9046 Review

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Name of Journal: World Journal of Biological Chemistry

ESPS Manuscript NO: 9046

Columns: TOPIC HIH!IHT

"J#C $t% &nni'ersar( Special Issues )*+: Proteomics

In 2014, can we do better than CA125 in the early detection of

ovarian cancer?

Co%en J et al, Earl( -etection of o'arian cancer

Jos%ua Co%en. Matt%e/ "%ite. &na Cru. 1o2in 3ariasEisner

Joshua G Cohen, atthew !hite, Ana Cru", #obin $arias%&isner,

5i'ision of (necoloic Oncolo(. 5epartment of O2stetrics an- (necolo(.

7ni'ersit( of California. !os &neles Me-ical Center, !os &neles. C& 9009$.

7nite- States

Author contributions'Co%en J. "%ite M an- Cru & performe- researc%an- ac8uisition of -ata Co%en J. "%ite M. Cru & an- 3ariasEisner 1

performe- s(nt%esis of -ata. -e'elope- ta2les an- ures. an- aut%ore-

manuscript,

Corres(ondence to' #obin $arias%&isner ), *h), 5epartment of

O2stetrics an- (necolo(. 7ni'ersit( of California. !os &neles Me-ical

Center. Peter Morton Me-ical #uil-in, *00 Me-ical Plaa. Suite **0, !os

&neles. C& 9009$. 7nite- States+ rfeisner;me-net,ucla,e-u

ele(hone'=0*06?9=4 $a-'=0*06*0$@

#eceived'Januar( =@. *0=4#evised' Marc% =*. *0=4

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Acce(ted' Ma( =4. *0=4

*ublished online'

Abstract

O'arian cancer is a let%al (necoloic malinanc( /it% reater t%an @0A of

/omen presentin /it% a-'ance- stae -isease, 5espite ne/ treatments.

lon term outcomes %a'e not sinicantl( c%ane- in t%e past >0 (ears /it%

t%e 'e(ear o'erall sur'i'al remainin 2et/een *0A an- 40A for stae III

an- IB -isease, In contrast patients /it% stae I -isease %a'e a reater t%an

90A 'e(ear o'erall sur'i'al, 5etection of o'arian cancer at an earl( stae

/oul- liel( %a'e sinicant impact on mortalit( rate, Screenin 2iomarers-isco'ere- at t%e 2enc% %a'e not translate- to success in clinical trials,

EDistin screenin mo-alities %a'e not -emonstrate- sur'i'al 2enet in

complete- prospecti'e trials, &-'ances in %i% t%rou%put screenin are

main it possi2le to e'aluate t%e -e'elopment of o'arian cancer in /a(s

ne'er 2efore imaine-, 5ata in t%e form of %uman FomesG inclu-in t%e

proteome. enome. meta2olome. an- transcriptome are no/ a'aila2le in

'arious pacae- forms, "it% t%e correct poolin of resources inclu-in

prospecti'e collection of patient specimens. interation of %i% t%rou%put

screenin. an- use of molecular %eteroeneit( in 2iomarer -isco'er(. /e

are poise- to mae proress in o'arian cancer screenin, T%is re'ie/ /ill

summarie current 2iomarers. imain. an- multimo-alit( screenin

strateies in t%e conteDt of emerin tec%noloies,

*0=4 #ais%i-en Pu2lis%in roup Inc, &ll ri%ts reser'e-,

.eywords' O'arian cancer Screenin #iomarer 5etection 5ianostic

imain Proteomics &-neDal mass

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Core ti(' O'arian cancer is a let%al (necoloic malinanc( /it% 'e(ear

sur'i'al of onl( *0A to 40A for a-'ance- stae -isease, 5etection at an

earl( stae /oul- liel( %a'e sinicant impact on mortalit( rate, &-'ances

in %i% t%rou%put screenin /it% t%e %uman FomesG inclu-in t%e

proteome. enome. meta2olome. an- transcriptome are no/ a'aila2le in

'arious pacae- forms, To mae proress in screenin /e nee- reater

emp%asis on prospecti'e collection of patient specimens. interation of %i%

t%rou%put screenin. an- use of molecular %eteroeneit( in 2iomarer

-isco'er(,

Co%en J. "%ite M. Cru &. 3ariasEisner 1, In *0=4. can /e -o 2etter t%an

C&=*$ in t%e earl( -etection of o'arian cancerWorld J Biol Chem*0=4 In

press

I/#)CI/

O'arian cancer is a let%al (necoloic malinanc( /it% reater t%an @0A of

/omen presentin /it% a-'ance- stae -isease =K, "orl-/i-e it is estimate-

t%ere are **$$00 ne/ cases of o'arian cancer an- =40*00 -eat%s e'er(

(ear inclu-in =40>0 -eat%s in t%e 7nite- States alone*.>K

,

Primar( treatmentfor a-'ance- stae -isease in'ol'es 2ot% surer( an- c%emot%erap(,

5espite ne/ treatments. lon term outcomes %a'e not sinicantl(

c%ane- in t%e past >0 (ears /it% t%e 'e(ear o'erall sur'i'al remainin

2et/een >0 an- 40A>K, reater t%an 60A of a-'ance- stae patients /ill

-e'elop recurrent -isease4K, Patients /it% a-'ance- stae -isease %a'e a

'e(ear o'erall sur'i'al 2et/een *0A an- 40A. in star contrast to t%e

reater t%an 90A 'e(ear o'erall sur'i'al of patients i-entie- an- treate-

/it% stae I -isease$@K,

i'en t%e poor pronosis for patients /it% a-'ance- stae -isease.

eLecti'e screenin mo-alities are nee-e- to i-entif( patients /it% earl(

stae -isease, T%e maorit( of /omen /it% earl( stae -isease are

as(mptomatic. an- unfortunatel( /%en t%e( -o present for -ianosis. t%ree

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8uarters are foun- to %a'e reional or -istant metastases@K, Preliminar(

e'aluations of screenin /it% serum marers. pel'ic ultrasoun-s. an-

multimo-alit( strateies %a'e -emonstrate- potential 2enet in t%e earlier

i-entication of o'arian cancer?.9K, "it% t%ese encourain results.

prospecti'e screenin trials %a'e 2een un-ertaen as t%e scientic

communit( continues to increase t%e num2er of potential 2iomarers an-

imain tests /%ic% mi%t assist /it% i-entication of earl( stae o'arian

cancer in as(mptomatic /omen,

In t%e 7nite- States a /omans lifetime ris of -e'elopin o'arian cancer is

= in @0 an- t%e pre'alence of o'arian cancer in postmenopausal /omen o'er

t%e ae of $0 is = in *$00 =0K,To minimie %arms /%ile i-entif(in /omen at

ris. a positi'e pre-icti'e 'alue )PPB+ of =0A is nee-e-. re8uirin a

sensiti'it( of reater t%an @$A an- specicit( of 99,6A to i-entif( one case

of o'arian cancer for e'er( ten operations=0K, It is unliel( t%at one 2iomarer

test /ill meet t%is criteria i'en t%e %i% specicit( nee-e-==K,

T%e i-eal 2iomarer or panel of 2iomarers is o2taine- t%rou%

nonin'asi'e means suc% as a 2o-il( ui-: 2loo-. sali'a. urine. an- cer'ical

mucous are possi2ilities=*K, &-'ances in %i% t%rou%put screenin %a'e

ma-e it possi2le to e'aluate t%e %uman enome /it% t%e %ope of 2etterun-erstan-in enetic an- epienetic c%anes associate- /it% t%e

-e'elopment of o'arian cancer, Enormous amounts of -ata in t%e form of

%uman FomesG inclu-in t%e proteome. enome. meta2olome. an-

transcriptome are no/ a'aila2le in 'arious pacae- forms, T%e Cancer

enome &tlas recentl( complete- a compre%ensi'e enomic an- epienomic

e'aluation of o'er t%ree %un-re- %i%ra-e serous o'arian cancer samples

/it% microarra( anal(ses an- massi'el( parallel se8uencin couple- /it%

%(2ri- anit( capture=>K,

O'arian cancer represents a 'er( -i'erse roup of tumors, Scientic

en-ea'ors suc% as t%e Cancer enome &tlas are no/ main it possi2le to

2etter -elineate c%aracteristics of 'arious su2t(pes, T%e continue- 8uest for

a strate( t%at meets t%e nee- to i-entif( as(mptomatic /omen in t%e

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eneral population ma( -epen- on t%e a2ilit( to parse out t%e oriins of

o'arian cancer, T%e epit%elial cateor(. /%ic% accounts for 90A of all o'arian

cancers. consists of t%e follo/in su2t(pes: )=+ serous )$0A+ )*+

en-ometrioi- )=0A*$A+ )>+ mucinous )$A=0A+ )4+ clear cell )4A$A+ )$+

un-iLerentiate- carcinomas )$A+ an- )6+ transitional cells )rare+=4K, T%ese

o'arian tumors are liel( -istinct -iseases /it% -iLerent cells of oriin an-

-ri'er mutations. unite- un-er one term -ue to t%eir pre-ilection for

-issemination to t%e o'ar( an- relate- pel'ic orans =$K, & pitfall of t%e past

ma( 2e failure to -e'elop screenin strateies 2ase- on -iLerences amon

t%ese tumors, It is not (et clear if one screenin strate( or separate

approac%es /ill 2e nee-e- to i-entif( patients /it% t%ese tumor t(pes at an

earl( stae of -isease, T%is re'ie/ /ill summarie current 2iomarers.

imain. an- multimo-alit( screenin strateies in t%e conteDt of emerin

tec%noloies,

IA#. A/) &I3I/G AG#I63

Initiall( -escri2e- 2( #ast et al=6Kin =9?=. cancer antien =*$ )C&=*$+ /as

reconie- 2( t%e murine monoclonal anti2o-( OC=*$ as an antienic

-eterminant on a %i% molecular/ei%t l(coprotein,

It is t%e most /i-el(stu-ie- 2iomarer in o'arian cancer screenin, Measurement of C&=*$ can

2e performe- /it% -iLerent commercial assa(s resultin in a certain -eree

of 'ariation, T%e maorit( of assa(s appear to 2e 2ot% clinicall( relia2le an-

correlati'e. nonet%eless. ne/ 8uantitati'e met%o-s inclu-in mass

spectrometr( are un-er in'estiation=@.=?K, &s part of its -e'elopment. C&=*$

un-er/ent molecular clonin an- /as foun- to %a'e c%aracteristics of mucin.

recei'in t%e name M7C=6=9K,

In a-ults. C&=*$ is eDpresse- in tissues -eri'e- from coelomic epit%elium

)mesot%elial cells of t%e peritoneum. pleura. an- pericar-ium+ an- Mullerian

)tu2al. en-ometrial. an- en-ocer'ical+ epit%elia. as /ell as epit%elia of t%e

pancreas. colon. all 2la--er. lun. i-ne(. an- stomac% *0.*=K, C&=*$ can 2e

ele'ate- in a num2er of con-itions unrelate- to o'arian cancer. resultin in

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-ecrease- specicit( an- PPB, 5i'erticulitis. en-ometriosis. li'er cirr%osis.

uterine 2roi-s. menstruation. prenanc(. 2enin o'arian neoplasms. an-

ot%er malinancies )pancreatic. 2la--er. 2reast. li'er. lun+ can all result in

an ele'ate- C&=*$==K,

"%en 'alues 2elo/ >$ 7Q! are -esinate- as normal. C&=*$ is ele'ate- in

?0A of epit%elial o'arian cancers**K, C&=*$ is ele'ate- in approDimatel(

$0A60A of stae I epit%elial o'arian cancers an- @$A90A of patients /it%

a-'ance- stae -isease*=.*>K, T%e sensiti'it( of C&=*$ to i-entif( earl( stae

-isease is limite- as a screenin tool, "it% e'aluation of **000 'olunteers

an- o'er $0000 serum C&=*$ samples /it% a me-ian follo/ up of ?,6 (ears.

Jaco2set al*4K -emonstrate- C&=*$ le'els in /omen /it%out o'arian cancer

remaine- static or -ecrease- o'er time /%ile le'els associate- /it%

malinanc( ten-e- to increase?.*4K, #ase- on t%ese n-ins. t%e 1is of

O'arian Cancer &lorit%m )1OC&+ /as -e'elope- incorporatin an

in-i'i-uals ae specic inci-ence of o'arian cancer an- C&=*$ prole to

triae /omen into 'arious ris cateories?K, 1OC& increase- t%e sensiti'it( of

C&=*$ from 6*A to ?6A for -etection of preclinical o'arian cancer /%ile

maintainin a specicit( of 9?A*$K, & ran-omie- control trial to e'aluate

1OC& consiste- of =>$?* postmenopausal /omen o'er t%e ae of $0 an--emonstrate- a specicit( of 99,?A )CI: 99,@A to 99,9A+ an- positi'e

pre-icti'e 'alue of =9A )CI: 4,=A to 4$,6A+*6K, T%is mo-el %as 2een

incorporate- into 'arious multimo-alit( screenin strateies in an attempt to

optimie sensiti'it(. specicit(. an- positi'e pre-icti'e 'alue,

T%e 8uest for ot%er 2iomarer can-i-ates %as continue- 2ecause a sinle

C&=*$ 'alue at a i'en time point /ill not reac% a specicit( of 99,6A. an-

approDimatel( *0A of o'arian cancers ma( not eDpress t%is antien, Human

epi-i-(mis protein )HE4+. foun- primaril( in t%e epit%elia of normal enital

tissues an- ma-e up of t/o /%e( aci-ic protein )"&P+ -omains an- a four

-isul-e core. is ele'ate- in epit%elial o'arian cancer*@.*?K, HE4 is

o'ereDpresse- in $0A of clear cell. 9>A of serous. an- =00A of en-ometrioi-

cancers 2ut is not o'ereDpresse- in mucinous tumors*?K,I-entie- initiall( as

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an m1N& transcript specic to t%e -istal epi-i-(mal tissue. enomic

a-'ances /it% microarra( ene eDpression prolin -emonstrate- HE4 is

%i%l(eDpresse- in o'arian cancer*9.>0K, HE4 %as reater specicit( in t%e

premenopausal ae roup t%an C&=*$ i'en it -oes not appear to 2e

eDpresse- at %i% le'els in t%e settin of 2enin con-itions suc% as

en-ometriomas>=>>K, HE4 represents a 'ictor( for enomic strateies in t%e

searc% for potentiall( eLecti'e 2iomarers /it% microarra( ene

eDpression>4K,

In a s(stemic re'ie/ of /omen /it% suspecte- (necoloic -isease HE4

-emonstrate- a %i%er specicit( )9>Avs @?A+ an- similar sensiti'it( )@9A+

to C&=*$ /%en -istinuis%in 2enin -isease from o'arian cancer >$K,Stu-ies

%a'e -emonstrate- a potential 2enet in com2inin HE4 an- C&=*$ /%en

8uantif(in ris potential malinanc( in t%e e'aluation of a pel'ic mass >6.>@K,

E'en /it% ne/ tec%nolo(. it is unliel( t%at an in-i'i-ual 2iomarer /ill

reac% a specicit( of 99,6A. positi'e pre-icti'e 'alue of =0A. an- sensiti'it(

reater t%an @$A /%en screenin an as(mptomatic eneral population,

In eLorts to furt%er triae /omen in t%e -etection of o'arian cancer.

proress %as 2een ma-e in t%e -e'elopment of alorit%ms to -elineate

malinanc( in t%e settin of an a-neDal mass, "oman appropriatel( referre-to a (necoloic oncoloist %a'e 2etter outcomes inclu-in sur'i'al.

-emonstratin t%e potential importance of t%ese triae tests>?.>9K,T%e 1is of

Malinanc( In-eD )1MI+. -e'elope- 2( Jaco2s et al40Kin =990. is a formula

/%ic% incorporates a /omans C&=*$ le'el. ultrasoun- score. an-

menopausal status to -etermine %er lieli%oo- of malinanc( in t%e settin

of an a-neDal mass, Since t%at time t/o ot%er alorit%ms %a'e 2een

-e'elope- for assessment of malinanc( ris in /omen /it% a-neDal

masses: t%e 1is of Malinanc( &lorit%m )1OM&+ an- t%e OB&= test 4=.4*K,T%e

1OM& alorit%m is 2ase- on serum le'els of HE4 an- C&=*$ /it%

menopausal status4=K, OB&=. /it% t%e eDception of C&=*$. is ma-e up of

2iomarers -isco'ere- t%rou% mass spectrometr(: 2eta* microlo2ulin.

transferrin. transt%(retin. an- apolipoprotein4*.4>K,Barious stu-ies %a'e 2een

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pu2lis%e- e'aluatin t%e eLecti'eness of 1MI. 1OM&. an- OB&=. as /ell as

ot%er strateies to %elp -elineate t%e lieli%oo- of malinanc( in t%e settin

of a pel'ic mass, Ta2le = pro'i-es a summar( of 'arious alorit%ms an-

assa(s use- to pre-ict lieli%oo- of malinanc(,

OB&= an- 1OM& eac% %a'e 2enets an- -isa-'antaes, Prospecti'e multi

institutional trials an- cost2enet anal(sis are nee-e- 2efore -eniti'e

conclusions can 2e -ra/n rear-in t%ese tests>4K,Ta2le * lists sensiti'ities

an- specicities for 'arious mo-alities in t%e settin of a pel'ic mass,#ase-

on a'aila2le -ata. OB&= an- 1OM& liel( %a'e similar sensiti'ities. 2ut 1OM&

appears to %a'e reater specicit( )@$A vs4>A+ /%ic% ma( impact cost

eLecti'eness an- referral patterns from eneral (necoloists reticent to

lose patients /it% 2enin masses to (necoloic oncoloists $>K, OB&=. 2ase-

larel( on mass spectrometr( /it% proteomics. an- 1OM&. ma-e possi2le 2(

t%e incorporation of a microarra( eneeDpression 2ase- -isco'er( in HE4.

represent %opeful a-'ancements in t%e a2ilit( to i-entif( /omen /it%

malinanc( earlier t%an %a- 2een in t%e past, T%ese are not screenin tests

for t%e eneral population. 2ut represent potential tools to furt%er triae of

/omen to t%e appropriate pro'i-ers once t%e -ecision for surical

inter'ention %as 2een ma-e,Barious ot%er 2iomarers an- 2iomarer panels are currentl( un-er

-e'elopment for 2ot% t%e pre-iction of malinanc( in t%e settin of a pel'ic

mass an- in as(mptomatic /omen, Ta2le > lists 'arious sinle 2iomarer an-

multi2iomarer panels /it% sensiti'ities an- specicities for o'arian cancer

-etection, &n important consi-eration /it% all of t%ese tests is t%e ultimate

nee- to -emonstrate 2enet for patients t%rou% re-uction in mor2i-it( an-

mortalit( /%ile minimiin %arm, T%e a-'ancements of tec%nolo( com2ine-

/it% our eDponentiall( ro/in no/le-e of t%e %uman FomesG %a'e

outpace- our a2ilit( to relia2l( test t%ese -isco'eries t%rou% clinical settins

in a timel( fas%ion,

A#&A3 $ G#!6 I/ IA#. )I3C7

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Hi% t%rou%put tec%nolo( in conunction /it% t%e Cancer enome &tlas

%as no/ ma-e it possi2le to com2ine multipleD assa(s /it% -ata from t%e

proteome. enome. meta2olome. an- transcriptome, "it%in proteomics.

2iomarer panels %a'e 2een -e'elope- in an attempt to increase sensiti'it(

for o'arian cancer -etection -ue to t%e %eteroeneous mae up of su2t(pes

)Ta2le >+, #iomarer -isco'er( in proteomics is usuall( 2ase- on t/o

-imensional el electrop%oresis. mass spectrometr( )MS+. an-Qor protein

microarra(s in com2ination /it% 2ioinformatics anal(sis6$K, MS /it% matriD

assiste- laser -esorption an- ioniation time of i%t )M&!5ITO3+ an-

surfaceen%ance- laser -esorption an- ioniation time of i%t )SE!5ITO3+

allo/ for t%e entire protein complement of a patient sample to 2e e'aluate-

in rapi- %i% t%rou%put fas%ion=*.64K, Protein microarra(s can 2e use- to

prole t%e proteome of cell populations usin antienanti2o-(

interactions66K, Protein microarra(s are ma-e up of t/o maor classes: )=+

for/ar-p%ase arra(s )3P&+ /it% anti2o-ies arra(e- an- pro2e- /it% cell

l(sates an- )*+ re'ersep%ase arra(s )1P&+ /it% cell l(sates arra(e- an-

pro2e- /it% anti2o-ies6$K,

7nfortunatel(. proteomics %as not resulte- in t%e maor 2reat%rou%s

pre'iousl( anticipate-, &n important consi-eration %ere is t%e 2ioloicalsamples use- /%en i-entif(in potential 2iomarers, Barious stu-ies %a'e

-emonstrate- protein 2iomarers perform 'er( -iLerentl( in t%e -etection of

o'arian cancer /%en anal(e- in prospecti'el( collecte- samples from

as(mptomatic [email protected]?K, 3uture proteomic -isco'er( ma( 2est focus on

samples from patients prospecti'el( follo/e- until -ianosis in larer

population 2ase- trials, Incorporation of met%o-s aime- at -epletion of

a2un-ant serum proteins suc% as acute p%ase reactants. an- t%e use of

multipleD 2ea-2ase- immunossa(s ma( allo/ for i-entication of lo/

a2un-ance or lo/ concentration proteins not pre'iousl( i-entie-=*K,

MS continues to ser'e as an important tool to eDplore t%e t%ousan-s of

proteins rele'ant to o'arian cancer an- %as no/ 2een eDten-e- to use in

l(comics. meta2olomics. M&!5IMS imain. an- autoanti2o-( sinatures

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for 2iomarer -isco'er(69K,l(cos(lation or t%e a--ition of car2o%(-rates to

nascent proteins is a common posttranslational mo-ication t%at is

potentiall( altere- in a malinant state69@=K, T%ere is e'i-ence to in-icate

'arious %istoloic su2t(pes of o'arian cancer eD%i2it -iLerent

l(coproteins@*K, T%is is encourain i'en t%e sinicant %eteroeneit( of

o'arian cancer, T%e -iLerences seen in l(comics ma( assist in screenin

alorit%ms /%ic% can 2e -e'elope- /it% t%is %eteroeneit( in min-,

E'aluation of t%e meta2olome t%rou% MS %as -emonstrate- -iLerences in

meta2olites in patients /it% an- /it%out epit%elial o'arian cancer@>.@4K,

EDistin concerns /it% t%e stu-( of meta2olites inclu-e t%e sinicant

'ariation in meta2olic response an- eDtensi'e 2iotransformation from t%e

site of malinanc( to ui-s suc% as serum or plasma@$K, Stu-( of t%e

pepti-ome /it%in t%e lo/molecular /ei%t proteome in o'arian cancer %as

2een limite- 2( t%e potential loss of pepti-es 2oun- to carrier proteins

-urin sample processin. alt%ou% attempts %a'e 2een ma-e to mitiate

t%is /it% isolation an- enric%ment of carrier proteins prior to MS

e'aluation69.@6K,O'arian cancer -ianoses ma( also 2e ai-e- /it% t%e uses of

antitumor autoanti2o-( sinatures an- M&!5IMS imain %o/e'er. t%ese

areas of researc% are preliminar( /it% MS@@.@?K

,Separate from t%e use of MS. t%ere is a ro/in role for micro1N&s in t%e

-e'elopment of o'arian cancer 2iomarers@9K,Micro1N&s are a class of small

nonco-in 1N&s /%ic% impact ene eDpression 2( taretin multiple

messener 1N&s an- trierin translation repression an-Qor 1N&

-era-ation?0K, &2errant eDpression of micro1N&s in o'arian cancer in-icate

t%e( ma( act as a no'el class of oncoenes or tumorsuppressor enes @9K,

3i'e micro1N&s )mi1*00a. mi1=00. mi1=4=. mi1*002. an- mi1*00c+

%a'e 2een foun- to 2e consistentl( -iLerentiall( reulate- in epit%elial

o'arian cancer an- ma( assist in t%e -e'elopment of 2iomarers?=K,T%e

future is promisin /it% t%ese tec%ni8ues %o/e'er. 'ali-ation strateies an-

appropriate patient samples are 'ital to impro'in success in clinical testin,

No in-i'i-ual 2iomarer or 2iomarer panel %as 2een -e'elope- /%ic% meets

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t%e sensiti'it(. specicit(. an- PPB criteria -esire- for screenin in a eneral

population,

IAGI/G

T%ere %as 2een an immense eLort place- in t%e e'aluation of screenin /it%

ra-ioloic tec%nolo(, & s(stematic approac% to t%e -ianosis of o'arian

tumors /it% imain is necessar( i'en t%e maorit( of /omen %a'e 2enin

lesions. an- unnecessar( inter'entions s%oul- 2e a'oi-e- /it%out placin

patients at riss for a-'ance- stae -isease?*K,&'aila2le imain mo-alities

inclu-e ultrasoun-. compute- tomorap%( )CT+. manetic resonance

imain )M1I+. an- =?3uoro-eoD(lucose positron emission tomorap%(

)35PET+, Pel'ic ultrasoun- %as 2een t%e most stu-ie- imain mo-alit( in

o'arian cancer screenin, Of 4?0$> postmenopausal /omen in t%e

ultrasoun- roup of t%e 7nite- Rin-om Colla2orati'e Trial of O'arian Cancer

Screenin )7RCTOCS+. 4>6@ as(mptomatic /omen )9,=ACI: ?,?A9,>A+ %a-

a2normal a-neDal morp%olo( /it% an o'erall a2solute ris of epit%elial

o'arian cancer of =,0?A )9$ACI: 0,@9A=,4>A+ an- a = in ** ris of

epit%elial o'arian cancer if t%e a2normal n-ins inclu-e- soli- elements?>K,

In a sinle arm prospecti'e screenin co%ort. t%e 7ni'ersit( of Rentuc(O'arian Cancer Screenin Trial. as(mptomatic /omen *$ (ears or ol-er /it%

a -ocumente- famil( %istor( of o'arian cancer an- as(mptomatic /omen $0

(ears or ol-er /ere screene- /it% annual trans'ainal ultrasoun-?4K, Serial

ultrasonoarap%( in t%is trial -emonstrate- man( o'arian a2normalities

resol'e in follo/ up: 6>,*A of /omen /it% an initiall( a2normal ultrasoun-

/ere foun- to %a'e resolution on su2se8uent imain ?$K, O2ser'ation /it%

serial imain ma( %elp impro'e positi'e pre-icti'e 'alue an- -ecrease false

positi'e results in screenin trials?$K, Of >@*9> /omen /%o un-er/ent

annual screenin. t%e 'e(ear -iseasefree sur'i'al rate for /omen /it%

o'arian cancer in t%e screenin roup. inclu-in t%ose /%o -e'elope-

o'arian cancer /it%in one (ear of a normal ultrasoun- )false neati'e+. /as

@4,?A 6,6A, In contrast. a roup of unscreene- /omen /it% o'arian

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cancer treate- at t%e same institution /it% t%e same surical an-

c%emot%erapeutic protocols %a- a 'e(ear -isease free sur'i'al of $>,@A

*,>A. P'alue 0,0=?6K, 7ltrasoun- screenin -oes not impact -iseasefree

sur'i'al 2( itself, 7ltimatel(. t%e oal of ultrasoun- screenin is to i-entif(

patients /it% earl( stae -isease /%o can 2e treate- 2efore t%e malinanc(

2ecomes a-'ance-, "%ile t%e results from t%is stu-( are encourain. t%e

mortalit( 2enet ma( %a'e 2een impacte- 2( a %ealt%( 'olunteer eLect an-

lea- time -etection rat%er t%an impact on t%e natural %istor( of o'arian

cancer?@K,

&lt%ou% screenin in an as(mptomatic population ultimatel( pro'i-es t%e

2est opportunit( to impro'e sur'i'al in /omen /it% o'arian cancer. t%ere

%as 2een proress ma-e in t%e -e'elopment of imain alorit%ms -esine-

for t%ose /omen /it% a no/n a-neDal mass, T%e International O'arian

Tumor &nal(sis )IOT&+ roup %as -e'elope- 'arious approac%es to

c%aracterie a-neDal masses as malinant or 2enin /it% ultrasoun-

ui-elines, T%ese approac%es can 2e -i'i-e- into t/o strateies: t%e rst

consistin of ris pre-iction /it% t/o loistic reression mo-els )!1 = an-

!1*+ 2ase- on -emorap%ic an- ultrasoun- 'aria2les )Ta2le =+. an- t%e

secon- 2ase- on simple ultrasoun- features t%at are -escriptors of 2enin ormalinant masses??K, In /omen /it% a pel'ic mass t%e sensiti'it( an-

specicit( of 1OM& an- t%e 1MI /ere compare- to su2ecti'e assessment 2(

sille- ultrasonorap%ers in a prospecti'e co%ort stu-( of /omen?9K, T%e

sensiti'it( of 1OM&. 1MI. an- eDpert ultrasonorap%ers /ere ?4,@A )@@,9A

to 90,0A+. @6,0A )6?,4A to ?*,6A+. an- 96,@A )9*,4A to 9?,9A+

respecti'el(. an- t%e specicit( /as @6,?A )@0,@A to ?*,*A+. 9*,4A )??,=A

to 9$,$A+. an- 90,*A )?$,$A to 9>,@A+ respecti'el(?9K, eneralia2ilit( of

t%ese results ma( not 2e possi2le 2ase- on its location. t%e co%ort. an- t%e

ultrasonorap%ers use-, T%e stu-( too place at one sinle tertiar( care

center in Europe /it% eDperience- ultrasonorap%ers an- a %i% pre'alence

of malinant -isease in t%e co%ort?9K,

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In a -iLerent stu-(. a crosssectional co%ort of >60 patients /it% a-neDal

masses un-eroin surer( /as retrospecti'el( e'aluate- /it% 1OM& an-

!1*90K,T%is stu-( -emonstrate- -ecrease- sensiti'it( an- specicit( for

1OM& vs !1* in 2ot% premenopausal an- postmenopausal patients. /it%

o'erall sensiti'it( ?4,0A vs 9>,?A. an- specicit( ?0A vs ?=,9A.

respecti'el(90K, "%ile t%is result in-icates !1* ma( 2e a more eLecti'e

screenin test in t%e settin of a-neDal mass. prospecti'e ran-omie-

control trials are nee-e- 2efore conclusions can 2e ma-e rear-in t%e use

of alorit%ms /%ic% inclu-e 2iomarers suc% as HE4 an- C&=*$ )1OM&+ vs

ultrasoun-2ase- pre-iction mo-els suc% as !1*, Ta2le * lists sensiti'ities

an- specicities for 'arious mo-alities in t%e settin of a pel'ic mass,

Currentl( no prospecti'e ran-omie- stu-ies support t%e use of imain as

a sinle strate( in screenin for o'arian cancer, &t t%is time. i'en

ultrasoun- is relati'el( ineDpensi'e. a'aila2le /i-el(. an- can pro'i-e tissue

specic information /it% a presumpti'el( risfree tec%nolo( it is t%e

met%o- of c%oice for initial e'aluation of an a-neDal mass an- estimatin

ris of malinanc(?*K, In as(mptomatic postmenopausal /omen. t%e

ultrasoun- screenin arm results of t%e 7RCTOCS eDpecte- in *0=$ /ill %elp

eluci-ate t%e role of ultrasoun- in population2ase- screenin strateies, &tt%is time is it unliel( ultrasoun- /ill sinicantl( re-uce mortalit( in primar(

screenin. 2ut it ma( 2e eDtremel( important in re-ucin false positi'e rates

in multimo-alit( screenin9=K, EDistin ultrasoun-2ase- strateies

e'aluatin t%e lieli%oo- of malinanc( in t%e settin of a no/n a-neDal

mass are 2ase- on t%ose /%o %a'e alrea-( 2een sc%e-ule- for surer(,

Comparati'e prospecti'e stu-ies are nee-e- to -etermine ecac( an- eLect

on sur'i'al in /omen /%o %a'e surer( 2ase- on pre-iction mo-els usin

propose- ultrasoun-2ase- strateies /it% an- /it%out 2iomarers suc% as

C&=*$ an- HE4,

I)AI8 3C#&&/I/G

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T%e promisin results of imain in population2ase- screenin for o'arian

cancer %a'e le- to lare scale multimo-alit( strateies, Prior prospecti'e

stu-ies -emonstratin C&=*$ an- ultrasoun- /ere feasi2le screenin

mo-alities %a'e i'en /a( to prospecti'e ran-omie- multimo-alit(

screenin trials in'ol'in ultrasoun-. serum 2iomarers. an- ris calculations

usin patient -emorap%ics9*.9>K, T%e Prostate. !un. Colorectal. an- O'arian

Cancer Screenin Trial )P!CO+ is a multicenter ran-omie- control trial of

@?*=6 as(mptomatic /omen ae- $$ to @4 (ears /%o un-er/ent

multimo-alit( screenin or usual care 2et/een No'em2er =99> an- Jul(

*00= /it% manaement of positi'e screens left to t%e -iscretion of t%e

patients p%(sician94K, Multimo-alit( screenin consiste- of annual testin

for t%ree (ears /it% trans'ainal ultrasoun- an- serum C&=*$ /it% a cutoL

of >$ 7Qm! follo/e- 2( C&=*$ alone for an a--itional t/o (ears 94K,&fter four

roun-s of screenin. t%e PPB an- cancer (iel- per =0000 /omen screene- in

t%e multimo-alit( screenin arm remaine- similar across screenin roun-s at

=,0A to =,>A an- 4,@ to 6,* cancers respecti'el( /it% t%e o'erall ratio of

sureries to screen-etecte- cancers =9,$ to =9$K, &fter a me-ian follo/ up of

=*,4 (ears )*$t%A to @$t%A. =0,9 to =>,0+. no mortalit( 2enet /as foun- /it%

com2ination trans'ainal ultrasoun- an- C&=*$ usin an a2solute cutoL:==? -eat%s -ue to o'arian cancer )>,= per =0000 person(ears+ in t%e

inter'ention roup an- =00 -eat%s )*,6 per =0000 person(ears+ in t%e usual

care roup )mortalit( rate ratio. =,=? 9$ACI: 0,?*=,@=+96K,

T%e Japanese S%iuoa Co%ort Stu-( of O'arian Cancer Screenin is a

ran-omie- control trial of ?*4?@ lo/ ris postmenopausal /omen 2et/een

=9?$ an- =999 /it% t%e inter'ention arm consistin of annual ultrasoun- an-

C&=*$ /it% a cutoL 'alue9@K,T%e strate( ac%ie'e- a sensiti'it( of @@,=A

an- specicit( of 99,9A /it% a nonsinicant -iLerence in t%e proportion of

stae I o'arian cancers i-entie-. 6>A in t%e screene- roup vs >?A in t%e

control roup. P'alue U 0,**?$9@K, Mortalit( results from t%is trial %a'e not

(et 2een pu2lis%e- an-. as suc%. conclusions cannot 2e -ra/n from t%is trial

rear-in t%e 2enet of screenin in an as(mptomatic population,

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T%e 7RCTOCS is a ran-omie- prospecti'e multiarm o'arian cancer

screenin stu-( in t%e 7nite- Rin-om, T%is trial. ma-e up of *0*6>? post

menopausal /omen ae- $0 to @4. ran-omies /omen in a *:=:= format to

t%ree arms: )=+ control )*+ annual screenin /it% ultrasoun- an- )>+ a

multimo-alit( strate( t%at taes a-'antae of 1OC& to triae /omen to

'arious su2strateies9?K, T%ese su2strateies inclu-e trans'ainal ultrasoun-

an-Qor repeat C&=*$ at -ene- time points 9?K, In t%e pre'alence screen of

t%e 7RCTOCS. ultrasonorap%( alone /as compare- to multimo-alit(

screenin )1OC& as a primar( test follo/e- 2( trans'ainal ultrasoun- as a

secon-ar( test or repeat C&=*$ if in-icate-+, "it% rear- to primar( in'asi'e

epit%elial an- tu2al cancers. t%e multimo-alit( screenin arm -emonstrate-

a %i%er specicit( compare- to t%e ultrasonorap%( arm )99,?A vs9?,*A+.

P'alue 0,00=. /%ile t%e -iLerence in sensiti'it( /as not statisticall(

sinicant )?9,4A vs ?4,9A+. P'alue U 0,$649?K,

& sinlearm prospecti'e co%ort stu-( of 40$= a'eraeris

postmenopausal /omen in t%e 7nite- States /as performe- o'er == (ears

usin a t/ostae o'arian cancer screenin strate( )C&=*$ interprete-

t%rou% 1OC& /it% su2se8uent repeat C&=*$ or trans'ainal ultrasoun- as

in-icate-+ /it% a PPB of 40A for in'asi'e o'arian cancer an- specicit( of99,9A )9$ACI: 99,@A=00A+=K,T%e results from 2ot% t%e 7RCTOCS an- t/o

stae strate( in t%e 7nite- States in-icate t%e use of 1OC& to interpret

C&=*$ ma( 2e eLecti'e in triain /omen to su2se8uent follo/up

cateories t%at impact 2ot% screenin outcomes,

"%en comparin t%e 7RCTOCS pre'alence screen results to t%e P!CO trial

results. 2ot% t%e 7RCTOCS multimo-alit( arm )?9,4A vs $=,@A+ an- t%e

ultrasoun- arm )@$,0A vs6@,4A+ %a- %i%er sensiti'ities99K, "%en C&=*$

'alues /ere retrospecti'el( e'aluate- /it% 1OC& /it%in t%e P!CO -ata set no

mortalit( 2enet /as seen 2estcase an- staes%ift scenarios resulte- in *$

an- =9 -eat%s pre'ente- /it% 1OC& for relati'e riss of 0,90 )9$ACI: 0,69F

=,=@+ an- 0,9$ )9$ACI: 0,@4F=,*>+. respecti'el(=00K, In a--ition to t%e use of

a2solute cutoL 'alue for C&=*$. ot%er concerns %a'e 2een raise- rear-in

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t%e PC!O trial -esin inclu-in lea'in manaement of positi'e screens to

t%e -iscretion of t%e treatin p%(sician an- 40,6A of o'arian cancer

-ianosis too place after t%e screenin en-e- =0=K, 7se of an in-i'i-ualie-

alorit%m t%at tracs a patient o'er time /ill liel( pro'i-e t%e 2est

com2ination of sensiti'it(. specicit(. an- PPB, 3or t%is reason. t%e 7RCTOCS

an- its incorporation of 1OC& in t%e multimo-alit( screenin arm. represents

t%e 2est opportunit( (et to i-entif( a potential screenin strate(, T%e results

from t%e nal mortalit( anal(sis in t%e 7RCTOCS /ill 2e reporte- in *0=$ an-

pro'i-e sinicant insi%t into /%et%er population2ase- screenin in

as(mptomatic /omen is possi2le /it% currentl( a'aila2le imain an-

2iomarers,

38*%A3&) 3C#&&/I/G

Screenin eLorts in o'arian cancer %a'e larel( focuse- on as(mptomatic

/omen in t%e eneral population or /omen /it% no/n a-neDal masses

re8uirin furt%er -ic%otomiation for treatment purposes, "omen /it%

o'arian cancer -o %a'e p%(sical s(mptoms suc% as a2-ominal pain. 2loatin.

an- 2o/el irreularit( t%at ma( ser'e as a potential trier for -ianosis, In a

casecontrol stu-( comparin /oman /it% o'arian cancer to ae an- racematc%e- controls. more t%an 90A of cases reporte- at least one s(mptom

an- s(mptoms /ere cite- as t%e most common reason for t%e -octor 'isit

lea-in to -ianosis )@4A+=0*K, T/o feasi2ilit( stu-ies %a'e 2een performe-

-emonstratin s(mptom2ase- screenin in /omen is possi2le=0>.=04K, &

s(mptom in-eD /as create- /it% a sensiti'it( of $6,@A for earl( stae

-isease an- @9,$A for a-'ance- stae -isease. an- a specicit( of 90A for

/omen reater t%an $0 (ears of ae an- ?6,@A for /omen less t%an $0

(ears of ae=0$K,#ase- on patient inter'ie/s performe- /it% ?=* /omen /it%

o'arian cancer an- =>=> population2ase- controls. t%e s(mptom in-eD an-

s(mptoms esta2lis%e- in consensus recommen-ations %a- a PPB of 0,6A

=,=A o'erall an- less t%an 0,$A for earl(stae -isease =06K, T%e i-entication

of specic s(mptoms associate- /it% o'arian cancer %as 'alue. 2ut

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reconition of s(mptoms alone /ill not sinicantl( impro'e o'erall sur'i'al

from o'arian cancer=0@K, & cross sectional stu-( of =60 /omen e'aluate-

/it% use of t%is s(mptom in-eD foun- t%at t%e a--ition of C&=*$. HE4. or t%e

1OM& to a positi'e s(mptom in-eD increase- PPB /%en -eterminin

malinanc( vs2enin process in patients /it% a no/n a-neDal mass=0?K, &t

t%is time. i'en no eLecti'e screenin tool %as 2een pro'en in a prospecti'e

mo-el. p%(sicians s%oul- continue to -iscuss potential s(mptoms /it% t%eir

patients in an eLort to increase selfa/areness rear-in /arnin sins for

o'arian cancer,

3C#&&/I/G I/ 6IG6 #I3. *AI&/3

3amilial enetic pre-isposition maes up approDimatel( =0A of o'arian

cancers /it% ermline mutations in BRCA1QBRCA2 an- mismatc% repair

)MM1+ enes in !(nc% s(n-rome 2ein t%e most common =09K, "omen /it%

#1C&= an- #1C&* mutations %a'e a cumulati'e lifetime ris of o'arian

cancer of 40AF$0A an- *0AF>0A respecti'el(. /%ile t%e 5N& MM1 enes.

inclu-in t%ose t%at pre-ispose to !(nc% s(n-rome. result in a cumulati'e

lifetime ris of o'arian cancer ranin from 6,@A to =*A ==0K, &s seen /it%

impro'e- sur'i'al in #1C&associate- o'arian cancers. in%erite- o'ariancancers ma( %a'e 2ioloical -iLerences /%ic% allo/ treatment at time of

screen -etection to %a'e sinicant 2enet===K,

Currentl(. no prospecti'e stu-ies eDist /%ic% -emonstrate a mortalit(

2enet 2( screenin %i% ris as(mptomatic patients, T%e 7nite- Rin-om

3amilial O'arian Cancer Screenin Stu-( )3OCSS+ %as recentl( complete- a

p%ase = trial in /%ic% >$6> /omen at reater t%an a =0A ris of o'arian or

fallopian tu2e cancer /ere screene- /it% annual trans'ainal ultrasoun- an-

C&=*$ for a mean of >,* (ears=09K, Sensiti'it( for -etection of inci-ent

o'arian an- fallopian tu2e cancers at one (ear after last annual screen /as

?=,>A )9$ACI: $4,>A96,0A+ if occult cancers /ere classie- as false

neati'es. an- t%e PPB /as *$,$A )9$ACI: =4,>A40,0A+ /it% onl( four

/omen un-eroin surer( for eac% case of -etecte- cancer=09K, &s part of

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p%ase II of t%e 3OCSS. screenin fre8uenc( /ill increase to e'er( four

mont%s. 1OC& /ill 2e incorporate- into t%e -ecision tree. an- t%e t%res%ol-

an- /orup for repeat tests /ill 2e per protocol, T%e (necoloic Oncolo(

roup )O+ an- Cancer enetics Net/or %a'e recentl( complete- O

=99. a prospecti'e stu-( screenin /omen at %i% ris of o'arian cancer /it%

t%e use of 1OC& an- trans'ainal ultrasoun-==*K,

3or /omen /it% Here-itar( #reastQO'arian Cancer S(n-rome /%o %a'e not

un-erone ris re-ucin 2ilateral salpinooop%orectom(. t%e National

Compre%ensi'e Cancer Net/or recommen-s screenin /it% trans'ainal

ultrasoun- an- C&=*$ e'er( 6 mo startin at ae >0 or $ to =0 (ears prior to

t%e earliest ae at -ianosis of o'arian cancer in relati'es ==>K, i'en t%e

potential 2ioloic -iLerences associate- /it% %i% ris patients. screenin

as(mptomatic /omen /it%in t%is population ma( %a'e reater 2enet t%an

in t%e eneral population, T%e 3OCSS p%ase II results an- O =99 /ill

pro'i-e e'i-ence rear-in potential screenin 2enets an- assist /it%

strate( optimiation,

$#& C/3I)AI/3

5espite t%e tec%noloical a-'ances /%ic% %a'e 2een ma-e. our currentapproac% to screenin strateies in o'arian cancer %as in%erent -iculties

/%ic% nee- to 2e o'ercome, 5irectl( impactin our a2ilit( to screen

as(mptomatic /omen for o'arian cancer is t%e e'ol'in reclassication of

t%is %eteroeneous roup of tumors, 1esults from t%e recentl( complete-

stu-( of serous o'arian cancer t%rou% t%e Cancer enome &tlas

-emonstrate sinicant enomic %eteroeneit( e'en /it%in one su2t(pe of

epit%elial o'arian cancer. %i% ra-e serous carcinoma=>K,

&s in colorectal cancer an- cer'ical cancer. i-entication of a precursor

lesion or lesions /ill impro'e our a2ilit( to screen for t%e -isease, T%ese

precursor lesions are liel( 'arie- 2ase- on t%e su2t(pe of o'arian cancer,

"it% %i% ra-e serous carcinoma. a precursor lesion ma( -e'elop in t%e

m2ria of t%e fallopian tu2e )serous tu2al intraepit%elial carcinoma also

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no/n as a STIC+ or in an o'arian cortical inclusion c(st -urin implantation

of m2rial epit%elium on t%e -enu-e- o'arian surface /it% o'ulation ==4K,

enetic e'aluation lins 2ot% clear cell an- en-ometrioi- carcinomas to

precursor lesions /it%in en-ometriosis==$K, & ne/ mo-el t%at consi-ers 2ot%

morp%oloic an- molecular c%aracteristics separates epit%elial o'arian

tumors into t/o cateories: t(pe I tumors are lo/ra-e serous. lo/ra-e

en-ometrioi-. clear cell. an- mucinous tumors /%ic% usuall( present as lare

c(stic masses /it%in one o'ar(. /%ile t(pe II tumors are compose- of %i%

ra-e serous. %i%ra-e en-ometrioi-. malinant miDe- meso-ermal

)carcinosarcoma+. an- un-iLerentiate- carcinomas /%ic% commonl( present

as a-'ance- stae -isease==6K,

& focus on i-entication of t%e oriins of t%ese roups of tumors /ill lea-

to more eLecti'e screenin strateies in an as(mptomatic population, 3or

eDample. e'aluatin 2loo- samples of patients foun- to %a'e STICs at t%e

time of prop%(lactic 2ilateral salpinooop%orectom( ma( pro'e useful in

i-entif(in 2iomarers for preclinical serous carcinoma=*K, T(pe I tumors ten-

to 2e eneticall( sta2le /it% mutations in 'arious enes inclu-in PTEN.

#1&3. 2etacatenin an- R1&S. /%ile t(pe II tumors %a'e a %i% le'el of

enetic insta2ilit( an- commonl( %a'e a TP$> mutation==@K

, #iomarerpanels an- multimo-alit( screenin ma( ac%ie'e 2etter sensiti'it( an-

specicit( /it% screenin strateies 2ase- on -iLerences in 2ot% cell oriin

an- enetics amon t%ese 'arie- tumors,

In a--ition to t%e 'arie- oriin an- molecular %eteroeneit(. t%e time

course of o'arian cancer -e'elopment still elu-es un-erstan-in, T%e time

re8uire- for -e'elopment of in'asi'e -isease or proression from stae I to

stae III remains unno/n==?K, T%is information is liel( specic to t%e 'arious

o'arian tumors. an- impro'e- cateoriation t%rou% molecular a-'ances

/ill 2etter eluci-ate t%e time course of -isease, 3or eDample. t(pe I tumors

appear to follo/ a -e'elope- pat% of transformation /it% step/ise

proression from a 2enin lesion to a malinant tumor==9K, It %as 2een

propose- t%at o'arian cancer screenin strateies s%oul- focus on t(pe II

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tumors /it% t%e oal to i-entif( lo/ 'olume -isease rat%er t%an earl( stae.

as %i% ra-e serous carcinomas represent @$A of all o'arian cancers an-

result in t%e maorit( of -eat%s==>.=*0K, !o/ 'olume a-'ance- stae -isease

ma( 2e more easil( resecta2le at t%e time of tumor -e2ulin. 2ut a-'ance-

stae patients still %a'e a /orse pronosis t%an t%ose patients /%o are

treate- /it% earl( stae -isease, I-entication of earl( stae -isease /ill

%a'e t%e reatest 2enet on mortalit(. an- /ill re8uire a s%ift from current

approac%es to incorporate a-'ances ma-e in t%e un-erstan-in of tumor

%eteroeneit( in t%is malinanc(,

3i'e p%ases of 2iomarer -e'elopment %a'e 2een pre'iousl( propose-: )=+

t%e preclinical eDplorator( p%ase )*+ t%e clinical assa( an- 'ali-ation stae

)>+ t%e retrospecti'e lonitu-inal stu-( )4+ prospecti'e screenin e'aluation

an- )$+ ran-omie- control trials=*=K, T%e preclinical eDplorator( p%ase must

tae a-'antae of -e'elopments in %i%t%rou%put screenin tec%noloies

to more eLecti'el( i-entif( potential 2iomarers amon t%e t%ousan-s of

can-i-ate molecules, 3or eDample. a 2iomarer -isco'er( platform /%ic%

incorporates proteome an- transcriptome comparisons of serum. tissue.

ascites. cancer cell lines. an- animal mo-els t%rou% mass spectrometr( an-

microarra( tec%nolo( maes it possi2le to tae a-'antae of t%eseimmense -ata sets=**K, 3olate receptor = protein. -e'elope- t%rou% use of

proteomics. transcriptomics. an- 2ioinformatics. -emonstrates t%e

incorporation of 'arious tec%noloic platforms t%at mae it possi2le to

i-entif( ne/ 2iomarers=*>K,

3urt%er eLorts must 2e -e'ote- to t%e collection of appropriate patient

specimens in prospecti'e trials, "it%in o'arian cancer. t%e maorit( of

2iomarers are e'aluate- /it% patient samples taen at t%e time of

-ianosis. usuall( a-'ance- stae -isease, It is not surprisin t%at

2iomarers -isco'ere- in an a-'ance- -isease settin -o not perform /it%

t%e same sensiti'it( or specicit( in a prospecti'e trial in /%ic% t%e oal is

-ianosis of earl( stae -isease, Prospecti'el( collecte- samples in

as(mptomatic /omen pro'i-e a 2etter un-erstan-in of t%e a2ilit( of

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can-i-ate 2iomarers to -etect cancer prior to p%(sical s(mptoms=*>K,T%e

prospecti'e specimen collection retrospecti'e 2lin-e- e'aluation )P1o#E+

stu-( -esin man-ates samples are collecte- prospecti'el(. store- in a

similar fas%ion. an- once outcome status is -ene-. use- to 'ali-ate

2iomarers in a 2lin-e- fas%ion /it% ran-oml( selecte- cases an-

controls=*$K, i'en t%e lo/ pre'alence of o'arian cancer in t%e eneral

population. poolin of resources is necessar( to mae a-'ances in 2iomarer

-isco'er(, T%e National Cancer Institutes Earl( 5etection 1esearc% Net/or

assists /it% -e'elopment of prospecti'e patient samples un-er t%e P1o#E

stu-( -esin=*6K, P!CO samples %a'e 2een use- in t%is fas%ion to test

potential [email protected]?K, 5e'elopment of a lare scale collection of

samples prospecti'el( in as(mptomatic /omen on a national or international

le'el /oul- pro'i-e t%e a2ilit( to 'ali-ate 2iomarers an- pre-ict lea- time in

t%e -isco'er( of o'arian cancer prior to p%(sical s(mptoms )3iure =+,

T%e nal p%ase of 2iomarer -esin is a ran-omie- control trial. /it% t%e

oal of o'arian cancer screenin to -emonstrate a mortalit( 2enet in t%e

stu-ie- population, T%is mortalit( 2enet must 2e consi-ere- in t%e conteDt

of t%e num2er nee-e- to treat to reac% suc% a 2enet, & s(stematic re'ie/

an- metaanal(sis of a'aila2le screenin trials in'ol'in as(mptomatic/omen foun- no re-uction in o'arian cancerspecic or allcause mortalit(

relati'e ris )11+. =,0? 9$ACI: 0,?4=,>? an- =,0 9$ACI: 0,?4F=,>?

respecti'el(K=*@K, "%ile t%is anal(sis -oes not inclu-e results from t%e

7RCTOCS /%ic% /ill not 2e a'aila2le until *0=$. it -oes -emonstrate t%at

prospecti'e trials /it%in current para-ims %a'e faile- to meet maor oals,

In t%e P!CO trial =0?0 /omen un-er/ent surer( in t%e settin of false

positi'e results an- =6> )=$A+ eDperience- a complication96K, #ase- on

re'ie/ of a'aila2le clinical trials. 6A of /omen /it% false positi'e screenin

results eDperience- a se'ere complication /%ile un-eroin surer(=*@K,

T%ese patients un-er/ent potential %arm /it%out 2enet, & mortalit( 2enet

is necessar( to ustif( t%e potential %arm associate- /it% false positi'es, If

t%e 7RCTOCS an-Qor t%e Japanese co%ort fail to s%o/ a 2enet in mortalit(.

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t%is ma( 2e eDplaine- 2( lea- time 2ias in /%ic% slo/ ro/in tumors are

-etecte- more commonl( 2( screenin t%an fast ro/in let%al serous

epit%elial o'arian cancers9=K, T(pe I tumors. /%ic% ten- to 2e slo/ ro/in

an- more in-olent t%an t(pe II tumors. /ere -etecte- t/ice as often as t(pe

II tumors in t%e ultrasoun- arm of t%e 7RCTOCS )>* 2or-erline or t(pe I

tumorsvs=$ t(pe II tumors+ -espite a %i%er pre'alence of t(pe II tumors in

epit%elial o'arian cancer?>K, If t%is same pattern is seen t%rou% t%e

7RCTOCS in *0=$. it is unliel( t%ere /ill 2e a mortalit( 2enet i'en t%e

2etter pronosis associate- /it% t%e maorit( of 2or-erline an- t(pe I tumors

compare- to t(pe II tumors,

"%ile furt%er prospecti'e screenin trials /ill tae place. o'arian cancer

screenin in t%e as(mptomatic eneral population results in potential %arms

/it%out pro'en 2enet at t%is time, ui-elines from t%e &merican Collee of

O2stetrics an- (necolo(. t%e Societ( of (necoloic Oncoloists. t%e

7nite- States Pre'enti'e Ser'ices Tas 3orce. an- t%e &merican Cancer

Societ( -o not recommen- screenin for o'arian cancer in as(mptomatic

lo/ris /omen in t%e eneral population=*?=>0K,

C/C3I/O'arian cancer is -ea-l( at a-'ance- stae. an- as t%e 8uest for an optimal

screenin strate( continues. it is apparent t%ere are riss associate- /it%

false positi'es an- in'asi'e tests, "%en sur'e(e-. ?0A of /omen /it%out

ris factors or s(mptoms for o'arian cancer in t%e 7ni'ersit( of Rentuc(

co%ort felt t%at t%e( /oul- -enitel( /ant to participate in o'arian cancer

screenin startin at ae $0=>=K,Barious a'enues continue to 2e in'estiate-

in o'arian cancer screenin inclu-in imain. protein proles. specic

s(mptoms. an- com2inations of t%ese. as /ell as ot%er mo-alities, &n

eDpan-e- an- s%are- 2io2an of patient specimens collecte- 2efore

-e'elopment of s(mptoms an- a-'ance- -isease is nee-e-, It is /it% t%ese

precious samples t%at %i% t%rou%put tec%nolo( an- %uman FomesG /ill

%a'e t%e most positi'e impact on i-entication of screenin mo-alities,

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Emerin tec%nolo( /ill allo/ science to e'aluate 2ioloical -ata in /a(s

ne'er imaine-, "it% t%e correct poolin of resources. inclu-in prospecti'e

collection of patient specimens. interation of %i% t%rou%put screenin.

an- use of molecular %eteroeneit( in 2iomarer -isco'er(. /e are poise- to

mae proress in o'arian cancer screenin, If /e are pru-ent in trial -esin

an- altruistic in t%e s%arin of resources suc% as 2ioloical samples.

i-entication of an eLecti'e screenin mo-alit( for o'arian cancer is /it%in

our capa2ilities,

#&$&/C&3

= u .6. Sates S. Hernan-e M&. #e-i 5. #e'ers T. !ee-s !. Moore 1.

ranai C. Harris S. Ne/lan- ". &-e(ina O. eLen J. 5ea'ers MT. Sun CC.

Horic N. 3ritsc%e H. #ast 1C, & *stae o'arian cancer screenin strate(

usin t%e 1is of O'arian Cancer &lorit%m )1OC&+ i-enties earl(stae

inci-ent cancers an- -emonstrates %i% positi'e pre-icti'e

'alue, Cancer*0=> 119: >4$4>46= PMI5: *>9?>04@ 5OI:

=0,=00*Qcncr,*?=?>K

* $erlay J. S%in H1. #ra( 3. 3orman 5. Mat%ers C. Parin 5M, Estimates of

/orl-/i-e 2ur-en of cancer in *00?: !O#OC&N *00?, Int JCancer*0=0 12:: *?9>*9=@ PMI5: *=>$=*69 5OI: =0,=00*Qic,*$$=6K

> 3ie;el #. Nais%a-%am 5. Jemal &, Cancer statistics. *0=>, CA Cancer J

Clin*0=> 0 PMI5: *>>>$0?@ 5OI: =0,>>**Qcaac,*==66K

4 3alani #. Santillan &. Va%ura M!. iuntoli 1!. ar-ner J. &rmstron 5R.

#risto/ 1E, Secon-ar( c(tore-ucti'e surer( for localie-. recurrent

epit%elial o'arian cancer: anal(sis of pronostic factors an- sur'i'al

outcome, Cancer*00@ 109: 6?$69= PMI5: =@*=944= 5OI:

=0,=00*Qcncr,**44@K

$ Cannistra 3A, Cancer of t%e o'ar(, N Engl J ed*004 =51: *$=9*$*9

PMI5: =$$909$4 5OI: =0,=0$6QNEJMra04=?4*K

6 6owlader /. Noone &M. Rrapc%o M. ars%ell J. Ne(man N. &lteruse S3.

Rosar( C!. Wu M. 1u%l J. Tatalo'ic% V. C%o H. Mariotto &. !e/is 51. C%en HS.

8/10/2019 9046 Review

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3euer EJ. Cronin R& )e-s+, SEE1 Cancer Statistics 1e'ie/. =9@$*0=0, SEE1

online. cite- *0=>04 &'aila2le from: 71!: %ttp:

QQseer,cancer,o'QcsrQ=9@$X*0=0Q

@ 6olschneider C6. #ere JS, O'arian cancer: epi-emiolo(. 2iolo(. an-

pronostic factors, !emin !urg "ncol*000 19: >=0 PMI5: =0??>0=? 5OI:

=0,=00*Q=09?*>??)*0000@Q0?+K

?Jacobs IJ. Sates SJ. Mac5onal- N. Menon 7. 1osent%al &N. 5a'ies &P.

"oolas 1. Je(araa% &1. Si2le( R. !o/e 5. Oram 5H, Screenin for o'arian

cancer: a pilot ran-omise- controlle- trial, #ancet=999 =5=: =*0@=*=0

PMI5: =0*=@0@9 5OI: =0,=0=6QS0=406@>6)9?+=0*6==K

9 van /a;ell J#. 5ePriest P5. 1ee-( M#. allion HH. 7elan- 31. Pa'li EJ.

Rr(scio 1J, T%e ecac( of trans'ainal sonorap%ic screenin in

as(mptomatic /omen at ris for o'arian cancer, $ynecol "ncol*000 :::

>$0>$6 PMI5: =0?>=>4= 5OI: =0,=006Q(no,*000,$?=6K

=0 ast #C. #re/er M. Vou C. Hernan-e M&. 5ale( M. Ools 1. !u R. !u V.

#a-/ell 5. Mills #. Sates S. V%an V. C%an 5. !os%in &. Wu W, Pre'ention

an- earl( -etection of o'arian cancer: mission impossi2le Recent Results

Cancer Res*00@ 1:4: 9==00 PMI5: =@>0*=?9 5OI: =0,=00@Q9@?>$40

>@696$X9K== /ossov 7. &mneus M. Su 3. !an J. Janco JM. 1e--( ST. 3ariasEisner 1,

T%e earl( -etection of o'arian cancer: from tra-itional met%o-s to

proteomics, Can /e reall( -o 2etter t%an serum C&=*$Am J "%stet

$ynecol*00? 199: *=$**> PMI5: =?46?$@= 5OI:

=0,=0=6Q,ao,*00?,04,009K

=* /olen . !os%in &E, Protein 2iomarers of o'arian cancer: t%e forest

an- t%e trees, &uture "ncol*0=* >: $$@= PMI5: **=490>$ 5OI:

=0,**=@Qfon,==,=>$K

=> , Interate- enomic anal(ses of o'arian carcinoma, Nature*0== 4:4:

6096=$ PMI5: *=@*0>6$K

=4 7au;han 3. Co/ar- JI. #ast 1C. #erc%uc &. #ere JS. #renton J5. Couos

. Crum CC. 5rapin 1. Etema-mo%a-am 5. 3rie-lan-er M. a2ra H. Ra(e

8/10/2019 9046 Review

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S#. !or- CJ. !en(el E. !e'ine 5&. McNeis% I&. Menon 7. Mills #. Nep%e/

RP. Oa &M. Soo- &R. Stronac% E&. "alca H. #o/tell 55. #al/ill 31,

1et%inin o'arian cancer: recommen-ations for impro'in outcomes, Nat

Rev Cancer*0== 11: @=9@*$ PMI5: *=94=*?> 5OI: =0,=0>?Qnrc>=44K

=$ Chen 7!. 1ui #. Rilleen J!. CotY T1. "u ZC. Correa CN, Pat%olo( an-

classication of o'arian tumors, Cancer*00> 9:: *6>=*64* PMI5:

=*@>>=*? 5OI: =0,=00*Qcncr,==>4$K

=6 ast #C. 3eene( M. !aarus H. Na-ler !M. Col'in 1#. Rnapp 1C,

1eacti'it( of a monoclonal anti2o-( /it% %uman o'arian carcinoma,J Clin

Invest=9?= : =>>==>>@ PMI5: @0*?@?? 5OI: =0,==@*QJCI==0>?0K

=@ !eiland $. Martin R. Oe%ler MR. HoLmann P, 5ecip%erin t%e Molecular

Nature of O'arian Cancer #iomarer C&=*$, Int J ol !ci*0=* 1=: =0$6?

=0$?* PMI5: **949??0 5OI: =0,>>90Qims=>0?=0$6?K

=? )avelaar &. 'an Ramp J. Berstraeten 1&. Renemans P, Comparison of

se'en immunoassa(s for t%e 8uantication of C& =*$ antien in serum, Clin

Chem=99? 44: =4=@=4** PMI5: 966$4=?K

=98in !. !lo(- RO, Molecular clonin of t%e C&=*$ o'arian cancer antien:

i-entication as a ne/ mucin. M7C=6,J Biol Chem*00= 2:@=*@>@$

PMI5: ==>69@?= 5OI: =0,=0@4Q2c,M=0>$$4*00K*0 .abawat 3&. #ast 1C. #%an &R. "elc% "1. Rnapp 1C. Col'in 1#, Tissue

-istri2ution of a coelomicepit%eliumrelate- antien reconie- 2( t%e

monoclonal anti2o-( OC=*$, Int J $ynecol Pathol=9?> 2: *@$*?$ PMI5:

6=96>09 5OI: =0,=09@Q00004>4@=9?>0>0000000$K

*=Jacobs I. #ast 1C, T%e C& =*$ tumourassociate- antien: a re'ie/ of t%e

literature, 'um Re(rod=9?9 4: ==* PMI5: *6$=469K

** Craer )!. O[1oure 5J. Bitonis &3. Matulonis 7&. 5io%nson 5&. Sluss

PM. Crum CP. !iu #C, C&=*$ immune compleDes in o'arian cancer patients

/it% lo/ C&=*$ concentrations, Clin Chem*0=0 5?4? 5OI: =0,=>@>Qclinc%em,*0=0,=$>=**K

*>!oolas #*. Zu 3J. Jaco2s IJ. Wu WJ. 5al( !. #erc%uc &. Soper JT. Clare

Pearson 5!. Oram 5H. #ast 1C Jr, Ele'ation of multiple serum marers in

8/10/2019 9046 Review

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patients /it% stae I o'arian cancer,J Natl Cancer Inst=99> >5: =@4?=@$=

PMI5: ?4==*$9 5OI: =0,=09>QnciQ?$,*=,=@4?K

*4Jacobs IJ. Sates S. 5a'ies &P. "oolas 1P. Je(eraa% &. "ei-emann P.

Si2le( R. Oram 5H, 1is of -ianosis of o'arian cancer after raise- serum C&

=*$ concentration: a prospecti'e co%ort stu-(, BJ=996 =1=: =>$$=>$?

PMI5: ?9$6699 5OI: =0,==>6Q2m,>=>,@069,=>$$K

*$ Gentry%ahara@ A. Menon 7, Screenin for o'arian cancer in t%e eneral

population, Best Pract Res Clin "%stet $ynaecol*0=* 2*$6 PMI5:

**=?*4=$ 5OI: =0,=0=6Q,2po2(n,*0==,==,006K

*6 3ates 3J. Menon 7. Mac5onal- N. 1osent%al &N. Oram 5H. Rnapp 1C.

Jaco2s IJ, Calculation of t%e ris of o'arian cancer from serial C&=*$ 'alues

for preclinical -etection in postmenopausal /omen,J Clin "ncol*00> 21:

*06s*=0s PMI5: =*@4>=>6 5OI: =0,=*00QJCO,*00>,0*,9$$K

*@ enon . Sates SJ. !e/is S. 1osent%al &N. 1uLor- #. Si2le( R.

Mac-onal- N. 5a/na( &. Je(araa% &. #ast 1C. Oram 5. Jaco2s IJ, Prospecti'e

stu-( usin t%e ris of o'arian cancer alorit%m to screen for o'arian

cancer,J Clin "ncol*00$ 2=: @9=9@9*6 PMI5: =6*$?09= 5OI:

=0,=*00QJCO,*00$,0=,664*K

*? 6ellstrB I. 1a(craft J. Ha(-en!e-2etter M. !e-2etter J&. Sc%ummer M.McIntos% M. 5resc%er C. 7r2an N. Hellstr\m RE, T%e HE4 )"35C*+ protein is

a 2iomarer for o'arian carcinoma, Cancer Res*00> 69$>@00 PMI5:

=*?>996=K

*9 )ra(in #. 'on Horsten HH. !in W. Mo SC. Crum CP. "elc% "1. Hec%t J!,

Human epi-i-(mis protein 4 )HE4+ is a secrete- l(coprotein t%at is

o'ereDpresse- 2( serous an- en-ometrioi- o'arian carcinomas, Cancer

Res*00$ 9*4K

>0 .irchho C. Ha22en I. I'ell 1. Rrull N, & maor %uman epi-i-(misspecic

c5N& enco-es a protein /it% se8uence %omolo( to eDtracellular proteinase

in%i2itors, Biol Re(rod=99= 45: >$0>$@ PMI5: =6?6=?@ 5OI:

=0,=09$Q2iolrepro-4$,*,>$0K

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>= oore #G. Mac!au%lan S. #ast 1C, Current state of 2iomarer

-e'elopment for clinical application in epit%elial o'arian cancer, $ynecol

"ncol*0=0 119 5OI:

=0,=0=6Q,((no,*009,09,04=K

>* 6uhtinen .. Su'itie P. Hiissa J. Junnila J. Hu'ila J. Ruari H. Set]l] M.

H]ri P. Jalanen J. 3raser J. M]inen J. &uranen &. Poutanen M. Per%eentupa

&, Serum HE4 concentration -iLerentiates malinant o'arian tumours from

o'arian en-ometriotic c(sts, Br J Cancer*009 100: =>=$=>=9 PMI5:

=9>>@*$* 5OI: =0,=0>?Qs,2c,660$0==K

>> oore #G. Miller MC. Stein%oL MM. Sates SJ. !u RH. !am2ertMesserlian

. #ast 1C, Serum HE4 le'els are less fre8uentl( ele'ate- t%an C&=*$ in

/omen /it% 2enin (necoloic -isor-ers,Am J "%stet $ynecol*0=* 20$=,e=>$=,e? PMI5: ***?496= 5OI: =0,=0=6Q,ao,*0==,=*,0*9K

>4 eun; $. 5iaman-is EP. Rulasinam B, 3rom 2enc% to 2e-si-e: -isco'er(

of o'arian cancer 2iomarers usin %i%t%rou%put tec%noloies in t%e past

-eca-e, Biomar) ed*0=* 6*$ PMI5: *>0@$*>9 5OI:

=0,**=@Q2mm,=*,@0K

>$ $erraro 3. #raa 3. !anoni M. #oracc%i P. #ianoli EM. Pante%ini M,

Serum %uman epi-i-(mis protein 4 's car2o%(-rate antien =*$ for o'ariancancer -ianosis: a s(stematic re'ie/,J Clin Pathol*0=> 4*6@=6 5OI: =0,==>6Qclinpat%*0=**0=0>=K

>6 /olen . Belio%atna(a !. Marranoni &. 5e eest R. !omain &. #ast

1C. !os%in &, Serum 2iomarer panels for t%e -iscrimination of 2enin from

malinant cases in patients /it% an a-neDal mass, $ynecol "ncol*0=0 11::

44044$ PMI5: *0>>490> 5OI: =0,=0=6Q,((no,*0=0,0*,00$K

>@ oore #G. #ro/n &R. Miller MC. Sates S. &llar- "J. Berc% T. Stein%oL M.

Messerlian . 5iSil'estro P. ranai CO. #ast 1C, T%e use of multiple no'el

tumor 2iomarers for t%e -etection of o'arian carcinoma in patients /it% a

pel'ic mass, $ynecol "ncol*00? 10>: 40*40? PMI5: =?06=*4? 5OI:

=0,=0=6Q,((no,*00@,=0,0=@K

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>? &n;elen J. Ros HE. "illemse PH. &al-ers J. -e Bries E. Sc%aap'el- M.

Otter 1. 'an -er Vee &, Surer( 2( consultant (necoloic oncoloists

impro'es sur'i'al in patients /it% o'arian carcinoma, Cancer*006 10699?$ 5OI: =0,=00*Qcncr,*=6=6K

>9 7ernooi@ $. Heint P. "itte'een E. 'an -er raaf W, T%e outcomes of

o'arian cancer treatment are 2etter /%en pro'i-e- 2( (necoloic

oncoloists an- in specialie- %ospitals: a s(stematic re'ie/, $ynecol

"ncol*00@ 105: ?0=?=* PMI5: =@4>>4** 5OI:

=0,=0=6Q,((no,*00@,0*,0>0K

40Jacobs I. Oram 5. 3air2ans J. Turner J. 3rost C. ru-insas J, & ris of

malinanc( in-eD incorporatin C& =*$. ultrasoun- an- menopausal status

for t%e accurate preoperati'e -ianosis of o'arian cancer, Br J "%stet

$ynaecol=990 9:: 9**9*9 PMI5: ***>6?4 5OI: =0,====Q,=4@=

0$*?,=990,t20*44?,DK

4= oore #G. McMeein 5S. #ro/n &R. 5iSil'estro P. Miller MC. &llar- "J.

ae/si ". Rurman 1. #ast 1C. Sates SJ, & no'el multiple marer 2ioassa(

utiliin HE4 an- C&=*$ for t%e pre-iction of o'arian cancer in patients /it%

a pel'ic mass, $ynecol "ncol*009 112: 4046 PMI5: =??$=?@= 5OI:

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