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F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

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F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

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Inh e r ited CRC synd r o m es w i th m u lti p le a d e no mat ou s po l yp s i n cl ud e F A P , M Y H - ass oc i a t ed po l ypos i s ( M AP) , a nd LS . I n s o me cases , t h e d ia gno sis is s u s p ecte d because o f a s tri k i n g famil y h ist o r y o f CRC , w h ile i n o t h ers , s u s p ici on a ri ses fr o m a ve r y young on set o f CRC o r fl o ri d po l ypo sis . A lt hough adeno m a t ous po l yp bu r d e n a nd famil y h ist o r y ma y s ugg est on e s ynd r o m e ove r ano t he r , an i n itial n e g ati v e g e n etic test res u lt s hou l d be fo ll ow e d by f u rt he r eva l ua ti o n f o r o t h er s ynd r o mes . F o r e x am p le , i n cli nical pr actice , a nega ti ve adeno m a to u s po l ypo sis c o li ( AP C ) g e n e test i n a p at ient w it h a su spec t ed CRC synd r om e is f o ll o we d by refle x testi ng f o r MAP and LS, as sh own i n F A P is an au t oso m a l do mi n a n t s ynd r o me t h at acc oun ts f o r <1 % o f t h e a nnu al C RC bu r den, i s caused by m u tati on s i n t h e t u m o r-s upp ress o r AP C g e n e . I t i s cha r ac t e ri zed by t h e p rese n ce o f ≥100 a d e no mat ou s po l yp s i n the c o l or ectum , nea rl y 100 % pen etra n ce , a nd a n i n e v ita b le ris k o f CRC if prophy l ac ti c co l ec t o m y i s no t p erf o rme d . Patie n ts wit h a less se v ere f o r m known as a tt enua t ed F A P ( A F AP) u s u all y p rese n t wit h <100 c o l o rectal

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

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a d e no ma s t ha t t end t o be p r ox imall y l o cate d. MAP is a n a u t o s o mal r ecessi v e synd r o m e t ha t o ft en p rese n ts ph e no t yp icall y as atte nu ate d po l ypo s is. Wh il e an es tim a t ed 2 % o f t h e g e n eral popu lati on are m ono all elic ca rr ie r s o f a m u t a t ed base - exc isi on -re p air MUTYH ( MYH ) g e n e , b ialleli c g e r mli ne m u t a ti ons m ay accoun t f o r 9 % t o 18 % o f p atie n ts wit h F AP o r A F A P pheno t ypes who have no d em on stra b le APC m u tati on LS ac coun t s f o r 1 % t o 4 % o f all n ewl y d ia gno se d CRC a nd is att r i bu ta b l e t o a ge rmli ne m u tati on i n on e o f t h e DNA MMR g e n es ( ML H1 , MSH2 , M SH6 , and PM S2 ) E p i g e n etic sile n ci ng o f t h e M S H 2 g e n e via a 3 ′ - e nd de l e ti on i n EP C AM ( T AC S TD 1 ) , a n ei ghbo r o f M S H 2 t h at p la y s a ro le i n c e ll adhes i on, a l so accoun ts f o r 20 % t o 25 % o f all s u s p ecte d M SH2 cases a nd 1 % t o 6 % o f LS ca ses ov erall LS is c h aracterize d by earl y a g e -of-onse t CRC, p r edo mi n a n ce o f lesi on s p r ox imal t o t h e s p le n ic fle xu r e, a n i n c r ea sed r a t e o f m e t ach r onou s CRC , a nd a un i qu e s p ectr u m o f b e n i gn a nd mali gnan t ex tr aco l on i c t umo rs . Lifetime ris k o f CRC i n p atie n ts wit h LS ma y be as h i gh as 80 % . MSI reflects a d eficie n c y i n DNA re p air sec ond ar y t o MMR gene m u tati on a nd is a h allmar k feat u re o f LS-ass o ciate d t u m o r s. V a r ia b ilit y i n pene tr ance, ph e no t yp ic e xp ressi on, a nd certai n t y o f d is ease d e v el opmen t m anda t e d i s ti nct l y d iffere n t s u r g ical a pp r o ac h es i n t h ese t hree s yndro m es, i nc l ud i ng t he t ype a nd timi ng o f ris k -re du ci ng c o l on a nd rec tal s u r g e r y .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

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Familial Adenomatous Polyposis

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

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S urv eilla nce o f a t-ri sk f a mil y mem b ers s hou l d b e g i n ar ound a g e 10 t o 15 y ea r s w it h an annua l co l onos c opy o r fle x i b le si g m o i do sc op y At-ris k i nd i v i du al s who be l ong t o f a milies wit h a n A F AP ph e no t yp e s hou l d und e r go co l onoscop i c sc r een i ng e v er y 2 t o 3 y ears starti ng i n t h eir late tee n s . In f o rm a ti ve gene ti c t es ti ng is po ssi b le i n families wit h a d em on st ra t ed AP C m u t a ti on, a nd m u tati on s are d etecte d i n m o st p e d i g re es. How e v e r , app r ox im a t e l y 25 % o f p atie n ts wit h F AP will h a v e a d e novo AP C m u t a ti on . S eve rit y o f po l ypo sis s hou l d b e esta b lis h e d du ri ng

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

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c o l ono sc op y , as t he timi ng o f s u r g er y a nd t h e ris k o f d e v el op i ng c o l o rect al is d e p e nden t on t he ex t en t o f p o l yp bu r d e n. Patie n ts wit h mil d po l ypo sis a nd a c o rr espond i ng l y l owe r CRC ris k ca n und e r go s u r g er y i n t h eir late tee n s . P a ti en t s w it h seve r e po l ypo sis , a h i gh d e g ree o f dy s p lasia , m u lti p l e a d e no ma s > 5 mm i n s i ze, and s y m p t o ms ( b lee d i ng, p ersiste n t d iarr h ea , a n emia , fa il u r e t o t h ri ve, psyc h o s o cial stress , etc . ) s hou l d und e r go ris k - r e du ci ng co l o r ec t a l su r ge r y a s s oon as is p ractical after d ia gno sis .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

How e v e r , i n ca r e f u ll y se l ec t ed, f u ll y as y m p t o matic p atie n ts w ho h a v e s mall a d e no ma s bu t a s tr ong f a mil y h ist o r y o f a gg ressi v e a bdo mi n al d esm o i d d isease , c ons i de r a ti on can be g i v e n t o d ela y i ng p r ophy lactic c o lect o m y , as t h e r is k o f des m o i d -r e l a t ed comp licati on ma y b e g reater t h a n t h e ris k o f CRC d ev e l op m en t . Th e t h r ee cu rr en t su r g i ca l o p ti on s f o r p atie n ts wit h F AP are t o tal pro ct o c o l ec t o m y (TP C ) w it h p erma n e n t ile o st o m y , t o tal c o lect o m y wit h ile or ect a l anas t o m os i s (I RA ) , a nd p r o ct o c o lect o m y wit h ileal pou c h -a n a l a n ast o m os i s (I P AA ) . I P AA can b e a doub le-sta p le d, e nd - o f- pou c h -t o -a nus a n ast o m os i s, wh i ch m ay l eav e b e h i nd a pp r ox imatel y 1 cm o f a n al tra n si tion z on e . A n a lt e r na ti ve app r oach, w h ic h is p referre d w h e n t h ere is car p eti ng o f t h e a n al t r ans iti on zone w it h a d e no mas , is t o p erf o rm a m u c o sal stri pp i n g o f t h e a n al t r ans iti on zone down t o t h e d e n tate li n e f o ll o we d by a h a nd -sew n p e r a n al anas t o m os i s o f pouc h t o t h e d e n tate li n e . Selecti on o f t h e op tim al pro ce du r e f o r an i nd i v i dua l pa tie n t is b ase d on se v eral fact o rs , i n cl ud i ng c h a r acteri s ti cs o f t he F A P synd r o me wit h i n t h e p atie n t a nd famil y , d i f f e r e nces i n li ke l y pos t ope rati v e f un cti on al ou tc o me , p re op erati v e a n al s ph i n cter s t a t us, and pa ti en t p refere n ce . TP C w it h pe rm anen t il eos t o m y , alt hough rarel y c ho se n as a p rimar y pro ce du r e, i s used i n pa ti en t s wit h i nv asi v e ca n cer i nvo l v i ng t h e s ph i n ct e r s or le v at o r co m p l ex, o r pa ti en ts f o r w ho m a n I P AA is no t tec hn icall y f easi b le ( seconda r y t o des m o id d isease a nd f o res ho rte n i ng o f t h e small bow el m esen t e r y , m ak i ng it su r g icall y im po ssi b le t o b ri ng t h e ileal pou c h to t h e a nu s) no r li ke l y t o l ead t o good f un cti on s u c h as massi v e ob esit y o r w ea k a na l sph i nc t e r s. Howev e r , TPC is o ccasi on all y c ho se n as a p rimar y pro ce du r e by pa ti en t s who pe rcei v e t h at t h eir lifest y le w ou l d b e

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

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c o m pro mi sed by t he fr equen t bo wel m ov eme n ts (fi v e t o si x p er d a y ) s o meti mes assoc i a t ed w it h t he I P AA p r o ce du re . In a dd iti on t o t hese i ssues, t h e k e y i n d eci d i ng b etwee n a n I P AA a nd an I R A is b a sed p rim a ril y on t he ris k o f rectal ca n cer d e v el op me n t if t h e r ect u m is l e ft i n s it u. T he ri sk o f rectal ca n cer f o ll o wi ng IRA ma y ra ng e fro m 3 % t o 10 % a t 10 yea r s, w h ile t h e ris k f o r a sec ond ar y p r o ctect o m y f o r un c on t ro ll ed r ec t a l po l ypos i s r a ng es fr o m 10 % t o 61 % at 20 y ears fo ll ow i ng i n iti a l co l ec t o m y wi t h IRA – T h e ma gn it ud e o f ris k i n a n i nd i v i du al pa ti en t i s, howeve r , relate d t o t h e ov erall e x te n t o f c o l o rectal po l ypo s is. I RA m ay be cons i d ere d f o r p atie n ts wit h <1,000 c o l o rectal po l yp s ( i nc l ud i ng t hose w it h a tte nu ate d F AP) a nd <20 rectal a d e no mas , a s t h ese i nd i v i dua l s have a r e l a ti v el y l o w ris k o f d e v el op i ng rectal ca n ce r .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

Patie n ts w it h seve r e r ec t a l ( >20 a d e no mas) o r c o l on ic ( >1,000 a d e no mas) po l ypo s is, an adeno m a >3 c m , o r a n a d e no ma wit h se v ere dy s p lasia s hould i d eall y unde r go a ri sk -r educ i ng p r o ce du re t h at will i n cl ud e a pro ctectom y Th e risk o f seconda r y r ec t a l e x cisi on, du e t o un c on tr o lla b le rectal po l ypo s is o r r ec t a l cance r , m ay b e estimate d by i d e n tif y i ng t h e s p ecific l o cati on o f t he causa ti ve AP C m u tati on. Patie n ts wit h m u tati on s l o cate d b et w ee n codons 1250 and 1464 h a v e b ee n s ho w n t o h a v e a si x -f o l d i n c r ease d ri sk o f deve l op i ng rectal ca n ce r , c o m p are d t o t ho se wit h m u tati ons p ri o r t o codon 125 0 o r after c odon 1464 (mea n nu m b er o f rec tal po l yp s 4 2 ve r sus 22, r espec ti v el y ) Alt hough t h e u se o f t h e g e no t yp e- ph e no t ype r e l a ti onsh i p t o gu i d e p atie n t ma n a g eme n t ma y b e a pp eali ng , it is im por t an t t o r ecogn i ze t he v aria b ilit y o f ph e no t yp ic e xp ressi on t h at e xists e v e n amo ng m e m be r s o f t he same famil y . T h is s ugg ests t h at at t h e c u rre nt time , t he cho i ce be t ween an IRA a nd a n I P AA s hou l d b e b ase d p rimarily on cli n ical ( r a t he r t han gene ti c ) g r ound s . Th e risk o f po l yp and can cer d e v el op me n t f o ll o wi ng p rimar y s u r g er y is no t limi ted t o pa ti en t s unde r go i ng IRA . I n p atie n ts und e r go i ng I P AA , n e op lasi a m ay occu r a t t he s ite o f ileal pou c h a n ast o m o sis; t h e fre qu e n c y a pp ea r s t o be g r ea t e r a ft e r s t ap le d a n ast o m o sis ( 28 % t o 31 %) t h a n after m u c o se c t o m y and hand - sewn a n ast o m o sis ( 10 % t o 14 %) . I n t h e case o f

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

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n e op lasi a deve l op i ng a t t he an al tra n siti on z on e after a sta p le d a n ast o m osis, t r a n sa n al m ucosec t o m y m ay b e p erf o rme d, f o ll o we d by a dv a n ceme n t o f the pou c h t o t he den t a t e li ne. O f add iti on al c on cer n is t h e d e v el op me n t o f a d e no mat ous po l yps i n t he il e al pou c h, w h ic h o cc u rs i n a pp r ox imatel y 45 % of p atie n t s by 10 - yea r f o ll ow - up C on se qu e n tl y , d e p e nd i ng on po l yp burd e n, lif e tim e endoscop i c su r v eilla n ce o f t h e rectal rem n a n t (after IR A ) e v e ry 6 t o 12 m on t hs o r t he il e al pou c h (after I P AA) e v er y 1 t o 3 y ears i s r e qu i r e d f o ll ow i ng e it he r p r o ce du re . Ano t he r im po rt an t cons i d erati on i n c hoo si ng b etwee n I P AA a nd IRA is po st op e ra ti ve bowe l f unc ti on a nd qu alit y o f life . S o me st ud ies h a v e ass o ciate d I P AA w it h h i ghe r fre qu e n c y o f bo t h d a y time a nd no ct u r n al bow el m ove m en t s, h i ghe r i ncid e n ce o f p assi v e i n c on ti n e n ce a nd i n ci d e ntal s o ili ng, and g r ea t e r pos t ope r a ti v e m o r b i d it y . H o we v e r , l ong -term f o ll o w- up d em ons tr a t es a co m pa r ab l e qu alit y o f life f o ll o wi ng I P AA f o r F AP r elati v e t o t he pa ti en t ’ s p r eop erati v e b aseli n e . T h eref o re , alt hough t h e c ho ice of p r ocedu r e m us t be caref u ll y i nd i v i du alize d, b eca u se o f t h e ris k o f r ectal ca nce r assoc i a t ed w it h IRA , t h e a u t ho rs fa vo r I P AA f o r m o st p ati ents w it h F A P wheneve r f eas i b l e. H o we v e r , a n IRA s hou l d b e c on si d ere d i n s p eci f ic c ir cu m s t ances, such a s w h e n t h ere is mil d rectal po l ypo sis (as i n A F A P ), o r a young pa ti en t w it h rectal s p ari ng w ho is no t i n tereste d i n und e r go i ng t he m u lti p l e p r oc e du res t h at acc o m p a ny a n I P AA a nd d i v ert ing l oop ile os t o m y , o r a young wo ma n i n tereste d i n h a v i ng c h il d re n a nd tr y in g t o a vo i d t he dec r eased f ecund it y ass o ciate d wit h a n I P AA p r o ce du re . T he u se of m i n im a ll y i nvas i ve t echn i qu es s u c h as la p ar o sc opy ma y re du ce th e r is k of i n f e rtilit y assoc i a t ed w it h I P AA T hough a d i v erti ng l oop ile o st omy shou l d be pe rf o rme d i n all I P AA p r o ce du res , it is no t alwa y s f easi b le due t o a nu m be r o f an at o mic fact o rs s u c h as body h a b it u s . Endoscop i c su r ve ill ance of t h e rectal se g me n t at 6 - t o 12 -m on t h i n ter vals a f te r t h e i ndex su r ge r y i s r eco mme nd e d, wit h s ub se qu e n t s u r v eilla n ce fr e qu e nc i es dependen t on t he nu m b er a nd size o f a d e no mas ob ser v e d .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

A lt hough s m a ll (< 5 mm) sca ttere d a d e no mas ca n b e safel y ob ser v e d o r r em ov e d w it h b i opsy f o r ceps, po l yp s >5 mm s hou l d b e rem ov e d by s n are . How e v e r , r epea t ed f u l gu r a ti on a nd po l yp ect o m y ov er ma ny y ears ca n le ad

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

nan nan

t o d i f f ic u lt y w it h subsequen t p o l yp ect o m y , re du ce d rectal c o m p lia n ce , an d d i f f ic u lt y i den tif y i ng fl a t can cers i n t h e b ac kg r ound o f scar tiss u e . T h e d e v el opmen t o f seve r e dysp l as ia a nd / o r v ill ou s a d e no mas no t ame n a b le to e ndo sc op i c r e m ova l i s i nd i ca t ion f o r p r o ctect o m y .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

Desmoids

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Desmoids

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

Desmoids

nan nan

D esm o i ds m ay occu r i n 10 % t o 25 % o f p atie n ts wit h F A P U n li k e t hose found i n t he gene r a l popu l a tio n, F AP-ass o ciate d d esm o i d s te nd t o b e i n tr a -a bdo mi na l and a ri se f o ll ow i ng a bdo mi n al s u r g er y Alt hough c onf licti ng r epo rt s ex i s t , it ap pears t h at female p atie n ts , t ho se wit h e x t r ac o lo n i c m an if es t a ti ons o f F A P , a po siti v e famil y h ist o r y o f d esm o i ds, a nd APC m u t a ti ons l oca t ed a t 3 ′ o f c odon 1440 are at i n crease d ris k o f d e v el oping des m o i ds . T h ese t u m o rs o fte n i nvo l v e t h e small bo we l mese n ter y as we ll as t he r e tr o perit on e u m a nd are o fte n life-t h reate n i ng due t o i nv as ion o r co m p r ess i on o f a d jace n t v iscera . F u rt h e r , rec u rre n ce a nd m orb i d it y r a t es a r e h i gh f o ll o wi ng attem p te d resecti on, wit h rec u rre n t d isease o ft en m o r e agg r ess i v e t h a n t h e i n itial d esm o i d. Estimate d 5 - y ear ov e r all su r v i va l f o r pa ti en t s wit h i n tra-a bdo mi n al d esm o i d s ca u si ng se ve r e s y m p t o m s such as s i gn ifi can t p ai n a nd se p tic fist u la/a b scess , d iameter >20 cm or r a p i d l y g r ow i ng, and / o r n ee d f o r p are n teral nu triti on is on l y 53 % .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

Familial Adenomatous Polyposis

Desmoids

nan nan

Th e r e fo r e, des m o i d r esec ti on is e v al u ate d on a n i nd i v i du alize d case- by -c ase b asis w it h su r ge r y r ese r ved f o r h i gh l y select cases . D esm o i ds t ha t i nvo l ve t he small bo wel mese n ter y ma y p recl ud e t h e for mati on o f an I P AA second ar y t o f o res ho rte n i ng o f t h e small bo wel mese n ter y , espec i a ll y i n pa ti en ts und e r go i ng p r o ctect o m y after a n i n itial I R A S u r ge r y f o r i n tr a - abdo mi n al a nd a bdo mi n al wall d esm o i d s s hou l d b e r ese rved f o r limit ed d i seas e w h ere t h e li k eli hood o f clear ma r g i n s is h i gh. In s y m p t o m a ti c cases wher e resecti on o f a n i n tra-a bdo mi n al d esm o i d ma y no t be f eas i b l e, i n t es ti na l byp ass o r u reteral ste n ti ng ma y b e n ecessar y t o alle v i a t e bowe l o r u ri na r y ob str u cti on sec ond ar y t o mass effect . I n a dd iti on t o su r g i ca l i n t e r ven ti on, se v eral me d ical op ti on s wit h v aria b le e f f icac y a r e ava il ab l e f o r t he ma n a g eme n t o f d esm o i d d isease a nd i n cl ude non ste ro i da l an ti-i n fl a mm a t o r y d r ug s (e .g., s u li nd ac) , selecti v e estr og e n r ece p t or m odu l a t o r s ( e.g., t a m ox ife n ) , imm uno m odu lat o rs (e .g., imati n i b, s or a f e n i b, i n t e rf e r on ) , doxo r ub i n - b ase d c y t o t ox ic c h em o t h era p y , a nd r a d iati on.

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

MYH -Associated Polyposis

nan nan

MYH -Associated Polyposis

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

MYH -Associated Polyposis

nan nan

M AP s hou l d be suspec t ed i n p atie n ts wit h >10 c o l o rectal a d e no mas , a we ak h ist ory o f CRC, and no f a mily h ist o r y o f F A P . T h e d ia gno sis is c on firm ed by MU T YH ( MY H ) gene t es ti ng . D e p en d i ng on t he po l yp b ur d e n, t h e ma n a g eme n t o f t h e c o l on a nd r ect u m o f a pa ti en t w it h a b i al lelic MYH m u tati on ca n b e e ndo sc op ic o r s u r g ical . If t he po l yp bu r den i s limite d a nd a n e ndo sc op ic a pp r o ac h is pur s u e d, co l onoscopy shou l d b e p erf o rme d e v er y 1 t o 3 y ears . If t h e po l yp bu r den i s no t a m enab l e t o a n e ndo sc op ic a pp r o ac h at t h e time o f d ia gno sis , t hen a r esec ti on i s i nd icate d. I n m o st cases i n w h ic h s u r g er y is d eeme d n ecessa r y , an I RA i s su f ficie n t . H o we v e r , if rectal po l ypo sis is se v e r e , an I P AA m ay be i nd i c ate d. I nd icati on s f o r s u r g er y f o ll o wi ng a n e ndo sc op i c su r ve ill ance p r og ram i n cl ud e i n creasi ng po l yp size o r nu m b e r , or wor s en i ng h i s t o l og y .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

MYH -Associated Polyposis

nan nan

Ex t raco l on i c m an if es t a ti o ns o f MAP are similar t o F AP a nd i n cl ud e o ste o ma s, des m o i ds, congen it a l hyp ertr ophy o f t h e reti n al p i g me n t e p it h eli u m , as we ll as cance r s o f t h e t hy r o i d, ov ar y , b la dd e r , se b ace ou s g la nd, a nd b r eas t . I n add iti on, p atie n ts wit h MAP are als o at a 4 % lifeti me r is k of deve l op i ng duodena l can cer a nd re qu ire upp er e ndo sc op ies e v er y 1 t o 3 y ea rs beg i nn i ng as ea rl y as a g es 18 t o 20 y ears a nd starti ng no later t h a n a g es 30 t o 35 yea r s ,

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

L ynch Synd r ome

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

Du e t o t he d i sco r dance assoc i a te d wit h t h e term h ere d itar y nonpo l ypo sis c o l or ectal cance r , t he use o f t h is term h as la r g el y b ee n a b a ndon e d wit h r e v e r si on back t o t he epony m LS , w h ic h refers t o i nd i v i du als wit h a pr e d is pos iti on t o CRC and o t h er mali gn a n cies as a res u lt o f a g ermli n e MMR m u t a ti on . Ove r a ll , C RC o cc u rs i n up t o 80 % o f p atie n ts wit h L S by t h ei r mi d - 40s . E ndo m e tri a l ca n cer o cc u rs i n 40 % t o 60 % , g astric ca n c e r i n 1 1% to 19 % , u ri na r y tr ac t ca n cer i n 5 % t o 18 % , a nd ov aria n ca n cer i n 9% t o 15 % o f a f f ec t ed i nd i v i du als . Th e A m s t e r da m c rit e ri a and re v ise d Bet h es d a gu i d eli n e s ( a r e u se d i n c li n i ca l p r ac ti ce t o i d e n tif y p atie n ts at ris k f o r LS w ho re qu ir e fur t h e r gene ti c eva l ua ti on. T h e Amster d am criteria , w h ic h le d t o t h e i d e n ti f ic a ti on o f t he LS- caus in g MMR g e n e m u tati on s re qu ire t h at t h ere be: Thr ee r e l a ti ves ( one a fir s t- d e g ree relati v e o f t h e o t h er tw o ) wit h c o l orec t a l , endo m e tri a l , s t o mac h, ov ar y , small bo wel , u reteral/re n al p el v i s, b r a i n, hepa t ob ili a r y , a nd / o r se b ace ou s ca n cer; In t wo o r m o r e success i ve g e n erati on s; W it h a t l eas t one case o f can cer d ia gno se d b ef o re t h e a g e o f 50 ; And t ha t F A P as a d i agnos is is e x cl ud e d .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

Though t he A m s t e r da m c rit e ria ca n b e u se d cli n icall y t o i d e n tif y po te n ti al p atie n ts wit h LS , us i ng it a l on e will res u lt i n i d e n tificati on o f on l y 42 % o f LS m u t a ti on ca rri e r s . F a milies meeti ng Amster d am criteria bu t lac k i ng an MMR m u t a ti on a r e r e f e rr ed t o as h a v i ng “familial c o l o rectal ca n cer t ype X” a nd a pp e a r t o have a l owe r i n ci d e n ce o f c o l o rectal a nd e x trac o l on ic ca nce r s t h a n t hose w it h a LS ge rmli ne MMR m u tati on (see ) . Of no te , t hey h a v e a n i nc r eased i nc i dence o f left-si d e d a nd non m u ci nou s micr o satellite sta b le t umo r s . Patie n t s w it h CRC who belong t o p e d i g rees s u s p ici ou s f o r LS s hou l d be o f f e r e d sc r een i ng by I HC f o r lo ss o f MMR p r o tei n e xp ressi on o r by MS I a n al y sis . As t he sens iti v it y o f IHC testi ng f o r l o ss o f MMR p r o tei n e xpr essi on i s co m pa r ab l e t o MSI testi ng, eit h er a pp r o ac h ca n b e pu rs u e d .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

How e v e r , I HC t es ti ng i s l ess exp e n si v e a nd ca n als o i d e n tif y a s p ecific MMR p r o t e i n l oss, wh i ch can h el p ta r g et s ub se qu e n t g ermli n e testi ng. R ou ti n e I HC t es ti ng f o r l oss o f MMR p r o tei n i n i nd i v i du als young er t h a n 50 y ea r s a t t he tim e o f CRC di a gno sis is feasi b le a nd h as le d t o t h e i d e n ti f ic a ti on o f pa ti en t s w it h LS w ho mi gh t o t h erwise h a v e b ee n misse d P a ti en t s w it h M SI- h i gh t u m o rs s hou l d und e r go testi ng f o r g e r mli ne MMR m u t a ti ons i n M S H 2 , MLH 1 , M S H 6 , a nd PM S2 . Refle x I H C a nd / or M SI t es ti ng on a ll new l y d ia gno se d CRC h as b ee n a dvo cate d by s o me e xpe rt g r oups and has b ee n s u ccessf u ll y im p leme n te d at s o me i n stit u ti ons . Howeve r , a maj o rit y o f ca n cer p r og rams n ati on wi d e c urr e n tly do no t have a p r o t o c o l f o r refle x testi ng f o r LS , citi ng lac k o f i n stit u ti ona l p r o t oco l s as we ll as fear o f non reim bu rseme n t . As s u c h, a un i f ie d move t owa r d un i ve r s al testi ng remai n s s o me time awa y . I n famil ies for wh ich t u m o r ti ssue i s no t a v aila b le , i n itial g ermli n e testi ng ma y b e c on si d e red t hough t he fi nanc ial bu r d e n is no t i n si gn ifica n t , wit h t h e c o st o f f i nd i ng a s i ng l e LS ca rri e r meas u ri ng a pp r ox imatel y $58,000 (c o m p are d to t h e $5,000 spen t i n fi nd i ng a s i ng le LS carrier u si ng IHC scree n i ng ) . As i n F A P , a m u t a ti on i n an a f f ec te d i nd i v i du al m u st b e esta b lis h e d f o r testi ng i n at -r is k i nd i v i dua l s t o be con cl u si v e . In lie u o f un i ve r sa l t es ti ng, se v eral p re d icti v e m od els s u c h as t h e MMR pr e d i c t , MMRp r o, and P REM M 1,2,6 h a v e b ee n d e v ise d i n o r d er t o assess a n i nd i v i dua l ’ s li ke li hood o f h ar bo ri ng LS . T h ese m od els qu a n ti fy an i nd i v i dua l ’ s ri sk f o r carr y i ng a n MLH 1 , M S H 2 , o r M S H 6 g e r mli ne m u t a ti on by us i ng c li n ical c h aracteristics s u c h as a g e at on set o f CRC a n d/ o r o t he r LS- assoc i a te d ca n cers , l o cati on o f CRC , famil y h ist o r y , h ist ory o f synch r onous o r m et ac h r onou s CRC , am ong o t h ers . A st udy o f t h ese pred i c ti ve m ode l s de m on strate d t h at t h e y all p erf o rme d b etter t h a n the r e v ise d Be t hesda gu i de li nes i n terms o f i d e n tif y i ng p atie n ts wit h g ermli ne m u tati ons f o r LS T he MM R p re d ict m od el a pp eare d t o h a v e t o b e t h e b est pr e d ict o r , w it h a sens iti v it y a n d s p ecificit y f o r LS o f 94 % a nd 91 % , r es p ecti ve l y . O t he r va li da ti on st ud ies , ho we v e r , h a v e no t d em on strate d t he s up e r i or it y o f MMRp r ed i c t co m p are d t o t h e o t h er af o reme n ti on e d m od els It appea r s t ha t t h e u se o f cli n ical c h aracteristics i n c o m b i n a tion

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

w it h MSI o r MMR p r o t e i n exp ressi on stat u s i n p re d icti v e m od els ma y po te n tiall y im p r ove ou r ab ilit y t o esta b lis h LS d ia gno ses i n p atie n ts wit h CRC . Howeve r , t he p r ac ti ca li ty a nd a pp lica b ilit y o f t h ese t oo ls i n a cli n i cal setti ng requ ir es f u rt he r assess me n t . A lt hough deve l op m en t o f C RC i n LS is no t a certai n t y , t h e 80 % lifetim e r is k, t h e 16 % t o 30 % ri sk o f m etac h r onou s CRC , a nd t h e po ssi b l y accele r at ed adeno m a -t o - ca r c i no ma se qu e n ce ma nd ate c on si d erati on o f prophy l ac ti c su r g i ca l op ti ons – Patie n ts wit h LS w ho h a v e a CRC o r m or e t h a n one advanced adeno ma s hou l d b e o f fere d t h e op ti on s o f prophy l ac ti c t o t a l co l ec t o m y w it h IRA o r se g me n tal c o lect o m y wit h a nnual po st op e ra ti ve su r ve ill ance co lo no sc op y . Caref u l s u r v eilla n ce is als o n ecessa r y a ft e r t o t a l co l ec t o m y a nd IRA , as t h e ris k o f h i gh -ris k a d e no ma s a nd ca nce r i n t he r e t a i ned r ec t u m at a me d ia n o f 104 m on t h s are 1 1 % a nd 8%, r es pec ti ve l y . A lt hough t h ere h as b ee n no st udy d em on strati ng a n im prov e d su r v i va l f o r pa ti en ts wit h LS und e r go i ng t o tal c o lect o m y a nd I R A v e r s u s s eg m en t a l co l ec t o m y , mat h ematical m od els s ugg est a sli gh t s u r v i val b e n e f it fo r t o t a l co l ec t o m y and IRA , es p eciall y f o r i nd i v i du als und er t h e a g e of 30 I n add iti on, bec a u se o f i n crease d rates o f metac h r onou s CRC d ev e l op m en t and t he ri sk o f m u lti p le a bdo mi n al s u r g eries i n t ho se und e r go i ng a seg m en t a l r esec ti on, a t o tal c o lect o m y a nd IRA h as eme r ged as t h e procedu r e o f cho i ce f o r t h e i nd e x ca n ce r , wit h c on si d erati on f o r T P C i n cases w he r e a h i gh ri sk o f metac h r onou s rectal ca n cer ca n b e pr e d icted . T a r ge t ed genet ic testi ng a pp r o ac h es — s u c h as t h e si ng le am p lic on M S H2 A636 P m u t at i on test i n As hk e n azi Jewis h p atie n ts wit h CRC —have de m ons tr a t ed ho w a ra p i d a nd i n e xp e n si v e p re op erati v e g e n etic tes t can he l p d ir ec t t he e x te n t o f c o l on resecti on . LS mu t a ti on ca rri e r s w it h a no rmal c o l on a nd wit hou t a h ist o r y o f CRC ma y als o be o f f e r ed p r ophy l a ctic c o lect o m y i n h i gh l y select sit u ati on s . One r ati on al e f o r t h i s app r oach i s t h e similarit y o f lifetime ca n cer ris k b etwe en p atie n ts wit h AP C and MMR g e n e m u tati on s , a nd t h e fact t h at t o tal a bdo mi na l co l ec t o m y w it h I RA p r odu ces less f un cti on al d ist u r b a n ce t h a n t h e prophy l ac ti c p r ocedu r e r e c o mme nd e d f o r F AP (TPC wit h I P AA) . How e v e r , an a lt e r na t e s tr a t egy f o r t h ese i nd i v i du als is s u r v eilla n ce by

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

nan nan

Moyer V A, US Preventive Services T ask Force. Risk Assessment, Genetic Counseling, and Genetic T esting for BRCA-Related Cancer in W omen: U.S. Preventive Services T ask Force Recommendation Statement. Ann Intern Med 2014;160. Robson ME, Storm CD, W eitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibilit y . J Clin Oncol 2010;28:893–901. Amir E, Freedman OC, Seruga B, et al. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 2010;102:680–691. Miki Y , Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71. W ooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265:2088–2090. Lux M P , Fasching P A, Beckmann M W . Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med 2006;84:16–28. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J 2012;18:310–319. Guillem JG, W ood WC, Moley J F , et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 2006;24:4642–4660. Saslow D, Boetes C, Burke W , et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammograph y . CA Cancer J Clin 2007;57:75–89. Domchek SM, Friebel TM, Singer C F , et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortalit y . JAMA 2010;304:967–975. US Equal Employment Opportunity Commission. Genetic information discrimination. Accessed January 2, 2014. Society of Su r gical Oncolog y . Position statement on prophylactic mastectom y .

F A M ILIAL ADEN OM A T OUS PO L YPOSIS, M Y H -ASSOCI A T E D POLU P OS I S, AND L YNCH SYNDR OM E

L ynch Synd r ome

Can c er R isk– Redu c ing Agen t s

nan nan

Can c er R isk– Redu c ing Agen t s

W H Y CANC E R PR E VEN T ION AS A CLINICAL ONCOLO G Y DISCIP L INE

nan nan

W H Y CANC E R PR E VEN T ION AS A CLINICAL ONCOLO G Y DISCIP L INE

W H Y CANC E R PR E VEN T ION AS A CLINICAL ONCOLO G Y DISCIP L INE

nan nan

Un til r e cen tl y , c li n i ca l onco l ogy h as b ee n d efi n e d as a me d ical s p ecialt y t h at attem p t s t o i n t e r vene i n o r d er t o sl o w o r re v erse t h e fi n al sta g e o f t he ca n ce r process— t he c l ona ll y d eri v e d, g e no micall y d ama g e d, i nv asi v e c ell mass . Ca nce r i s a l ong p r ocess, a ste p wise carci nog e n ic p r og ressi on t h at e n c o m p a sses c riti ca l m o l ecu l a r e v e n ts t h at c u lmi n ate i n t h e l o ss o f k e y cell u la r con tr o l ho m eos t a ti c f un cti on s (e .g., c on tr o l o f p r o liferati on, a pop t o sis , i nvas i on, ang i ogene sis) . T h ese e v e n ts o cc u r p ri o r t o a nd du ri ng t h e m orpho l og i c changes t ha t h a v e h ist o ricall y d efi n e d n e op lasia . M orpho l og i c changes, such as s ub tle i n creases i n cell u lar p r o liferati on t hat progr ess t o ea rl y and l a t e p r ec a n cer ou s lesi on s c on tai n i ng dy s p lastic cell s, c h a r acteri ze t he ca r c i nogenes is p r o cess ( O ppo rt un ities f o r i n te rv e n ti on i n t h i s p r ocess can i n cl ud e d i v erse , nonph armac o l og ic a ppro ach es ( e.g., obes it y m an a g eme n t v ia d iet/lifest y le i n ter v e n ti on s) o r ph a r ma co l og i c i n t e r ven ti ons ( e .g., d r ug s o r nu trie n ts/ nonnu trie n t s ub sta nces u se d as dr ugs ) a im ed a t de l aying o r re v ersi ng t h e carci nog e n esis p r o cess pr i or t o o r f o ll ow i ng t he appe ara n ce o f earl y m o r pho l og ic c h a ng es . Ca nce r sc r ee n i ng and ea rl y de t ec ti on s trate g ies (e .g., s u r v eilla n ce e ndo sc op y , fe cal o cc u lt b l ood t es ti ng, m a mm og ra phy ) i d e n tif y no t on l y t ho se i nd i v i du als w it h ea rly s t age, cu r ab l e m a li gn a n t tra n sf o rmati on s , bu t als o t ho se

W H Y CANC E R PR E VEN T ION AS A CLINICAL ONCOLO G Y DISCIP L INE

nan nan

i nd i v i du al s w it h non i nvas i ve n e op lasias w ho are at ris k f o r p r og ressi on t o t r a n s formed i nvas i ve m a li gnan cies . Rec ogn i z i ng t ha t cance r i s a c on ti nuu m , on c o l og ists are i n creasi ng l y e xp ecte d t o be know l edgeab l e a bou t a d i v erse arra y o f ca n cer-relate d t o p ics i n cl ud i ng lif es t y l e behav i o r s su c h as d iet a nd e x ercise , ris k assessme n t , sc r ee n i ng, o t he r p r even ti ve i n ter v e n ti on s , i n a dd iti on t o c u rre n t treatme n t s for a dv a nced m a li gnanc y . T h e und ersta nd i ng, u se , a nd ma n a g eme n t o f

W H Y CANC E R PR E VEN T ION AS A CLINICAL ONCOLO G Y DISCIP L INE

nan nan

i n te rv e n ti ons des i gned t o de l ay o r re v erse t h e carci nog e n esis p r o cess h a ve b ec o me in t eg r a l co m ponen t s o f t h e t h is r o le .

DEFINING CANC E R RIS K –R E DUCING AGENTS (CHEMOPR E VE N TI O N)

nan nan

DEFINING CANC E R RIS K –R E DUCING AGENTS (CHEMOPR E VE N TI O N)

DEFINING CANC E R RIS K –R E DUCING AGENTS (CHEMOPR E VE N TI O N)

nan nan

Ca n ce r ri sk r educ ti on, co mm on l y referre d t o as c h em op re v e n ti on, is t h e use of a r a nge o f i n t e r ven ti ons fr o m d r ug s t o is o late d d ietar y c o m pon e n ts t o who le -d i e t m odu l a ti on t o b l ock, re v erse , o r p re v e n t t h e d e v el op me n t o f i nv asi v e cance r Hu m an ca ncer ris k re du cti on asserts t h at on e ca n i n te rv e ne a t m any s t eps i n t he carci nog e n ic p r o cess , w h ic h o cc u rs ov er ma ny yea r s. T h i s p r o l onged late n c y p r ov i d es oppo rt un ities t o i n ter v e n e at ma ny tim e po i n t s and a t m u lt ip le e v e n ts i n t h e carci nog e n ic p r o cess . S u ccess fu l dep l oy m en t o f can cer ris k– re du ci ng a g e n t i n ter v e n ti on s re qu ir es e v i d e n ce o f r educed cance r - as s o ciate d i n ci d e n ce a nd / o r m o rtalit y . Th e concep t o f fi e l d ca r c in og e n esis was first d escri b e d i n t h e earl y 1950 s a s fi e l d cancer i za ti on i n s qu am ou s cell carci no mas o f t h e h ea d a nd n ec k, a nd subsequen tl y asc ri b e d t o ma ny e p it h elial sites . T h e fiel d ca r ci no g enes i s concep t i s t ha t p atie n ts h a v e a wi d e s u rface area o f pr eca n c e r ous o r cance r ous ti ssu e c h a ng e t h at ca n b e d etecte d at t h e g r o s s (or al pre m a li gnan t l es i ons, polyp s) , micr o sc op ic (meta p lasia , dy s p lasia) , a nd / or m o l ecu l a r ( gene l oss o r am p lificati on ) le v els . Rece n t m o lec u lar st ud ies de t ec ti ng p r o f ound gen etic alterati on s i n h ist o l og icall y no rmal ti ssue fro m h i gh -ri sk i nd i v i dua l s hav e p r ov i d e d str ong s uppo rt f o r t h e fiel d ca r ci no g enes i s concep t . T he im p licati on o f t h e fiel d e f fect is t h at m u ltifo cal, g e n eticall y d i s ti nc t , and c l ona ll y relate d p remali gn a n t lesi on s ca n p r og res s ov e r a b r oad ti ssue r eg i on T h e esse n ce o f ca n cer ris k re du cti on, t h e n, is i n te rv e n ti on w it h i n t he m u lti st e p carci nog e n ic p r o cess a nd t h r oughou t a w i d e f iel d.

ID E NTI F YING P OTE NTIAL CANC E R RIS K – REDUCING A GE NTS

nan nan

ID E NTI F YING P OTE NTIAL CANC E R RIS K – REDUCING A GE NTS

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

nan nan

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

nan nan

Simila r t o t he deve l op m en t o f t h era p e u tic i n ter v e n ti on s , t h e assessme n t o f e f f icac y and t ox i c it y o f s i ng l e c h emicall y s yn t h esize d e n tities , a g e n ts d esi gn e d i n s ili c o , bo t an i ca l s, nu trie n ts/ nonnu trie n t s ub sta n ces u se d as drug s fo r cance r ri sk– r educ i ng a g e n t e f ficac y p r o cee d s t h r ough a t r a n slatio na l pa r ad i g m t ha t i den tifies efficac y i n cell c u lt u re m od els , i n l ive a n imal m ode l s, and i n hu m an s . Precli n ical m od els t h at sim u late t h e

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

nan nan

ca r ci no g enes i s p r ocess i n t a r g et e p it h elia i d e n tif y m o lec u lar b i o mar k ers fo r m odu lati on by i n t e r ven ti ons. Th ese m od els ca n b e u se d t o i d e n tif y po te ntial t ox icit y o f i n t e r ven ti ons and t o assess t h e effect o f i n ter v e n ti on s on t h e d e v el opmen t and p r og r ess i on o f p re n e op lasia/ n e op lasia . Th e U. S . Na ti ona l Cance r In stit u te ’ s (NCI) PREVENT Ca n cer P r ecli n ic a l D r ug Deve l op m en t Pr og ram is a p rime e x am p le o f a rati on al st r ate gy t o se l ec t p r o mi s i ng ag e n ts f o r cli n ical trials t h r ough a ste p wise a ppro ach o f p r ec li n i ca l i n v itro testi ng f o ll o we d by i n viv o scree n i ng –

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

nan nan

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

Biochemical P r esc r eening Assays

nan nan

P r esc r ee n i ng assays a r e a se ries o f s ho rt-term , mec h a n istic assa y s d e v el op e d t o eva l ua t e t he ab ilit y o f a test c o m pound t o m odu late b i o c h e m i ca l even t s p r esu m ed t o b e mec h a n isticall y li nk e d t o ca r ci no g enes i s T hese i n v itr o assa y s are ra p i d l y c o m p lete d f o r po te n tia l ca n ce r risk– r educ i ng agen t s. E x am p les o f s u c h assa y s i n cl ud e carci nog e n - DNA b i nd i ng, p r os t ag l and i n s yn t h esis i nh i b iti on, g l u tat h i on e – S-tra n sfer ase i nh i b iti o n , and o r n it h i ne deca r boxy lase i nh i b iti on.

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

In V it r o Efficacy Models

nan nan

In V it r o Efficacy Models

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

In V it r o Efficacy Models

nan nan

In v it ro assays t es t t he cance r ris k– re du ci ng acti v it y o f a scree n e d c o m pound i n f ou r ep it he li a l c ell s y stems ( p rimar y rat trac h eal e p it h elial cells , hu m an l ung t u m o r [ A427 ] cells , m ou se mammar y o r g a n c u lt u res [ MM O C] , and hu m an f o r esk i n e p it h elial cells) . T h e assa y s meas u re t h e a b ilit y o f po t en ti a l cance r ri s k – re du ci ng a g e n ts t o re v erse tra n sf o rmati o n in nor mal e p it he li a l ce ll s exposed t o carci nog e n s . F o r e x am p le , after treatm ent w it h a car c i nogen such as 7,12 - d emet hy l b e n z(a)a n t h race n e , MMOCs d e v el op l es i ons s imil a r t o a l veo lar nodu les t h at are c on si d ere d p reca n cer ous i n m ou s e m a mm a r y g l ands i n v i vo . Pretreatme n t o f o r g a n c u lt u res b ef o r e ca r ci no g en exposu r e m easu r es t h e e f fect o f ca n cer ris k– re du ci ng a g e n ts in

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

In V it r o Efficacy Models

nan nan

t h e i n itiati on s t age o f ca r c i nog e n esis , w h ereas treatme n t after carci nog e n e xpo s ure m easu r es ac ti v it y d uri ng t u m o r p r o m o ti on. T h ree o f t h ese assay s (u si ng ra t tr achea l ep it he li a l , A 427, a nd MMOC cells) h a v e s ho w n pr e d icti ve va l ues o f 76 % t o 83 % f o r ca n cer ris k– re du ci ng a g e n t efficac y in i n v i vo m ode l s .

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

P r eclinical In V ivo Models for Cancer Risk–Reducing Agent Efficacy T esting

nan nan

P r eclinical In V ivo Models for Cancer Risk–Reducing Agent Efficacy T esting

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

P r eclinical In V ivo Models for Cancer Risk–Reducing Agent Efficacy T esting

nan nan

An imal m ode l s r e m a i n a c r uc ial li nk i n t h e efficac y assessme n t o f ca n cer r is k–r e duc i ng agen t s f o r ep it h elial ca n ce r . C h emical carci nog e n esis m odels prov i d e t he r ep r oduc i b l e deve l op me n t o f t u m o rs i n a n imals f o ll o wi ng t he a d mi n is t r a ti on o f a known ch emical i n itiat o r o r c o m b i n ati on i n itiat or/p r o m o t e r and have b ee n t h e p rimar y i n v i vo scree n i ng t oo l f o r ca n ce r risk– r educ i ng agen t s ( ) . Carci nog e n esis m od els em p l oy i ng gene ti ca ll y eng i ne ere d mice p ermit t h e i n terr og ati on o f ta r g et ed p at hw a y s and t he co rr espond i ng e f ficac y o f ca n cer ris k– re du ci ng a g e n ts . A lt hough use f u l f o r m echan i s tic st ud ies , kno c kou t o r g e n etic m u tati on al m od els cr ea t e acce l e r a t ed ne o p lastic p r og ressi on t h at do es no t acc u ratel y r eca p it u l a t e t he m o r e co m p l e x , ste p wise , hu ma n carci nog e n esis p r o cess . Rec o m b i nan t a ll e l es can be d ri v e n by t h e a dd iti on o f d r ug -se n siti v e r e gu lat o r y e l e m en t s, such as tetrac y cli n e o r tam ox ife n a n al og s . T h e d r ug -se n siti ve r egu l a t o r y e l e m en t s ac h ie v e tem po ral c on tr o l ov er a g e n e pro m o ter t h r ough t he ad mi n i s trati on o f t h e d r ug t h at b i nd s t o t h e re gu lat o r y eleme n t. S uch a sys t e m pe rm i ts t h e i nh i b iti on o r ov ere xp ressi on o f t h e o r g a n- s pec ifi c gene us i ng C re rec o m b i n ase , a site-s p ecific DNA

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

P r eclinical In V ivo Models for Cancer Risk–Reducing Agent Efficacy T esting

nan nan

PREC L INICAL D E VELOPMENT O F CANC E R RISK–REDUC I NG AGENTS

P r eclinical In V ivo Models for Cancer Risk–Reducing Agent Efficacy T esting

nan nan

m ou se mode l s t ha t m ay be used f o r ca n cer ris k– re du ci ng a g e n t testi ng.

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

nan nan

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Special Featu r es of Cancer Risk–Reducing Agent Development

nan nan

Special Featu r es of Cancer Risk–Reducing Agent Development

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Special Featu r es of Cancer Risk–Reducing Agent Development

nan nan

Th e cli n i ca l e f fi cacy assess me n t o f ca n cer ris k– re du ci ng a g e n ts em p l oys ph ase d t es ti ng ( phase I t o III) m od els u se d f o r d e v el op me n t o f d r ug s but w it h c ruc i a l d i f f e r ences i n s t udy d esi gn a nd e nd po i n ts . S p ecial feat u res f o r t h e cli n i ca l deve l op m en t o f c a n cer ris k– re du ci ng a g e n ts create t h e

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Special Featu r es of Cancer Risk–Reducing Agent Development

nan nan

fo ll ow i ng cha ll enges t o be ov erc o me: ( 1 ) t h e n ee d f o r lar g e t h era p e u tic i nd e x (doses assoc i a t ed w it h po te n tial t ox icit y o f a n i n ter v e n ti on n ee d t o s ub sta n ti a ll y exceed doses a ime d at d ela y i ng o r re v ersi ng tra n sf o rmati on ) for u se i n i nd i v i dua l s who a r e as y m p t o matic y et ma y b e n efit fr o m a n e x te nd ed ( yea r s ) tr ea tm en t cou rse; ( 2 ) t h e l ong late n c y t o mali gn a n t t r a n s forma ti on ( an assess m ent o f e f fecti v e n ess b ase d on t h e re du cti on i n ca n ce r i nc i dence r equ ir es s t u dies lasti ng f o r y ears a nd i nvo l v i ng t hou sa nds of p a r tic ipan t s ); ( 3 ) adhe r enc e ( on ce- d ail y do si ng re g ime n s u si ng i n te rv e n ti ons t ha t have su f fi c i en tl y l ong h alf-li v es ma y mi n imize t h e im pact of a mis sed dose ye t m a i n t a i n t h e b i o l og ic im p act on t h e phy si o l og ic ta r get; mi n imal t ox i c it y and s tr ong p s y c ho l og ical c o mmitme n t t o p re v e n ti v e goals als o e nhance adhe r enc ); an d ( 4 ) c o m p le x ris k assessme n t f o r ca n cer ( i nd i v i d u a l s w it h h i gh l y pene tra n t bu t i n fre qu e n t , g erm-li n e g e n etic s u sce p ti b ilit y t o b r eas t and colon ca n cer s are e x celle n t ca nd i d ates f o r ca n ce r risk– r educ i ng agen t s and are li k el y t o acce p t s o me t ox icit y f o r r e du ce d cance r ri sk ) . F o r i nd i v i du als at m o re m od estl y i n crease d ris k (e .g., l ong- te rm, cu rr en t s m oke r s ; p ers on s wit h a famil y h ist o r y o f ca n cer; w omen w it h mamm og r aph i ca ll y dense b reasts) , qu a n titati v e ris k assessme n t al gor it h m s m ay be use f u l i n t h e f u t u re t o i d e n tif y op timal ca n cer ris k– r e du ci ng agen t s. T he r e fi ne m en t o f ca n cer ris k calc u lat o rs f o r b reast ,

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Special Featu r es of Cancer Risk–Reducing Agent Development

nan nan

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Special Featu r es of Cancer Risk–Reducing Agent Development

nan nan

c o l on and p r os t a t e cance r p r o mises t o a pp r op riatel y select h i gh -ris k i nd i v i du al s f o r cance r ri sk– r edu ci ng a g e n ts s u c h t h at a n tici p ate d b e n efit s e x cee d po t en ti a l ri sks.

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Biomarkers as Cancer Risk–Reducing Agent T argets and Efficacy End Points

nan nan

A b i o m a r ke r i s a cha r ac t e ri s ti c t h at is meas u re d a nd e v al u ate d as a n i nd icat o r o f no rm a l b i o l og i c p r o cesses , p at hog e n ic p r o cesses , o r ph a r ma co l og i c r esponses t o t h era p e u tic i n ter v e n ti on s . A s u rr og ate e nd po i n t fo r cance r p r even ti on as s u mes t h at a meas u re d b i o l og ic feat u re wi ll pr e d ict th e p r esence o r f u t u r e d e v el op me n t o f a ca n cer ou tc o me .

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Biomarkers as Cancer Risk–Reducing Agent T argets and Efficacy End Points

nan nan

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Biomarkers as Cancer Risk–Reducing Agent T argets and Efficacy End Points

nan nan

Bi o ma rke r s enab l e a r educ ti on i n t h e size a nd du rati on o f a n i n ter v e n ti on

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Biomarkers as Cancer Risk–Reducing Agent T argets and Efficacy End Points

nan nan

t r ial by r ep l ac i ng a r a r e o r d i s tal e nd po i n t wit h a m o re fre qu e n t , p r ox im ate e nd po i n t . I n tr aep it he li a l ne o p lasia h as ser v e d a nd c on ti nu es t o ser v e as a b i o ma rk er f o r i nvas i ve m a li gn a n c y ( . Alt hough ma ny a dvo ca te t h e u se o f i n tr aep it he li a l neop lasia- b ase d b i o mar k ers as re gu lat o r y s u rr ogate e nd po i n t s, o t he r s cau ti on t ha t i n trae p it h elial n e op lasias ma y no t ser v e a s s u f f icie n tl y r obus t su rr oga t e bi o mar k ers f o r ca n cer i n ci d e n ce o r m o rtalit y . In or d e r t o be use f u l as end po i n ts f o r ca n cer ris k– re du ci ng a g e n t e f f icac y t es ti ng as r egu l a t o r y e nd po i n ts , a ny b i o mar k er m u st h a v e statistic a l accu r ac y , p r ec i s i on, a nd e f fecti v e n ess o f res u lt s t h at d em on str ate pr e d icti on o f a ha r d d i sease end po i n t — ca n cer i n ci d e n ce o r m o rtalit y . A n i nd e p e nden t va li da ti on da t a se t m u st a dd ress d efi n e d sta nd ar d s o f v ali d a tion t h at mi n imi ze b i as i n t he s t ud y d esi gn a nd t h e popu lati on s st ud ie d . T he b i o ma rk er m us t be gene r a li zab le t o t h e s p ecific cli n ical o r scree n i ng popu lati on ( .

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Phases of Cancer Risk–Reducing Agent Development

nan nan

Phases of Cancer Risk–Reducing Agent Development

CLINICAL D E VEL OPME NT OF CANC E R RISK–REDUC I NG AGENTS

Phases of Cancer Risk–Reducing Agent Development

nan nan

MIC R ONU T RIENTS

Definition

nan nan

Definition

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Overview and Mechanisms

nan nan

Reti no i ds a r e t he na t u r a l de rivati v es a nd s yn t h etic a n al og s o f v itami n A .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Ca n ce r ri sk– r educ ti on i n t e r ve nti on st ud ies h a v e e v al u ate d t h e p are n t c o m pound (r e ti no l , t yp i ca ll y g i v e n as reti ny l acetate o r p almitate) , n at u r ally o cc urr i ng r e ti no i ds such as a l l -tra n s – reti no ic aci d ( A TRA) a nd 13 -cis- r eti no ic ac i d ( 13cRA ) , and a ls o s yn t h etic reti no i d s s u c h as etreti n ate a nd f e nr eti n id e ( 4 - hyd r oxy [ pheny l]reti n ami d e [ 4 HPR]) . T h ese a g e n ts h a v e been of i n te r est f o r cance r ri sk r edu cti on f o r d eca d es . Mec h a n isticall y , reti no i ds h a v e b e en shown t o m odu l a t e cell u lar g r o wt h a nd d iffere n tiati on, as wel l as a pop t o sis A l a r ge body o f researc h i nd icates t h at reti no i d s h a v e acti v it y in t h e pro m o ti on and p r og r ess i on ph ases o f carci nog e n esis , i n cl ud i ng e x te n si ve ev i dence o f e f fi cacy i n t h e setti ng o f p remali gn a n t lesi on s , lea d i ng t o t he ir eva l ua ti on i n hu ma n P h ase III trials . N u clear reti no ic aci d r ece p t ors m ed i a t e m any o f t h e reti no i d -si gn ali ng effects; ho we v e r , reti noids i n te r act w it h o t he r s i gna li ng p at h wa y s , s u c h as estr og e n si gn ali ng i n b rea st ca n ce r . Ca roteno i ds a r e a g r oup o f n at u rall y o cc u rri ng p la n t p i g me n ts , on l y s o me of wh i ch a r e f ound i n app recia b le le v els i n t h e hu ma n d iet a nd hu m an tiss u es , inc l ud i ng be t a - ca r o t en e , al ph a-car o te n e , l y c op e n e , l u tei n, a nd β-c ryp t oxan t h i n . O f t hese, t he m o st wi d el y st ud ie d car o te no i d s f o r ca n cer

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Epidemiology

nan nan

Epidemiology

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Epidemiology

nan nan

ca ro te n oi ds o ft en tr end t oge t h er i n e p i d emi o l og ic fi nd i ng s . V itami n E , i n c on t r ast , i s f ound i n d i f f e r en t f ood s , es p eciall y nu ts , see d s , a nd v e g eta b le o ils; i n t ake and b l ood concent rati on s are s o mew h at i n c on siste n tl y ass o ciate d w it h cance r ri sk . Sele n i u m , b ei ng a trace mi n eral , is d iffic u l t to meas ur e i n t he d i e t , bu t h i ghe r sele n i u m stat u s h as b ee n ass o ciate d wit h a l ow e r r is k o f ce rt a i n cance r s, alt hough t h e res u lts are no t e n tirel y c on siste n t .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Preclinical In V ivo Models

nan nan

In pr eclini ca l m ode l s, r e ti no i d s i ndu ce d iffere n tiati on as well as arrest pro li f e ra ti o n o f va ri ous can cers , ma k i ng t h em attracti v e a g e n ts f o r ca nce r r is k r e duc ti on T he I n t e r na tio n al A g e n c y f o r Researc h on Ca n cer re v ie wed t h e pr ec l i n i ca l r esea r ch i nvo l v i ng b eta-car o te n e , c on cl ud i ng t h at t h ere wa s “s u f f ici en t ” ev i dence o f canc er p re v e n ti v e acti v it y , p artic u larl y i nvo l v i ng m ou se s k i n t u m o r m ode l s and t h e h amster bu ccal pou c h m od el N o ta b l y , t h e r e was i ncons i s t en t ev i denc e o f e f ficac y i n res p irat o r y tract m od els . L y c op e ne has been eva l ua t ed i n nu mer ou s cell c u lt u re s y stems a nd i n a v a r iet y o f m ode l s o f p r os t a t e carci nog e n esis , i n cl ud i ng c h emicall y i ndu c ed, or t ho t op i c im p l an t a ti on, tr ansg e n ic , a nd x e no tra n s p la n tati on, wit h mi x e d e v i d e n ce o f e f fi cac y E v i den ce , p rimaril y fr o m cell c u lt u re st ud ies , s ugg ests t ha t l ycopene m e t abo lites ma y b e at least p artiall y res pon si b le f o r a n tica r c inogen i c ac ti v it y

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

Ma ny t ria l s o f cance r ri sk– r e d u ci ng a g e n ts h a v e b ee n don e i n t h e setti ng o f s qu am ous ce ll ca r c i no m as o f th e h ea d a nd n ec k, i n lar g e p art b eca u se o f the s ub sta n ti a l c li n i ca l p r ob l e m o f relati v el y h i gh rates o f rec u rre n ces a nd sec ond p rim a r y t u m o r s i n cu rati v el y treate d ca n cer p atie n ts . Earl y w o r k d em on st ra t ed t ha t h i gh - dose 13 cRA ( 50 t o 100 m g / m 2 p er d a y ) p r odu ce d no si gn i f ic an t d i f f e r ences i n d i sea se rec u rre n ce (l o cal , re g i on al , o r d ista n t) but si gn i f ic an tl y l owe r ed t he r a t e o f sec ond p rimar y i nv asi v e n e op lasms , with t h e b e n e f it s pe r s i s ti ng f o r a t least 5 y ears . S ub sta n tial reti no i d t ox icit y , how e v e r , i nc l ud i ng sk i n d r yn ess a nd p eeli ng, c h eilitis , c on j un cti v itis , a nd

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

hyp e r t r i g l yce ri de mi a, was ev i d e n t i n a lar g e p r opo rti on o f p atie n ts . S ub se quen t tri a l s t hus used l ow er do ses o f reti no i d s ( 13 cRA o r a s yn t h e tic r eti no i d, e tr e ti na t e ) , bu t f a il ed t o s ho w efficac y i n re du ci ng sec ond p rimar y t u m or fo rm a ti on ( ) . S upp l e m en t a l be t a - ca r o t en e h as als o b ee n st ud ie d as a si ng le a g e n t a nd i n c o m b i na ti on w it h o t he r agen ts f o r t h e p re v e n ti on o f sec ond p rimar y ca n ce r s o f t he m ou t h and t h r o at ( ) . O n e trial o f b eta-car o te n e al on e obse r ved no ha rm o r ben efi ; a no t h er ob ser v e d non si gn ifica n tl y f e w e r sec ond head and neck ca n cers bu t m o re l ung ca n cer s a nd a t h ir d g a v e b eta- ca r o t ene w it h α -t ocoph er o l ( 400 IU p er d a y ) . I n t h e t h ir d tria l, b eta - ca ro t ene was d i scon ti nu e d earl y du e t o a dv erse fi nd i ng s fr o m l ung ca n ce r preven ti on tri a l s ( see t h e f o ll o wi ng ); ho we v e r , after a me d ia n f o llo w - up of 6. 5 yea r s, a ll- cause m o r t alit y was i n crease d, w h ic h t h e a u t ho rs att r i bu te d t o t he supp l e m en t a l α -t o c oph er o l . As will b e d isc u sse d late r , a dv e r se e f f ec t s o f an ti ox i dan t nu trie n ts are no t limite d t o h ea d a nd n ec k ca n ce r p ati en t s ; po t en ti a l m ech a n isms f o r a dv erse e f fects are d isc u sse d fur t h e r .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

Acti v e sm ok ers a nd rece n t qu itters h a v e m u lti p l e p r e i nvas i ve m e ta p lastic a nd dy s p lastic lesi on s i n t h e pu lm ona r y tr ee. Mos t o f t hes e lesi on s res o l v e upon sm ok i ng cessati on, but s o me r em a i n and p r og r ess t o i nv asi v e n e op lasms . U n f o rt un atel y , mic ronut ri en t o r r e ti no i d i n t e r v e n ti on s h a v e no t d em on strate d p re v e n ti v e e f f icac y i n m os t ri go r ous tri a l s i n p atie n ts wit h earl y lesi on s . F o r e x am ple, a U S t r ial rando mi zed 755 asbe st o s w o r k ers t o recei v e b eta-car o te n e ( 50 mg p e r d a y) and r e ti no l ( 25,000 I U e v er y o t h er d a y ) v ers u s p lace bo ; s pu t u m at yp ia was no t r educed a ft e r 5 y ears As a no t h er e x am p le , eli g i b le sm ok e r s w it h l ung m e t ap l as i a o r dy s p lasia were ra ndo mize d t o 6 m on t hs o f 13 cR A or p l acebo. T he ex t ent o f meta p lasia d ecrease d similarl y (i n a pprox im a t e l y 50 % o f sub j ect s) i n bo t h st udy arms . O n l y sm ok i ng

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

cessati on was assoc i a t ed w it h a si gn ifica n t re du cti on i n t h e meta p lasia i nd e x du ri ng t he 6 -m on t h i n ter v e n ti on.

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Clinical T rials: Retinoids, Carotenoids, and Antioxidant Nutrients

nan nan

La r g e , ph ase III e f ficac y trials o f b et a -ca ro te n e p l us o t he r mi c r onu trie n ts f o r p rimar y p re v e n ti on o f l ung ca n cer h a v e b e en co m p l e t ed, as su mmarize d i n T h e Al ph a- T o c oph er ol, Beta - ca ro t ene ( A T BC ) T ri a l i nvo l v e d 29,133 me n fr o m Fi n la nd w ho we re h ea vy cig a r e tt e s m oke r s a t en tr y I n a tw o - by -tw o fact o rial d esi gn, p a r tici pan t s we r e r ando mi zed t o recei v e eit h er s upp leme n tal α -t o c oph er ol, b eta - ca ro t ene, t he co m b i na ti on, o r p lace bo. U n e xp ecte d l y , p artici p a n ts r ecei v i ng be t a - ca r o t ene ( a l one o r i n c o m b i n ati on wit h α -t o c oph er o l) h a d a statistic a ll y s i gn ifi can t 18 % i n crease i n l ung ca n cer i n ci d e n ce a nd a n 8% i n c r ease i n t o t a l m o rt a lit y r e lati v e t o p artici p a n ts recei v i ng p lace bo. α - T o c ophe r o l had no e f f ec t . Th e find i ng o f an i nc r ease d i n ci d e n ce o f l ung ca n cer i n t h e b eta-ca ro te n e –supp l e m en t ed s m ok ers was re p licate d i n t h e Car o te n e a nd Reti nol E f f icac y T ri a l ( CAR ET) , a l a r g e ra ndo mize d trial o f s upp leme n tal b eta-ca ro te n e p l us r e ti no l ve r sus p lace bo i n as b est o s w o r k ers a nd sm ok ers .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Th is t r ia l was t e rmi na t ed ea rl y , bu t , at t h e time o f termi n ati on, ov erall l u n g ca n ce r i nc i dence was i nc r eased by 28 % i n t h e s upp leme n te d s ub jects a nd t o tal m o rt a lit y was a l so i nc r e ase d by 17 % . I n c on trast , t h e P hy sicia n s’ H ealt h St udy (P H S) o f supp leme n tal b eta-car o te n e v ers u s p lace bo i n 22,071 male U S phys i c i ans r epo rt ed no si gn ifica n t effect —po siti v e o r n e g ati v e— o f 12 y ea r s o f supp l e m en t a ti on o f b eta-car o te n e on t o tal ca n ce r , l ung ca n ce r , or ca rd i ovascu l a r d i sease ( see . T w o o t h er trials i nvo l v i ng s upp leme n t a l be t a - ca r o t ene a lo n e (t h e W o me n ’ s Healt h St ud ) o r wit h o t h e r a n ti ox i dan t nu tri en t s (t h e Me d ical Researc h C oun cil/Britis h Heart F ound ati on Hea rt Pr o t ec ti on S t ud y on ov erall ca n cer i n ci d e n ce als o fa iled t o ob se rve e f fi cac y .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

EUROSCAN was a m u ltice n t e r tri a l e m p l oy i ng a tw o - by -tw o fact o rial d esi gn t o test reti ny l p almitat e and N - ace t y l cys t e i n e (als o a c o m pound wit h kno w n a n ti ox i d a nt

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

acti v it y) i n p r even ti ng second p rimar y i nv asi v e n e op lasms i n p atie n ts wi th ea r l y sta ge cance r s o f t he head a nd n ec k o r l ung. N on e o f t h e i n ter v e n ti ons r e du ce d second a ir way p rim a r y i nv asi v e n e op lasms . T h e L ung I n te r g r oup T r ial r an do mi zed pa ti en t s w it h s u r g icall y resecte d l ung ca n cer t o 13 cRA v e r s u s p l acebo and f ound no si gn ifica n t d i f fere n ces b etwee n t h e tw o arm s i n sec ond p rim a r y t u m o r s . N o ta b l y , sm ok i ng stat u s m od ifie d t h e e f fect o f t h e 13 cR A i n t e r ven ti on, wh i ch was h armf u l i n c u rre n t sm ok ers y et b e n e f icial i n f o rm e r s m oke r s. Thu s , phase III tri a l s o f bo t h car o te no i d s/a n ti ox i d a n ts a nd reti no i d s i nd icate t ha t t hese agen t s ove rall do no t re du ce t h e ris k o f d e v el op i ng i nv asi v e l ung cance r s, no r do t h e y p re v e n t t h e d e v el op me n t o f sec ond pr ima ry i nvas i ve neop l as m s. H o we v e r , t h e fi nd i ng t h at f o rmer sm ok ers seeme d t o bene fit fr o m bo t h 1 3 cR A a nd b eta-car o te n e is i n tri gu i ng. Mec h a n i s ti c wo r k sugges t s t hi s i n teracti on is real rat h er t h a n c h a n ce (se e t h e fo ll ow i ng ) , sugges ti ng t h at ( 1 ) ris k -re du cti on i n sm ok ers is es p eciall y c h alle nging , and ( 2 ) tri a l s i n f o rmer sm ok ers ma y merit c on si d erati on.

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

M oon et a l fir s t showed t ha t fe n reti n i d e was a p r o misi ng ca n cer ris k– r e du ci ng agen t f o r t he b r eas t , h a v i ng a h i gh t h era p e u tic i nd e x a nd s yn e r g is t i c i n t e r ac ti on w it h t amox ife n i n mammar y carci nog e n esis m odel st ud ies . T h i s l abo r a t o r y wo r k le d t o a la r g e-scale ra ndo mize d trial o f f e nr eti n id e ( ve r sus no tr ea tm en t) f o r 5 y ears t o p re v e n t c on tralateral b re ast ca n ce r i n wo m en aged 30 t o 70 y ears wit h a h ist o r y o f resecte d earl y b re ast ca n ce r a nd no p ri o r ad j uvan t th era p y T h e i n ter v e n ti on p r odu ce d no si gn i f ic an t ove r a ll e f f ec t , a lt hough fe n reti n i d e re du ce d c on tralateral a nd i p silate ra l b r eas t cance r r a t es i n p reme nop a u sal w o me n, wit h a n oppo site ( a dv e r se ) tr end obse r ved i n po stme nop a u sal w o me n. T h e re du ce d i n ci d e nce of sec on d b r eas t cance r i n p r em e nop a u sal p atie n ts p ersiste d wit h l ong er fo ll ow-up. Reti no i d X r ecep t o r ( RXR ) – selecti v e reti no i d s are als o b ei ng e v al u ate d i n pr ecli n i ca l and c li n i ca l s t ud ies . O ngo i ng w o r k s ugg ests t h at c o m b i n ati on

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

t r eatme n t m ay r ep r esen t a p r o misi ng n ew strate gy t o s upp ress bo t h estr ogen r ece p t or–nega ti ve and es tr og e n rece p t o r –po siti v e b reast t u m o rs , a nd t h e c o m b i na ti on o f r e ti no i ds w it h a n tiestr og e n s ma y b e p artic u larl y e f fecti ve

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

i n te rv al [ C I] , 1.02 t o 1.34 ) and s qu am ou s cell s k i n ca n cer (HR = 1.25 ; 95 % C I, 1.03 t o 1.51 ) .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

of four d i f f e r en t nu tri en t co mbi n ati on s at i nh i b iti ng t h e d e v el op me n t o f es oph a gea l and gas tri c cance rs . T ho se w ho were g i v e n t h e c o m b i n ati on o f b eta - ca ro t ene, v it a mi n E , and sele n i u m h a d a 13 % re du cti on i n t o tal ca nce r d eat h s , a 4 % r educ ti on i n esoph a g eal ca n cer d eat h s , a nd a 21 % re du cti on in g ast r ic ca nce r dea t hs ( see . N on e o f t h e o t h er nu trie n t c o m b i na ti ons r educed gas tri c o r es oph a g eal ca n cer d eat h s si gn ifica n tl y i n t h is t r ial . T he tr ea tm en t bene f i t h as b ee n s ho w n t o p ersist f o r 10 y ears po sti n te rven ti on, w it h g r ea t e r e f ficac y see n i n p artici p a n ts und er a g e 55 y ea r s . T h i s fi nd i ng s t ands i n c on trast t o m o st o t h er a n ti ox i d a n t nu trie n t s upp leme n t i n t e r ven ti on tri a l s, s ugg esti ng t h at t h e a pp lica b ilit y o f t h ese r es u lts f or popu l a ti ons w it h ad e qu ate nu triti on al stat u s a nd f o r o t h er t u m o r sites ma y be limit ed . Th e o t he r Li nx i an tri a l ev al u ate d a m u lti v itami n /m u ltimi n eral pr e p a r ati on p l us be t a - ca r o t en e ( 15 m g p er d a y ) i n resi d e n ts wit h es oph a geal dy s p lasi a T he r e was no c l e ar e v i d e n ce o f e f ficac y , alt hough c on fi d e n c e i n te rv al s we r e w i de.

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Of t h e r a ndo mi zed tri a l s a im e d at t h e p re v e n ti on o f rec u rre n t c o l o rectal a d e no ma s w it h mi c r onu tri en ts t h at h a v e b ee n c o m p lete d, s o me u se d b eta-ca ro te n e a l on e o r w it h o t he r non micr onu trie n t i n ter v e n ti on s . Ot h ers e v al u ate d be t a - ca r o t ene w it h and wit hou t s upp leme n tal v itami n s C a nd E .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Non e of t he tri a l s obse r ved ben efit wit h s upp leme n tati on. A s ub se qu e n t r e por t fr om one tri a l no t ed t h at alc oho l i n ta k e a nd ci g arette sm ok i ng m od i f ie d t he e f fi cacy o f be t a - c ar o te n e . Am ong non sm ok ers a nd nondr i nke r s, be t a - ca r o t ene w as ass o ciate d wit h a si gn ifica n t d ecrease i n the r is k of one o r m o r e r ecu rr en t ad e no mas (relati v e ris k [RR] = 0.56 ) . Am o n g p e r s on s who s m oked and a l so d ra nk m o re t h a n on e alc oho lic d ri nk p er d a y , b eta - ca ro t ene s i gn ifi can tl y i nc rease d t h e ris k o f rec u rre n t a d e no ma (RR = 2.07).

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Th e r e a r e now a nu m be r o f trials d em on strati ng t h at s upp leme n tal b eta-ca ro te n e/r e ti no i ds g i ven t o cu rre n t sm ok ers ca n p r odu ce i n creases rat h er t h a n r e duc ti ons i n cance r i nc ide n ce . I n t ob acc o u sers , b eta-car o te n e a nd o t h e r ca ro t eno i ds m ay p r oduc e ox i d ati v e car o te no i d b rea kdo w n p r odu cts t h at alter r e ti no i d m e t abo li s m a nd si gn ali ng p at h wa y s , al ong wit h p r o - ox i d ati on F o r r e ti no i ds such as 13 cRA , sm ok i ng ma y i ndu ce g e n etic a nd e p i g e n et ic changes i n t he l ung t h at affect reti no i d acti v it y ; f o r e x am p le , t ob acc o sm ok i ng can a f f ec t R AR-β e xp ressi on . T h e a dv erse e f fects o f

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

s upp leme n t a l nu tri en t s a r e no t limite d t o sm ok ers; α -t o c oph er o l i n crease d r at h e r t h a n r educed p r os t a t e c a n cer i n SELECT (w h ic h h a d relati v el y fe w sm ok e r s) and se l en i u m i nc r eas e d p r o state ca n cer am ong me n wit hou t a b aseli n e se l en i u m de fi c i enc y T h is ma y b e a c on se qu e n ce o f t h e relati vely h i gh doses used i n SELE C T , bu t certai n l y calls i n t o qu esti on t h e no ti on t h at r e duc i ng ox i da ti ve s tr ess i s a p i vo tal ca n cer ris k– re du cti on strate g y , e v e n i n nons m oke r s. I t h a s beco m e c l ea r t ha t r e acti v e oxyg e n s p ecies (ROS) , s u c h as hydrog e n pe r ox i de, can ac t as im po rta n t phy si o l og ic re gu lat o rs o f i n t r acell u l a r s i gna li ng pa t hway s . Data i n m ou se m od els h a v e s ho w n that v itami n E acce l e r a t es l ung t umo r g r o wt h by d isr up ti ng t h e ROS –p53 a x i s, po te n tiall y by r e m ov i ng ox i d ati v e d ama g e t o DNA , w h ic h ca n ser v e as a po te n t s t im u l us f o r p53 ac ti vat i on . Alt hough s o me o f t h e la r g e ca n cer r is k–r e duc i ng tri a l s m ay have faile d i n t h eir p rimar y ob jecti v e , t h e y ma y i nd i r ectl y con tri bu t e t o a c l ea rer und ersta nd i ng o f ca n cer b i o l og y , lea d i ng to t h e r ec o g n iti on t ha t t he r o l e o f ox i d ati v e stress a nd ROS i n hu ma n d isea se is m u c h m o r e nuanced t han o ri gin all y hypo t h esize d . A s fo r t he r e ti no i ds, t hese a g e n ts are g e n erall y t oo t ox ic t o b e u se d as si ng le a gen t s f o r ri sk -r educ i n g e f ficac y ; ho we v e r , a maj o r area o f ongo i ng r esea r c h i s exa mi n i ng r e ti no i d s (l o w do ses) g i v e n i n c o m b i n ati on wit h othe r a g e n ts , espec i a ll y t hose t ha t r egu late t h e e p i g e no me , s u c h h ist on e d eacet y l ase ( HDAC ) i nh i b it o rs

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Folic Acid and Other B V itamins

nan nan

F o late is a wate r -s o l ub le B v itami n f ound i n food s , whe r eas f o li c ac i d i s t h e s yn t h etic f o rm f ound i n s upp leme n ts a nd for ti f ie d f oods. Adequa t e f o l at e is critical f o r DNA met hy lati on, re p ai r , and s yn t h esi s. T he m e t hy l a ti on stat u s o f g e n es ca n p la y a k e y r o le i n g e n e sile n ci n g and gene exp r ess i on, le nd i ng p la u si b ilit y t o t h e i d ea t h at f o late c ou l d be a key nu tri en t i n r egu lati ng cell g r o wt h a nd p r o liferati on.

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Folic Acid and Other B V itamins

nan nan

E p i de mi o l og ic st ud ies h a v e li nk e d l o w f o late i n ta k e wit h h i gh e r risk o f seve r a l cance r s , m o st no ta b l y c o l o rectal ca n ce r . L ong -ter m u se of mu lti v it a mi n supp l e m en ts , w h ic h are a maj o r s ou rce o f f o late a nd o t h e r B v it a mi ns, has been as s o ciate d wit h a re du cti on i n t h e ris k o f c o l on ca n ce r i n so m e s t ud i es, i nc l ud i ng rece n t ( po stf o rtificati on ) fi nd i ng s .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Ris k -re du ci ng e f ficac y f o r s upp leme n t a l f o li c ac i d has b ee n p rimaril y e v al u ate d i n t h e setti ng o f pr e v e n ti on o f r ecu rr en t co l o rectal a d e no mas (i . e ., i n p atie n ts wit h p ri o r a d e no ma s ) . O f s i x r ando mi ze d trials o f f o lic aci d, tw o small trials re po rt ed s ugg esti ons o f bene fit o f f o li c aci d s upp leme n tati on . H o we v e r , b e n ef its w e r e not obse r ved i n t wo m u c h la r g er trials , t h e As p iri n /F o late P o l yp P r e v e n ti on St udy ( A FPPS) ( d ose: 1 m g o f f o lic aci d d ail y ) a nd t h e U nited K i ngdo m Co l o r ec t a l Adeno m a Pre v e n ti on ( uk CAP) trial ( do se: 500 μg o f fo lic aci d da il y ) A FPPS f ound i nd icati on s o f a n i n crease d ris k f o r a dv a n ce d l es i ons and m u lti p le a d e no mas wit h p r o l ong e d treatme n t a nd fo ll ow-up. A t h ir d l a r ge tri a l , th e N u rses Healt h St udy /Healt h Pr o fessi onals F o ll ow-up St udy ( NH S/ H PFS) f o lic aci d po l yp p re v e n ti on trial , s ho we d no ov e r all r i sk r educ ti on . T he mo st rece n t trial , don e i n a C h i n ese popu la tion > 50 y ear s o f age , r epo rt ed t h at 1 m g f o lic aci d p er d a y re du ce d s po ra dic c o l or ectal adeno m as when co m p are d t o no i n ter v e n ti on ( no t a p lace bo -c on t ro ll ed s t udy ) . One poss i b le e xp la n ati on f o r t h e d iscre p a n c y o f t h e C h i n ese tri a l ve r sus No rt h A merica n a nd E u r op ea n trials is t h e b aseli n e p lasma f o l a t e s t a t us. I n t he Ch i n ese trial , t h e mea n b aseli n e f o late c on ce n t ra ti on o f 5 ng /m was h alf o f t h e re po rte d 10 ng /mL i n a U n it ed States t ria l , whe r e f o l a t e f or tificati on o f t h e f ood s upp l y o cc u rs .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Calcium and V itamin D

nan nan

Calcium and V itamin D

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

Calcium and V itamin D

nan nan

T h ere are tw o maj o r f o rms o f v itami n D: e r go calc i f e r o l ( D 2 ) and cho l e calcifer o l ( D 3 ) . V itami n D 2 is a b s o r b e d t h r ough d ieta ry sou r ces such as f o rtifie d mil k p r odu cts , a nd D 3 is s yn t h esize d v ia u lt r a v i o let ( UV ) B li gh t i so m e rizati on o f 7 - d e hyd r o c ho lestr o l i n t h e e p i d e r mi s . V it a mi n D 3 i s conv erte d t o calcitri o l ( 1, 25 -[OH ] 2 D 3 ) i n a t wo -ste p pro c ess r equ iri ng bo t h hep atic a nd re n al hyd r oxy lati on. Calcitri o l b i nds t o t h e v it a mi n D r ecep t o r , whi c h tra n sl o cates t o t h e nu cle u s a nd b i nd s t o m u lti p le gene p r o m o t e r s it es. Th r ough t h is mec h a n ism , v itami n D re gu l ates c y t op lasmi c s i gna li ng pa t hway s t h at im p act cell u lar d i f fere n tiati on a nd grow t h t h r ough p r o t e i ns such as Ras a nd mit og e n -acti v ate d p r o tei n k i n a se ( M A P K ) , p r o t e i n li pase A, p rosta g la nd i n s , c y clic a d e no si n e m onopho s phate (A MP ), pr o t e i n k i nase A, and pho s ph ati dy l i no sit o l 3 k i n ase .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

1,25(OH ) 2 D 3 r egu l a t es ce ll u l a r p r o liferati on a nd a pop t o sis . F o r e x am p le , 1,25(OH ) 2 D 3 can i nduce c l eav a g e o f cas p ase 3, po l y (ADP-ri bo se) po l y me r a se ( P AR P) , and MAP K , lea d i ng t o a pop t o sis . 1,25 (OH ) 2 D 3 i nh ib its t h e e xpress i on and phospho r yl ati on o f A k t , a k e y re gu lat o r o f cell u lar pro li f e ra ti on. T he d i f f e r en ti a ti on p r op erties o f 1,25 (OH ) 2 D 3 are me d iate d t hrough tr ansc ri p ti ona l ac ti va ti on o f t h e CDK i nh i b it o r p21. T h e e f fects o f v itami n D on m u lti p l e s i gna l tra n s du cti on p at h wa y s op erati on al i n ca n cer cells a r e r ev i ewed by Deeb e t al .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Obse r va ti ona l e p i d emi o l og ic st ud ies h a v e s ho w n a relati vely c on siste n t i nve r se assoc i a ti on b etwee n l o w calci u m i n ta k e , i n cl ud i ng t h at fro m s upp l e m en t s, and i nc r ea se d c o l o rectal a nd c o l on ca n cer ris k .

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

V itami n D exposu r e i s t yp i ca ll y assesse d by meas u ri ng 25 (OH) v itami n D in p lasma because exposu r e i s d eri v e d no t on l y fr o m d iet a nd s upp leme n ts , but als o fro m cu t aneous syn t hes is f o ll o wi ng d ermal e xpo s u re t o UV ra d iati o n . A la r g e nu m be r o f obse r va ti on al st ud ies h a v e e v al u ate d t h e ass o ciati on b et w ee n v it a mi n D s t a t us and ca n cer ris k, as s y stematicall y re v iewe d by the Ag e n c y fo r Hea lt hca r e Resear c h a nd Q u alit y (AHRQ) . T h e e v i d e n ce i s i n c on sist en t f o r m os t cance r s ites , wit h t h e e x ce p ti on o f st ud ies s ho wi ng

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

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t h at i nd i v i dua l s w it h l owe r b lo od v itami n D le v els h a v e a h i gh er ris k o f c o l or ectal cance r o r adeno m a. Alt hough s o me ob ser v ati on al st ud ies h a ve r e por te d t ha t h i ghe r se r u m v it a mi n D is ass o ciate d wit h l o wer b reast ca nce r r is k, t h e assoc i a ti on i s i ncons iste n t . Als o, t h ere are s o me st ud ies s ugg esti ng h i gh se r u m v it a mi n D is ass o ciate d wit h i n creases i n certai n ca n ce r s , pa rti cu l a rl y panc r ea tic ca n ce r

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

nan nan

Cli n ic a l Effi cacy i n t he Co l on. Bar on et al ra ndo mize d s ub jects wit h a r ece n t his t o r y o f co l o r ec t a l ad e no mas t o eit h er calci u m car bon ate ( 1,200 mg p e r d a y o f e l e m en t a l ca l c i u m) o r p lace bo. Res u lts s ho we d si gn ifica n t b e n e f it fo r t he ca l c i u m a rm ( ad j u ste d RR = 0.81 ; 95 % CI , 0.67 t o 0.99 ; p = 0.04). I n a s m a ll e r , s imil a r s tu dy o f calci u m g l u c ono lactate a nd car bon at e ( 2 g element a l ca l c i u m da il y ) , t h e a d j u ste d odd s rati o (OR) f o r a d e no ma r ec urr e nce was 0.66 ( 95 % C I , 0.38 t o 1.17 ; p = 0.16 ) f o r calci u m t r eatme n t and wh il e no t s t at isticall y si gn ifica n t , it was similar t o t h e d a ta of Ba ron e t a l . In t he l a r ges t tri a l o f ca l c i u m a nd v itami n D wit h p rimar y ca n cer e nd po i n ts (e.g., co l on, b r eas t) , t he US W o me n ’ s Healt h I n itiati v e (WHI) e v al u ate d t he co m b i na ti on o f 4 00 IU o f v itami n D p er d a y p l u s 1,000 m g o f calci u m pe r day i n 36,282 po stme nop a u sal w o me n. F o r c o l on ca n ce r , t he r e w as no bene fit obse r ved a lt hough t h e mea n b aseli n e i n ta k e o f calci um w as al r e ady ve r y h i gh (m o r e th a n 1,151 m g p er d a y ) . W it h re g ar d t o v itami n D as a s i ng l e agen t , t h ere was als o no s ugg esti on o f b e n efit f o r c o l on can ce r i nc i dence i n a 5 - y ear Britis h trial o f v itami n D ( 100,000 IU e v e ry 4 m on t hs ) t ha t r epo rt ed c o l on ca n cer i n ci d e n ce alt hough t h is w as no t a pr im a r y end po i n t . Cli n ic a l Effi cacy i n t he B r east . V itami n D h as recei v e d c on si d era b le atte n ti on f o r a poss i b l e r o l e i n t h e p re v e n ti on o f b reast ca n ce r , alt hough no t r ials have ye t i nves ti ga t ed v itami n D as a si ng le a g e n t f o r b reast ca nce r r is k r e duc ti on. T he l a r ge WH I trial g a v e a c o m b i n ati on o f calci u m a nd v itami n D, as no t ed p r ev i ous l y , a nd t h ere was no si gn ifica n t e f fect o f t h i s

MIC R ONU T RIENTS

Retinoids, Ca r otenoids, and Antioxidant Nutrients

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L a pp e e t a l conduc t ed a tri a l t h at e x ami n e d t h e relati on b etwee n calci um p l u s v it a mi n D ( 1,100 I U pe r d a y ) s upp leme n tati on ( v ers u s calci u m al one or p laceb o ) i n 1,179 hea lt hy po stme nop a u sal w o me n i n Ne b ras k a

MIC R ONU T RIENTS

Summary and Conclusion: Mic r onutrients

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Ce r tai n a gen t s, i nc l ud i ng t he reti no i d s , b eta-car o te n e , f o lic aci d, calci u m p l u s v it a mi n D, v it a mi n E , an d sele n i u m , h a v e recei v e d s ub sta n tial atte ntion for a po s s i b l e r o l e i n r educ i ng t h e ris k o f ca n cer i n hu ma n s . As re v iewe d h e r ei n, s o m e o f t he tri a l s hav e ob ser v e d statisticall y si gn ifica n t re du cti ons i n t h e r i sk o f t he p rim a r y end po i n t (e .g., reti no i d s i n s k i n carci nog e n esi s m od els , c a l c i u m i n co l o r ec t a l a d e no mas , a n ti ox i d a n t nu trie n ts i n Li nx ian , C h i n a , fo r gas tri c cance r p r even ti on ) , w h ereas o t h ers h a v e ob ser v e d statistic a ll y s i gn ifi can t i nc r ea ses i n t h e ris k o f t h e p rimar y e nd po i n ts ( b e ta -ca ro te n e and r e ti no i d l ung can cer p re v e n ti on trials i n sm ok ers , v itami n E a nd pros t a t e cance r , se l en i u m a nd non mela no ma s k i n ca n cer) . C on si d erin g t h e c o m p l e t ed tri a l s, t he r e i s clear e v i d e n ce a g ai n st t h e g e n eral u se o f nu t r ie n t supp l emen t s f o r cance r p re v e n ti on, w h ic h is t h e c on cl u si on als o r eac h e d by t he W o rl d Cance r R esearc h F und /America n I n stit u te f o r Ca nce r Resea r c h . No t e t ha t t he r e i s no e v i d e n ce t h at f ood s ou rces o f t h ese nu t r ie n t s i nc r ease ri sk. H a v i ng no t ed t ha t , t he r e a re o t h er k e y t h emes emer g i ng fr o m t h is grow i ng body o f r esea r ch. On e s u c h t h eme is t h at nu trie n t s upp leme n tati on ma y b e o f bene fit t o so m e bu t no t all . O n e s u c h popu lati on t h at ma y b e ne f it i n cl ud es pe r sons who a r e l ow i n t h e nu trie n t o f i n terest at b aseli n e . T h i s

MIC R ONU T RIENTS

Summary and Conclusion: Mic r onutrients

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w as i n iti a ll y sugges t ed i n t he Li nx ia n C oun tr y trial ( don e i n a mic ronut ri en t- de fi c i en t popu l a ti on ) , wit h g r o wi ng s uppo rt fr o m s ubg r oup a n al y ses o f seve r a l co m p l e t ed trials . H o we v e r , t h e hypo t h esis t h at nu tri ent s upp leme n t a ti on can r educe c a n cer ris k i n s ubg r oup s selecte d b ase d on i n a d e qu at e nu triti ona l s t a t us h as , t o d ate , no t b ee n f o rmall y e v al u ate d i n i n te rv e n ti on tri a l s. Ano t he r cons i s t en t t he m e i s t h at lifest y le fact o rs (e .g., sm ok i ng ) a nd g e n etics ( po l y m o r ph i s m s ) m ay d etermi n e w ho is m o st li k el y t o b e n efit fr om s upp leme n t a ti on. T ri a l da t a wi ll li k el y b e i n creasi ng l y mi n e d t o i d e n tif y g e n etic pr o fil es assoc i a t ed w i th bo t h b etter ou tc o mes (ris k p re d icti on ) a nd r es pon s e t o i n t e r ven ti on . Ultimatel y , a m o re p ers on alize d a pp r o ac h to ca n ce r risk r educ ti on m ay e m e r g e , c on siste n t wit h t h e m ov eme n t t o ward a m or e p er sona li zed app r oach f o r ca n cer treatme n t . Fi n all y , nea rl y a ll o f t hese trials i n itiate i n ter v e n ti on wit h o l d er a du lts (who a re m o r e li ke l y t o deve l op ca n cer e nd po i n ts du ri ng t h e f o ll o w- up ) ; bu t , a n im a l m ode l s sugges t t ha t t h e timi ng o f e xpo s u re ma y li k el y b e qu i te r ele v a n t. F o r exa m p l e, f o li c ac i d ma y p r o tect a g ai n st i n itiati on, bu t ma y als o promo t e t he p r o lif e r a ti on o f e x isti ng n e op lasms . T hu s , t h e do se , f o r m (food v e rsus supp l e m en t) , timi ng, a nd nu triti on al a nd lifest y le c h a r acteri s ti cs m ay a ll be r e l ev a n t i n affecti ng t h e e f ficac y o f ris k -re du cin g i n te rv e n ti ons i nvo l v i ng nu tri en ts a nd relate d s ub sta n ces . F u rt h er researc h, dr a w i ng upon newe r t oo l s now a v aila b le t h r ough t h e fiel d o f nu triti on al g e no mi cs, w ill be needed t o ga i n g reater clarit y on t h e h eter og e n e ou s b i o l og ic e f f ec t s obse r ved i n n utrie n t- b ase d ris k re du cti on.

ANTI-INFLA MM A T O R Y DRUGS

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ANTI-INFLA MM A T O R Y DRUGS

ANTI-INFLA MM A T O R Y DRUGS

Mechanism

nan nan

Mechanism

ANTI-INFLA MM A T O R Y DRUGS

Mechanism

nan nan

Non ste r oi da l an ti-i n fl a mm a t ory d r ug s (NSAIDs) re p rese n t a class o f d r ugs t h at r e duce ce ll u l a r i n fl a mm a ti on t h r ough m u lti p le mec h a n isms , t h e m ost pro mi n e n t o f t he m be i ng t he modu lati on o f eic o sa no i d meta bo lism .

ANTI-INFLA MM A T O R Y DRUGS

Mechanism

nan nan