9046 review
TRANSCRIPT
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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
mailto:[email protected]:[email protected] -
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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,
<%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$6QNEJMra04=?4*K
6 6owlader /. Noone &M. Rrapc%o M. ars%ell J. Ne(man N. <eruse S3.
Rosar( C!. Wu M. 1u%l J. Tatalo'ic% V. C%o H. Mariotto &. !e/is 51. C%en HS.
-
8/10/2019 9046 Review
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3euer EJ. Cronin R& )e-s+, SEE1 Cancer Statistics 1e'ie/. =9@$*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=* >: $$@= PMI5: **=490>$ 5OI:
=0,**=@Qfon,==,=>$K
=> , Interate- enomic anal(ses of o'arian carcinoma, Nature*0== 4:4:
6096=$ PMI5: *=@*0>6$K
=4 7au;han 3. Co/ar- JI. #ast 1C. #erc%uc &. #ere JS. #renton J5. Couos
. Crum CC. 5rapin 1. Etema-mo%a-am 5. 3rie-lan-er M. a2ra H. Ra(e
-
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S#. !or- CJ. !en(el E. !e'ine 5&. McNeis% I&. Menon 7. Mills #. Nep%e/
RP. Oa &M. Soo- &R. Stronac% E&. "alca H. #o/tell 55. #al/ill 31,
1et%inin o'arian cancer: recommen-ations for impro'in outcomes, Nat
Rev Cancer*0== 11: @=9@*$ PMI5: *=94=*?> 5OI: =0,=0>?Qnrc>=44K
=$ Chen 7!. 1ui #. Rilleen J!. CotY T1. "u ZC. Correa CN, Pat%olo( an-
classication of o'arian tumors, Cancer*00> 9:: *6>=*64* PMI5:
=*@>>=*? 5OI: =0,=00*Qcncr,==>4$K
=6 ast #C. 3eene( M. !aarus H. Na-ler !M. Col'in 1#. Rnapp 1C,
1eacti'it( of a monoclonal anti2o-( /it% %uman o'arian carcinoma,J Clin
Invest=9?= : =>>==>>@ PMI5: @0*?@?? 5OI: =0,==@*QJCI==0>?0K
=@ !eiland $. Martin R. Oe%ler MR. HoLmann P, 5ecip%erin t%e Molecular
Nature of O'arian Cancer #iomarer C&=*$, Int J ol !ci*0=* 1=: =0$6?
=0$?* PMI5: **949??0 5OI: =0,>>90Qims=>0?=0$6?K
=? )avelaar &. 'an Ramp J. Berstraeten 1&. Renemans P, Comparison of
se'en immunoassa(s for t%e 8uantication of C& =*$ antien in serum, Clin
Chem=99? 44: =4=@=4** PMI5: 966$4=?K
=98in !. !lo(- RO, Molecular clonin of t%e C&=*$ o'arian cancer antien:
i-entication as a ne/ mucin. M7C=6,J Biol Chem*00= 2:@=*@>@$
PMI5: ==>69@?= 5OI: =0,=0@4Q2c,M=0>$$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,=$>=**K
*>!oolas #*. Zu 3J. Jaco2s IJ. Wu WJ. 5al( !. #erc%uc &. Soper JT. Clare
Pearson 5!. Oram 5H. #ast 1C Jr, Ele'ation of multiple serum marers in
-
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patients /it% stae I o'arian cancer,J Natl Cancer Inst=99> >5: =@4?=@$=
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.
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>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
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"ncol*0=0 119 5OI:
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>* 6uhtinen .. Su'itie P. Hiissa J. Junnila J. Hu'ila J. Ruari H. Set]l] M.
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=9>>@*$* 5OI: =0,=0>?Qs,2c,660$0==K
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>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:
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>? &n;elen J. Ros HE. "illemse PH. &al-ers J. -e Bries E. Sc%aap'el- M.
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oncoloists an- in specialie- %ospitals: a s(stematic re'ie/, $ynecol
"ncol*00@ 105: ?0=?=* PMI5: =@4>>4** 5OI:
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$ynaecol=990 9:: 9**9*9 PMI5: ***>6?4 5OI: =0,====Q,=4@=
0$*?,=990,t20*44?,DK
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