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T H E U SE OF P ARP INHI B I T ORS IN SPORAD I C CANCERS

nan nan

i nh i b it or sens iti v it y i n p r ec li n ical m od els , po ssi b l y b eca u se PTEN- nu ll c ells d is p la y B RCAness pheno t yp es , s u c h as t h e i n a b ilit y t o efficie n tl y re p air ce r tai n fo rm s o f DNA da m ag e . T r a d i t i ona l h i s t opa t ho l og ic met hod s a nd, m o re rece n tl y , g e n e e xp ress ion prof ili ng app r oaches have sh ow n t h e ph e no t yp ic ov erla p b etwee n tri p le- n e g ati v e b r eas t cance r s, basa l - li k e b reast ca n cers , a nd BRCA 1 familial br east c ance r s , I n gene ex pressi on p r o fili ng st ud ies , it h as b ee n ob ser ved t h at BRC A 1 f a mili a l cance r s s tr ong l y se g re g ate wit h b asal-li k e t u m o rs a nd s h a r e f eat u r es such as h i gh - g r ad e a nd pu s h i ng ma r g i n s , Alt hough th e ov e r la p i s no t abso l u t e, it l ea ds t o t h e hypo t h esis t h at t h ere ma y b e a s ubset of s por a d i c b r eas t cance r s t ha t e xh i b its feat u res o f BRCA n ess , i n cl ud i ng d e f icie nc i es i n HR and t ha t m ay b e s u sce p ti b le t o treatme n t wit h d r ug s s uch as P A R P i nh i b it o r s Th e r e have been seve r a l s t ud ies o f P ARP i nh i b it o rs i n s po ra d ic ov ari an ca n ce r . A s t udy by L ede rm an s ho we d i n a mai n te n a n ce st udy f o ll o wi ng t h e r es ponse t o p l a ti nu m t he r apy a si gn ifica n t b e n efit i n terms o f progr ess ion -fr ee su r v i va l (PF S ) o f o la p ari b c o m p are d t o p lace bo. T h is was e v e n m o r e p r onounced when t h e s ubg r oup o f BRCA m u tati on carriers we r e e x ami n ed I n bo t h cases, t he ov erall s u r v i v al (OS) a dv a n ta g e was less t han t h e PFS , bu t i n t he case o f t he BRCA m u tati on g r oup, t h is reac h e d statistic a l s i gn ifi cance. Ge lm o n als o s ho we d acti v it y i n s po ra d ic ov aria n ca n ce r . I n con tr as t , a s t udy i n s po ra d ic tri p le- n e g ati v e b reast ca n cer faile d to ob se rv e any bene fit , a lt hough t h e st udy was small a nd t h e p atie n ts were h ea v il y p r e tr ea t ed In i p ari b (i n iti a ll y r epo rt ed as a P ARP i nh i b it o r) s ho we d a n ov erall s urv i v al bene fit i n a P hase II t rial o f tri p le- n e g ati v e b reast ca n cer i n c o m b i na ti on w it h ge m c it ab i n e a nd car bop lati n c o m p are d wit h c h em o t he r apy a l one Howe ve r , a s ub se qu e n t P h ase III st udy s ho we d no im prov e men t i n PFS T he reas on s f o r t h is are un certai n, bu t si gn ifica n t qu esti on s have been r a i sed abou t w h et h er i n i p ari b is i nd ee d a bon a fi d e P A R P i nh i b it o r . T he r e f o r e, it is no w g e n erall y c on ce d e d t h at st ud ies o f i n i p a r i b have no im p li ca ti ons fo r P ARP i nh i b it o rs as a d r ug class .

T H E U SE OF P ARP INHI B I T ORS IN SPORAD I C CANCERS

nan nan

Wh i ch popu l a ti on o f pa ti en ts lac k i ng a BRCA 1 o r BRCA 2 m u tati on mi gh t b e ne fit fr o m P AR P i nh i b it o rs remai n s un clea r . T h is is li k el y t o r e qu i r e th e deve l op m en t o f a cli n ical test t o i d e n tif y p r o s p ecti v el y t u m o r s w it h i n tri ns i c sens iti v it y . Pr es e n tl y , m o st e f f o rts are d irecte d at d e v el op in g assa y s o f DNA r epa ir de fi c i en c y

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

nan nan

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

nan nan

Resista n c e t o t a r ge t ed t he r apy fre qu e n tl y o cc u rs , bu t it was un clear ho w r esista nce mi gh t a ri se t o a syn t h etic let h al t h era p y . P o te n tial mec h a n is ms of r esista nce t o P AR P i nh i b itors h a v e , ho we v e r , b ee n el u ci d ate d bo t h d i r ectl y i n v itr o, i n m ouse m o dels , a nd i n t h e cli n ic . A n i n v itr o m od el f o r r esista nce was deve l oped by p r odu ci ng cells fr o m t h e h i gh l y P ARP i nh i b it or–sens iti ve BRCA2 - d eficie n t cell li n e CA P AN 1, w h ic h carries a c .6174de lT BR C A 2 fr a m esh if t m u tati on. CA P AN 1 cells ca nno t f o rm d ama g e - i nduced RAD51 f oc i, are d efecti v e f o r HR , a nd are e x tremel y se n siti ve t o tr ea tm en t w it h P ARP i nh i b it o rs P ARP i nh i b it o r – resista n t cl on es we r e h i gh l y r es i s t an t ( ov er 1,000 -f o l d ) t o t h e d r ug a nd were als o c ro ss -r e s i s t an t t o t he DNA c r o ss-li nk i ng a g e n t cis p lati n, bu t no t t o t h e mic ro t ubu l e - s t ab ili z i ng d r ug do ceta x el . P ARP i nh i b it o rs a nd cis p lati n both e x e r t t he ir e f f ec t s on BRCA - d eficie n t cells by i n creasi ng t h e fre qu e n c y o f mis r e p a i r ed D S Bs i n t he absen ce o f e f fecti v e HR . T h eref o re , t h is ob se rv ati on i nd i ca t es t ha t t he resista n ce o f P ARP i nh i b it o r – resista n t cl ones t o P A R P i nh i b it o r s mi gh t be b eca u se o f rest o re d HR . T h is c on te n ti on wa s s uppor t ed by t he acqu i s iti on i n P ARP i nh i b it o r – resista n t cl on e cells o f t he a b ilit y t o f o rm RAD51 f oc i a fter P ARP i nh i b it o r treatme n t o r e xpo s u re t o i rr a d iatio n. DNA sequenc i ng o f P AR P i nh i b it o r – resista n t cl on es re v eale d t h e un e xp ect ed p r esence o f nove l BRCA 2 alleles t h at res u lte d i n t h e elimi n at ion of t h e c .6174de lT m u t a ti on and rest o rati on o f a n op e n rea d i ng frame .

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

nan nan

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

nan nan

Th e r e fo r e, i n t h i s case, r es i s t an ce arises b eca u se o f g ai n o f f un cti on

MECHANI S MS OF R E SIS T ANCE T O P ARP IN H IBI T ORS

nan nan

m u tati ons i n t he syn t he ti c l e t h al p art n er (BRCA 2 ) rat h er t h a n t h e d irect drug ta r ge t ( P AR P) . A lt e r na ti v e mec h a n isms o f P ARP i nh i b it o r resista nce h a v e als o been desc ri bed . A m ou se m od el o f BRCA 1 - ass o ciate d mamm a r y g la nd can ce r de m ons tr a t ed t h e e f ficac y o f o la p ari b i n v i vo a nd was u se d to st udy m echan i s m s o f r es i s t anc e Resista n ce seeme d t o b e ca u se d by t he upr e gu l a ti on o f AB C B 1a / b , wh ic h e n c od e P- g l y c op r o tei n pu m p s; t h is e f f ect c ou l d be r eve r sed w it h t he P- g l y c op r o tei n i nh i b it o r tari qu i d a r . I n a dd iti on, o t h e r alt e r a ti ons i n DNA r epa ir p at h wa y s h a v e b ee n p r opo se d t o c o m p e n s a t e f o r BRCA1 de fi c ie n c y res u lti ng i n P ARP i nh i b it o r d eficie nc y . St ud ie s o f t he m echan i s m s o f resista n ce t o P ARP i nh i b it o rs i n p atie n t mate r ial a r e s till a t an ea rl y s ta g e . I n itial st ud ies a dd resse d t h e mec h a n ism of r esista nce t o p l a ti nu m sa lt s i n BRCA m u tati on carriers . Cis p lati n a nd ca rbop l a ti n a r e pa rt o f t he s t and ar d o f care f o r t h e treatme n t o f ov aria n ca n ce r , i nc l ud i ng i nd i v i dua l s wit h BRCA 1 o r BRCA 2 m u tati on s . Plati num salts a r e t hough t t o exe rt t he ir BRCA-selecti v e e f fects by a similar mec h a n ism t o P AR P i nh i b it o rs Cli n ical ob ser v ati on s s ugg est t h at BR CA m u tati on ca rri e r s w it h ova ri an ca n cer u s u all y res pond b etter t o t h ese a g e nts t h a n p ati en t s w it hou t BR C A m u tati on ; ho we v e r , resista n ce do es e v e n t u al ly occu r . T o i nves ti g ate t h is e f fect , BRCA 1 a nd BRCA 2 h a v e b ee n se qu e n c ed i n t u m o r m a t e ri a l fr o m m u tati on carriers . T h ese st ud ies r e v eale d m u t a ti ons i n BR C A 1 o r BRCA 2 t h at rest o re d t h e op e n rea d i ng fr ame a nd li ke l y con tri bu t ed t o p lati nu m resista n ce . T h ese ob ser v ati on s s ugg est t ha t spec ifi c m u t a ti ons i n BRCA 1 o r BRCA 2 a nd se n siti v it y t o t h e r a p euti cs i n ce ll li nes and p atie n ts ca n b e s upp resse d by i n tra g e n ic d eleti on. Pr esu m ab l y , t hese m u tati on s o cc u r ra ndo ml y a nd are t h e n selec ted for by di f f e r en ti a l d r ug sens iti v it y . T h eref o re , t h e b est u se o f t h ese a g e n t s is li k el y t o be ea rli e r i n t he d i se ase p r o cess w h e n t h e d isease bu r d e n is smalle r , wh i ch w ill r educe t h e p r ob a b ilit y o f resista n ce b ase d on st o c h as tic g e n etic reve r s i on. Recen tl y , s imilar ob ser v ati on s o f re v erta n t BRCA allel es w e r e m ade i n t wo pa ti en t s who b ecame resista n t after a n i n itial res pon se to o la p a r i b A lt hough p r e limi n ar y , t h ese res u lts s ugg est t h at t h is mec h a n i sm is r es pons i b l e f o r a t l eas t so m e o f t h e cli n ical resista n ce ob ser v e d.

PROS P ECTS

nan nan

PROS P ECTS

PROS P ECTS

nan nan

C urr e n tl y , t he tr ea tm en t s f o r ca n cers arisi ng i n carriers o f BRCA 1 o r BR CA2 m u tati ons a r e t he sa m e as t hos e t h at o cc u r s po ra d icall y matc h e d f o r t u mor p at ho l ogy and age o f onse t . Ho we v e r , t u m o rs i n BRCA 1 o r BRCA 2 m u tati on ca rri e r s l ack w il d -t y pe BRCA 1 o r BRCA 2, bu t no rmal tiss u es r etai n a si ng l e w il d -t ype copy o f t h e rele v a n t g e n e . T h is is a po te n tiall y ta r g eta ble a lt e r a ti on t ha t p r ov i d es t h e b asis f o r n ew mec h a n ism- b ase d a ppro ach es t o t he tr ea tm en t o f ca n ce r . T h e b i o c h emical d i f fere n ce i n ca p acit y t o ca rr y ou t HR be t w ee n t h e t u m o r a nd no rmal tiss u es , i n a BR CA1 or BR C A2 ca rri e r , p r ov i des t he rati on ale f o r t h is a pp r o ac h. I nh i b iti ng t h e DNA r e pa ir p r o t e i n P AR P r esu lts i n t h e g e n erati on o f s p ecific DNA lesi ons t h at r e qu ir e BRCA1 and BR CA 2 s p ecialize d re p air f un cti on (s) f o r t h eir r em ov al . Pr ec li n i ca l da t a i nd icate t h at t u m o rs d efecti v e i n wil d -t yp e BRC A1 o r BRCA2 cou l d be mu c h m o re se n siti v e t o P ARP i nh i b iti on t han un a f f ect ed he t e r ozygous ti ssu es , p r ov i d i ng a po te n tiall y lar g e t h era p e u ti c w i ndo w . T he sa f e t y and e f fi ca c y o f t h is a pp r o ac h is c u rre n tl y b ei ng teste d i n cli n ic a l tri a l s, wh i ch, if suc cessf u l , ma y lea d t o re g istrati on f o r r ou ti ne cli n ical u se o f one o r m o r e P ARP i nh i b it o rs S yn t he ti c l e t ha lit y by co mbi n at o rial tar g eti ng o f DNA re p air p at h wa ys ma y h a ve use f u l ness as a t he ra p e u tic a pp r o ac h b e yond familial ca n cers . The maj or it y o f so li d t u m o r s a l so e xh i b it g e no mic i n sta b ilit y a nd a n e up l o i d y . Th is s ugges t s t ha t pa t hways in vo l v e d i n t h e mai n te n a n ce o f g e no mic sta b ilit y a r e dys f unc ti ona l i n a si gn ifica n t p r opo rti on o f n e op lastic d is ord e rs. Unde r s t and i ng wh ic h s p ecialize d DNA d ama g e res pon se a nd r e p ai r pa t hways a r e ab r oga t ed i n s po ra d ic t u m o r s ub t yp es ma y all o w f o r the d e v el opmen t o f t he r ap i es t ha t ta r g et t h e resi du al re p air p at h wa y s on w h ic h t h e ca n c e r , bu t no t no rm a l ti ssu e , is no w c o m p letel y d e p e nd e n t . T h ese po te n tial t he r ap i es m ay s i gn ifica n tl y im p r ov e res pon se rates w h ile ca u si ng

PROS P ECTS

nan nan

f e w e r t r e a tm en t-r e l a t ed t ox i c i t ies . H o we v e r , t h ese a pp r o ac h es ma y b e ass o ciate d w it h m echan i s m- as s o ciate d resista n ce , a nd caref u l c on si d erat ion of t h ei r op tim a l use w ill be r equ ire d.

PROS P ECTS

nan nan

Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cance r . J Natl Cancer Inst 2003;95:1482–1485. T urner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 2006;25:5846–5853. Ledermann J, Harter P , Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cance r . N Engl J Med 2012;366:1382–1392. Ledermann JA, Harter P , Gourley C. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). J Clin Oncol 2013;31 (suppl; abstr 5505). Gelmon KA, T ischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly di f ferentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised stud y . Lancet Oncol 20 1 1;12:852–861. O’Shaughnessy J, Osborne C, Pippen J, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cance r . N Engl J Med 20 1 1;3:205–214. Mateo J, Ong M, T an DS, et al. Appraising iniparib, the P ARP inhibitor that never was—what must we learn? Nat Rev Clin Oncol 2013;10:688–696. Lord CJ, Ashworth A. The DNA damage response and cancer therap y . Natu r e 2012;481:287–294. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013;19:1381–1388. Edwards S, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in BRCA2 . Natu r e 2008;451(7182): 1 11 1– 11 15. Rottenbe r g S, Jaspers JE, Kersbe r gen A, et al. High sensitivity of BRCA 1 -deficient mammary tumors to the P ARP inhibitor AZD2281 alone and in combination with platinum drugs. P r oc Natl Acad Sci U S A 2008;105:17079–17084. Cass I, Baldwin RL, V arkey T , et al. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003;97:2187–2195. Pal T , Permuth- W ey J, Kapoor R, et al. Improved survival in BRCA2 carriers with ovarian cance r . Fam Cancer 2007;6: 1 13– 1 19. Sakai W , Swisher EM, Karlan B Y , et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2 -mutated cancers. Natu r e 2008;451: 1 1 16– 1 120. Barber LJ, Sandhu S, Chen L, et al. Secondary mutations in BRCA2 associated with clinical resistance to a P ARP inhibito r . J Pathol 2013;229:422–429.

PROS P ECTS

Misc e l l aneous

nan nan

Misc e l l aneous

PROS P ECTS

Ch e mo t herap e utic Agents

nan nan

Ch e mo t herap e utic Agents

H OMOH ARRING T ONINE AND O MA CE T A X INE

nan nan

H OMOH ARRING T ONINE AND O MA CE T A X INE

H OMOH ARRING T ONINE AND O MA CE T A X INE

nan nan

Ho m oha rri ng t on i ne and it s c o ng e n e r , h arri ng t on i n e , are ce ph al o ta x i n e este r s is o l a t ed fr o m t he eve r g ree n tree Ce pha l o t a x u s ha i nan e n sis , w h ic h a r e d ist r i bu t ed t h r oughou t sou t hern a nd no rt h easter n C h i n a . T h e tw o d iffer only by a si ng l e m e t hy l ene g r oup, bu t bo t h h a v e a similar acti v it y a g ai n st m urine le uk emi a . T he p rim a r y ac ti o n o f ho m oh arri ng t on i n e a pp ears t o b e t h e i nh i b iti o n o f p r o t e i n syn t hes i s a nd c h ai n el ong ati on t h r ough b i nd i ng t o 8 0 S r i bo s o m e i n euka r yo ti c ce ll s . DNA e f fects ma y als o b e im po rta n t , i nvo l v i n g a b l ock i n p r og r ess i on o f cells fr o m G 1 ph ase i n t o S ph ase a nd fro m G2 phase i n t o M phase . H o m oh arri ng t on i n e e xh i b its a tri ph asic p lasma decay w it h a t e rmi na l h alf-life o f 65.3 hou rs a nd a pp are n t vo l u m e o f d ist r i bu ti on o f 2.4 L/ kg I n ea rl y ph ase I st ud ies , ho m oh arri ng t on i n e wa s a d mi n is te r ed as a 10 t o 360 mi nu te i n f u si on d ail y f o r 10 d a y s . D o se-limiti ng ca r d i ovascu l a r t ox i c it y wit h hypo te n si on b e g a n 4 o r m o re hou rs a f te r drug ad mi n i s tr a ti on, wh i ch was alle v iate d by i n terr up ti ng t h e i n f u s ion or by f l u i d ad mi n i s tr a ti on and p r o l ong i ng t h e du rati on o f a d mi n istrati on. In itial cli n i ca l s t ud i es w it h ho m oh arri ng t on i n e i n C h i n a s ho we d acti v it y a g ai n st acu t e m ye l o i d l euke mia (AML) a nd c h r on ic ph ase c h r on ic m y el oid le uk emi a ( CM L) . V a ri ab l e ac ti v it y was ob ser v e d i n t h e i n itial series o f

L -A S P ARAGINASE

nan nan

L -A s p a r a g i nase ( L - aspa r ag i ne ami nohyd r o lase , EC 3.5.1.1 ) , w h ic h catal yzes t h e hydro l ys i s o f t he essen ti a l ami no aci d L -as p ara g i n e t o L -as p artic aci d a nd am mon i a, i s a na t u r a ll y oc c u rri ng e n z y me i n s o me micr oo r g a n isms ,

L -A S P ARAGINASE

nan nan

L -A S P ARAGINASE

nan nan

Cli n ical tri a l s have de m ons trate d t h e efficac y , safet y , a nd t o lera b ilit y o f P EG- L - a spa r ag i nase ad mi n i s tere d i n tram u sc u larl y , s ub c u ta n e ou sl y , o r i n t r a v e nous l y as pa rt o f m u ltia g e n t c h em o t h era py re g ime n s i n t h e ma n a g e men t o f new l y d i agno se d a nd rela p se d p e d iatric a nd a du lt ALL . L - A s p a r a ginase can an t agon i ze an ti n e op lastic effects o f met ho tre x ate if g i ven c on c urren tl y o r imm ed i a t e l y b ef o re . T h ese tw o d r ug s s hou l d b e a d mi n is te r ed sequen ti a ll y a t least 24 hou rs a p art . L -As p ara g i n ase h as also b ee n s hown t o i nh i b it t he m e t abo lic cleara n ce o f v i n cristi n e a nd ca n res ult i n i n c r e ased neu r o t ox i c it y . T ox icit y is less p r onoun ce d if L -as p ara g i n ase is a d mi n is te r ed a ft e r v i nc ri s ti ne. H yp erse n siti v it y reacti on s o cc u r i n up t o 25% of p a ti en t s as a sk i n r ash a nd u rticaria o r seri ou s a n a phy lactic r eacti ons. T he ri sk i nc r eases wit h re p eat e xpo s u re , a nd as a si ng le-a g e n t use

L -A S P ARAGINASE

nan nan

w it hou t s t e r o i ds. PE G - L - aspa ra g i n ase is less imm unog e n ic t h a n t h e n ati ve nonp e gy l a t ed f o rm s o f t he en z y me . A nu m b er o f o t h er si d e effects are ob se rv e d t ha t a r e seconda r y t o t h e i nh i b it o r y effects o f L -as p ara g i n ase on cell u la r p r o t e i n syn t hes i s. De crease d ser u m le v els o f i n s u li n, k e y li popro t e i ns, and a l bu mi n hav e b ee n re po rte d. L -As p ara g i n ase ca n ca u se alte r ati ons i n t hy r o i d f unc ti on tests as earl y as 2 d a y s after a n a d mi n istere d do se , poss i b l y seconda r y t o a re du cti on i n t h e ser u m le v els o f t hy r ox i n e- b i nd i ng g l obu li n. A lt e r a ti ons in c o a gu lati on p arameters wit h p r o l ong e d t hro m b i n tim e, p r o t h r o m b i n time , a nd p artial t h r o m bop lasti n time h a v e b ee n ob s e r ved. P a ti en t s tr ea t ed wit h L -as p ara g i n ase are at a n i n crease d ri sk for b lee d i ng o r t h r o m boe m bol ic e v e n ts . L -As p ara g i n ase is c on trai nd ica ted i n p atie n t s w it h a p ri o r h i s t o r y o f p a n creatitis , b eca u se t h ere is a 10 % i n ci d e n ce o f acu t e panc r ea titis . Ne u r o l og ic t ox icit y i n cl ud es let h a r g y , c onfu si on, ag it a ti on, ha ll uc i n ati on s , a nd / o r c o ma . I n c on trast t o t h e o t h er a n tica n c e r agen t s used t o tr eat ALL , m y el o s upp ressi on is rare .

B LEO MYCIN

nan nan

B LEO MYCIN

B LEO MYCIN

nan nan

Ble o m y ci n i s a g l ycopep ti de an ti b i o tic p r odu ce d by t h e b acteri u m S t r e p t omyces ver ti c ill u s . T he mo st acti v e c h em o t h era p e u tical f o rms are b le o m yc i n A 2 and B 2 T he e f fect o f b le o m y ci n is cell c y cle s p ecific , b eca u se it s m a i n e f f ec t s a r e me d iate d i n t h e G 2 a nd M ph ases o f t h e cell c y cle . T he exac t m echan i s m f o r DNA stra nd scissi on h as b ee n s ugg est ed t o b e due t o b l eo m yc i n ’ s che lati ng o f metal i on s ( p rimaril y ir on ) a nd produ ci ng a pseudoenzy m e that reacts wit h oxyg e n t o p r odu ce s up er ox i de -a nd hyd r ox i de -fr ee r ad i ca l s, t hu s clea v i ng DNA . Alter n ati v el y , b le o m y ci n ma y b i nd a t spec ifi c s it es i n the DNA stra nd a nd i ndu ce scissi on by a b st r acti ng t he hyd r ogen a t o m fr o m t h e b ase , res u lti ng i n stra nd clea v a g e as t h e b ase unde r goes a C ri egee -t yp e rearra ng eme n t , o r b le o m y ci n ma y f o r m a n al k al i -l ab il e l es i on . B l eo m y ci n is u se d i n t h e treatme n t o f H odgk i n l y m pho m a ( as a co m ponen t o f t h e ABVD a nd BEACOPP re g ime n ) , s qu am ous ce ll ca r c i no m as, and testic u lar ca n cer; i n t h e treatme n t o f p la nta r

B LEO MYCIN

nan nan

w a r ts , as a m eans o f e f f ec ti ng p le u r od esis , as well as a n i n tralesi on al a g e n t wi t h e l ec tr oche m o t he r apy i n t h e ma n a g eme n t o f c u ta n e ou s mali gn a nc i es Th e o r a l b i oava il ab ilit y i s poo r . It m u st b e a d mi n istere d v ia IV o r IM rou tes . The i n iti a l d i s tri bu ti on h alf-life is 10 t o 20 mi nu tes wit h a termi nal h al f- li f e o f 3 hou r s. B l eo m yc i n ca n b e a d mi n istere d v ia t h e i n traca v itar y rou te t o c on tr o l m a li gnan t p l eu ral e f f u si on s o r ascites , o r bo t h. Approx i ma t e l y 45 % t o 55 % o f a n a d mi n istere d i n traca v itar y do se o f b le o m yc i n i s abso r bed i n t o t h e s y stemic circ u lati on. Elimi n ati on is pr ima r il y v i a t he k i dneys, and a pp r ox imatel y 60 % t o 70 % o f a n a d mi n is te r ed dose i s exc r e t ed un c h a ng e d i n t h e u ri n e . D o se re du cti on s a re r e qu i r e d if c r ea ti n i ne c l ea r an ce is less t h a n 25 mL p er mi nu te . Ble omyc i n -i nduced pneumon itis , t h e do se-limiti ng t ox icit y o f t h e d r ug, o cc ur s i n 10 % o f pa ti en t s, and is d e p e nd e n t on t h e c u m u lati v e do se . T he r is k i n c reases i n pa ti en t s o l der t h a n 70 y ears a nd i n t ho se w ho recei v e a t o tal c u m u l a ti ve dose g r ea t e r t h a n 400 U . I n a dd iti on, p atie n ts wit h a n und e r l y i ng l ung d i sease, p ri o r irra d iati on t o t h e c h est o r me d iasti nu m , a nd e xpo s ure t o h i gh concen tr a ti on s o f i n s p ire d oxyg e n are at i n crease d ris k. In c r ease d use o f g r anu l ocy t e c o l ony -stim u lati ng fact o r (G-CSF) h as b ee n p a r allel ed by an i nc r eased i nc i d e n ce o f b le o m y ci n -i ndu ce d pu lm on ar y t ox icit y . T he exace r ba ti ng e f fects o f G-CSFs seem t o b e ass o ciate d wit h a ma rk e d i n filtr a ti on o f ac ti va t ed n e u tr oph ils al ong wit h t h e l ung i n j u r y ca u se d by t he d ir ec t e f f ec t s o f b le o m y ci n . I n a retr o s p ecti v e re v ie w , 18 % of a t o tal o f 141 pa ti en t s w it h H odgk i n l y m pho ma treate d wit h a b le o m yc i n - con t a i n i ng r eg im en d e v el op e d pu lm on ar y t ox icit y . G-CSF u s e w as on e o f t he key f ac t o r s ass ociate d wit h t h e d e v el op me n t o f t h is c o m p lic a ti on, and o mi ss i on o f b le o m y ci n h a d no im p act on cli n ical ou tc o m es Simil a rl y t he co m b i n ati on o f b re n t ux ima b v e do ti n a nd ABV D w as ass oc i a t ed w it h excess i v e pu lm on ar y t ox icit y , i nd icati ng t h at br e n t ux im ab vedo ti n and b l eo m y ci n s hou l d no t b e u se d t og et h e r . Patie n t s w it h b l eo m yc i n -in du ce d pu lm on ar y t ox icit y ma y p rese n t wit h c ough, dyspnea, d r y i nsp ir a t o r y crac k les , a nd i n filtrates on c h est r a d i ogr a ph. P u lm ona r y f unc ti on testi ng is t h e m o st se n siti v e a pp r o ac h t o

B LEO MYCIN

nan nan

m on it or pa ti en t s, and pu lm ona r y f un cti on tests s hou l d b e ob tai n e d at b aseli n e and be f o r e each cyc le o f t h era p y , wit h a s p ecific f o c u s on t h e ca rbon monox i de d i f f us i on c a p acit y a nd v ital ca p acit y . A d ecrease g reat e r t h a n 15 % i n e it he r d i f f us i on c a p acit y o f car bon m onox i d e o r v ital ca p aci ty s hou l d manda t e imm ed i a t e d isc on ti nu ati on o f b le o m y ci n. Earl y cli n ical t r ials a n d i so l a t ed case r epo rt s s ugg est t h at b le o m y ci n -i ndu ce d ac u te hyp e r se ns iti v it y r eac ti ons occu r i n 1 % o f p atie n ts wit h l y m pho ma a nd les s t h a n 0.5 % o f t hose w it h so li d t u m o rs . T h e reacti on s are mai n l y c h a r acteri zed by h i gh - g r ade f ev e r , c h ills , hypo te n si on, a nd, i n a few cas es, ca rd i ovascu l a r co ll apse, wh i ch ca n lea d t o d eat h. T h e e x act mec h a n ism o f t h ese r e ac ti ons i s unc l ea r , bu t is t hough t t o b e relate d t o t h e release o f e ndog e nous py r ogens fr o m t h e ho st cells . S uppo rti v e care , i n cl ud i ng hydr ati on, s t e r o i ds, an ti py r e tics , a nd a n ti h istami n es , ma y res o l v e t h e s y m p t o m s. Cli n i c i ans shou l d m on it o r t h eir p atie n ts f o r a ny si gn s a nd s y m p t o ms o f ac u te hy p e r py r ex i c r eac ti ons du ri ng b le o m y ci n a d mi n istrati on. Beca u se the on set of t he r eac ti ons can occu r wit h a ny do se o f b le o m y ci n a nd at a ny time , rou ti ne t es t dos i ng does no t seem t o p re d ict w h e n d r ug reacti on s m ay o cc u r . Mucocu t aneous t ox i c it y p rese n ts as m u c o sitis , er y t h ema , hyp e rp i g m en t a ti on, i ndu r a ti on, hyp er k erat o sis , a nd s k i n p eeli ng, w h ic h may progr ess t o u l ce r a ti on, and usu all y d e v el op s i n t h e 2nd a nd 3 r d wee k o f t r eatme n t and a ft e r a cu m u l a t iv e do se o f 150 t o 200 U o f t h e d r ug. Le v el s o f b le o m yc i n hyd r o l ase a r e r e l a t iv el y l o w i n l ung a nd s k i n tiss u e , p er h a p s o f f e r i ng an exp l ana ti on as t o why t h ese no rmal tiss u es are m o re a dv ersel y a f f ecte d by b l eo m yc i n. Mye l o s upp ressi on a nd imm uno s upp ressi on are r elati v el y mil d. I n r a r e cases, v asc u lar e v e n ts , i n cl ud i ng m yo car d ial i nf a r cti o n , s tr oke, and Raynaud ph e no me non, h a v e b ee n re po rte d.

PROCARB A ZINE

nan nan

Or i g i n all y p r epa r ed as a m on oami n e ox i d ase i nh i b it o r , p r o car b azi n e is a prodrug , wh i ch a ft e r ox i da ti o n o f t h e hyd razi n e i n t h e li v e r , und e r go es a

PROCARB A ZINE

nan nan

c o m p le x enzy m a ti c and che mical b rea kdo w n t o its al ky lati ng a nd met hy lati ng spec i es . T he precise mec h a n ism o f acti on is un certai n, but ma y i nvo l ve da m ag i ng t he D NA , RNA o r tra n sfer RNA , a nd t h e i nh i b iti on of pro te in syn t hes i s. Pr oca r baz i n e is a cell-c y cle ph ase- non s p ecific a n ti n e op l as ti c agen t . T h i s agen t was i n itiall y a pp r ov e d by t h e U . S . F ood a nd Drug Ad mi n i s tr a ti on (F D A) i n 1969 as p art o f t h e MOPP ( mec h l o r e t ha mi ne, v i nc ri s ti n e , p r o car b azi n e , a nd p re dn is on e) re g ime n f o r t h e t r eatm en t o f Hodgk i n l y m pho ma . Si n ce t h e n, it h as als o d em on strate d cli n ical a c ti v it y i n non - Hodgk i n l y m pho ma , c u ta n e ou s T -cell l y m pho ma , a nd br ai n t u m o r s. P ro c a r baz i ne i s r ap i d l y and c o m p letel y a b s o r b e d fr o m t h e g ast ro i n t es ti na l tr ac t . F o ll ow i ng o ral a d mi n istrati on, p ea k d r ug le v els ar e r eac h e d wit h i n 10 t o 15 mi nu tes . Pr o car b azi n e cr o sses t h e b l ood–b rai n b a rr ie r a nd r ap i d l y equ ili b r a t e s b etwee n p lasma a nd cere b r o s p i n al fl u i d a f te r or a l ad mi n i s tr a ti on. P ea k cere b r o s p i n al fl u i d d r ug c on ce n trati on s a re r eac h e d wit h i n 30 t o 90 mi nu tes after d r ug a d mi n istrati on. T h e b i o l og ic h al f- li f e o f p r oca r baz i ne hyd r o c h l o ri d e i n bo t h p lasma a nd cere b r o s p i n a l f l u i d is app r ox im a t e l y 1 hou r . Pr o car b azi n e is meta bo lize d t o acti v e a nd i n acti v e m e t abo lit es by che mical b rea kdo w n i n a n a qu e ou s s o l u ti on a nd the li v e r micr oso m a l P- 450 sys t em. A pp r ox imatel y 70 % o f p r o car b azi n e is e x c r ete d i n u ri ne w it h i n 24 h o u rs , a nd less t h a n 5 % t o 10 % o f t h e d r ug is elimi n at ed i n an unchanged f o rm . A ca re f u l f ood and d r ug h ist o r y is re qu ire d b ef o re starti ng a p atie n t on pro ca rbaz i ne t he r ap y , because t h ere are se v eral po te n tial d r ug–d r ug a nd drug–fo o d i n t e r ac ti ons. P a ti en ts s hou l d a vo i d t y rami n e-c on tai n i ng f ood s , s u c h as d a r k bee r , w i ne, chee se , yogu rt , b a n a n as , a nd sm ok e d f ood s . P ro ca rb a z i ne p r oduces a d i su lfiramli k e reacti on wit h c on c u rre n t u se o f alc oho l . Acu t e hype rt ens i ve r e acti on s ma y o cc u r wit h c o a d mi n istrati on o f t r ic y clic an ti dep r essan t s and sy m p at ho mimetic d r ug s . C on c u rre n t u se o f pro ca rbaz i ne w it h an ti h i s t a mi n es a nd o t h er ce n tral n er vou s s y stem (CN S ) d e pr ess an t s can r esu lt i n CN S a nd / o r res p irat o r y d e p ressi on. Do se-limiti ng t ox i c it y i s m y el o s upp ressi on, m o re c o mm on l y t hro m bocy t open i a, and t he nad ir i n p latelet c oun t is g e n erall y ob ser v e d at 4

PROCARB A ZINE

nan nan

w ee k s . P a ti en t s w it h g l ucose - 6 - pho s ph ate d e hyd r og e n ase d eficie n c y ca n d e v el op he m o l y ti c ane mi a wh ile recei v i ng p r o car b azi n e t h era p y . Ste p wi se do se i n cr e m en t s ove r t he fir s t few d a y s o f d r ug a d mi n istrati on ma y mi n imize gas tr o i n t es ti na l i n t o lera n ce . O n rare o ccasi on s , p r o car b azi n e may i ndu ce i n t e r s titi a l pneu m on itis , w h ic h ma nd ates t h e d isc on ti nu ati on o f t h e r a p y . Azoospe rmi a and i n f e rtilit y after treatme n t wit h MOPP ca n b e att r i bu te d, i n pa rt , t o p r oca r ba zi n e . Pr o car b azi n e is ass o ciate d wit h a n i n c r ease d ri sk o f seconda r y mali gn a n cies , es p eciall y ac u te le uk emia .

VISMOD EG IB

nan nan

VISMOD EG IB

VISMOD EG IB

nan nan

VISMOD EG IB

nan nan

V ism odeg i b i s app r oved f o r the treatme n t o f a du lts wit h metastatic b asal-

VISMOD EG IB

nan nan

cell ca r ci no m a t ha t has r ecu rre d f o ll o wi ng s u r g er y o r i n t ho se w ho are not ca nd i d ate s f o r su r ge r y and w h o are no t ca nd i d ates f o r ra d iati on . No dose -limiti ng t ox i c e f fects o r g ra d e 5 e v e n ts h a v e b ee n ob ser v e d. How e v e r , 54 % o f pa ti en t s r ec ei v i ng v ism od e g i b d isc on ti nu e d t h e me d icat ion ow i ng t o s i de e f f ec ts , a nd on l y on e ou t o f g i v e eli g i b le p atie nts w as a b l e t o con ti nue v i s m odeg i b f o r 18 m on t h s . A bdo mi n al p ai n, fati gu e , w ei gh t l oss, dysgeus i a, and ano re x ia were reas on s f o r d isc on ti nu ati on o f the drug. When v i s m odeg i b was wit hd raw n, dy s g e u sia a nd m u scle cram p s cease d wit h i n 1 m on t h, and sc al p a nd body h air starte d t o re g r o w wit h i n 3 m on t h s . O t he r s i de e f f ec t s r epo rte d i n cl ud e hypon atremia , dy s pn ea , m u s cle s p asm , a tri a l fi b rill a ti on, asp irati on, b ac k p ai n, c o r n eal a b rasi on, d e hydr a t i on, ke r a titi s, l y m phop e n ia , pn e u m on ia , u ri n ar y tract i n fecti on, and a pro l onged Q T i n t e r va l

ADO-TRAS T UZU M AB E M T ANSI N E

nan nan

ADO-TRAS T UZU M AB E M T ANSI N E

ADO-TRAS T UZU M AB E M T ANSI N E

nan nan

Ado- t r ast uzu m ab e mt ans i ne ( T -DM 1 ) , is a HER 2 -ta r g ete d a n ti body - d r u g c on j ug a te ( ADC ) . It i s a nove l c o m pound c o m po se d o f trast u z u ma b, a sta b le t hioe t he r li nke r , and D M 1. DM 1, a d eri v ati v e o f ma y ta n si n e , is a mic ro t ubu l e po l y m e ri za ti on i nh i b it o r wit h acti v it y similar t o t h at o f v i n c a al k al o i d s . T - DM1 i s t aken up i n t o cells after b i nd i ng t o HER 2, all o wi ng f o r c y t o t ox i c d r ug de li ve r y spec i f icall y t o cells ov ere xp ressi ng HER 2. It h a s a drug- t o-an ti body r a ti o o f app r ox imatel y 3.5 : 1. T -DM 1 is a d mi n istere d i n t r a v e nous l y eve r y 3 weeks a nd h as b ee n teste d i n a ph ase I trial at do se s r a ng i ng fr o m 0.3 t o 4.8 m g / kg. T h e ma x imall y t o lerate d do se is 3.6 m g / kg, wh ic h was t he dose used i n f u rt h er ph ase II – III trials . T -DM 1 is meta bo li zed by t he li ve r , v i a CYP 3 A 4 / 5, a nd h as a h alf-life o f 3.5 d a y s . T -DM1 i s app r oved f o r us e i n p atie n ts wit h metastatic HER 2 - po siti ve br east c ance r who have r ece ive d p ri o r trast u z u ma b a nd a ta x a n e . T h is a pprov a l was based on t he r e s u lts o f t h e EMILIA trial , w h ic h ra ndo mize d 991 p ati en t s w it h H E R2 - pos iti v e un resecta b le , l o call y a dv a n ce d o r metastati c b r eas t cance r t o T -DM 1 3.6 m g / kg IV e v er y 21 d a y s o r la p ati nib

ADO-TRAS T UZU M AB E M T ANSI N E

nan nan

1,250 m g da il y p l us capec it ab i n e 1,000 m g / m 2 on d a y s 1 t h r ough 14 e v e ry 21 d a y s . A ll pa ti en t s we r e p r ev i ou sl y treate d wit h trast u z u ma b a nd a ta x a ne. T -D M 1 resu lt ed i n a p r og r ession -free s u r v i v al o f 9.6 m on t h s c o m p are d t o 6.4 m on t hs f o r l apa ti n i b p l us ca p ecita b i n e ( h azar d rati o [HR] 0.65 ; 95 % c onf i d e nce i n t e r va l [ C I] 0.55 to 0.77 ; p <0.001 ) . T h e res pon se rate a nd ov e r all su r v i va l was a l so h i ghe r wit h T -DM 1 c o m p are d t o la p ati n i b p l u s ca p ecita b i ne . A lt hough m ay t ans i ne it se lf is ass o ciate d wit h si gn ifica n t t ox icit y , T - D M 1 is ve r y we ll t o l e r a t ed ov erall , w h ic h is li k el y du e t o t h e ta r g ete d n at ur e o f t he co m pound. Si de e f fects fr o m T -DM 1 i n cl ud e t hro m bocy t open i a, hepa t o t ox icit y , hyp erse n siti v it y /i n f u si on reacti on s , a nd ca rd i o t ox i c it y . Nausea, f a ti gu e , h ea d ac h es , a nd a n emia are als o c o mm on. Th e le f t v en tri cu l a r e j ec ti on f r acti on s hou l d b e m on it o re d p ri o r t o a nd at least e ve r y 3 m on t hs du ri ng t h era py b eca u se o f t h e po te n tial f o r car d iac dy s fun c t i on.

SIROLIMUS AND TEM SIROL I MUS

nan nan

SIROLIMUS AND TEM SIROL I MUS

SIROLIMUS AND TEM SIROL I MUS

nan nan

On ce -w e ek l y I V t e m s ir o lim us, 25 m g, p r o l ong e d t h e me d ia n ov erall s urv i v al o f pa ti en t s w it h poo r p r ogno stic feat u res by 49 % fr o m 7.3 m on th s (95% CI , 6.1 t o 8.8 m on t hs ) i n t h e i n terfer on arm t o 10.9 m on t h s ( 95 % C I ,

EVER OL IMUS

nan nan

EVER OL IMUS

EVER OL IMUS

nan nan

Ev e ro lim us ( RAD001 ) i s an o rall y acti v e hyd r oxy et hy l et h er a n al og o f r a p am yc i n t ha t con t a i ns a 2 - hyd r oxy et hy l c h ai n s ub stit u ti on. T h is m o lec ule is si gn i fican tl y m o r e wa t e r solub le t h a n sir o lim u s . As wit h sir o lim u s a nd temsi ro lim us, eve r o lim us t a r g ets m T OR by f o rmi ng a c o m p le x wit h m T O R a nd F KB P , r esu lti ng i n i nh i b iti on o f m T OR acti v it y . Few d ata are a v aila ble r e g a rd i ng t he ac t ua l d i f f e r ence s i n t h e a b ilit y o f temsir o lim u s a nd

EVER OL IMUS

nan nan

e v e ro lim us t o i nh i b it m T OR. O n e p recli n ical i n v itr o st udy s ho we d t h at the b i nd i ng o f eve r o lim us t o F KB P was a pp r ox imatel y t h reef o l d wea k er t h a n t h at of sir o lim us . I n v i vo s t ud ies , ho we v e r , h a v e do c u me n te d similar e f f icac y o f t he t wo agen t s i n terms o f imm uno s upp ressi v e acti v it y as we ll as a n tit u m o r ac ti v it y . I n p r ec li n ical m od els , t h e a d mi n istrati on o f e v er o lim us r es u lts i n t he i nh i b iti on o f m T OR , similar t o w h at h as b ee n ob ser v e d wit h t h e o t h er r apa m yc i n ana l ogs . I n terms o f cli n ical ph armac o l og y , p ea k d r ug le v els a re ach i eved w it h i n 1 t o 2 hou rs after o ral a d mi n istrati on, a nd f ood w it h a h i gh f a t con t en t r educe s o ral b i o a v aila b ilit y by up t o 20 % . T h is c o m pound i s m e t abo li zed i n t h e li v e r , mai n l y by t h e CYP 3 A 4 s y stem , a nd si x mai n m e t abo lit es have be e n i d e n tifie d. I n g e n eral , t h ese meta bo lites a r e less acti ve t han t he pa r en t co m pound. Elimi n ati on is mai n l y h e p atic wit h e x c r eti on i n f eces, and cau ti on s hou l d b e u se d i n p atie n ts wit h m od erate li v e r im pa irm en t ( Ch il d -P ugh class B) . I n t h is setti ng, t h e d ail y do se o f drug s hou l d be r educed t o 5 m g. I n p atie n ts wit h se v ere li v er dy sf un cti on ( C h il d-Pugh c l ass C ) , t he use o f t h is d r ug is c on trai nd icate d. En c ou r ag i ng c li n i ca l ac ti v it y was i n itiall y ob ser v e d i n ph ase 1 / 2 trial s in p atie n ts wit h non–s m a ll- ce ll l ung, g astric , a nd es oph a g eal ca n cers , sa r c o ma s, panc r ea ti c neu r oendo cri n e t u m o rs , as well as h emat o l og ic mali gn a nc i es Pr esen tl y , ev er o lim u s is i nd icate d a nd a pp r ov e d f o r t he t r eatme n t o f adu lt s w it h advan ce d RCC after fail u re wit h s un iti n i b o r s or a f e n i b ; advanced ho rm one rece p t o r - po siti v e , HER 2 - n e g ati v e b reast ca n ce r i n co m b i na ti on w it h ex emesta n e; a nd p r og ressi v e un resecta b le , l o call y advanced, o r m e t as t a tic n e u r o e ndo cri n e t u m o rs o f p a n creatic o ri gin (PNET) . T he r eco mm ended do se o f e v er o lim u s f o r t h ese i nd icati on s is 10 m g t aken o r a ll y once da il y . Th e sa f e t y p r o fil e o f eve r o lim u s is similar t o w h at h as b ee n ob ser v e d w it h tem s ir o lim us. T he m os t c o mm on a dv erse e v e n ts i n cl ud e ast h e n ia a nd f ati gu e , d r y sk i n w it h acne if o rm s k i n ras h, n a u sea/ vo miti ng, m u c o sitis , and a nor e x i a. Hype rli p i de mi a w it h i n crease d ser u m tri g l y ceri d es a nd / o r c ho lester o l as we ll as hype r g l y cemia o cc u r i n up t o 90 % o f p atie n ts . A lle r g ic , hype r sens iti v it y r ea cti on s h a v e b ee n ob ser v e d i n a bou t 10 % o f p atie n ts , and pu lm ona r y t ox i c it y , p rese n ti ng as i n crease d c ough, dy s pn ea ,

EVER OL IMUS

nan nan

f e v e r , a nd pu lm ona r y i n filtr a t e s , are a relati v el y rare e v e n t , o cc u rri ng i n less t h a n 1% o f pa ti en t s. Howeve r , t h e ris k o f pu lm on ar y t ox icit y i n creases i n p atie n ts wit h an unde rl y i ng pu lm on ar y d isease .

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

nan nan

Th ali do mi de and it s a mi no - sub stit u te d a n al og s , le n ali do mi d e a nd po mali do mi de, a r e s m a ll-m o l e c u le g l u tamic aci d d eri v ati v es t h at po sses s a w i d e r a nge o f b i o l og i c p r ope rties , i n cl ud i ng imm uno m odu lati ng, a n tia ng i ogen i c, and ep i gene tic e f fects . T h e y are classifie d as class I ( non– pho s pho p hod i es t e r ase - 4 i nh i b it o r y ) imm uno m odu lat o r y d r ug s (IMiDs) . A lt hough t he ir p rim a r y m echan ism o f acti v it y a g ai n st mali gn a n c y is un ce r tain , it i s be li eved t ha t IMiDs e x ert t h eir a n tica n cer e f fects bo t h d i r ectl y on cance r ce ll s and i nd irectl y v ia effects on t h e t u m o r mic ro e nv ir on m en t and hos t an tit u m o r imm un it y . S p ecific mec h a n isms i n cl ud e t he i nh i b iti on o f nuc l e ar fact o r k a pp a B (NF- κ B) tra n scri p ti on al acti v it y i n m a li gnan t ce ll s w it h a res u lta n t d ecrease i n t h e p r odu cti on o f a n tia pop t o ti c m o l ecu l es ; t he i nh i b iti on o f s u rface a dh esi on m o lec u le e xpr essi on on bo t h m u lti p l e my el o ma cells a nd bon e marr o w str o mal ce lls; t h e i nh i b iti on o f t he p r oduc ti on a nd release o f v ari ou s g r o wt h fact o rs ( i n cl ud i ng vascu l a r endo t he li a l g r o wt h fact o r , b asic fi b r ob last g r o wt h fac to r , t u m or nec r os i s f ac t o r a l pha, and i n terle uk i n [IL] 6 ) t h at re gu late a ng i og e nes i s and t u m o r ce ll pro liferati on ; a nd c o stim u lati on o f IL- 2 a nd i n te rf e r o n ga mm a (IF N - γ ) r e l e ase wit h T - h el p er 1 s ub set s k ewi ng a nd a ug me nta ti on o f cy t o t ox i c T -cell a nd n at u ral k iller cell e f fect o r f un cti on

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

nan nan

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

nan nan

Un li k e t ha li do mi de, bo t h l enal i do mi d e a nd po mali do mi d e res u lt i n cell c y cle a r r es t and apop t os i s o f my el o ma cells i n v itr o, b elie v e d i n p art t o b e r elate d t o ep i gene ti c e f f ec t s. T h e y are als o m o re po te n t stim u lat o rs o f I L - 2 a nd IN F- γ p r oduc ti on and T - ce ll p r o liferati on t h a n t h ali do mi d e , a nd a pp e a r t o a dd iti ona ll y i nh i b it T -r egu lat o r y cells . Cli n icall y , le n ali do mi d e h as acti v it y i n pa ti en t s w it h t ha li do mi d e-resista n t m u lti p le m y el o ma , a nd

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

nan nan

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

nan nan

Du e t o t he po t en ti a l ri sk o f s i gn ifica n t terat og e n icit y , t h ali do mi d e , le n ali dom i de, and po m a li dom i d e ca n on l y b e p rescri b e d by lice n se d pr esc r i be r s who a r e r eg i s t e r e d i n restricte d d istri bu ti on p r og rams .

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

Thalidomide

nan nan

Th ali do mi de fr equen tl y cau ses d r o wsi n ess , c on sti p ati on, a nd fati gu e . Pe r i ph e ra l neu r opa t hy i s a co mm on a nd po te n tiall y se v ere a nd irre v ersi ble si d e e f f e c t occu rri ng i n up t o 30 % o f p atie n ts . I n crease d i n ci d e n ces o f v e nou s t h r o m boe m bo li c even ts , s u c h as d ee p v e nou s t h r o m bo sis a nd pu lm ona r y e m bo l us, have a l s o b ee n ob ser v e d wit h t h ali do mi d e , p artic u l a r ly wh e n u s ed i n co m b i na ti on w it h d e x amet h as on e o r a n t h rac y cli n e- b ase d c h em o t he r ap y . P a ti en t s who ar e a pp r op riate ca nd i d ates ma y b e n efit fr om c on c urren t p r ophy l ac ti c an ti co a gu lati on o r as p iri n treatme n t . Ot h er si d e e f f ects o f t ha li do mi de i nc l ud e ras h, n a u sea , d izzi n ess , o rt ho static hypo te ns i on, b r adyca r d i a, and m ood c h a ng es . I n 2013, a dd iti on al alerts w e r e r ele ased li nk i ng t ha li do mi d e t o a n i n crease d ris k o f d e v el op i ng sec ond pr ima ry m a li gnanc i es ( bo t h a c u te m y el og e nou s le uk emia a nd m y el odysp l as ti c synd r o m e ) and arterial t h r o m bo em bo lic e v e n ts .

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

Pomalidomide

nan nan

P o mali do mi de ( 4 - a mi no - 2 -[ 2,6 - d i oxop i p eri d i n - 3 - y l]- 2,3 - d i hyd r o - 1 H-is o i ndo l e - 1,3 - d i one ; P o m a l yst ) is a no t h er t h ali do mi d e d eri v ati v e d esi gned t o b e m o r e po rt en t and l ess t ox ic t h a n bo t h t h ali do mi d e a nd le n ali do mi de. I t is c urr e n tl y F DA app r oved ( 4 -m g on ce d ail y do se o rall y on d a y s 1 t h r ough 21 of a 28 - day cyc l e, w it h o r wit hou t d e x amet h as on e) f o r u se i n p atie n ts w it h prog r ess i ve m u lti p l e m ye l o ma w ho h a v e recei v e d at least tw o p ri o r t h e r a p ies , i nc l ud i ng l ena li dom i d e a nd bo rtez o mi d. P o mali do mi d e is a d mi n is te r ed o r a ll y and i s r apid l y a b s o r b e d. Ma x im u m p lasma c on ce n t ra ti on i s r eached 2 t o 3 hou rs after i ng esti on, wit h a pp r ox imatel y 12% t o 44 % p r o t e i n b i nd i ng T h e h alf-life o f elimi n ati on is b etwee n 7.5 a nd 9.5 hou r s. P o m a li do mi de is meta bo lize d i n t h e li v e r ,v ia C YP1A 2/ CY P 3A4 (m a j o r) and CYP 2 C 19 /CYP 2 D 6 (mi no r) , a nd e x cret ion o cc ur s pr im a ril y t h r ough t he k i dn e y s ( 73 %; 2 % as un c h a ng e d d r ug ) . L i k e l ena li do mi de, po m a lid o mi d e is b etter t o lerate d t h a n t h ali do mi d e at a pprov e d doses w it h l ess con sti p ati on, fati gu e , a nd n e u r op at h y . T h e

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

Pomalidomide

nan nan

Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce m T ORC2 signaling and inhibit AKT activation in AML. Blood 2007;109:3509–3512. Kapoor A, Figlin RA. T a r geted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma. Cancer 2009; 1 15:3618–3630. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian ta r get of rapamycin kinase inhibito r , in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909–918. Hudes G, Carducci M, T omczak P , et al. T emsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–2281. Smith SM, van Besien K, Karrison T , et al. T emsirolimus has activity in non-mantle cell non-Hodgkin ’ s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 2010;28:4740–4746. Duran I, Siu LL, Oza AM, et al. Characterization of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 2006;42:1875–1880. Schuler W , Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycine derivative: pharmacological properties in vitro and in vivo. T ransplantation 1997;64:36–42. Dudkin L, Dilling MB, Cheshire PJ, et al. Biochemical correlates of m T OR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001;7:1758–1764. Kirchner GI, Meie r - W iedenbach I, Manns M P . Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004;43:83–95. Doi T , Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cance r . J Clin Oncol 2010;28:1904–1910. Y ao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69–76. Y ee K W , Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian ta r get of rapamycin inhibitor everolimus(RAD001) in patients with relapsed or refractory hematological malignancies. Clin Cancer Res 2008;12:5165–5173. Okuno S. Mammalian ta r get of rapamycin inhibitors in sarcomas. Curr Opin Oncol 2006;18:360– 362. Y ao JC, Shah MH, Ito T , et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 20 1 1;364:514–523. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-recepto r -positive advanced breast cance r . N Engl J Med 2012;366:520–529. Shortt J, Hsu AK, Johnstone R W . Thalidomide-analogue biology: immunological, molecular and epigenetic ta r gets in cancer therap y . Oncogene 2013;32:4191–4202. Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk L ymphoma 2013;54:683– 687. Escoubet-Lozach L, Lin IL, Jensen-Pergakes K, et al. Pomalidomide and lenalidomide induce p21 W AF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res 2009;69:7347–7356. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood 20 1 1; 1 18:1763–1765.

T H ALIDOMIDE, LENALIDOMIDE, AND P OM ALIDOMIDE

Pomalidomide

nan nan

Lacy MQ, T e f feri A. Pomalidomide therapy for multiple myeloma and myelofibrosis: an update. Leuk L ymphoma 20 1 1;52:560–566. Ito T , Ando H, Suzuki T , et al. Identification of a primary target of thalidomide teratogenicit y . Science 2010;327:1345–1350. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 20 1 1; 1 18:4771–4779. Lopez-Girona A, Mendy D, Ito T , et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012;26:2326–2335. Schuster SR, Kortuem KM, Zhu YX, et al. Cereblon expression predicts response, progression free and overall survival after pomalidomide and dexamethasone therapy in multiple myeloma. ASH Ann Meeting Abstracts 2012;120:194. Bennett CL, Angelotta C, Y arnold PR, et al. Thalidomide- and lenalidomide-associated thromboembolism among patients with cance r . JAMA #2006;296:2558–2560. Rao K V . Lenalidomide in the treatment of multiple myeloma. Am J Health Syst Pharm 2007;64:1799–1807. Lenalidomide. Drugs@FDA. Food and Drug Administration W eb site. Published December 2008. Pomalidomide. Drugs@FDA. Food and Drug Administration W eb site. Revised February 2013. Lacy MQ, McCurdy AR. Pomalidomide. Blood 2013;122:2305–2309.

IN T RODUCTION

nan nan

Hor m ona l agen t s a r e co mm on l y u se d as a treatme n t o f ho rm on all y r es pon siv e cance r s, such as br east , p r o state , o r e ndo metrial carci no mas . O t h e r uses f o r so m e ho rm onal t h era p ies i n cl ud e t h e treatme n t o f p a r a n e op l as ti c synd r o m es, su c h as carci no i d s ynd r o me , a nd s y m p t o ms ca u se d by cance r , i nc l ud i ng ano re x ia . T h is c h a p ter d isc u sses t h e maj o r hor m ona l agen t s f o r such t he ra p y , first wit h a n ov er v iew o f t h eir u se i n pr actice , t hen w it h m o r e de t a i l e d ph armac o l og ic i n f o rmati on re g ar d i ng t h em ) .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

T am ox i f e n con ti nues t o be an im po rta n t ho rm on al t h era py f o r t h e pr e v e n ti on and tr ea tm en t o f br east ca n cer w o rl d wi d e . T h e c on ti nu e d im por ta nce o f t a m ox if en i s r e flecte d i n t h e fact t h at it is t h e on l y ho rm o n al a g e n t a p pr oved by t he U. S . Fo od a nd Dr ug A d mi n istrati on (FDA) f o r t he pr e v e n ti on o f p r e m enopausa l b reast ca n ce r t h e treatme n t o f du ctal ca r ci noma i n s it u ( DC IS) and t h e treatme n t o f s u r g icall y resecte d pr eme nopausa l es tr ogen r ecep t o r (ER) –po siti v e b reast ca n ce r Th e s t anda r d da il y dose o f tam ox ife n is 20 m g, a nd t h e op timal du rat ion d e p e nd s on t he unde rl y i ng c li n ical setti ng. Alt hough t h e rec o mme nd e d dur ati on i n t he p r even ti on and DCIS setti ng s is 5 y ears , rece n tl y pub lis h e d

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

pro s p ecti ve s t ud i es have de mo n strate d t h at f o r t h e a d j uv a n t treatme n t o f i nv asi v e b r eas t cance r , a du r a ti on o f 10 y ears (c o m p are d t o 5 y ears) f u rth e r r e du ce d t he ri sk o f b r eas t can cer m o rtalit y a nd im p r ov e d ov erall s u r v i v al . Th e m os t co mm on t ox i c it y fr o m tam ox ife n is ho t flas h es , affecti ng a pprox im a t e l y 50 % o f tr ea t ed w o me n. T h ese ho t flas h es are o f v ar y i ng i n te n sit y and du r a ti on. T a m ox ife n -i ndu ce d ho t flas h es a pp ear t o i n crease ov e r t h e fir s t 3 m on t hs o f t he ra py a nd t h e n p latea u. T h e y a pp ear t o b e m o r e pro mi n e n t i n wo m en w it h a h ist o r y o f ho t flas h es o r estr og e n re p lacemen t u se . T am ox if en -i nduced ho t flas h es ca n b e ameli o rate d by a nu m b er o f d i f f e r e n t pha rm aco t he r ap i es, i n cl ud i ng l o w do ses o f me g estr o l a n ti d e pressan t s such as ven l a fa x i n e d es v e n lafa x i n e cital op ram ,

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

escital op r a m , and pa r oxe ti n e a nd t h e a n tic onvu lsa n t d r ug s g a b a p e n ti

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

a nd pr e gaba li n . T he r e i s ev ide n ce t h at d r ug s t h at i nh i b it CYP 2 D 6 (e .g., p a rox eti ne ) a lt e r t he m e t abo lic acti v ati on o f tam ox ife n t o e ndox ife n, a c r itical m e t abo lit e assoc i a t ed wit h i n v i vo tam ox ife n e f ficac y Th e es tr ogen i c p r ope rti es o f tam ox ife n are res pon si b le f o r bo t h b e n e f icial and de l e t e ri ous s i de e f fects . T am ox ife n i n creases t h e i n ci d e n ce o f e ndo me t ri a l cance r i n pos tm enop a u sal ( bu t no t p reme nop a u sal) w o me n, w it h t h e i nc r ease i n t he annual i n ci d e n ce o f e ndo metrial ca n cer b ei ng a pprox im a t e l y 2.58 (r a ti o o f i n ci d e n ce rates) . T h e a b s o l u te ris k d e p e nd s on t h e du r a ti on o f t a m ox if en a d mi n istrati on. F o r w o me n w ho recei v e 10 y ea r s of ad j uvan t t a m ox if en, th e c u m u lati v e ris k is 3.1 % (m o rtalit y , 0.4 %) v e r s u s 1.6 % (m o rt a lit y , 0.2 %) f o r 5 y ears o f tam ox ife n . T h e i n ci d e n ce o f a r a r e r for m o f u t e ri ne cance r , u teri n e sarc o ma , is als o i n crease d after tam ox i fen use T h i s f o rm o f e ndo metrial ca n cer c o m p rises a pp r ox imat ely 15% of all u t e ri ne m a li gnanc i e s t h at d e v el op after tam ox ife n u se .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T amoxifen

nan nan

Be n e f ici a l es tr ogen i c e f f ec t s fr o m tam ox ife n i n cl ud e a d ecrease i n t o tal c ho lester o and t he p r ese r vat i on o f bon e d e n sit y i n po stme nop a u sal wo me n. I n p r e m enopausa l w o me n, ho we v e r , tam ox ife n h as a n e g ati v e e f f ect on bone dens it y A lt hough m o st p atie n ts do no t c o m p lai n o f v a g i nal s y m p t o m s, a f ew co m p l a i n o f v a g i n al d r yn ess , w h ereas o t h ers h a v e i n c r ease d vag i na l sec r e ti ons and d isc h ar g e , t h e latter o f w h ic h is a n i nd icati on o f t he es tr ogen i c ac ti v it y o f tam ox ife n on t h e v a g i n a . I n t h e

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

T am ox i f e n ac t s by b l ock i ng e str og e n stim u lati on o f b reast ca n cer cells , i nh i b iti n g bo t h tr ans l oca ti on and nu clear b i nd i ng o f t h e ER . T h is alters t r a n sc r i p ti ona l and pos ttr anscr i p ti on al e v e n ts me d iate d by t h is rece p t o r .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

T am ox i f e n has agon i s ti c, pa rtial a gon istic , o r a n ta gon istic e f fects d e p e nding on t h e s pec i es, ti ssue, o r endpo i n ts t h at h a v e b ee n assesse d. A dd iti on all y , t h e r e a re m a r ked d i f f e r ences b etwee n t h e a n ti p r o liferati v e p r op erties o f tam ox i fen and it s m e t abo lit es . Resi s t ance t o t a m ox if en can b e i n tri n sic o r ac qu ire d, a nd t h e po te n tia l mec h a n ism s f o r t h i s r es i s t anc e are re v iewe d i n t h e f o ll o wi ng p ara g ra ph s . At eac h ste p o f t he s i gna l tr ansdu cti on p at h wa y wit h w h ic h tam ox ife n o r its meta bo lit es i n t e rf e r es, t he r e i s t h e po te n tial f o r a n alterati on i n res pon se . Th e m o st im po rt an t f ac t o r app ears t o b e t h e le v el o f ER , w h ic h is h i gh l y pr e d icti ve f o r a r esponse t o t a m ox ife n. T am ox ife n is i n e f fecti v e i n ER- n e g ati v e b r eas t cance r . A lt hough d ecrease d o r a b se n t e xp ressi on o f t h e prog ester one r ecep t o r (P R ) i s ass o ciate d wit h a w o rse p r ogno sis , t h e r elati v e ri sk r educ ti on i n t a mo x ife n -treate d p atie n ts is t h e same re g ar d le ss of t h e pr e sence o r absence o f t h e PR .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

F o ll ow i ng b i nd i ng t o t he E R , s ub se qu e n t tra n sl o cati on o f t h e tam ox i fen /E R co m p l ex t o t he nu cle u s a nd b i nd i ng t o a n estr og e n -res ponse eleme n t m ay occu r . T h i s b i nd i ng p re v e n ts tra n scri p ti on al acti v ati on o f est rog e n -r espons i ve genes. La bo rat o r y a nd cli n ical d ata h a v e d em on stra ted t h at E R -pos iti ve b r eas t cance rs t h at ov ere xp ress HER 2 ma y b e less r es pon siv e t o t a m ox if en and t o ho rm on al t h era py i n g e n eral . I n t h ese t u m or s , li gand -i ndependen t ac ti v ati on o f t h e ER by mit og e n -acti v ate d pro tei n k i nase ( MA P K ) pa t hw a y s ma y c on tri bu te t o resista n ce . I n a dd iti on, t he exp r ess i on o f A I B1, a n estr og e n -rece p t o r c o acti v at o r , h as b een ass o ciate d w it h t a m ox if en r es ista n ce i n p atie n ts w ho se b reast ca n cers ov e r e xp r ess H E R2 I n so m e cases , resista n ce ma y res u lt fr o m a d ecrea se or l o ss o f E R exp r ess i on Alt hough m u tati on s i n t h e ER li g a nd b i nd i ng do mai n (L BD ) a r e r a r e i n ne wl y d ia gno se d b reast ca n ce r , ER m u tati on s ar e pr ese n t i n up t o 20 % o f r ecu rre n t b reast ca n cers . T h ese m u tati on s le ad t o a c onfo rm a ti ona l change i n t h e LBD , w h ic h mimics t h e c on f o rmati on o f acti v ate d li gand - bound r ecep t o r a nd c on stit u ti v e , li g a nd -i nd e p e nd e n t t r a n sc r i p ti ona l ac ti v it y , r esu lt ing i n resista n ce t o ho rm on al t h era p y . P r ecli n ic a l s t ud i es sugges t t ha t s o me o f t h ese m u tati on s , alt hough i n se n siti ve t o a r o m a t ase i nh i b it o rs , retai n se n siti v it y t o h i gh er do se selec tive est rog e n -r ecep t o r m odu l a t o r s (SERM) , s u c h as e ndox ife n, as well as fu l v est ran t Th e ca r c i nogen i c po t en ti a l o f tam ox ife n h as b ee n rec ogn ize d i n rat st ud ie and i n hu m ans ( endo metrial ca n cer) . It h as b ee n p r opo se d t hat t h e g e n e ra ti on o f r eac ti ve i n t er me d iates t h at b i nd c ov ale n tl y t o mac ro m o l ecu l es unde rli es t he p r o cess . S u c h reacti v e i n terme d iates h a v e b ee n d em ons tr a t ed i n v itr o – I n a dd iti on, t h e i ndu cti on o f c ov ale n t D NA a ddu cts i n r a t li ve r s tr ea t ed w it h tam ox ife n h as b ee n re po rte d . B o t h c on stit ut i ve and i nduc i b l e cy t o c h r o me P- 450 (CYP) e n z y mes h a v e b ee n im p licat ed i n t he f o rm a ti on of meta bo lites wit h tam ox ife n , , a nd t h e f la von e -con t a i n i ng m onooxyg e n ase h as b ee n im p licate d i n t h e f o rmati on o f t h e N -o xi de o f t a m ox if en. Re acti v e i n terme d iates fr o m s u c h meta bo lic s teps a r e b ei n g eva l ua t ed f o r t he ir carci nog e n ic po te n tial i n v itr o a nd i n v i vo.

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

M u lti p l e s t ud i es t o eva l ua te t u m o r g e n e e xp ressi on p r o fili ng h a v e i d e n ti f ie d gene exp r ess i on pa tter n s o r s p ecific g e n es ass o ciate d wit h r esista nce t o t a m ox if en t he r ap y . A c o mm on l y u tilize d g e n e e xp ressi on assa y , Onco t ype DX 21 gene assa y (Ge no mic Healt h, Re d w ood Cit y , Cali forn i a ) , m easu r es t he exp ressi on o f g e n es kno w n t o b e i nvo l v e d i n est rog e n s i gna li ng ( e.g., E R, PR) , HER 2, p r o liferati on (e .g., Ki- 67 ) , a nd o t h e r s . In m u lti p l e d i f f e r en t d ata sets , t h e rec u rre n ce sc o re h as b ee n ass o ciate d w it h a h i ghe r ri sk o f b reast ca n cer rec u rre n ce i n p atie n ts treat ed w it h hor m ona l t he r apy ( e.g., tam ox ife n o r ar o matase i nh i b it o rs) wit hou t c on c o m i t an t che m o t he r ap y – Th e pha rm acok i ne ti cs o f t a m ox ife n is c o m p le x. T h e c h emical str u ct ure a nd met abo li c pa t hway o f t amox ife n are s ho w n i n . Meta bo li c acti v atio n o f t a m ox if en i s asso ciate d wit h g reater ph armac o l og ic acti v it y . Th e t wo m os t ac ti ve t a m ox if en meta bo lites are 4 - hyd r oxy tam ox ife n ( 4 - OH tam ox i fen ) and 4 - OH - N - desm et hy ltam ox ife n (e ndox ife n ) . A series o f st ud ies ca rri ed ou t t o cha r ac t e rize e ndox ife n ph armac o l ogy h a v e d em on st ra t ed t ha t it has equ i v ale n t po te n c y i n v itr o t o 4 - hyd r oxy tam ox if en i n E R -α and - be t a (E R -β) b i nd i ng , f o r t h e s upp ressi on o f ER- d e p e nd e nt hu ma n b r eas t cance r ce ll li ne p r o liferati on , a nd i n g l ob al ER-res pon si ve g e n e e xp r ess i on . A r ecen t s t udy s ugg ests t h at e ndox ife n ’ s e f fect on t h e E R ma y d i f f er fr o m 4 - hyd r oxy t a m ox ife n b ase d on t h e ob ser v ati on o f ER- α d e gr a d a t i on .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

In wo m en who r ece i ve t amox ife n at a do se o f 20 m g p er d a y , p lasma e ndox i fen s t eady - s t a t e concen trati on s are g e n erall y 6 t o 10 times h i gh er t h a n 4-hyd r oxy t a m ox if en Alt hough t h e meta bo lism o f tam ox ife n t o 4 - OH- tam ox if en i s ca t a l yzed by m u lti p le e n z y mes , e ndox ife n is f o rme d pr e do mi nan tl y by t he CY P 2D6 -me d iate d ox i d ati on o f N -

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

D 6 g e n etic v a ri a ti on (l ead i ng t o l o w o r a b se n t CYP 2 D 6 acti v it y ) o r t h e d r ug -i ndu ce d i nh i b iti on o f CY P 2D6 si gn ifica n tl y l o wers e ndox ife n c on ce n t ra ti ons T he C YP 2D6 g e n e is h i gh l y po l y m o r ph ic , wit h m o re t h a n 70 m a j o r a ll e l es w it h f ou r well- d efi n e d ph e no t yp es: poo r meta bo liz e r s

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

(P M ), i n t e rm ed i a t e m e t abo li z ers (IM) , e x te n si v e meta bo lizers (EM) , a nd u lt r a r a p id m e t abo li ze r s ( UM ). Th e c li n i ca l s t ud i es t o eva l u ate t h e ass o ciati on b etwee n CYP 2 D 6 po l y m orph i s m s and t a m ox if en ou tc o mes h a v e y iel d e d c on flicti ng res u lts . In itia and f o ll ow - up da t d em on strate d t h at CYP 2 D 6 PM h a d a n a pprox im a t e l y t wo - t o t h r ee f o l d h i gh er ris k o f b reast ca n cer rec u rre n ce ( c o m p a red t o CY P 2D6 E M ) and t h ese d ata le d a n FDA s p ecial em ph asi s p a n el t o r eco mm end a t a m ox ife n la b el c h a ng e t o i n c o r po rate d ata t h at t he C YP2D6 geno t ype was an im po rta n t b i o mar k er ass o ciate d wit h tam ox ife n e f f icac y Howeve r , t h i s l abe l c h a ng e h as b ee n d ela y e d, i n p art b eca u se o f c onf licti ng da t a fr o m secondary a n al y ses o f 5 - y ear tam ox ife n p r o s p ecti ve t r ials ( A T AC, B I G 1 - 98, and ABCSG 8 as well as meta-a n al y ses

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

wh ic h d em ons tr a t e t ha t t he CY P 2 D 6 g e no t yp e is ass o ciate d wit h tam ox if en e f f icac y when t a m ox if en i s ad mi n istere d as m ono t h era py f o r t h e a d j uv a nt t r eatme n t o f pos tm enopausa l , ER- po siti v e b reast ca n ce r . A dd iti on al s uppo r t for t h e i mpo rt ance o f endox ife n c on ce n trati on s came fr o m a sec ond ar y a n al y sis o f a p r ospec ti ve s t ud y , w h ic h d em on strate d a h i gh er ris k o f r ec urr e nce f o r wo m en w it h l ow e ndox ife n c on ce n trati on s Ma ny d r ugs a r e known t o inh i b it CYP 2 D 6 acti v it y . I n tam ox ife n -trea ted wo me n, t he coad mi n i s tr a ti on o f po te n t CYP 2 D 6 i nh i b it o rs , s u c h as p a rox eti ne, conve rt s a pa ti en t wit h no rmal CYP 2 D 6 meta bo lism t o a ph e no t yp i c P M Many o t he r cli n icall y im po rta n t d r ug s h a v e b ee n re ported t o i nh i b i t t he CY P 2D6 enzym e s y stem , bu t t h eir effects on tam ox ife n meta bo li s m have no t been p r o s p ecti v el y st ud ie d. As wit h t h e d ata re g ard ing C YP2D6 geno t ype, t he da t a re g ar d i ng CYP 2 D 6 i nh i b it o rs h as a dd iti on a lly b ee n c on tr ove r s i a l , i nc l ud i ng tw o st ud ies t h at re po rte d oppo site fi nd i ng s w it h r e ga r d t o CY P 2D6 i nh i bi t o r u se a nd b reast ca n cer rec u rre n ce o r d eat h. A lt hough t he C YP 2D6 d ata remai n c on tr ov ersial , we c on cl ud e t h at un til r esu lt s fr o m p r ospe cti v e a d j uv a n t st ud ies are a v aila b le , w o me n s hou l d b e counse l ed r ega r d i ng t h e po te n tial im p act o f t h e CYP 2 D 6 g e no t ype on t he e f f ec ti veness o f a d j uv a n t tam ox ife n, a nd po te n t CYP 2D6 i nh i b it ors shou l d be avo i ded. A dd iti on al ca u ti on s hou l d b e u se d wit h d r ugs t h at i nduce CY P 3A, such as rifam p ici n, as a t h ese d r ug s h a v e b ee n

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

d em on st ra t ed t o subs t an ti a ll y re du ce ( up t o 86 %) t h e c on ce n trati on s o f tam ox i fen and it s m e t abo lit es . St r ate g i es t o ove r co m e l o w e ndox ife n c on ce n trati on s i n cl ud e do se escalati on o f t a m ox if en t o 40 m g p er d a y , w h ic h h as b ee n d em on strate d to si gn i f ic an tl y i nc r ease endox ife n c on ce n trati on s , as well as t h e d irect a d mi n is t r a ti on o f endox if en it s elf . T h e latter strate gy is ongo i ng i n m u lti ple d i f f e r e n t c li n i ca l tri a l s, and ea rl y re po rts s ugg est cli n ical acti v it y i n a ro matas e i nh i b it o r s ( A I)-r es ista n t b reast ca n ce r . F o ll ow i ng t he m e t abo li c a cti v ati on o f tam ox ife n, t h e hyd r oxy late d meta bo lit es unde r go bo t h g l u c u r on i d ati on a nd s u lfati on. Pea k p lasma le vels of tam ox if en (m ax im u m conc e n trati on [Cma x ]) are see n 3 t o 7 hou rs aft e r or al a d mi n i s tr a ti on. Assu mi n g a n o ral b i o a v aila b ilit y o f 30 % , t h e vo l u m e o f d ist r i bu ti on has been ca l cu l a te d t o b e 20 L/ kg, a nd p lasma cleara n ce ra nges fro m 1.2 t o 5.1 L pe r hou r T h e termi n al h alf-life o f tam ox ife n h as b ee n r e por te d t o r ange be t ween 4 and 1 1 d a y s . T h e elimi n ati on h alf-life o f tam ox i fen i nc r eases w it h suc cessi v e do ses , w h ic h is c on siste n t wit h sat ur a b le k i ne ti cs . T he d r ug ’ s d istri bu ti on i n tiss u es is e x te n si v e . Le vels of t h e pa r en t d r ug and m e t ab olites h a v e b ee n re po rte d t o b e h i gh er i n tiss ue t h a n i n p l as m a i n an im a l s t ud ies . Re po rts o f tam ox ife n c on ce n trati ons 10- t o 60 -f o l d h i ghe r t han p l as ma c on ce n trati on s i n t h e li v e r , l ung s , b rai n, p a n c r ea s, sk i n, and bones a r e re po rte d . Ele v ate d le v els o f tam ox ife n w it h b ili a r y obs tr uc ti on have bee n re po rte d . T am ox if en has been r epo rte d t o i n teract wit h warfari n , – d i g it ox i n, ph e ny t o i n, and m ed r oxyp r og ester on e . T am ox ife n -i ndu ce d acti v ati on o f hu ma n tr ansc ri p ti on f ac t o r p r egn a n e X rece p t o r ( h PXR) , res u lti ng i n t h e i ndu cti on o f CY P 3A4, m ay i n crease t h e elimi n ati on o f c on c o mita n tl y a d mi n is te r ed CY P 3A subs tr a tes , s u c h as a n astr o z o le

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T o r emifene

nan nan

T or emi fene i s an agen t s imil ar t o tam ox ife n. It is a v aila b le i n t h e U n ite d States fo r t he tr ea tm en t o f pa t i e n ts wit h metastatic b reast ca n ce r , a nd is a pprov e d i n o t he r coun tri es for t h e a d j uv a n t treatme n t o f ER- po siti v e b r east

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

T o r emifene

nan nan

ca n ce r . C li n i ca l tri a l s have de m on strate d no d iffere n ce i n eit h er d isease-fr ee or ov e r all su r v i va l when t o r e mife n e was c o m p are d wit h tam ox ife n f o r t he t r eatme n t o f E R - pos iti ve b r ea st ca n ce r , nd e v i d e n ce e x ists f o r maj o r c ro ss -r e s i s t ance be t ween t a m ox ife n a nd t o remife n e

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

T or emi fene i s an an ti es tr ogen wit h a c h emical str u ct u re t h at d i f fers fr o m t h at of t a m ox if en by t he subs t i t u ti on o f a c h l o ri n e f o r a hyd r og e n at o m t hat is r etai n e d when t o r e mif ene und e r go es meta bo lism Li k e tam ox ife n, t or emi f en e i s m e t abo li zed by CYP 3 A , wit h a sec ond ar y meta bo lism t o for m hyd r oxy l a t ed m e t abo lit es t h at a pp ear t o h a v e similar b i nd i ng a f fi n i ties t o 4-OH t a m ox if en . T he i mpo rta n ce o f t h ese meta bo lites o r t h e r o le o f meta bo li s m t o t he hyd r oxy l a te d meta bo lites is unkno w n, bu t ma y p la y a ro le g i v e n t he s tr uc t u r a l s imil a rit y o f t o remife n e t o tam ox ife n. Alt hough the or al b i o a va il ab ilit y has no t been d efi n e d, t o remife n e ’ s o ral a b s o r p ti on a pp ea r s t o be good. T he tim e t o p ea k p lasma c on ce n trati on s after o ral a d mi n is t r a ti on r anges fr o m 1.5 t o 6.0 hou rs wit h t h e termi n al h alf-li v e s for t or e m if ene and one m e t abo lite , 4 - hyd r oxy t o remife n e , b ei ng 5 t o 6 d a y s T he appa r en t c l ea r a nce is 5.1 L p er hou r . T h e termi n al h alf-life f o r t h e maj o r m e t abo lit e, N - des met hy lt o remife n e , is 21 d a y s . T h e time t o r eac h p l as m a s t eady - s t a t e con ce n trati on s is 1 t o 5 wee k s . Plasma p r o tei n b i nd i ng i s m o r e t han 99 % . A s wit h tam ox ife n, t o remife n e is p rese n t at h i gh e r c oncen tr a ti ons i n ti ssu es c o m p are d t o p lasma wit h a h i gh a pp are nt vo l u me o f d i s tri bu ti on ( 958 L ). Se v e n t y p erce n t o f t h e d r ug is e x crete d i n f eces as me t abo lit es. St ud i es i n p atie n ts wit h im p aire d li v er f un cti on o r t ho se on an ti convu l san t s known t o i ndu ce CYP 3 A h a v e d em on strate d t h a t h e p atic d ys f unc ti on dec r eases t h e cleara n ce o f t o remife n e a nd N - d esmet hy lt o r e mif ene whe reas t ho se p atie n ts on a n tic onvu lsa n ts h a d a n i n c r ease d c l ea r ance. A lt houg h t o remife n e a pp eare d t o b e less carci nog en ic t h a n tam ox if en i n p r ec li n i ca l m od els , o f t h e rates o f e ndo metrial ca n ce r i n t he ad j uvan t s t ud i es h a v e b ee n similar t o tam ox ife n .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Raloxifene

nan nan

Ral ox i fene i s an es tr ogen agon ist a nd a n ta gon ist o ri g i n all y d e v el op e d t o t r eat o st eopo r os i s. L a r ge p l ac e bo -c on tr o lle d ra ndo mize d trials d em on str ated r e du ce d r a t es o f os t eopo r os i s a nd a re du cti on i n n ew b reast ca n cers i n t r eate d wo m en, l ead i ng t o t he d e v el op me n t o f a sec ond - g e n erati on b reas t ca n ce r c he m op r even ti on tri a l ( Nati on al S u r g ical A d j uv a n t Breast a nd B ow el P r o j ec t , N S A P B P 2 ) i n w h ic h ral ox ife n e was c o m p are d wit h tam ox i fen i n h i gh -ri sk pos tme nop a u sal w o me n. I n t h is st ud y , tam ox ife n w as s upe ri o r t o r a l ox if ene i n terms o f bo t h i nv asi v e a nd non i nv asi v e ca nce r e v e n ts , bu t was assoc i a t ed w i th a h i gh er ris k o f t h r o m bo em bo lic e v e n ts and e ndo me t ri a l cance r

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

Ral ox i fene i s pa rti a ll y es tr og e n ic i n bon e a nd l o wers c ho lester o l . It i s a n tiest r o gen i c i n m a mm a r y ti s s u e a nd u teri n e tiss u e . Th e pha rm acok i ne ti cs o f ral ox ife n e h a v e b ee n st ud ie d p ri n ci p all y i n po stme nopausa l wo m en P h armac ok i n etic p arameters o f ral ox ife n e s how c ons i de r ab l e i n t e ri nd i v i du al v ariati on. Limite d i n f o rmati on is a v aila b le on t he pha rm acok i n etics o f ral ox ife n e i n i nd i v i du als wit h h e p a tic im p ai r me n t , r ena l im pa irm ent, o r bo t h. Ral ox if ene i s r ap i d l y abso r b e d fr o m t h e g astr o i n testi n al tract . Beca u s e r al ox i f en e unde r goes ex t ens ive first- p ass g l u c u r on i d ati on, o ral b i o a v ail ab ilit y o f unchanged d r ug is l o w . Alt hough a pp r ox imatel y 60 % of a n or al dose i s abso r bed, t he a b s o l u te b i o a v aila b ilit y as un c h a ng e d r al ox i f en e i s on l y 2 % . Howe ve r , s y stemic a v aila b ilit y o f ral ox ife n e ma y be gr eate r t han t ha t i nd i ca t ed i n b i o a v aila b ilit y st ud ies , b eca u se circ u lati ng g l u c uron i de con j uga t es a r e c o nv erte d b ac k t o t h e p are n t d r ug i n v ari ou s tiss u es . Af te r t he o r a l ad mi n i s tr a tio n o f a si ng le 120 - o r 150 -m g do se o f r al ox i f en e hyd r och l o ri de, peak p lasma c on ce n trati on s o f ral ox ife n e a nd its g l u c uron i de con j uga t es a r e ach ie v e d at 6 hou rs a nd 1 hou r , res p ecti v el y .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

Af te r t he o r a l ad mi n i s tr a ti on of ra d i o la b ele d ral ox ife n e , less t h a n 1 % o f t o tal ci r c u l a ti ng r ad i o l abe l ed m aterial i n p lasma re p rese n ts t h e p are n t d r ug. Res u lt s o f a s i ng l e - dose s t udy i n p atie n ts wit h li v er dy sf un cti on i nd ica te t h at p las ma r a l ox if ene conce ntrati on s c o rrelate wit h ser u m b ilir ub i n c on ce n t ra ti ons and a r e 2.5 times h i gh er t h a n i nd i v i du als wit h no rmal h e p atic func ti on. I n pos tm eno pa u sal w o me n w ho recei v e d ral ox ife n e i n cli n ical t ri a l s, p l as m a concen trati on s o f ral ox ife n e a nd t h e g l u c u r on i d e c on j ug a tes i n t hose w it h r ena l im p airme n t (i . e ., estimate d creati n i n e clea r a n c e va l ues as l ow as 23 mL p er mi nu te) were similar t o v al u es i n wo me n wit h no rm a l r ena l f un cti on. Ral ox if ene and it s m onog l u c u r on i d e c on j ug ates are m o re t h a n 95 % bound t o p l as m a p r o t e i ns. Ra l ox ife n e b i nd s t o al bu mi n a nd α 1 -aci d g l y c opro t e i n. Ra l ox if ene unde r go es e x te n si v e first- p ass meta bo lism t o t he g l u c uron i de con j uga t es r a l ox i f e n e 4 ′- g l u c u r on i d e , 6 - g l u c u r on i d e , a nd 6,4′ - d i g l u c uron i de. UG T 1A1 and - 1 A 8 h a v e b ee n f ound t o catal y ze t h e for mati on o f bo t h t he 6 -β- and 4 ′-β- g l u c u r on i d es , w h ereas UGT 1 A 10 for me d on l y t he 4′ -β- g l ucu r on i d e . T h e meta bo lism o f ral ox ife n e do es not a pp ea r t o be m ed i a t ed by CY P e n z y mes (s u c h as CYP 2 D 6 ) , b eca u se meta bo lit es o t he r t han g l ucu r on i d e c on j ug ates h a v e no t b ee n i d e n tifie d. Th e p l as m a e limi na ti on ha lf-life o f ral ox ife n e at stea dy state a v era g es 32.5 hou r s (r ange, 15.8 t o 86.6 hou rs) . Ral ox ife n e is e x crete d p ri n ci p all y in f eces as a n unabso r bed d r ug a nd v ia b iliar y elimi n ati on as g l u c u r on i d e c on j ug a tes, wh i ch, subsequent l y , are meta bo lize d by b acteria i n t h e g ast ro i n t es ti na l tr ac t t o t he par e n t d r ug. After o ral a d mi n istrati on, less t h a n 0.2% of a r a l ox if ene dose i s ex crete d as t h e p are n t c o m pound a nd less th an 6% as g l ucu r on i de con j uga t es i n u ri n e .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Fulvestrant

nan nan

F u l v est ran t i s an E R an t agon ist t h at h as no kno w n a gon ist acti v it y a nd r es u lts i n E R down r egu l a ti on . Li k e tam ox ife n, f u l v estra n t c o m p etiti ve l y b i nds t o t he E R bu t wit h a h i gh er affi n it y— a pp r ox imatel y

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Fulvestrant

nan nan

100 time s g r ea t e r t han t ha t o f tam ox ife n , – t hu s p re v e n ti ng e ndog e nous es tr ogen fr o m ex erti ng its e f fect i n ta r g et cells . Res u lt s fr o m t wo phase III cli n ical trials u si ng t h e 250 m g p er m on t h do se d em ons tr a t ed f u l ves tr ant t o b e as e f fecti v e as a n astr o z o le i n t h e t r eatme n t o f pos tm enopausa l w o me n wit h a dv a n ce d ho rm on e rece p t o r – po siti v e b r eas t cance r p r ev i ou sl y treate d wit h a n tiestr og e n t h era py (mai nly tam ox i fen ) I n t he se tti ng o f first-li n e ho rm on e-res pon si v e metastat ic br east c ance r , a r ando mi zed ph ase III cli n ical trial t o c o m p are tam ox ife n to fu l v est ran t ( 250 m g pe r m on t h ) d em on strate d no d i f fere n ces i n res pon se o r time t o p r og r ess i on . Becaus e o f ph armac o l ogy d ata ( d isc u sse d i n t h e fo ll ow i ng pa r ag r aphs ) , t he 500 m g p er d a y do se was d e v el op e d. A r a ndo mi zed tri a l co m pa ri ng the 250 m g p er m on t h wit h 500 m g p er m o n th do se d em ons tr a t ed a 4 -m on t h im p r ov eme n t i n me d ia n ov erall s u r v i v al a dv a n tag e f o r t he h i ghe r dose F o r t h is reas on, t h e h i gh er do se is no w the sta nd a rd r eco mm ended dose. F u l v e s tr an t i s we ll t o l e r a t e d . T h e m o st c o mm on d r ug -relate d e v e n ts (gr eate r than 10 % i nc i dence ) fr o m t h e ra ndo mize d ph ase III st ud ies wer e i n jecti on - s it e r eac ti ons and ho t flas h es . C o mm on e v e n ts ( 1 % t o 10 % i n ci d e n ce) i nc l uded as t hen i a, h ea d ac h e , a nd g astr o i n testi n al d ist u r b a n ces s u c h as n ausea, vo miti ng, and d iarr h ea , wit h mi no r g astr o i n testi n al d ist urb a nces be i ng t he m os t co mm on l y d escri b e d a dv erse e v e n t .

SELEC T IVE E STROGEN R E CEP T OR MO D UL A T ORS

Pharmacology

nan nan

F u l v est ran t i s a s t e r o i da l m o lec u le d eri v e d fr o m E 2 wit h a n al ky ls u l phon y l si d e c h ai n i n t he 7 - α pos iti on ) . Beca u se f u l v estra n t is poo rl y s o l ub le a nd has l ow and unp re d icta b le o ral b i o a v aila b ilit y , a p are n teral for m u la t i on o f f u l ves tr an t wa s d e v el op e d i n a n attem p t t o ma x imize d eli v e ry o f t he d r ug . T he i nt ram u sc u lar f o rm u lati on p r ov i d es p r o l ong e d r elease o f t he d r ug ove r seve ral wee k s . T h e ph armac ok i n etics o f t h ree d i f f e r e n t s i ng l e doses o f f u l ves tra n t ( 50, 125, a nd 250 m g ) h a v e b ee n pub lis h e d I n t h i s phase I/II m u ltice n ter st ud y , po stme nop a u sal w o me n w it h pr i ma r y b r eas t cance r who were awaiti ng c u rati v e s u r g er y recei v e d

AROM A T ASE IN H I B I T ORS

nan nan

AROM A T ASE IN H I B I T ORS

AROM A T ASE IN H I B I T ORS

nan nan

A t me nopause, t he syn t hes i s o f ov aria n ho rm on es ceases . H o we v e r , est rog e n con ti nues t o be conv erte d fr o m a nd r og e n s ( p r odu ce d by t h e a dr e n al gl ands ) by a r o m a t ase, a n e n z y me o f t h e CYP s up erfamil y . Aro mat ase i s t he enzy m e co m p le x res pon si b le f o r t h e fi n al ste p i n estr ogen s yn t h esi s v i a t he conve r s i on o f a nd r og e n s , a nd r o ste n e d i on e a nd test o ste rone, t o es tr ogens, es t ron e ( E 1 ) a nd E 2 . T h is b i o l og ic p at h wa y ser ved as t h e bas i s f o r t he deve l op me n t o f t h e a n tiar o matase class o f c o m pounds. A lte r ati ons i n a r o m a t ase exp ressi on h a v e b ee n im p licate d i n t h e p at hog e nes i s o f es tr ogen - dep e nd e n t d isease , i n cl ud i ng b reast ca n ce r , e ndo me t ri a l cance r , and endo metri o sis . T h e im po rta n ce o f t h is e n z y me is als o h i gh li gh t ed by t he f ac t t ha t selecti v e ar o matase i nh i b it o rs are c o mm on l y used as fir s t-li ne t h era py f o r t h e treatme n t o f po stme nop a u sa l wo me n wit h es tr ogen -r espons i v e b reast ca n ce r . Ami nog l u tet h imi d e was the f i r st cli nica ll y used a r o m a t as e i nh i b it o r . W h e n it b ecame a v aila b le , it was u se d t o c ause a med i ca l ad r ena lect o my . Beca u se o f t h e lac k o f selecti v it y

AROM A T ASE IN H I B I T ORS

nan nan

for a ro m a t ase and t he r esu lt an t s upp ressi on o f al do ster on e a nd c o rtis o l , ami nog l u t e t h imi de i s no l ong er rec o mme nd e d f o r treati ng metastatic b rea st ca n ce r . A mi nog l u t e t h imi de i s als o o ccasi on all y u se d t o tr y t o re v erse e x c ess hor m one p r oduc ti on by ad r eno c o rtical ca n cers . Aro m a t ase ( cy t och r o m e P- 450 19 [CYP 19 ]) is e n c od e d by t h e CYP 1 9 g e n e , w hi ch i s h i gh l y po l y m orph ic . S o me o f t h ese v aria n ts are f un cti on a lly im por ta n and m ay have c li n ical si gn ifica n ce Aro m a t ase i nh i b it o r s have b ee n classifie d i n a nu m b er o f d iffere n t wa ys, i n cl ud i ng fir s t , second, and t hi r d g e n erati on ; ster o i d al a nd non ster o i d al; and r e v e r si b l e (i on i c b i nd i ng ) and irre v ersi b le (s u ici d e i nh i b it o r , c ov ale n t b i nd i ng) T he nons t e r o i da l a r o matase i nh i b it o rs i n cl ud e ami nog l u t e t h imi de (fir s t gene rati on ) , r og letimi d e a nd fa d r o z o le (sec ond g e n e r atio n ) , and anas tr ozo l e, l etr o z o le , a nd vo r o z o le (t h ir d g e n erati on ) . The ste ro i d a l a r o m a t ase i nh i b it o r s i n cl ud e f o rmesta n e (sec ond g e n erati on ) a nd e x emest ane (t h ir d gene r a ti on ) . Ste roida l and nons t e r o i da l ar o matase i nh i b it o rs d iffer i n t h eir m od es o f i n te r acti on w it h, and t he ir i na cti v ati on o f , t h e ar o matase e n z y me . Ster o i dal i nh i b it ors co m pe t e w it h t he e n dog e nou s s ub strates , a nd r o ste n e d i on e a nd test o ste rone, f o r t he ac ti ve s it e o f t h e e n z y me a nd are p r o cesse d i n t o i n te r me d i a t es t ha t b i nd irr eve rsi b l y t o t h e acti v e site , ca u si ng irre v ersi b l e e n z y me inh i b iti on . Nons t e r o i d al i nh i b it o rs als o c o m p ete wit h t h e e ndog e nous subs tr a t es f o r ac cess t o t h e acti v e site , w h ere t h e y t h e n f o r m a r e v e r si b l e bond t o t he he m e i ron at o m s o t h at e n z y me acti v it y ca n rec ove r i f t h e i nh i b it o r i s r e m oved ; howev e r , i nh i b iti on is s u stai n e d w h e n e v er t h e i nh i b it or i s p r esen t .

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

Let r ozole and Anast r ozole

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

B o t h letr ozo l e and anas tr ozo l e h a v e b ee n e x te n si v el y st ud ie d i n t h e metastati c and ad j uvan t se tti ng s . W h e n c o m p are d t o tam ox ife n, bo t h let ro z o l e and anas tr ozo l e hav e d em on strate d s up eri o r res pon se rates a nd progr ess ion -fr ee su r v i va l i n t h e metastatic setti ng . , I n t h e a d j uv a n t setti ng, two tri a l s have been pe rf o rme d a nd d em on strate d s up eri o rit y i n

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

te r ms of r e l apse -fr ee su r v i va l s o f bo t h a n astr o z o le ( A T AC) a nd letr o z ole ( B IG 1-98 ) Add iti ona ll y , an astr o z o le h as b ee n st ud ie d i n a se qu e n tial a ppro ach , and t he sequence o f tam ox ife n f o ll o we d by a n astr o z o le is s up e r i or t o 5 yea r s o f t a m ox if en al on e . A n astr o z o le h as rece n tl y b ee n c o m p a red t o p l acebo i n wo me n at a n i n crease d ris k o f d e v el op i ng b reast ca n ce r a nd was de m ons tr a t ed t o si gn ifica n tl y re du ce t h e i n ci d e n ce o f i nv asi v e b r eas t cance r Th e s i de e f f ec t s o f bo t h ana str o z o le a nd letr o z o le are similar a nd i n cl ude a r t hr al g ia s and m ya l g i as i n up t o 50 % o f p atie n ts . B o t h letr o z o le a nd a n ast ro z o l e a r e assoc i a t ed w it h a h i gh er rate o f bon e fract u re , c o m p are d w it h t h e t a m ox if en . A t t he prese n t time , mi n imal l ong -term (l ong er t han 5 y ea r s ) c l i n i ca l da t a r ega r d i ng t h e effect o f ar o matase i nh i b it o rs on bon es a r e a v aila b le . When o f f e ri ng anas tr o z o le f o r e x te nd e d p eri od s o f time t o p atie n ts wit h ea rl y b r eas t canc e r , atte n ti on t o bon e h ealt h is p aram oun t , and bon e d e ns it y shou l d be m on it o re d i n all p atie n ts . Pr o s p ecti v e st ud ies h a ve d em on st ra t ed t ha t b i sphosphon ates p re v e n t ar o matase-i nh i b it o r – i ndu ce d bon e l o ss and a m e t a - ana l ys i s p rese n te d at t h e 2013 Sa n A n t on i o Breast Ca n ce r S y m pos i u m de m ons tr a te d t h at b is pho s phon ates re du ce bon e r ec urr e nces and p r o l ong ove r a ll s u r v i v al . T h eref o re , b is pho s phon ates s hou l d b e cons i de r ed i n A I-tr e ate d p atie n ts , bo t h i n t ho se wit h a nd wit hout a n i n c r ea sed ri sk o f bone fr ac t u res . A m e t a - ana l ys i s o f t ox i c iti e s c o m p ari ng ar o matase i nh i b it o rs wit h tam ox i fen has de m ons tr a t ed a 30 % i n crease i n g ra d e 3 a nd 4 car d iac e vents w it h a ro m a t ase i nh i b it o r s . H o we v e r , p r o s p ecti v e d ata d em on strate no d i f f e r e nces i n m yoca r d i a l even ts c o m p ari ng a n astr o z o le wit h p lace bo, alt hough an i nc r ease i n hype rte n si on was ob ser v e d . No im pac t has been seen w it h a n astr o z o le on a d re n al ster o i dog e n esis at up t o 10 tim es t he c li n i ca ll y rec o mme nd e d do se . Alt hough letr o z o le may d ec r eas e basa l and ad r enoco rtic o tr op ic ho rm on e – stim u late d c o rtis o l s yn t h esi s, t he c li n i ca l e f fect a pp ears t o b e mi n imal . Ar o matase i nh i b it ors appea r t o have d i f fere n tial e f fects on li p i d s . I n a st udy o f ov er 900 p atie n ts wit h m e t as t a ti c d i sea se , a n astr o z o le s ho we d no mar k e d e f fect on li p i d pr ofil es co m pa r ed w it h b aseli n e C onv ersel y , t h e a d mi n istrati on o f

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

let ro z o l e i n wo m en w it h adva nce d b reast ca n cer res u lte d i n si gn ifica n t i n c r ease s i n t o t a l cho l es t e r o l and l o w- d e n sit y li pop r o tei n, fr o m b aseli n e , a f te r 8 a nd 16 weeks o f t he r ap y I n t h e Breast I n ter n ati on al Gr oup 1 - 98 t r ial , m ore wo m en who r ece i v e d letr o z o le e xp erie n ce d g ra d e 1 hyp e r c ho l es t e r o l e mi a co m pa r ed t o w o me n w ho recei v e d tam ox ife n . L et rozo l e i s a nons t e r o i da l ar o matase i nh i b it o r wit h a h i gh s p ecificit y f o r t h e i nh i b iti on o f es tr ogen p r odu cti on ( ) . Letr o z o le is 180 times m or e po t en t t han a mi nog l u t e t h imi d e as a n i nh i b it o r o f ar o matase i n v itr o. A l do ster one p r oduc ti on i n v it ro is i nh i b ite d by c on ce n trati on s 10,000 ti mes h i gh e r t han t hose r equ ir ed f o r i nh i b iti on o f estr og e n s yn t h esis . I n a nor mal ma l e vo l un t ee r s t ud y , letr o z o le was s ho w n t o d ecrease E 2 a nd ser um E 1 le v el s t o 10 % o f base li ne w it h a si ng le 3 -m g do se . I n ph ase I st ud ies , let ro z o l e caused a s i gn ifi can t d ecli n e i n p lasma E 1 a nd E 2 wit h i n 24 hou r s o f a si ng le o r a l dose o f 0.1 m g After 2 wee k s o f treatme n t , t h e b l ood le v els o f E 2 , E 1 , and es tr one su lfate were s upp resse d 95 % o r m o re fr o m b aseli n e . T h i s con ti nued ove r t h e 12 wee k s o f t h era p y . T h ere was no a pp a r e n t a lt e r a ti on i n p l as m a le v els o f c o rtis o l a nd al do ster on e wit h let ro z o l e o r a ft e r co rti co tr op in stim u lati on . I n po stme nop a u sal w o me n w it h a dvanced b r eas t cance r , t h e d r ug d i d no t h a v e a ny e f fect on f o llicle - stim u lati ng ho rm one (FS H ) , lutei n izi ng ho rm on e (LH) , t hy r o tr op i n (pr e v i ou sl y t hy r o i d - s tim u l a ti ng ho rm on e) , c o rtis o l , 17 - α - hydroxy pr oges t e r one, and r os te n e d i on e , o r al do ster on e b l ood c on ce n t ra ti ons

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

An astr ozo l e i s a nons t e r o i d al ar o matase i nh i b it o r t h at is 200 -f o l d m o r e po te n t t han a mi nog l u t e t h imi d e . N o e f fect on t h e a d re n al g la nd s h as b e en d etecte d. I n hu m an s t ud i es, t he t max is 2 t o 3 hou rs after o ral i ng esti on

AROM A T ASE IN H I B I T ORS

Let r ozole and Anast r ozole

nan nan

p lasma anas tr ozo l e and anas tr o z o le meta bo lite c on ce n trati on s , as well as pr et r eatm en t and pos t d r ug p l a sma E 1 , E 2 , a nd E 1 c on j ug ate a nd estr og e n pr ec ur sor ( and r os t ened i one and test o ster on e) c on ce n trati on s . F u rt h er r esea r c h i s needed t o de t e rmi n e t h e b asis f o r t h e wi d e v aria b ilit y i n t h e ph a r ma cok i ne ti cs o f anas tr ozo le a nd w h et h er t h ese fi nd i ng s are cli n icall y r ele v a n t.

AROM A T ASE IN H I B I T ORS

Exemestane

nan nan

Ex emest ane has a s t e r o i da l s t ru ct u re a nd is classifie d as a t yp e 1 ar o mat ase i nh i b it o r , a l so known as an a r o m a t a se i na ctiv a t o r , b eca u se it irre v ersi b l y b i nd s wi t h and pe rm anen tl y i n acti v ates t h e e n z y me . E x emesta n e h as been c o m p a red t o t a m ox if en i n bo t h t h e metastatic a nd a d j uv a n t setti ng s . I n t he setti ng o f t a m ox if en -r e fr ac t o r y metastatic b reast ca n ce r , e x emesta n e is s up e r i or t o m eges tr o l ace t a t e, as d em on strate d i n a ph ase III trial i n w h ic h im prov e men t s i n bo t h m ed i an time t o t u m o r p r og ressi on a nd me d ia n s urv i v al we r e obse r ved I n t h e a d j uv a n t setti ng, t h e i n ter n ati on al e x emest ane s t udy co m pa r ed 2 t o 3 y ears o f tam ox ife n wit h 2 t o 3 y ears o f e x emest ane i n wo m en who had p re v i ou sl y c o m p ete d 2 t o 3 y ears o f a d j uv a nt t a m ox if en. I n t h i s trial , a switc h t o e x emesta n e res u lte d i n s up er io r d isease -f r ee and ove r a ll su r v i v al i n t h e ho rm on e rece p t o r –po siti v e s ub t y p e. F ur t h e rmo r e, exe m es t ane has b ee n c o m p are d wit h t h e non ster o i d al a g e nt a n ast ro z o l e i n t he ad j uvan t treatme n t o f ER- po siti v e b reast ca n ce r , a nd t he r e w e r e no d i f f e r ences i n d i seas e-free o r ov erall s u r v i v al . Fi n all y , e x emest ane has been co m pa r ed t o p lace bo i n p atie n ts at i n crease d ris k o f br east c ance r , and a s i gn ifi can t re du cti on i n t h e ris k o f d e v el op i ng i nv asi ve br east c ance r was obse r ved .

AROM A T ASE IN H I B I T ORS

Side Effects of Exemestane

nan nan

Side Effects of Exemestane

AROM A T ASE IN H I B I T ORS

Side Effects of Exemestane

nan nan

A lt hough p r ec li n i ca l s t ud i es h a v e s ugg este d t h at e x emesta n e p re v e n te d bon e l o ss i n ova ri ec t o mi zed rats t h e I n te r g r oup E x emesta n e a d j uv a n t t r ial still de m ons tr a t ed a h i gh er rate o f bon e fract u re f o r p atie n ts r a ndo mi zed t o t he exe m es t an e arm a nd t h ere were no d iffere n ces i n frac tu r e

AROM A T ASE IN H I B I T ORS

Side Effects of Exemestane

nan nan

r ates c o m pa ri ng anas tr ozo l e wit h e x emesta n e . Si d e e f fects , i n cl ud i ng a r t hr al g ia s and m ya l g i as, app ear t o b e similar t o t h e o t h er AIs . W it h re ga r d t o ste ro i dogenes i s, no im pac t on eit h er c o rtis o l o r al do ster on e le v els was see n i n a s m a ll s t udy a ft e r t he a d mi n istrati on o f e x emesta n e f o r 7 d a y s .

AROM A T ASE IN H I B I T ORS

Side Effects of Exemestane

nan nan

Fi n all y , exe m es t ane has weak a nd r og e n ic p r op erties , a nd its u se at h i gh e r do ses has been assoc i a t ed w it h ster o i d al-li k e si d e effects , s u c h as wei gh t g ai n a nd acne . , Howeve r , t h ese si d e e f fects h a v e no t b ee n ob ser v e d with t h e F DA - app r oved dose ( 25 mg p er d a y ) .

AROM A T ASE IN H I B I T ORS

Pharmacology

nan nan

Ex emest ane i s m e t abo li zed by CYP 3 A 4 . Alt hough d r ug–d r ug i n teract ions h a v e not been f o rm a ll y r epo rt ed f o r e x emesta n e , t h ere is t h e po te n tial f o r i n te r acti ons w it h d r ugs t ha t a f fect CYP 3 A 4

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan

Gon a do tr op i n -r e l eas i ng ho rm on e (G n RH) a n al og s res u lt i n a me d ic a l o r c h iecto my i n m en and a r e u se d as a mea n s o f p r ov i d i ng a nd r og e n a b la tion for hor m one - sens iti ve and ca strati on refract o r y metastatic p r o state ca n ce r .

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan

Beca u se t he i n iti a l agon i s t ac t iv it y o f G n RH a n al og s ca n ca u se a t u m o r fl a r e from t e m po r a ril y i nc r ea se d a nd r og e n le v els , c on c o mita n t u se o f t h e

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan

a n tia ndrogen fl u t a mi de o r b i ca l u tami d e h as b ee n u se d t o p re v e n t t h is e f f ect. Gn R H a na l ogs can a l so cause t u m o r re g ressi on s i n ho rm on all y res pon si ve br east c ance r and have r ec ei v e d FDA a pp r ov al f o r t h e treatme n t o f metastati c b r eas t cance r i n p reme nop a u sal w o me n. Data s ugg est t h at t h e se drug s m ay be use f u l as ad j uv a n t t h era py o f p reme nop a u sal w o me n wit h r esecte d b r eas t cance r . T he use o f t h ese d r ug s i n c o m b i n ati on wit h tam ox i fen o r exe m es t ane i n p reme nop a u sal w o me n wit h p rimar y b reast ca n ce r i s t he sub j ec t o f l a r ge, ongo i ng, i n ter n ati on al cli n ical trials . T h e pr ima ry t ox i c iti es o f GnRH an al og s are sec ond ar y t o t h e a b lati on o f se x ste ro i d concen tr a ti ons and i n cl ud e ho t flas h es , sweati ng, a nd n a u sea .

G O NADOTRO P IN-RELEASING HOR MO NE ANA LO GS

nan nan