u tic tar g ets .

ESTR OGE N RECEP T OR PA TH W A Y

nan nan

ESTR OGE N RECEP T OR PA TH W A Y

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

nan nan

Therapeutic T argets in B r east Cancer

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Estrogen Signaling

nan nan

Estrogen Signaling

ESTR OGE N RECEP T OR PA TH W A Y

Therapeutic T argets in B r east Cancer

Estrogen Signaling

nan nan

M o st breas t cance r s a r e i n timatel y li nk e d wit h e xpo s u re t o estr og e n a nd alte r ati ons i n t he es tr ogen r ecep t o r si gn ali ng p at h wa y . Estr og e n is a ster oid hor m one t ha t exe rt s it s ac ti ons by b i nd i ng t o t h e nu clear ER . U pon acti v atio n by it s li gand, E R b i nd s i n a c oo r d i n ate d fas h i on wit h a nu m b er o f c or e gu l a t o r y p r o t e i ns t o es tr og e n res pon se eleme n ts i n t h e p r o m o ter re g i on of est rogen -r espons i ve genes. T h is i n t u r n d irects t h e tra n scri p ti on o f nu me rous g r ow t h - p r o m o ti ng g e n es , i n cl ud i ng PR . T h e le v el o f ER e xpr essi on i s no t on l y o f b i o lo g ic i n terest , bu t it is als o a h i gh l y e f fecti ve pr e d ict o r f o r r esponse t o an ti e str og e n s , w h ic h is a rec o mme nd e d treatm ent for all ER - exp r ess i ng t u m o r s. A lt hough E R i s ove r exp r e sse d i n as ma ny as 70 % o f i nv asi v e b reast ca n ce r s , t he p r ec i se m echan i s m by w h ic h t h is o cc u rs is un clea r . A m p li f ic a ti on o f t he gene app ears t o b e on e mec h a n ism (a pp r ox imatel y 50% of c ases w it h E R ove r exp ressi on i n on e st udy ) , s ugg esti ng t h at t r a n sc r i p ti ona l de r egu l a ti on and po sttra n scri p ti on al m od ificati on s (s u c h as alte r ati on o f m RNA l eve l s by miRNAs) ma y als o p la y a r o le . I n a dd iti on, r ece n t st ud i es sugges t E R m u tati on s ca n lea d t o c on stit u ti v e acti v ati on o f t h e p at hway and m ay be a m ech a n ism o f resista n ce t o a n tiestr og e n t r eatme n t E st rogen exe rt s it s ac ti ons t h r ough bo t h g e no mic ( d escri b e d p re v i ou sl y ) a nd nongeno mi c m echan i s m s. I n c on trast t o t h e g e no mic acti on s o f ER , nong e no mi c ac ti ons o f E R a re e x tremel y ra p i d (wit h i n sec ond s t o mi nu te s of est rogen exposu r e ) and a r e b elie v e d t o res u lt fr o m t h e ho rm on e- d e p e nd e n t ac ti va ti on o f m e m b ra n e- bound o r c y t o s o lic ERs . T h ese nonnu cl ea r E R ac ti ons r esu lt i n ra p i d pho s pho r y lati on a nd acti v ati on o f im por ta n t g r ow t h r egu l a t o r y k i n ases , i n cl ud i ng EGFRs , i n s u li n li k e g r owth f act or 1R (I G F- 1R ) , c -Sr c, S h c , a nd t h e p85α re gu lat o r y s ubun it o f PI 3K .