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Also, in th)-4.8(is )6.5(group of)]TJ T* -0.0001 Tc 0.1057 Tw [(brea)-6.6(st )-6.5(canc)-5.1(er patien)-5.1(ts, ser)-5.3(u)1.4(m HER2 positiv)-4.7(i)0.1(ty w)-4.9(a)-0.1(s a signifi-)]TJ T* -0.0003 Tc 0.0605 Tw [(c)-5.3(a)-0.3(nt progn)-5.3(o)2.7(stic )-6.5(fa)-6.8(ctor)-5.5( [8].)-5.1( Othe)-5.3(rs showed th)-5.3(at seru)-5.3(m HER2)]TJ T* 0.0007 Tc 0.3062 Tw [(positivity was sig)4.3(n)2.2(if)5.5(icantly )]TJ 12.0455 0 TD 0.0005 Tc 0.3064 Tw [(more common in )6.5(patients )6.5(with)]TJ -12.0455 -1.2727 TD -0.0008 Tc -0.0105 Tw [(r)-6(ecur)-6(ren)-5.8(t)-1( )6.5(bre)-5.8(a)-0.8(st c)-5.8(a)-0.8(nce)-5.8(r than in)-5.8( those)-5.8( )6.5(w)-5.6(i)-0.6(th primary bre)-5.8(a)-0.8(st c)-5.8(a)-0.8(n-)]TJ 0 -1.2662 TD -0.0002 Tc -0.037 Tw [(c)-5.2(e)1.3(r, a)-6.7(n)1.3(d th)-5.2(at ther)-5.4(e was a good association betwee)-5.2(n HER2 tis-)]TJ 0 -1.2727 TD -0.0001 Tc 0.1577 Tw [(sue)-5.1( expression)-5.1( and )6.5(se)-5.1(rum HER2 leve)-5.1(ls [9]. Me)-5.1(asu)-5.1(r)1.2(ing this)]TJ T* -0.0003 Tc 0.0085 Tw [(protein in the )6.5(se)-5.3(rum )6.5(c)-5.3(o)2.7(ul)-6.6(d provide an )6.5(e)-5.3(a)-0.3(sier and )6.5(mor)-5.5(e)1.2( )6.5(ac)-5.3(ces-)]TJ T* -0.0175 Tw [(sible meth)-5.3(od of di)-6.6(agnosing pati)]TJ 13.2468 0 TD 0.0004 Tc -0.0182 Tw [(ents who may benefit from tar-)]TJ -13.2468 -1.2727 TD -0.0009 Tc 0.0286 Tw [(gete)-5.9(d ther)-6.1(apie)-5.9(s \(trastu)-5.9(z)0.5(umab\) )]TJ 13.0649 0 TD 0.0009 Tc 0.0268 Tw [(as com)5.7(p)-2(ared)4.5( with assessm)5.7(ent)]TJ -13.0649 -1.2727 TD -0.0002 Tc 0.2032 Tw [(of )6.5(ti)-6.5(ssue)-5.2( expression)-5.2(. Also, it has open)-5.2(ed )6.5(th)-5.2(e possibility of)]TJ T* 0.0734 Tw [(mea)-6.7(s)4.8(u)-5.2(r)1.1(ing the 're)-5.2(a)-0.2(l-time' expression)-5.2( )6.5(of this )6.5(onc)-5.2(o)2.8(gene)-5.2(, whic)-5.2(h)]TJ 0 -1.2662 TD 0.0019 Tw [(may)-4.8( )6.5(be useful)-6.5( )6.5(in)-5.2( )6.5(a)-6.7(s)4.8(sessing treatme)-5.2(n)1.3(t effe)-5.2(cts [10,11].)]TJ 0 -2.5455 TD -0.0001 Tc -0.0371 Tw [(The pote)-5.1(ntial rol)-6.4(e)1.4( )6.5(for serum EG)]TJ 13.1299 0 TD 0.0009 Tc -0.0381 Tw [(FR)5.6( assessments in b)4.5(r)2.2(east )6.5(can-)]TJ -13.1299 -1.2727 TD 0 Tc 0.1056 Tw [(c)-5(e)1.5(r )-6.5(is not quite)-5( as )-6.5(clear)-5.2(,)1.7( h)-5(o)3(we)-5(ver)-5.2(.)1.7( Although )-6.5(raised pretr)-5.2(e)1.5(at-)]TJ T* -0.0005 Tc -0.0627 Tw [(men)-5.5(t)-0.7( leve)-5.5(ls h)-5.5(a)-0.5(ve been)-5.5( )6.5(shown)-5.5( )6.5(to be)-5.5( associated with)-5.5( )6.5(dec)-5.5(r)0.8(eased)]TJ T* -0.0003 Tc 0.0215 Tw [(progr)-5.5(e)1.2(ssion-fre)-5.3(e and )6.5(overa)-6.8(ll )6.5(sur)-5.5(v)1.6(ival in metastatic br)-5.5(east )6.5(c)-5.3(a)-0.3(n-)]TJ 0 -1.2662 TD -0.0007 Tc 0.0609 Tw [(c)-5.7(e)0.8(r patien)-5.7(ts [)-5.9(6)4.4(,)-5.5(1)-2.1(2])-5.9(, seve)-5.7(ral studies hav)-5.3(e)0.8( shown th)-5.7(at pat)-7.4(i)-0.5(ents)]TJ 0 -1.2727 TD -0.0001 Tc -0.0696 Tw [(w)-4.9(i)0.1(th )-6.5(some solid epithe)-5.1(lial c)-5.1(a)-0.1(nce)-5.1(rs in )-6.5(fact e)-5.1(x)-0.2(hibit decr)-5.3(eased le)-5.1(v-)]TJ T* -0.0003 Tc 0.028 Tw [(e)-5.3(l)-0.1(s )6.5(of se)-5.3(rum EGFR compared )6.5(w)-5.1(i)-0.1(th health)-5.3(y)1.6( )6.5(c)-5.3(o)2.7(ntr)-5.5(o)2.7(l individuals)]TJ T* -0.0005 Tc -0.0497 Tw [([)-5.7(6)4.6(,)-5.3(1)-1.9(3])-5.7(. The biological )-6.5(bac)-5.5(k)3(ground and the)-5.5( clin)-5.5(ical r)-5.7(e)1(lev)-5.1(a)-0.5(nce )-6.5(of)]TJ T* 0.0022 Tw [(th)-5.5(ese observ)-5.1(ation)-5.5(s)4.5( ar)-5.7(e not y)-5.1(e)1(t known)-5.5(.)]TJ 0 -2.539 TD 0.0003 Tc 0.2092 Tw [(Presently anti-EGFR/HE)-6.1(R2 ther)]TJ 13.8896 0 TD -0.0006 Tc 0.2101 Tw [(apy for re)-5.6(curr)-5.8(ent/)-5.3(m)4.2(e)-5.6(t)-0.8(astatic)]TJ -13.8896 -1.2727 TD -0.0009 Tc 0.0026 Tw [(brea)-7.4(st can)-5.9(cer)-6.1( )6.5(is base)-5.9(d on im)]TJ 12.2857 0 TD -0.0007 Tc 0.0024 Tw [(mu)-5.7(nohistoc)-5.7(hemistry an)-5.7(d fluores-)]TJ -12.2857 -1.2727 TD -0.0015 Tc 0 Tw [(c)-6.5(enc)-6.5(e )]TJ /F5 1 Tf 2.8766 0 TD 0 Tc 0.0002 Tw [(in)-3.5( situ)-3.5( )]TJ /F4 1 Tf 2.8831 0 TD -0.0002 Tc 0.0019 Tw [(hy)-4.8(bridization of the primar)-5.4(y breast can)-5.2(cer)-5.4( tissu)-5.2(e)]TJ -5.7597 -1.2727 TD -0.0001 Tc 0.0148 Tw [([)-5.3(1)5(4])-5.3(. Still, the)-5.1( value)-5.1( of the)-5.1( )6.5(se)-5.1(rum expression of th)-5.1(ese markers)]TJ T* 0.0013 Tc 0.3251 Tw [(in pred)4.9(icting resp)4.9(onse )-6.5(to )-6.5(su)]TJ 13.1883 0 TD -0.0002 Tc 0.3331 Tw [(c)-5.2(h)1.3( therapies re)-5.2(main)-5.2(s )6.5(lar)-5.4(g)3.4(e)-5.2(l)0(y)]TJ -13.1883 -1.2727 TD -0.0009 Tc -0.0493 Tw [(u)-5.9(ncle)-5.9(a)-0.9(r. In)-5.9( the presen)-5.9(t stu)-5.9(d)2.7(y)-5.5(,)0.8( we)-5.9( )6.5(a)-7.4(n)0.6(alyz)-6(ed ser)-6.1(u)0.6(m expression)-5.9( of)]TJ T* -0.0001 Tc -0.0436 Tw [(EG)-6.3(FR an)-5.1(d )-6.5(HER2 in )-6.5(paired sampl)-6.4(e)1.4(s \(at )-6.5(time of primary )-6.5(dia)-6.6(g)3.5(no-)]TJ 0 -1.2662 TD 0.0003 Tc 0.0079 Tw [(sis and a)-6.2(t)0.1( metastasis\))-4.9( and we ai)]TJ 13.6104 0 TD 0.0006 Tc 0.0076 Tw [(med to correla)-5.9(te this with the)]TJ -13.6104 -1.2727 TD -0.0006 Tc 0.4764 Tw [(tissue)-5.6( expression)-5.6(. Furthe)-5.6(rmor)-5.8(e, we)-5.6( analy)-5.2(z)0.8(ed the se)-5.6(rum)]TJ T* 0.0027 Tc -0.0269 Tw [(exp)6.3(r)-2.5(e)4.2(s)1.2(s)7.7(i)-3.6(o)5.7(n)4.2( )-6.4(o)5.7(f)1( th)4.2(es)7.7(e mar)4(k)-0.3(e)4.2(r)4(s i)2.9(n)4.2( )-6.4(an)4.2( un)4.2(se)4.2(l)2.9(e)4.2(cte)4.2(d)6.3( )-6.4(g)6.3(r)-2.5(o)5.7(u)4.2(p of)7.5( )-6.4(h)4.2(e)4.2(a)2.7(l)2.9(t)2.5(hy)]TJ T* -0.0005 Tc -0.0173 Tw [(in)-5.5(div)-5.1(i)-0.3(du)-5.5(als and consec)-5.5(utive)-5.5( br)-5.7(east can)-5.5(cer )-6.5(patie)-5.5(n)1(ts diagn)-5.5(o)2.5(sed)]TJ T* 0.0282 Tw [(in)-5.5( )6.5(our un)-5.5(it. )6.5(Finall)-6.8(y, the associa)-7(t)-0.7(ion of these)-5.5( )6.5(w)-5.3(i)-0.3(th )6.5(tu)-5.5(mour)-5.7( )6.5(mark-)]TJ T* -0.0007 Tc 0.3661 Tw [(e)-5.7(r)0.6(s carc)-5.7(inoe)-5.7(mbry)-5.3(on)-5.7(ic antigen \()-5.9(C)2.5(EA\) and can)-5.7(cer an)-5.7(tige)-5.7(n)]TJ 0 -1.2662 TD 0.0002 Tc 0.0015 Tw [(\(CA\)15.3 was det)-6.5(e)1.7(rmined.)]TJ /F2 1 Tf 10.98 0 0 10.98 56.28 182.22 Tm 0.0003 Tc 0.0019 Tw (Materials and methods)Tj 9 0 0 9 56.28 171.84 Tm -0.0007 Tc 0 Tw (Patients)Tj /F4 1 Tf 9.24 0 0 9.24 56.28 159.9001 Tm 0.0008 Tc -0.025 Tw (Between October 1992 and Octobe)Tj 15.526 0 TD -0.0186 Tw [(r 2)5.9(004, 5)5.9(7)-0.6( )6.4(patients )6.4(were)]TJ -15.526 -1.2727 TD -0.0002 Tc 0.0084 Tw [(iden)-5.2(tifie)-5.2(d)3.4( from wh)-5.2(om pair)-5.4(ed )6.5(bl)]TJ 12.8896 0 TD 0.0005 Tc 0.0012 Tw [(ood samples were)-4.5( availabl)-5.8(e for)]TJ -12.8896 -1.2662 TD -0.0002 Tc -0.0695 Tw [(an)-5.2(alysis \()-5.4(b)3.4(oth at )-6.5(diagn)-5.2(o)2.8(sis of primary )-6.5(br)-5.4(east c)-5.2(a)-0.2(ncer)-5.4( [P)-5.1(BC])-5.4( and)]TJ 0 -1.2727 TD 0.0002 Tc 0.1379 Tw [(at metastasis\). Blood)3.8( sam)5(p)-2.7(les )]TJ 13.552 0 TD -0.0006 Tc 0.1322 Tw [(were)-5.6( collec)-5.6(t)-0.8(ed from )-6.5(pat)-7.3(i)-0.4(ents)]TJ -13.552 -1.2727 TD 0 Tc 0.1121 Tw [(atte)-5(nding )6.5(brea)-6.5(st cli)-6.3(n)1.5(ics who gav)-4.6(e)1.5( writte)-5(n, informed )6.5(c)-5(o)3(n)-5(s)5(e)-5(n)1.5(t)]TJ T* -0.0005 Tc 0.1776 Tw [(u)-5.5(n)1(der a study )-6.4(protoc)-5.5(ol approv)-5.1(ed by)-5.1( the )-6.4(institutional e)-5.5(t)-0.7(hics)]TJ T* -0.0001 Tc 0.1512 Tw [(c)-5.1(o)2.9(mmittee.)-4.9( )6.5(Bl)-6.4(ood spe)-5.1(c)1.4(imens we)-5.1(re allowed to stand )6.5(befor)-5.3(e)]TJ T* 0.0002 Tc 0.0145 Tw [(being centrif)5(u)-4.8(gated )-6.5(at 1,250 )]TJ /F5 1 Tf 12.487 0 TD -0.003 Tc 0 Tw (g )Tj /F4 1 Tf 0.8507 0 TD 0.0007 Tc 0.014 Tw (for 5 minutes, serum removed)Tj -13.3377 -1.2662 TD -0.0001 Tc 0.0018 Tw [(and stor)-5.3(ed )6.5(at -20C.)]TJ 27.9675 68.6688 TD -0.0005 Tc -0.0497 Tw [(Furthe)-5.5(rmore)-5.5(,)1.2( pr)-5.7(eoper)-5.7(a)-0.5(tive seru)-5.5(m sampl)-6.8(e)1(s )6.5(w)-5.3(e)1(re collec)-5.5(t)-0.7(ed )6.5(from)]TJ 0 -1.2727 TD 0.0004 Tc 0.2156 Tw [(96 PBC )-6.5(pati)-5.9(ents )-6.5(and 49 healthy individuals attendi)-5.9(n)1.9(g )-6.5(the)]TJ T* -0.0005 Tc 0.2165 Tw [(National He)-5.5(alth Serv)-5.1(ice Br)-5.7(ea)]TJ 12.9286 0 TD -0.0004 Tc 0.2164 Tw [(st Sc)-5.4(ree)-5.4(n)1.1(ing Programme)-5.4( and)]TJ -12.9286 -1.2727 TD 0.0004 Tc -0.0182 Tw [(had a normal mammography or )]TJ 13.3182 0 TD 0.0001 Tc -0.0178 Tw [(were attending a symptomatic)]TJ -13.3182 -1.2662 TD 0 Tc -0.0113 Tw [(breast )6.5(c)-5(linic and )6.4(dischar)-5.2(g)3.6(e)-5(d)3.6( with no )6.5(detecte)-5(d)3.6( abn)-5(o)3(r)-5.2(m)4.8(ali)-6.3(t)-0.2(y )6.5(fol-)]TJ 0 -1.2727 TD -0.0004 Tc -0.0498 Tw [(lowing tr)-5.6(iple)-5.4( assessme)-5.4(n)1.1(t )-6.5(\(age)-5.4( )]TJ 12.7143 0 TD 0.002 Tc -0.0522 Tw [(range 19 to 71 ye)]TJ 7.4416 0 TD -0.0006 Tc -0.0431 Tw [(ars, mean age)]TJ -20.1558 -1.2727 TD 0.0007 Tc 0.0075 Tw [(54 years\). All PBC )-6.5(and )-6.5(nor)-4.5(m)-1(al sa)]TJ 14.2078 0 TD 0.0015 Tc 0.0067 Tw [(mples from healthy ind)5.1(i)1.7(vid)5.1(u)-3.5(-)]TJ -14.2078 -1.2727 TD 0.0003 Tc 0.0404 Tw [(als were )-6.5(collected during )-6.5(a 12-)]TJ 13.3896 0 TD 0.0013 Tc 0.0394 Tw [(m)6.1(o)-2.2(nth period in 2004)6.4(. Of the)]TJ -13.3896 -1.2727 TD 0.0003 Tw [(57 patients with paired)5( )-6.5(b)5(l)1.6(oo)4.4(d sa)]TJ 13.7338 0 TD [(mples, paired)4.9( )-6.5(tis)6.3(s)-0.2(ue samp)4.9(les)]TJ -13.7338 -1.2727 TD -0.0004 Tc 0.0021 Tw [(\(primary)-5( )6.5(an)-5.4(d metastasis\) we)-5.4(re also av)-5(ailable)-5.4( )6.5(from 8.)]TJ 0 -2.539 TD 0.0001 Tc 0.0925 Tw [(Clinical )-6.5(data were)-4.9( c)-4.9(o)3.1(lle)-4.9(cted from th)-4.9(e )-6.5(unit's )-6.5(da)-6.4(tabase, which)]TJ 0 -1.2727 TD -0.0008 Tc 0.2233 Tw [(was pr)-6(ospectiv)-5.4(ely upda)-7.3(ted \(follo)]TJ 14.3961 0 TD -0.0003 Tc 0.2163 Tw [(w)-5.1(i)-0.1(ng eac)-5.3(h)1.2( )-6.5(clinic)-5.3( c)-5.3(o)2.7(nsu)-5.3(l)-0.1(ta-)]TJ -14.3961 -1.2727 TD 0.0005 Tc 0.1701 Tw [(tion\). )-6.5(Any change in a )-6.5(patien)]TJ 12.9091 0 TD 0.0008 Tc 0.1698 Tw [(t's treatment or progres)5.8(s)-0.7( was)]TJ -12.9091 -1.2727 TD -0.0056 Tw [(entered )-6.5(into our database.)]TJ /F2 1 Tf 9 0 0 9 314.7 512.58 Tm -0.003 Tc 0 Tw [(Me)-6.7(tho)-4.7(d)1(s)]TJ /F4 1 Tf 9.24 0 0 9.24 314.7 500.7 Tm -0.0019 Tc 0.166 Tw [(S)-3.7(e)-0.4(ru)-6.9(m )-6.5(EGFR)-3.7( an)-6.9(d H)-6.7(E)-1.8(R2)-3.3( e)-6.9(s)3.1(ti)-8.2(matio)-5.4(n)-0.4( w)-6.7(a)-1.9(s)-3.4( do)-5.4(ne u)-6.9(s)-3.4(ing)-4.8( B)-2.2(a)-1.9(yer)]TJ T* 0.0009 Tc -0.0187 Tw [(microtitre Im)5.7(munoassays )-6.5(\(ADVIA Centaur)]TJ 6.42 0 0 6.42 477 491.22 Tm 0.0081 Tc 0 Tw ( )Tj 9.24 0 0 9.24 484.02 488.94 Tm 0.0003 Tc -0.0116 Tw [(Immunoassay s)5.3(y)-4.3(s-)]TJ -18.3247 -1.2727 TD -0.0003 Tc 0.1644 Tw [(tem, Baye)-5.3(r )6.5(Healthc)-5.3(a)-0.3(re Diagnostic)-5.3(s)4.7( Divisions, Bayer)-5.5( )6.5(House,)]TJ T* 0.028 Tw [(Strawber)-5.5(ry Hill, N)-6.6(e)1.2(wbury BERK, )-6.5(RG)-6.5(14 1JA, UK)-5.2(\). The )-6.5(nor)-5.5(m)-2(al)]TJ T* 0.0008 Tc 0.1503 Tw [(range f)5.6(o)-2.7(r EGFR was 45 to 78 ng/m)5.6(l a)-5.7(n)2.3(d for HER)5.5(2)-0.6( it was)]TJ T* -0.001 Tc -0.0232 Tw [(un)-6(der)-6.2( )6.5(15 )6.5(ng/ml \(base)-6(d)2.6( on the me)]TJ 14.0909 0 TD 0.0019 Tc -0.0326 Tw [(an)3.4( valu)3.4(e o)4.9(f)0.2( he)3.4(alth)3.4(y ind)5.5(i)2.1(vid)5.5(u)-3.1(al)]TJ -14.0909 -1.2662 TD 0.0013 Tc 0.0783 Tw [( 2 )-6.5(standard deviatio)4.3(ns)6.3(\). )-6.5(T)4.3(i)1.5(ss)]TJ 12.9286 0 TD -0.0003 Tc 0.0864 Tw [(ue HE)-6.7(R2 expression was )6.4(e)-5.3(s)-1.8(ti-)]TJ -12.9286 -1.2727 TD 0.0215 Tw [(mated using the H)-5.1(e)1.2(rc)-5.3(epTest kit pr)-5.5(otocol)-6.6( \(Dako Ltd, De)-5.3(nmark)]TJ T* -0.0368 Tw [(House,)-5.2( )6.5(Angel Drove)-5.4(,)1.3( Ely, Cambr)-5.6(i)-0.2(dgeshir)-5.6(e)1.1(, CB7 4ET, UK\).)-5.2( The)]TJ T* 0.0003 Tc -0.031 Tw [(immunohistochemic)-4.7(al expression )]TJ 14.1818 0 TD -0.0011 Tc -0.0231 Tw [(w)-5.9(a)-1.1(s qu)-6.1(antified )6.5(as )6.5(0, 1+, 2+,)]TJ -14.1818 -1.2727 TD -0.0567 Tc 0 Tw [(o)-60.2(r)-55.4( 3)-58.1(+)-58.5(.)-55( H)-55(E)-56.6(R)-58.5(2)-58.1( p)-59.6(o)-53.7(s)-58.2(i)-56.5(t)-56.9(i)-56.5(v)-61.3(i)-56.5(t)-56.9(y)-54.8( w)-61.5(a)-56.7(s)-58.2( d)-53.1(e)-61.7(f)-51.9(i)-56.5(n)-61.7(e)-55.2(d)-59.6( a)-56.7(s)-58.2( 3)-58.1(+)-52(.)-61.5( T)-53.7(i)-63(s)-51.7(s)-58.2(u)-55.2(e)-61.7( E)-56.6(G)-56.4(F)-60.2(R)-52( )-6.5(i)-56.5(m)-58.4(m)-51.9(u)-61.7(-)]TJ T* -0.0004 Tc -0.0238 Tw [(nohistochemistry)-5( was perfor)-5.6(me)-5.4(d w)-5.2(i)-0.2(th mou)-5.4(s)4.6(e)-5.4( monoclonal an)-5.4(ti-)]TJ 0 -1.2662 TD -0.0001 Tc 0.4564 Tw [(bodies against EGFR in)-5.1( accordance)-5.1( with th)-5.1(e pr)-5.3(otocol)]TJ 0 -1.2727 TD -0.0007 Tc 0.1063 Tw [(prov)-5.3(ide)-5.7(d)2.9( by)-5.3( )6.5(Novocastra Ltd )6.5(and the expression)-5.7( )6.5(wa)-7.2(s scor)-5.9(ed)]TJ T* -0.0002 Tc 0.1383 Tw [(acc)-5.2(o)2.8(rding to the perc)-5.2(entage of cells exh)-5.2(i)0(biti)-6.5(ng e)-5.2(i)0(ther)-5.4( mem-)]TJ T* -0.0004 Tc 0.119 Tw [(brane)-5.4( or c)-5.4(y)1.5(toplasmic )-6.5(staining \()-5.6(N)-0.2(ov)-5(oca)-6.9(s)4.6(tr)-5.6(a La)-6.9(boratories L)-5.4(t)-0.6(d,)]TJ T* -0.0006 Tc 0.0478 Tw [(New)-5.4(c)0.9(astle upon Ty)-5.2(ne,)-5.4( )6.5(N)-6.9(E)-0.5(12 8EW)-5.6(,)1.1( UK\).)-5.4( The)-5.6( cut-off for)-5.8( posi-)]TJ T* -0.0008 Tc 0.035 Tw [(tive)-5.8( )6.5(e)-5.8(x)-0.9(pre)-5.8(s)-2.3(sion was de)-5.8(fi)-7.1(ned )6.5(as 10% )6.5(or more)-5.8( )6.5(of ce)-5.8(lls )6.5(staine)-5.8(d.)]TJ T* 0.0005 Tc 0.1636 Tw [(Serum )-6.5(CA15)5.6(.3 and CEA estimation was done using Auto-)]TJ 0 -1.2662 TD -0.0002 Tc -0.0175 Tw [(mated Immunoassay on)-5.2( the Bay)-4.8(e)1.3(r Centa)-6.7(u)1.3(r Immun)-5.2(o)2.8(assay an)-5.2(a-)]TJ 0 -1.2727 TD -0.0006 Tc 0.0478 Tw [(lyz)-5.7(e)0.9(r. )-6.5(Th)-5.6(e normal r)-5.8(a)-0.6(nge for)-5.8( CA15.3 w)-5.4(a)-0.6(s )-6.5(0 to )-6.5(35 )-6.5(kU/)-5.3(l)-0.4( and for)]TJ T* 0.0006 Tc 0.0011 Tw [(CEA it was 0 )6.5(to 5 )6.5(kU/l.)]TJ 0 -2.5455 TD 0.0003 Tc 0.1378 Tw [(Tumour)-4.9( gra)-6.2(d)3.9(e w)-4.5(a)0.3(s )6.5(a)-6.2(s)5.3(sessed using the Nottingham method)]TJ 0 -1.2727 TD 0.0026 Tc 0.0965 Tw [([)3.9(15])3.9(.)4.3( Ly)4.5(mp)6.2(h )6.5(no)5.6(de)4.1( stag)6.2(e )6.5(was )6.5(de)4.1(ter)3.9(m)0.9(i)2.8(n)4.1(e)4.1(d)-0.3( f)7.4(r)-2.6(o)5.6(m)0.9( th)4.1(e)4.1( r)3.9(e)-2.4(s)7.6(u)-2.4(l)2.8(t)2.4(s )6.5(of)]TJ 0 -1.2662 TD 0 Tc 0.1056 Tw [(axillar)-5.2(y)1.9( node)-5( )6.5(sampling or)-5.2( )6.5(dissect)]TJ 14.1558 0 TD 0.0003 Tc 0.1053 Tw [(ion. )6.5(For)-4.9( patie)-4.7(n)1.8(ts diagnosed)]TJ -14.1558 -1.2727 TD 0.0728 Tw [(with primary breast cancer )]TJ 11.8052 0 TD 0.0005 Tc 0.0727 Tw [(before 1995, oestrogen receptor)]TJ -11.8052 -1.2727 TD -0.0002 Tc 0.1967 Tw [(\(ER\) a)-6.7(c)1.3(tivity)-4.8( was measur)-5.4(ed using the )-6.5(stan)-5.2(dar)-5.4(d)3.4( r)-5.4(a)-0.2(dioligand)]TJ T* 0.0009 Tc -0.0576 Tw [(binding assay )-6.5(on tissue cytosol sa)]TJ 14.2013 0 TD 0.0005 Tc -0.0572 Tw [(mples, )-6.5(with the threshold )-6.5(for)]TJ -14.2013 -1.2727 TD -0.0017 Tc -0.0615 Tw [(d)-4.6(e)-0.2(s)-3.2(i)-1.5(gn)-6.7(ation)-6.7( o)-5.2(f)-3.4( ER)-3.5( )-6.5(po)-5.2(si)-8(tivity )-6.5(b)-4.6(e)]TJ 12.6039 0 TD 0.0009 Tc -0.0576 Tw [(ing )6.5(10 f)5.7(m)-0.8(ol/mg )6.5(of)5.7( pro)3.9(t)0.7(ein. Since)]TJ -12.6039 -1.2727 TD -0.0002 Tc -0.037 Tw [(the)-5.2(n)1.3(, ER sta)-6.7(t)-0.4(us )6.5(h)-5.2(a)-0.2(s )6.5(bee)-5.2(n)1.3( de)-5.2(termine)-5.2(d)3.4( using immunocytoch)-5.2(em-)]TJ 0 -1.2662 TD -0.001 Tc 0.0092 Tw [(ical )-6.5(me)-6(thods. An H)-5.8(-)-1.2(sc)-6(or)-6.2(e above)-6( 50 has be)-6(en u)-6(s)-2.5(ed )-6.5(to identi)-7.3(f)3.8(y)]TJ 0 -1.2727 TD 0.0001 Tc 0.0016 Tw [(ER p)3.7(o)-3.4(sitive tumours for ad)]TJ 11.2403 0 TD -0.0009 Tc 0.0026 Tw [(juv)-5.5(a)-0.9(nt endoc)-5.9(rine)-5.9( )6.5(th)-5.9(erapy.)]TJ /F2 1 Tf 9 0 0 9 314.7 101.3401 Tm -0.0001 Tc 0.0024 Tw [(Statistical an)3.9(al)5.2(ysis)]TJ /F4 1 Tf 9.24 0 0 9.24 314.7 89.4001 Tm 0.0003 Tc 0.1638 Tw [(Statistical )-6.5(analysis )-6.5(was performed with the SPSS )-6.5(software)]TJ 0 -1.2727 TD -0.0004 Tc 0.0476 Tw [(package)-5.4( )6.5(\(v)-5(ersion 12.)-5.2(0)-1.8( )6.5(for Window)-5.2(s; SPSS )6.5(I)-5.2(nc.)-5.2(, Burlin)-5.4(game,)]TJ 0 -1.2662 TD -0.0001 Tc 0.281 Tw [(CA, )-6.5(USA\). )-6.5(Becau)-5.1(s)4.9(e)-5.1( the distribution of se)-5.1(rum EGFR and)]TJ ET endstream endobj 17 0 obj<> endobj 18 0 obj<> endobj 19 0 obj<> endobj 20 0 obj<> endobj 21 0 obj<> endobj 22 0 obj<>/Font<>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 23 0 obj<>stream /GS1 gs BT /F2 1 Tf 7.98 0 0 7.98 315.48 744.42 Tm /Cs6 cs 0 0 0 scn 0.0015 Tc -0.0018 Tw [(Availa)5.6(b)-5.1(l)7.8(e o)-5.1(n)4(line)]TJ /F3 1 Tf 7.7444 0 TD 0 Tc 0 Tw ( )Tj /F4 1 Tf 0.2782 0 TD 0.0034 Tc [(htt)9.7(p)1.5(:)3.7(/)-1.9(/)5.6(b)1.5(re)5.6(ast-c)5.6(an)5.6(c)5.6(e)-1.9(r-r)8.1(e)-1.9(se)5.6(ar)8.1(ch)5.6(.c)5.6(o)4(m)0(/)5.6(c)-1.9(o)4(n)-1.9(t)9.7(e)-1.9(n)5.6(t)2.2(/9)7.5(/6)7.4(/R7)7.5(5)]TJ 17.0752 -89.7143 TD 0.0008 Tc -0.0011 Tw (Page 3 of 8)Tj /F5 1 Tf 6.96 0 0 6.96 436.14 18.54 Tm 0.0017 Tc -0.0006 Tw [(\(page numb)-5.3(er not for cita)-6.9(tion purposes)6.6(\))]TJ /F4 1 Tf 9.24 0 0 9.24 56.82 700.44 Tm -0.0008 Tc 0.2168 Tw [(serum H)-5.6(E)-0.7(R2 le)-5.8(vels wa)-7.3(s n)-5.8(o)2.2(nparame)-5.8(t)-1(ric, th)-5.8(e Mann)-5.8(-Whitn)-5.8(ey)]TJ 0 -1.2727 TD 0.0019 Tc 0.2141 Tw [(te)3.4(st w)3.6(a)1.9(s )6.5(use)3.4(d)5.5( to )6.5(co)4.9(mpar)3.2(e)3.4( me)3.4(di)2.1(an)3.4( v)3.8(a)1.9(l)2.1(u)3.4(es.)3.6( )]TJ /TT1 1 Tf 19.3247 0 TD 0 Tc 0 Tw <0046>Tj /F4 1 Tf 6.42 0 0 6.42 240.42 691.02 Tm 0.0058 Tc (2 )Tj 9.24 0 0 9.24 247.38 688.6801 Tm 0.0011 Tc 0.2084 Tw [(analysis and)]TJ -20.6234 -1.2727 TD -0.0003 Tc 0.015 Tw [(Fishe)-5.3(r)1('s exact w)-5.1(e)1.2(re)-5.3( )6.5(u)-5.3(s)-1.8(ed to compare)-5.3( )6.5(n)-5.3(u)1.2(mbers in eac)-5.3(h)1.2( gr)-5.5(oup.)]TJ T* -0.0031 Tc 0 Tw (A )Tj /F5 1 Tf 1.2143 0 TD 0.0034 Tc (P )Tj /F4 1 Tf 1.2532 0 TD -0.0005 Tc 0.2944 Tw [(valu)-5.5(e of le)-5.5(ss )-6.5(than 0.05 was )-6.5(con)-5.5(s)-2(ider)-5.7(ed statistically)]TJ -2.4675 -1.2662 TD -0.001 Tc 0 Tw [(sign)-6(ific)-6(ant.)]TJ /F2 1 Tf 10.98 0 0 10.98 56.82 628.74 Tm -0.0007 Tc [(Res)-4.3(u)2.2(l)-3.8(t)3.6(s)]TJ 9 0 0 9 56.82 618.36 Tm 0.0014 Tc -0.0524 Tw [(EG)4.7(F)6.4(R)-3.9( )6.7(an)5.4(d H)4.7(E)0.7(R2 se)4.4(rum)4.1( e)4.4(x)2.4(pre)4.4(ssion)5.4( in)5.4( he)4.4(a)4.4(l)0.1(thy)8.1( ind)5.4(i)0.1(vi)6.7(du)5.4(al)6.7(s )]TJ 0 -1.3067 TD -0.0017 Tc -0.0026 Tw [(versu)-4.4(s)-0.7( brea)-5.4(st ca)-5.4(ncer)-6.7( p)-4.4(a)1.3(tien)-4.4(ts)]TJ /F4 1 Tf 9.24 0 0 9.24 56.82 594.66 Tm -0.0004 Tc -0.0433 Tw [(Heal)-6.7(thy )-6.5(individuals h)-5.4(a)-0.4(d )-6.5(sign)-5.4(ificantly hi)-6.7(ghe)-5.4(r)0.9( se)-5.4(rum E)-6.8(G)-0.1(FR )-6.5(leve)-5.4(ls)]TJ 0 -1.2662 TD 0.0003 Tc 0.0274 Tw [(\(median 75.3 )-6.5(ng/ml, range 43.2 )]TJ 13.9091 0 TD 0.0001 Tc 0.0276 Tw [(to 114.2 ng/ml\) tha)-6.4(n)1.6( did )-6.5(the)]TJ -13.9091 -1.2727 TD -0.0005 Tc 0.0282 Tw [(PBC pa)-7(tients \(me)-5.5(d)3.1(ian)-5.5( 59.)-5.3(3)-1.9( ng/ml, ra)-7(nge)-5.5( 21.3 to )-6.5(94.)-5.3(1)4.6( )-6.5(ng/)-5.2(m)-2.2(l;)]TJ T* 0.0005 Tc -0.0183 Tw (U = 3,599.0, )Tj /F5 1 Tf 5.7273 0 TD 0.0034 Tc 0 Tw (P )Tj /F4 1 Tf 0.9156 0 TD 0.0006 Tc -0.0184 Tw [(< 0.001\)\). For serum HER2, no significant dif)5.4(-)]TJ -6.6429 -1.2727 TD -0.0008 Tc 0.1843 Tw [(feren)-5.8(ce was obser)-6(v)1.1(ed be)-5.8(twee)-5.8(n the he)-5.8(althy in)-5.8(div)-5.4(i)-0.6(du)-5.8(als )6.4(an)-5.8(d)]TJ T* 0.0032 Tc 0.1154 Tw [(P)4.8(B)2.9(C pati)3.4(en)4.7(ts \(m)8(ed)6.8(i)3.4(a)3.2(n )-6.5(1)8.3(2)1.8(.2)8.3( )-6.5(n)4.7(g)0.3(/)5(m)1.5(l)3.4(,)-1.6( ran)4.7(g)0.3(e)4.7( )-6.5(7)8.3(.)-1.6(8 to )-6.5(20)8.3(.9 ng)6.8(/m)8(l)]TJ T* 0.0004 Tc 0.1377 Tw [(and median 12.5 )-6.5(ng/ml, rang)]TJ 12.8117 0 TD 0.0009 Tc 0.1372 Tw [(e 6.9 to 122.2 ng/ml, respec-)]TJ -12.8117 -1.2727 TD 0.0005 Tc 0.0402 Tw (tively; U = 2,383.5, )Tj /F5 1 Tf 8.5909 0 TD 0.0034 Tc 0 Tw (P )Tj /F4 1 Tf 0.9805 0 TD 0.0008 Tc 0.0399 Tw [(= 0.511)5.9(\). Ten out of 96 \(10.4%\) PBC)]TJ -9.5714 -1.2662 TD -0.0008 Tc 0.1194 Tw [(patie)-5.8(n)0.7(ts had se)-5.8(rum EGFR le)-5.8(vels above)-5.8( the re)-5.8(fe)-5.8(renc)-5.8(e range)]TJ 0 -1.2727 TD 0.0006 Tc 0.144 Tw [(\(45 to 78 ng/ml\), as)5.6( compared)]TJ 13.7727 0 TD 0.001 Tc 0.1436 Tw [( with 2)6.1(0)-0.4( out of)5.8( 49 \(40.8%\))]TJ -13.7727 -1.2727 TD -0.0005 Tc 0.1256 Tw [(health)-5.5(y)1.4( )-6.5(individuals. )-6.5(For ser)-5.7(u)1(m H)-5.3(E)-0.4(R2 )-6.5(\(re)-5.5(fe)-5.5(renc)-5.5(e r)-5.7(a)-0.5(nge < )-6.5(15)]TJ T* -0.0002 Tc 0.1253 Tw [(ng/ml\), )-6.5(the )-6.5(respectiv)-4.8(e n)-5.2(u)1.3(mbers w)-5(e)1.3(re )-6.5(22 ou)-5.2(t of )-6.5(96 \(22.9%\))]TJ T* 0.0011 Tc 0.0006 Tw [(and )6.5(10 out of 4)6.2(9)-0.3( \(20.4%\).)]TJ /F2 1 Tf 9 0 0 9 315.3 700.62 Tm -0.0015 Tc -0.0028 Tw [(T)-6.2(u)2.5(mour)-6.5( ch)-4.2(aracte)-5.2(ristics )-6.6(of )]TJ 12.38 0 TD -0.0007 Tc -0.0036 Tw [(patients for )-6.6(whom paired )]TJ -12.38 -1.3067 TD 0.0002 Tc 0.0021 Tw [(blo)5.2(o)-1.5(d)4.2( samp)4.2(les were avai)5.5(lable)]TJ /F4 1 Tf 9.24 0 0 9.24 315.3 676.92 Tm 0.0025 Tc -0.0397 Tw [(Th)4(e d)6.1(e)4(mog)6.1(r)-2.7(ap)6.1(hi)2.7(c)4(s)1( o)5.5(f)0.8( th)4(e 57)7.6( )-6.5(p)6.1(a)2.5(ti)2.7(en)4(ts an)4(d th)4(e)4(i)2.7(r tu)4(mo)5.5(ur)3.8( c)4(h)4(a)2.5(rac)4(-)]TJ 0 -1.2727 TD -0.0008 Tc 0.0999 Tw [(te)-5.8(ristics a)-7.3(r)0.5(e )-6.5(sh)-5.8(ow)-5.6(n in)-5.8( Table)-5.8( 1. )-6.5(Th)-5.8(e me)-5.8(dian)-5.8( inte)-5.8(rval )-6.5(betwee)-5.8(n)]TJ 0 -1.2662 TD 0.0003 Tc 0.0339 Tw [(primary and )6.5(meta)-6.2(static diagnosis was 23 months )6.5(\()-4.9(r)1.6(ange 5 to)]TJ 0 -1.2727 TD 0.0006 Tc 0.0011 Tw (132 months\).)Tj /F5 1 Tf 9.48 0 0 9.48 315.3 618 Tm 0.0004 Tc -0.0013 Tw [(EG)-5.1(FR and HER2 )-6.4(serum l)-4.8(e)2.4(vels at tim)-5.1(e)2.4( of pri)-4.8(m)1.3(ary and )]TJ 0 -1.2405 TD 0.0007 Tc -0.0016 Tw [(subsequ)4.7(e)-3.6(nt metastatic diag)4.7(nosis)]TJ /F4 1 Tf 9.24 0 0 9.24 315.3 594.66 Tm -0.0001 Tc 0.1187 Tw [(EG)-6.3(FR levels wer)-5.3(e)1.4( significantly higher)-5.3( at the time of pr)-5.3(imar)-5.3(y)]TJ 0 -1.2662 TD 0.0003 Tc 0.1638 Tw [(diagnosis \(median )6.5(56.3 ng/ml,)]TJ 13.3636 0 TD 0.0001 Tc 0.164 Tw [( range )6.5(29.1 to 1)5.2(42.7 ng/ml\))]TJ -13.3636 -1.2727 TD 0.0005 Tc 0.0597 Tw [(than a)-6(t)0.3( the time )-6.5(of meta)-6(s)5.5(t)0.3(atic diagnosis )-6.5(\(median 30.9 )-6.5(ng/ml,)]TJ T* 0.0006 Tc -0.0313 Tw [(range 10.9 to 106.4 ng/ml; )6.5(U)-6.2( )6.5(= 2168.0, )]TJ /F5 1 Tf 17.1104 0 TD -0.0031 Tc 0 Tw (P )Tj /F4 1 Tf 0.9091 0 TD 0.0007 Tc -0.0314 Tw (< 0.001\). Eighteen)Tj -18.0195 -1.2727 TD -0.0002 Tc -0.0435 Tw [(of the 57 patients \()-5.4(3)4.9(1.)-5(6%)-6.8(\) had ele)-5.2(v)1.7(ated seru)-5.2(m E)-6.6(G)0.1(FR lev)-4.8(e)1.3(ls at)]TJ T* -0.0003 Tc 0.0215 Tw [(primary)-4.9( dia)-6.8(g)3.3(nosis. In)-5.3( )6.5(six \()-5.5(1)4.8(1%\))-5.5( a chan)-5.3(g)3.3(e)-5.3( )6.5(occ)-5.3(u)1.2(rre)-5.3(d from ov)-4.9(er-)]TJ T* 0.0029 Tc -0.0596 Tw [(exp)6.5(r)-2.3(e)4.4(ssi)3.1(o)5.9(n)4.4( )-6.5(\()4.2(>)1.1(78 ng)6.5(/m)7.7(l)3.1(\))-2.3( to no)5.9(r)4.2(m)1.2(al)3.1( )-6.5(e)4.4(x)2.8(pr)4.2(e)4.4(ssi)3.1(on)4.4( )-6.5(\()4.2(4)1.5(5)8( )-6.5(to 78 ng)6.5(/m)7.7(l\))4.2(.)]TJ T* 0 Tc -0.0502 Tw [(N)-6.3(o)3( patien)-5(t chan)-5(g)3.6(e)-5(d)3.6( from normal expression at primary)-4.6( di)-6.3(agn)-5(o)3(-)]TJ 0 -1.2662 TD 0.0005 Tc 0.0012 Tw [(sis to over-expression )6.5(at metastasis \(Fig)4.1(ure 1\).)]TJ 0 -2.5455 TD -0.0004 Tc 0.0021 Tw [(The)-5.4( c)-5.4(o)2.6(nv)-5(erse)-5.4( w)-5.2(a)-0.4(s tr)-5.6(ue )-6.5(for)-5.6( H)-5.2(E)-0.3(R2; )]TJ 14.4545 0 TD 0.0086 Tw [(the)-5.4( leve)-5.4(ls were significan)-5.4(tly)]TJ -14.4545 -1.2727 TD 0.1059 Tw [(h)-5.3(i)-0.1(gh)-5.3(er )-6.5(at me)-5.3(tasta)-6.8(s)4.7(is )-6.5(\(median )-6.5(12.2 n)-5.3(g)3.3(/)-5(m)4.5(l,)-5.1( r)-5.5(a)-0.3(nge 5.)-5.1(7 )-6.5(to 85.0)]TJ T* 0 Tc -0.0372 Tw [(n)-5(g)3.6(/)-4.7(m)4.8(l)-6.3(\))1.3( than )-6.5(at pr)-5.2(esentation of PBC \(median 17.7 ng/ml, )-6.5(range)]TJ T* 0.0013 Tc 0.0459 Tw [(6.3)6.4( to )6.5(3,3)6.4(37.4 ng/ml; )]TJ /F5 1 Tf 9.539 0 TD -0.0031 Tc 0 Tw (P )Tj /F4 1 Tf 0.987 0 TD 0.0013 Tc 0.0394 Tw [(< 0.0)6.4(01\). Sixteen )-6.5(of)6.1( )-6.5(the 57 )-6.5(patients)]TJ -10.526 -1.2662 TD 0.0006 Tc -0.0508 Tw [(\()-4.6(2)-0.8(8)5.7(.)-4.2(2)5.7(%)-6(\) had elevated serum HER2 at the time of primary diag-)]TJ 0 -1.2727 TD -0.0004 Tc -0.0238 Tw [(n)-5.4(o)2.6(sis. In 18 \(32%\) a )6.5(ch)-5.4(ange )6.5(occ)-5.4(u)1.1(rre)-5.4(d from nor)-5.6(m)4.4(a)-6.9(l)-0.2( )6.5(expre)-5.4(s)4.6(sion)]TJ T* 0.0602 Tc 0 Tw [(\()55(<)64.9(1)58.8(5)58.8( n)55.2(g)63.8(/)62(m)58.5(l)60.4(\))55( t)60(o)63.2( o)56.7(v)62.1(e)61.7(r)55(-)60(e)61.7(x)60.1(p)57.3(r)61.5(e)61.7(s)58.7(s)58.7(i)60.4(o)63.2(n)55.2( \()61.5(>)58.4(1)58.8(5)65.3( n)55.2(g)63.8(/)55.5(m)58.5(l)60.4(\))61.5(.)61.9( I)61.9(n)55.2( f)58.5(i)60.4(v)62.1(e)61.7( \()55(8)65.3(.)55.4(8)58.8(%)60.1(\))61.5( a)]TJ T* -0.0002 Tc 0.2097 Tw [(c)-5.2(h)1.3(ange )-6.5(oc)-5.2(cur)-5.4(red in)-5.2( th)-5.2(e )-6.5(opposite )-6.5(direction,)-5( w)-5(here)-5.2(a)-0.2(s in)-5.2( 34)]TJ T* -0.0001 Tc -0.0436 Tw [(\()-5.3(5)-1.5(9.6%)-6.7(\) levels remaine)-5.1(d)3.5( in)-5.1( the same group )6.5(of expression)-5.1( \(nor-)]TJ T* -0.0003 Tc 0.002 Tw [(mal or ov)-4.9(erexpre)-5.3(s)4.7(sion\) betwe)-5.3(en ev)-4.9(ent periods \(Figu)-5.3(r)1(e 1\).)]TJ 0 -2.539 TD 0.0007 Tc 0.001 Tw (At diagnosis of metastasis, se)Tj 12.6688 0 TD -0.0008 Tc 0.009 Tw [(ru)-5.8(m )6.5(EGFR leve)-5.8(ls wer)-6(e)0.7( )6.5(ele)-5.8(v)1.1(ated)]TJ -12.6688 -1.2727 TD 0.001 Tc 0.1501 Tw [(\(>)5.7(78 ng/ml\) in 12 patients \()]TJ 12.5584 0 TD 0.0007 Tc 0.1504 Tw [(21.1%\), whereas serum HER2)]TJ -12.5584 -1.2727 TD -0.0005 Tc 0.1386 Tw [(w)-5.3(a)-0.5(s )6.5(el)-6.8(evate)-5.5(d)3.1( \(>15 ng/ml\) in 31 \(54.4%\).)-5.3( )6.5(In)-5.5( )6.5(sev)-5.1(en patients)]TJ T* -0.0008 Tc 0.0025 Tw [(\()-6(1)-2.2(2.)-5.6(3%)-7.4(\) both markers wer)-6(e)0.7( elev)-5.4(ated.)]TJ /F5 1 Tf 9.48 0 0 9.48 315.3 289.0201 Tm 0.0009 Tc -0.0018 Tw [(Associ)-4.3(at)6.1(i)-4.3(o)4.9(n between change )]TJ 12.7089 0 TD 0.0013 Tc -0.0022 Tw [(in serum HER-2 and seru)5.3(m )]TJ -12.7089 -1.2405 TD 0.001 Tc -0.0019 Tw [(EGF)6(R)-2.9( exp)5(r)-2.5(ession and adjuvant hor)3.9(mone therapy)]TJ /F4 1 Tf 9.24 0 0 9.24 315.3 265.6801 Tm -0.0383 Tw [(Of)5.9( 57 patients 35 were ER posi)]TJ 13.3507 0 TD 0.0008 Tc -0.038 Tw [(tive, and)4.4( notes on assessm)5.6(ent)]TJ -13.3507 -1.2727 TD -0.0003 Tc -0.0045 Tw [(of treatmen)-5.3(t )6.5(w)-5.1(e)1.2(re)-5.3( )6.5(av)-4.9(ailable for 28. Of these,)-5.1( )6.5(16 patients we)-5.3(re)]TJ T* 0.1839 Tw [(n)-5.4(o)2.6(t rec)-5.4(e)1.1(ivi)-6.7(n)1.1(g adjuv)-5(a)-0.4(nt hor)-5.6(m)-2.1(one)-5.4( )6.4(tr)-5.6(eatment; of remain)-5.4(ing )6.4(12)]TJ T* 0.0011 Tc 0.0006 Tw [(were receiving )-6.5(tamoxifen \()]TJ /F5 1 Tf 11.0714 0 TD -0.003 Tc 0 Tw (n )Tj /F4 1 Tf 0.8442 0 TD 0.0001 Tc 0.0081 Tw [(= 10\), goserelin and tamoxifen \()]TJ /F5 1 Tf 13.5649 0 TD 0 Tc 0 Tw (n)Tj /F4 1 Tf -25.4805 -1.2727 TD 0.0004 Tc 0.0987 Tw [(= 1\),)2.1( or anastrozole \()]TJ /F5 1 Tf 9.2727 0 TD -0.003 Tc 0 Tw (n )Tj /F4 1 Tf 0.9416 0 TD 0.0011 Tc 0.098 Tw [(=)5.8( 1\). )6.5(Table 2 )6.5(shows the as)6.1(sociation)]TJ -10.2143 -1.2662 TD -0.0005 Tc 0.0542 Tw [(betw)-5.3(een)-5.5( re)-5.5(ceiv)-5.1(i)-0.3(ng or n)-5.5(o)2.5(t )-6.5(rec)-5.5(e)1(ivin)-5.5(g )-6.5(hormon)-5.5(e tr)-5.7(eatment )-6.5(at th)-5.5(e)]TJ 0 -1.2727 TD -0.0003 Tc 0.015 Tw [(time)-5.3( )6.5(of )6.5(me)-5.3(tastati)-6.6(c)1.2( diagnosis,)-5.1( and )6.5(w)-5.1(heth)-5.3(e)1.2(r a chan)-5.3(g)3.3(e occu)-5.3(rred)]TJ T* -0.0002 Tc 0.0214 Tw [(in)-5.2( serum HE)-6.6(R2 or serum EGFR. Adjuv)-4.8(a)-0.2(nt hormone tre)-5.2(a)-0.2(tme)-5.2(n)1.3(t)]TJ T* -0.0006 Tc 0.2231 Tw [(w)-5.4(a)-0.6(s )6.5(significan)-5.6(tly associa)-7.1(t)-0.8(ed w)-5.4(i)-0.4(th no c)-5.6(h)0.9(ange \(re)-5.6(du)-5.6(ction)-5.6(\))0.7( in)]TJ T* 0.0005 Tc -0.0637 Tw [(se)-4.5(rum EGFR levels betwe)-4.5(en pr)]TJ 12.9935 0 TD 0.0007 Tc -0.0639 Tw (imary diagnosis and metastasis)Tj -12.9935 -1.2727 TD 0 Tc 0 Tw (\()Tj /F5 1 Tf 0.3117 0 TD -0.0031 Tc (P )Tj /F4 1 Tf 0.8831 0 TD 0.0008 Tc -0.051 Tw [(= 0.039\). No such treatment ef)]TJ 12.9935 0 TD 0.0006 Tc -0.0508 Tw [(fect was seen with regard )-6.5(to)]TJ -14.1883 -1.2662 TD -0.0002 Tc 0.0019 Tw [(se)-5.2(rum HER2 leve)-5.2(ls.)]TJ /F5 1 Tf 9.48 0 0 9.48 315.3 112.7401 Tm 0.0014 Tc -0.0782 Tw [(HER2 and EGFR exp)5.4(r)-2.1(ession in )]TJ 13.3544 0 TD 0.0015 Tc -0.0783 Tw [(tissue samp)5.5(les )]TJ 6.5063 0 TD 0.0017 Tc -0.0722 Tw [(fr)4.6(om pr)4.6(imar)4.6(y )]TJ -19.8608 -1.2405 TD 0.0015 Tc -0.0024 Tw [(an)5.5(d subsequ)5.5(e)-2.8(nt)6.7( )-6.4(metastatic dis)5.8(e)-2.8(ase)]TJ /F4 1 Tf 9.24 0 0 9.24 315.3 89.4001 Tm 0.0009 Tc 0.1437 Tw [(Of)5.7( the 57 )6.5(patients)5.9( from whom )6.5(paired)4.5( serum samp)4.5(les)5.9( were)]TJ 0 -1.2727 TD 0 Tc -0.0437 Tw [(available \(primary and me)-5(tastatic\), in on)-5(ly eight was me)-5(tastatic)]TJ 0 -1.2662 TD 0.0002 Tc 0.0794 Tw [(breast )-6.5(tissue available for)-5( an)]TJ 12.3766 0 TD -0.001 Tc 0.0806 Tw [(aly)-5.6(s)-2.5(is.)-5.8( The tissue)-6( obtain)-6(ed )-6.5(fr)-6.2(om)]TJ ET q 1 i 56.82 417.6 240.48 -2.88 re W* n 56.82 415.62 m 56.82 415.92 l f Q q 1 i 56.82 415.92 240.48 -0.35999 re W n 56.82 415.62 240.48 0.29999 re f Q BT /F2 1 Tf 7.98 0 0 7.98 56.82 420.24 Tm 0.0029 Tc -0.0032 Tw [(Ta)7(ble)7( 1)]TJ ET q 1 i 56.82 398.76 240.48 -2.88 re W* n 56.82 396.78 m 56.82 397.08 l f Q q 1 i 56.82 397.08 240.48 -0.35999 re W n 56.82 396.78 240.48 0.29999 re f Q BT 7.98 0 0 7.98 56.82 401.46 Tm 0.0024 Tc -0.0027 Tw [(Tu)4.9(mou)4.9(r)1.5( cha)6.5(r)1.5(acte)6.5(ristic)6.2(s wh)4.9(ere)6.5( )-7.5(p)4.9(a)-1.1(ire)6.5(d)-2.6( s)4.6(e)-1.1(ru)4.9(m av)6.2(ailable)]TJ /F4 1 Tf 0.5038 -2.3684 TD 0 Tw [(Cha)6.2(r)-0.4(acter)7.1(i)-0.1(sti)7.4(c)-14130.7(Va)6.2(lue)]TJ ET q 1 i 56.82 380.46 240.48 -2.88 re W* n 56.82 378.48 m 56.82 378.78 l f Q q 1 i 56.82 378.78 240.48 -0.36002 re W n 56.82 378.48 240.48 0.29999 re f Q BT 7.98 0 0 7.98 60.84 366.42 Tm 0.0037 Tc -0.004 Tw [(Tu)5.9(mou)5.9(r)0.9( siz)7.2(e)-4926.4(T1)-8902(21 \()8.4(36.)7.1(8\))]TJ 10.0451 -1.9474 TD 0.0042 Tc -0.0045 Tw [(T2)-8901.5(30 \()8.9(52.)7.6(6\))]TJ 0 -1.9399 TD 0.0043 Tc -0.0046 Tw [(T3)-8901.4(5 \(8)8.4(.8\))]TJ T* 0.005 Tc -0.0053 Tw [(No)5.6(t)3.8( k)4.4(n)7.2(ow)4.7(n)-5436.4(1)1.5( \(1)9.1(.8\))]TJ -10.0451 -1.9474 TD 0.0043 Tc -0.0046 Tw [(Gr)9(ad)2.4(e)-7324.3(1)-9450.3(2 \(3)8.4(.5\))]TJ 10.0451 -1.9398 TD 0.0035 Tc -0.0038 Tw [(2)-9451.1(14 \()8.2(24.)6.9(6\))]TJ T* [(3)-9451.1(35 \()8.2(61.)6.9(4\))]TJ 0 -1.9474 TD 0.005 Tc -0.0053 Tw [(No)5.6(t)3.8( k)4.4(n)7.2(ow)4.7(n)-5436.4(6)1.5( \(1)9.1(0.5)9.1(\))]TJ -10.0451 -1.9398 TD 0.0026 Tc -0.0029 Tw [(Lymph)4.8( node)4.8( statu)4.8(s)-1962(Non)4.8(e)-7739.6(22 \()7.3(38.)6(6\))]TJ 10.0451 -1.9398 TD 0.0027 Tc -0.003 Tw [(1 to 3)-7489.5(22 \()7.4(38.)6.1(6\))]TJ 0 -1.9474 TD 0.0032 Tc -0.0035 Tw [(>3)-8782.2(10 \()7.9(17.)6.6(5\))]TJ 0 -1.9398 TD 0.005 Tc -0.0053 Tw [(No)5.6(t)3.8( k)4.4(n)7.2(ow)4.7(n)-5436.4(3)1.5( \(5)9.1(.3\))]TJ -10.0451 -1.9399 TD 0.0063 Tc 0 Tw [(NP)7.2(I)]TJ /TT1 1 Tf 10.0451 0 TD 0 Tc <0064>Tj /F4 1 Tf 0.5489 0 TD 0.0029 Tc -0.0032 Tw [(3.4)-8083.3(5)-0.6( \(8)7(.8\))]TJ -0.5489 -1.9474 TD 0.0033 Tc -0.0036 Tw [(3.5)7.4( to )-7.5(5)7.4(.)-0.8(4)-5857.3(23 \()8(40.)6.7(4\))]TJ 0 -1.9398 TD 0.0034 Tc -0.0037 Tw [(>5.)6.8(4)-7970(19 \()8.1(38.)6.8(3\))]TJ T* 0.0028 Tc -0.0031 Tw [(Not kn)5(own)-5438.6(10 \()7.5(17.)6.2(5\))]TJ -10.0451 -1.9474 TD 0.0029 Tc [(ER sta)6.7(t)1.7(us)-5924.1(Ne)5.1(gati)7.9(ve)-6280.6(22 \()7.6(38.)6.3(6\))]TJ 0 -1.9398 TD 0.0038 Tc -0.0041 Tw [(Ag)9.4(e \(ye)6(a)0(rs\))-15187(53 \()8.5(30)7.9(86\))]TJ ET q 1 i 56.82 98.1 240.48 -2.94 re W* n 56.82 96.12 m 56.82 96.42 l f Q q 1 i 56.82 96.42 240.48 -0.35999 re W n 56.82 96.12 240.48 0.29996 re f Q BT 7.98 0 0 7.98 60.84 86.76 Tm 0.0022 Tc -0.0025 Tw [(Pa)6(ired serum)6.3( sampl)7.2(e)-3.1(s were )-7.5(a)6(v)3.1(ail)7.2(a)-1.6(ble for)6.9( 57 pa)6(tients.)5.6( Va)6(lues )]TJ 0 -1.0075 TD 0.0029 Tc -0.0032 Tw [(expr)7.6(ess)8.2(e)-2.4(d a)6.7(s)0.7( )]TJ /F5 1 Tf 5.8872 0 TD 0.0069 Tc 0 Tw (n )Tj /F4 1 Tf 0.8346 0 TD 0.0019 Tc -0.0022 Tw [(\()6.6(%)-4.4(\))6.6( apar)6.6(t from age)4.1(,)-2.2( wh)4.1(ich)4.1( is e)4.1(x)-0.6(pre)4.1(sse)4.1(d as m)6(e)-3.4(dia)5.7(n)-3.4( )]TJ -6.7218 -1 TD 0.0012 Tc 0.006 Tw [(\(ra)5(nge\).)4.6( E)3.7(R)-1(,)4.6( oestrogen )7.5(receptor; )7.5(NP)]TJ 15.3684 0 TD -0.0003 Tc 0 Tw [(I)-4.4(,)3.1( )-7.5(Nottingha)-4.1(m)-3.7( Progn)-5.6(o)0.3(stic)-5.6( In)-5.6(dex.)]TJ ET endstream endobj 24 0 obj<> endobj 25 0 obj<>/ColorSpace<>/Font<>/ProcSet[/PDF/Text/ImageC]/ExtGState<>>> endobj 26 0 obj<>stream /GS1 gs BT /F3 1 Tf 7.98 0 0 7.98 56.28 744.42 Tm /Cs6 cs 0 0 0 scn 0.0018 Tc 0.0054 Tw [(Breast)6.5( C)5.6(a)-5.1(n)7.4(c)-2(er )7.5(Research)]TJ /F4 1 Tf 11.0226 0 TD 0.0007 Tc -0.001 Tw [( )-7.5( )7.5(Vol 9 No)-6.2( 6 )-7.5( )7.5(Asgeirsso)-6.2(n)2.9( )]TJ /F5 1 Tf 11.7895 0 TD -0.0022 Tc 0.0034 Tw [(et)-9.4( al)-6.3(.)]TJ /F4 1 Tf -22.812 -89.7143 TD 0.0051 Tc -0.0054 Tw [(Pa)8.9(ge 4)9.2( )-7.5(o)5.7(f)5.4( 8)]TJ /F5 1 Tf 6.96 0 0 6.96 56.28 19.2 Tm 0.0006 Tc 0.0005 Tw [(\(pag)-9.1(e num)-9.1(ber no)-9.1(t for c)-8(i)5.5(tati)5.5(on)-9.1( purpo)-9.1(s)5.5(e)-4.3(s\))]TJ /F4 1 Tf 9.24 0 0 9.24 56.28 181.92 Tm -0.0009 Tc 0.113 Tw [(th)-5.9(ese sample)-5.9(s were)-5.9( as follow)-5.7(s)-2.4(: th)-5.9(ree)-5.9( skin re)-5.9(cur)-6.1(renc)-5.9(es, fou)-5.9(r)]TJ 0 -1.2727 TD -0.0008 Tc 0.2168 Tw [(r)-6(e)0.7(gi)-7.1(onal re)-5.8(cur)-6(renc)-5.8(es and )6.5(one in-)-7.5(b)2.8(re)-5.8(ast )6.5(r)-6(ecur)-6(renc)-5.8(e. All fiv)-5.4(e)]TJ T* -0.0006 Tc 0.0802 Tw [(patien)-5.6(ts w)-5.4(i)-0.4(th re)-5.6(gional r)-5.8(ecur)-5.8(ren)-5.6(ces and in-brea)-7.1(s)4.4(t r)-5.8(ecur)-5.8(ren)-5.6(ces)]TJ 0 -1.2662 TD 0.0003 Tc -0.0635 Tw [(were also diagnosed with distant metastases at )-6.5(the same t)-6.4(i)0.5(me.)]TJ 0 -1.2727 TD -0.0005 Tc 0.275 Tw [(Of th)-5.5(ese e)-5.5(i)-0.3(gh)-5.5(t rec)-5.5(u)1(rre)-5.5(nce)-5.5(s )-6.5(in total, se)-5.5(ven )-6.4(had no HER2)]TJ T* -0.0012 Tc 0.0224 Tw [(e)-6.2(x)-1.3(pr)-6.4(essi)-7.5(on at the time of pr)-6.4(ima)-7.7(r)0.1(y dia)-7.7(g)2.4(nosis )6.5(an)-6.2(d on)-6.2(e exhibited)]TJ T* -0.0003 Tc 0.3916 Tw [(ove)-5.3(r)1(-expression)-5.3( \()-5.5(3)-1.7(+\))-5.5( on )-6.5(immunohistoc)-5.3(hemistry)-4.9(.)1.4( )-6.5(Of th)-5.3(ese)]TJ T* 0.0929 Tw [(sev)-4.9(en w)-5.1(i)-0.1(th no HER2 tissu)-5.3(e)1.2( expression)-5.3( at primar)-5.5(y dia)-6.8(g)3.3(nosis,)]TJ T* -0.0007 Tc -0.0041 Tw [(n)-5.7(o)2.3(ne)-5.7( exhi)-7(bited a c)-5.7(h)0.8(ange in)-5.7( tissu)-5.7(e)0.8( expre)-5.7(s)4.3(sion at metastasis. I)-5.5(n)]TJ 0 -1.2662 TD -0.0235 Tw [(only)-5.3( on)-5.7(e of these )-6.4(seve)-5.7(n was )-6.4(a cha)-7.2(nge)-5.7( in )-6.4(se)-5.7(rum H)-5.5(E)-0.6(R2 )-6.5(expres-)]TJ 0 -1.2727 TD -0.0005 Tc 0.4698 Tw [(sion )6.5(from )6.5(n)-5.5(o)2.5(rmal to ov)-5.1(er-expre)-5.5(ssion observe)-5.5(d)3.1( be)-5.5(twee)-5.5(n)]TJ 27.9675 12.7143 TD -0.0001 Tc 0.1187 Tw [(ev)-4.7(ents. The remain)-5.1(ing )6.5(patien)-5.1(t )6.5(w)-4.9(i)0.1(th tissu)-5.1(e)1.4( )6.5(ove)-5.1(r)1.2(-expression at)]TJ 0 -1.2727 TD 0.0008 Tc 0.1568 Tw [(both events)5.8( exhibited )6.5(a chan)]TJ 12.7597 0 TD 0.0002 Tc 0.1574 Tw [(ge in serum HER2 expression)]TJ -12.7597 -1.2727 TD -0.0004 Tc 0.0021 Tw [(betwe)-5.4(en ev)-5(ents \(from normal to over)-5.6(-expression)-5.4(\).)]TJ 0 -2.539 TD -0.0002 Tc 0.3006 Tw [(Only five)-5.2( tissue )-6.5(sample)-5.2(s )-6.5(wer)-5.4(e)1.3( available for EG)-6.4(FR tissue)]TJ 0 -1.2727 TD -0.0005 Tc 0.4308 Tw [(expression ana)-7(l)-0.3(ysis \(one re)-5.5(gional r)-5.7(ecu)-5.5(rren)-5.5(ce,)-5.3( three)-5.5( skin)]TJ T* -0.001 Tc 0.0417 Tw [(re)-6(curr)-6.2(ence)-6(s an)-6(d )-6.5(on)-6(e i)-7.3(n)0.5(-br)-6.2(e)0.5(ast r)-6.2(ecu)-6(rren)-6(ce\).)-5.8( W)-6(hen)-6( membrane)]TJ T* 0.0013 Tc 0.1498 Tw [(staining)4.9( was assessed)4.9(,)-3.5( )6.5(one )6.5(of)]TJ 13.3377 0 TD -0.0008 Tc 0.1519 Tw [( )6.5(th)-5.8(ese five sample)-5.8(s ch)-5.8(anged)]TJ -13.3377 -1.2727 TD -0.0004 Tc 0.0541 Tw [(from negative)-5.4( )6.5(expre)-5.4(s)4.6(sion to )6.5(posi)-6.7(tive \(>10% of cells expr)-5.6(ess-)]TJ 0 -1.2662 TD 0.0005 Tc 0.1571 Tw [(ing EGF)3.5(R)-1.3(\). )-6.5(C)3.7(y)-4.1(to)3.5(plasmic staining was unchanged in )-6.5(all five)]TJ 0 -1.2727 TD 0.0012 Tc 0.0265 Tw [(samp)4.8(les)6.2( )-6.5(\(all five exhibited po)4.2(siti)]TJ 13.487 0 TD 0.0005 Tc 0.0337 Tw [(ve expressio)3.5(n)-4.5( )6.5(both at )6.5(primary)]TJ ET q 1 i 56.28 698.58 498.9 -2.88 re W* n 56.28 696.6 m 56.28 696.9 l f Q q 1 i 56.28 696.9 498.9 -0.35999 re W n 56.28 696.6 498.9 0.30005 re f Q BT /F2 1 Tf 7.98 0 0 7.98 56.28 701.28 Tm 0.0066 Tc -0.0069 Tw [(Fi)5.4(g)9.1(u)1.6(r)5.7(e)10.7( 1)]TJ /F4 1 Tf 1 1 1 scn 0 -41.5865 TD 0.0027 Tc -0.003 Tw [(EGF)3.3(R)0.5( an)4.9(d HER-2)6.8( )-7.5(s)8(e)-2.6(ru)4.9(m le)4.9(v)3.6(e)-2.6(l)7.7(s)]TJ 0 0 0 scn 0 0 TD 0.0014 Tc -0.0168 Tw [(EGFR and HER-2 serum l)6.4(e)-3.9(vels. )]TJ /F3 1 Tf 13.5865 0 TD -0.0006 Tc 0 Tw [(\()-7.5(a\) )]TJ /F4 1 Tf 1.5038 0 TD 0.0003 Tc -0.0157 Tw [(Epiderm)-3.1(a)4.1(l gro)-6.6(w)0(th fa)-3.5(ctor re)-5(ce)-5(ptor )7.5(\(E)-4.7(GFR\) )7.5(a)-3.5(n)2.5(d )]TJ /F3 1 Tf 19.6241 0 TD 0 Tw (\(b\) )Tj /F4 1 Tf 1.5489 0 TD 0.0033 Tc -0.0262 Tw [(h)5.5(u)-2(ma)7.1(n epid)8.9(erm)7.4(a)-0.5(l gro)4(w)3(th )-7.5(f)3.6(a)7.1(cto)3.9(r)0.5( rec)5.5(e)5.5(p)1.4(tor)8( )-7.5(\(HE)5.8(R)1.1(\)2 ser)8(u)-2(m lev)4.2(e)5.5(ls )]TJ -36.2632 -1.188 TD 0.0016 Tc -0.0019 Tw [(at tim)5.7(e)-3.7( of \(1\) pr)6.3(ima)5.4(r)-1.2(y and \(2\) m)5.7(e)-3.7(ta)5.4(stati)6.6(c)-3.7( dia)5.4(g)]TJ 18.9173 0 TD 0.0018 Tc -0.0021 Tw [(nosi)6.8(s. sEGFR)7.1(,)-2.3( serum)5.9( EGFR; sHER2)5.9(,)-2.3( serum)5.9( H)-6(E)4.3(R2.)]TJ ET q 1 i 56.28 351.78 498.9 -2.94 re W* n 56.28 349.8 m 56.28 350.1 l f Q q 1 i 56.28 350.1 498.9 -0.36002 re W n 56.28 349.8 498.9 0.30002 re f Q q 1 i 56.28 317.34 498.9 -2.88 re W* n 56.28 315.36 m 56.28 315.66 l f Q q 1 i 56.28 315.66 498.9 -0.36002 re W n 56.28 315.36 498.9 0.30002 re f Q BT /F2 1 Tf 7.98 0 0 7.98 56.28 320.04 Tm 0.0021 Tc -0.0024 Tw (Table 2)Tj ET q 1 i 56.28 298.56 498.9 -2.94 re W* n 56.28 296.58 m 56.28 296.88 l f Q q 1 i 56.28 296.88 498.9 -0.36002 re W n 56.28 296.58 498.9 0.29999 re f Q BT 7.98 0 0 7.98 56.28 301.2 Tm -0.0023 Tw [(The)6.1( )-7.5(a)6.1(s)-3.3(s)4.2(o)2.9(ciation)4.5( )-7.5(betw)4.5(een)4.5( ad)4.5(juva)6.1(nt hormone trea)6.1(tmen)4.5(t )]TJ 26.1729 0 TD 0.0024 Tc -0.0027 Tw [(and)4.9( ch)4.9(an)4.9(ge in)4.9( se)6.5(rum EGFR an)4.9(d s)4.6(e)-1.1(rum HER2 )-7.5(l)8.7(e)-1.1(ve)6.5(ls)]TJ /F4 1 Tf -4.8346 -2.3684 TD 0.0011 Tc -0.0014 Tw [(Change i)6.1(n)-4.2( serum EGFR)]TJ 20.8421 0 TD -0.0055 Tc 0.0052 Tw [(Ch)-10.8(a)-9.3(n)-3.3(g)-7.4(e)-3.3( i)-8(n)-10.8( s)-7.7(e)-3.3(r)-8.3(u)-3.3(m)-8.9( H)-5.8(E)-10.5(R2)]TJ ET q 1 i 226.56 280.26 328.62 -2.94 re W* n 226.56 278.28 m 226.56 278.58 l f Q q 1 i 226.56 278.58 328.62 -0.35999 re W n 226.56 278.28 328.62 0.29996 re f Q BT 7.98 0 0 7.98 226.56 265.08 Tm -0.0017 Tc 0 Tw [(No)-9174(Yes)-8800.9(N)-0.5(o)-9174(Y)-8.3(es)]TJ ET q 1 i 56.28 260.22 498.9 -2.88 re W* n 56.28 258.24 m 56.28 258.54 l f Q q 1 i 56.28 258.54 498.9 -0.36002 re W n 56.28 258.24 498.9 0.29999 re f Q BT 7.98 0 0 7.98 60.24 238.8 Tm -0.001 Tc -0.0219 Tw [(On)-6.3( a)-4.8(d)-2.9(ju)-6.3(va)-4.8(nt trea)-4.8(tm)-4.4(en)-6.3(t)]TJ 10.4211 0.9248 TD 9.8381 Tc 0 Tw [(N)9839.3(o)665.8(8888)]TJ 0 -1.9474 TD [(Y)9839(e)9832.8(s)1046.4(1)9842.2(1)579(184)]TJ /F5 1 Tf 20.8421 -1.9398 TD 0.0006 Tc (P )Tj /F4 1 Tf 0.9398 0 TD 0.0029 Tc -0.0032 Tw [(= 0)7(.)-1.2(03)7(9)]TJ /F5 1 Tf 19.9023 0 TD 0.0081 Tc 0 Tw (P )Tj /F4 1 Tf 0.9398 0 TD 0.003 Tc -0.0033 Tw [(= 0.4)7.1(5)-0.5(9)]TJ ET q 1 i 56.28 210.36 498.9 -2.94 re W* n 56.28 208.38 m 56.28 208.68 l f Q q 1 i 56.28 208.68 498.9 -0.36 re W n 56.28 208.38 498.9 0.29997 re f Q BT 7.98 0 0 7.98 60.24 199.0201 Tm -0.0003 Tc 0 Tw [(EG)-7.8(FR, e)-5.6(p)-2.2(ide)-5.6(r)-3.1(ma)-4.1(l gro)-7.2(w)-0.6(th fa)-4.1(cto)-7.2(r)4.4( re)-5.6(ceptor; HE)-5.3(R,)]TJ 19.8947 0 TD 0.0039 Tc -0.0042 Tw [( )-7.5(h)6.1(u)6.1(m)0.5(an)6.1( epi)8.9(d)2(er)8.6(mal)8.9( )-7.5(g)9.5(r)1.1(o)4.6(w)-3.9(t)10.2(h)-1.4( f)4.2(a)0.1(c)6.1(t)2.7(o)4.5(r)1.1( re)6.1(ce)6.1(pto)4.5(r)1.1(.)]TJ ET 1 1 1 scn 56.28 383.76 498.9 308.94 re f q 1 i 56.28 692.7 498.9 -308.94 re W* n q 498.87793 0 0 309.184753 56.2584 383.756409 cm /Im1 Do Q Q endstream endobj 27 0 obj<>stream HkH7ohh:yI-ʱ'0D&M$BV^2E=ZZvzQatB)3+uR#G0,f阚:}{w =kg͗w~ ~>R#===ЍbPQQ3>>#Bpݺuϟ7pk:::RJKKKK˶6ARREQ?ׯd@ 0\oӽ}Pu?n~eJѣGk޼y3:: jmm%K rZP(۵Z>|տ6.))Ҿݰްϒ}T*ҳ[n釲ѲѲѰ˗S,HJLfjjJB???Vk&?|P[[Kni ;;;---+++ýggg䤻{llcɁ]]]l"֮]K]]]ؼ͛x"BTWW/Xh4R4!!a޽D–rCBJeV;;;-4M3SLt'Nx]vO{ogϚ}Mrss-[MLKKcAdddaVݼy3SUU400OxWflmmp8$4663\ B43% zyy:thÆ dU*%OOP->>>abb 444^p?~|ý`qjNuuRtt4;;;_xEV>jzzM lllrss|ttɉ&999InW455=xNMMMmmm=ȷǯ/-&&ҹsj.YS,Hӧ$ܶmV5\ B43{.$!!!{t /_I^^yꕽ}vv6899%&&+dR9>>>11AOD)))NJNN&&!!A,o?ĥK(46777'iss3֮Z)H$lqYYUBAniדT*e ?nbb"h|nnnӦM ,..&'IJJ yȈӱcݻw$&+**ZyըBLW?Y4uuuNXX~7nΎp87UUUleVV^zՠ* r M˗\.W,?&߿wttc;;3g,8s;wT;vyKK |6_QQWEQQѳg~vȈ EQ<onn͛mmm)=BP$1㐐)2(($VVVmUPhfJt~a ++\RUTTz&w644DOOZ&ぁ$,YXXdffɓa^C8?jԨ/Еɽ6DQ7eYmZdաDEeSٍ.VRYv񮣖EÜӱ3ٲ9ϋy_< ̤UUUv| )0G"ZNЋ^ʕ+Gedd,\pŊ'O|ݛ7o>|h>fG_&ZN$PJNz֭[Ǐ3dȐiӦM3rȰ0٢3g.X`ܹ.kС+W4{n޼ۙeVkׯ߄ Nʔ)'N8p87nzjRR1ĈaРAUVݼy$H)ֶS 4 !RSw…pqniSZZz~qqqf$##uuu4K֭>})9ٻcccuuݻwN|royL!CZZZLHKK3Ũ۷+#)v &!Rv? ee;߿+..u'33 sν}̙3}1GlNNNdd5k˗/7# ͟dee-^{n:G]SS߳~zS zW= I)ֶS 4 !RSֿ;*W}86mZwf߿ ׯ_///^WVV<4/Z {&''ϟ??b\.W]]ݧUUU/_^]t5ʜs޽h-)v &!Rv -o쉏?/ms_6v4JJJܹSYYP/((ugNUWWߦ/eܰaCWWl].W]]]@sMMMggvڵsԨQQ9@ORjmڵkO>#O 2aQ)! 0{/[P,A͜9s' BtttT(i׮]344PVV֗AAh[AAA/`2EEECiՕ1W[[۔{FGGSiyYYy󦥥%8KSi֐͓Ÿmݚbl@蟈Z ~__Q\bI-ZqFzZ[[kbb111 `!UTzMMCGGBp8޽EUVK]OGڄ$I}W  Lnn.ɡ,EFF E]zŋL&,Ք{fddBMo~JLϯ(@)R̐;v$0׫ oرcr4z*aC 8APP [l3\˜ 99yʳ***ϝ;WRRrj*$`99 N7 l2h҃lšfB] $I}W  S|>e$V}s΍*SCM `ZWW |JTT5i MLLP\\bT:{"H60H3w]}WOZ[[ VX!)EV?~Nb;g_TTqj{{P:)ςϟ9p#GZZZ@ ڡ:ĉL&D(Bub|||CC:#A$*AAeٔH$ZQ*6mڰaCHH>|x…LH$ZXSSchhx ZYv-eS[hȟTKRtFDtf|tҘ˗-Jb0al|c! ^͛Z[[gdd i%r Z*rIII91&&r5EhI=<88kZ ԴdBtqA@AAt`ttǏuuu,$fɓ'Ϟ=H`<==a 5cmϜ9677JBBn]vzcc#ɜl&#Rn `ϘQ\b $B4};==0)]ձճv<.,ȴ&oȑ---83o޼ׯ6l/ܲe޽{{Um{>'0a9T[[;`s655uttӧϞ=;tvv޼ys…≸UVmذ~fee͙3gv*--=&vĎW 55uW^سgٗ4lȐ!omhh%ϧ>:&&&2;;޹-(((ў<=?<1u%÷GGt]ymII=w.] wcbb)~РAc׬Y]SSZlwK#գDV{O~H z}@ pΝ^oRr!D㓓`wߍ;{ɓ'nj3cƌTNN·vϒ/Μ9s7nܰv5k߱c]*RJuOtԩӦGRvҥܹIII)))]ϟ5jxb񕕕񜜜ׇof̘aDEEϢJJJZ[[_%RJ~D >|x&?AM^"R ޽?=rm۶655u Ǐw W\yfʍ7޽#vW\ ^ׇ?:@2Ƹ7I)֮+BEE9rG;sPJc\WZk~/"8:@2Ƹ7I)֮+:~ӄ BZ9SJc\WZkxMXUTԺ*(82Ƹ7I)֮+# ?X\o/R$Z@O?>yٳٖ&7ݳľ2Ƹ7)֮+;ܮ]+ҤǏЧ&)uӕջ28xʿ)qǒR] ݯ?pȵUϴ:ʴܰ-'駭UsٖR$ԴܻUgǎ]!@sC)eq]oRj]WZZ-^B؊R9zR$Z7Դi˅m:@(1+MRJ 8xv7~[CE^R$ZcM?mr2! 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Nei)-6.7(t)-0.6(her one of these sample)-5.4(s)]TJ 0 -1.2727 TD -0.0239 Tw [(exhibited )6.5(a differ)-5.5(ence)-5.3( )6.5(in serum EGFR expression)-5.3( )6.5(betwe)-5.3(en )6.5(pri-)]TJ T* 0.0001 Tc -0.0049 Tw [(mary )6.5(diagnosis and metastasis, )]TJ 13.4675 0 TD -0.0114 Tw [(although two of the )-6.5(remaining)]TJ -13.4675 -1.2727 TD 0 Tc 0.0926 Tw [(thre)-5(e exhibited a dec)-5(r)1.3(ease in)-5( )6.5(se)-5(rum EGFR expression \(from)]TJ T* -0.0005 Tc 0.0022 Tw [(ov)-5.1(er-ex)-7.1(p)3.1(re)-5.5(ssion to n)-5.5(o)2.5(rmal lev)-5.1(e)1(ls of expression)-5.5(\).)]TJ /F5 1 Tf 9.48 0 0 9.48 56.82 197.7601 Tm 0.0006 Tc -0.0015 Tw (Association between serum )Tj 12.2025 0 TD 0.0015 Tc 0.004 Tw [(HER2 and)6.5( E)6.2(G)-4(FR )6.4(expr)4.4(es)5.8(sion )]TJ -12.2025 -1.2405 TD -0.0003 Tc -0.0006 Tw [(and )-6.4(tum)-5.8(o)3.7(ur marker )-6.4(expressi)-5.5(on at m)-5.8(e)1.7(tastasis)]TJ /F4 1 Tf 9.24 0 0 9.24 56.82 174.42 Tm 0.2229 Tw [(Tab)-3.3(l)-0.2(e 3 )6.5(sh)-5.4(ows the)-5.4( )6.5(ser)-5.6(u)1.1(m )6.5(le)-5.4(vels of on)-5.4(cog)-3.3(e)1.1(n)-5.4(e)1.1( and)-3.3( )6.5(tumo)-3.9(ur)]TJ 0 -1.2727 TD 0.0023 Tc 0.2007 Tw [(mar)3.6(k)5.8(er)3.6( exp)5.9(r)-2.9(e)3.8(ssi)2.5(o)5.3(n)3.8( )-6.5(at tim)7.1(e)-2.7( of)7.1( )]TJ 13.2078 0 TD 0.0007 Tc 0.2088 Tw [(metastatic d)4.3(i)0.9(ag)4.3(nosis. )6.5(All f)5.5(o)-2.8(ur)]TJ -13.2078 -1.2727 TD -0.0007 Tc -0.0041 Tw [(marke)-5.7(r)0.6(s w)-5.5(e)0.8(re )-6.5(avail)-7(a)-0.7(bl)]TJ 9.1039 0 TD 0.0013 Tc -0.0061 Tw [(e for 50 patients)6.3(. In 52% of the patients)]TJ -9.1039 -1.2727 TD 0.0004 Tc -0.0506 Tw [(\(26/50\) )-6.5(either tumour marker )]TJ 12.4091 0 TD -0.0004 Tc -0.0433 Tw [(CA15.3 or)-5.6( )6.5(CEA was ele)-5.4(v)1.5(ated. In)]TJ -12.4091 -1.2727 TD 0.0005 Tc -0.0377 Tw [(64)5.6(%)-6.1( \(32/50\) either HER)5.2(2)-0.9( or EGFR was elevated, and in 7)5.6(8)-0.9(%)]TJ 0 -1.2662 TD -0.0007 Tc 0.0154 Tw [(\(39/50\) on)-5.7(e of th)-5.7(ese fou)-5.7(r)0.6( markers was el)-7(evate)-5.7(d)2.9(. The)-5.7(r)0.6(e wa)-7.2(s a)]TJ 0 -1.2727 TD -0.0004 Tc 0.0021 Tw [(sign)-5.4(ific)-5.4(ant associa)-6.9(t)-0.6(ion betwe)-5.4(en a raise)-5.4(d)3.2( HER2 serum expre)-5.4(s)4.6(-)]TJ T* 0.0001 Tc -0.0373 Tw [(sion and raised )6.5(se)-4.9(rum leve)-4.9(ls )6.5(of the)-4.9( )6.5(tu)-4.9(mour)-5.1( )6.5(markers CA15.3 \()]TJ /F5 1 Tf 25.3766 0 TD 0 Tc 0 Tw (P)Tj /F4 1 Tf -25.3766 -1.2727 TD 0.0013 Tc -0.0126 Tw [(= 0.019\) )-6.5(and CEA \()]TJ /F5 1 Tf 8.5 0 TD 0.0034 Tc 0 Tw (P )Tj /F4 1 Tf 0.9286 0 TD -0.0001 Tc -0.0047 Tw [(= )6.5(0.005; )6.5(Table 4)5(\))-5.3(. S)4.6(u)-5.1(ch an associa)-6.6(t)-0.3(ion)]TJ -9.4286 -1.2727 TD -0.0006 Tc -0.0626 Tw [(was not )6.5(obse)-5.6(rved be)-5.6(twee)-5.6(n EGFR seru)-5.6(m e)-5.6(x)-0.7(pre)-5.6(s)-2.1(sion and these)]TJ T* 0.0003 Tc 0.0014 Tw [(tumour mark)3.8(ers \(Table 4\).)]TJ /F2 1 Tf 10.98 0 0 10.98 315.3 314.22 Tm 0.0033 Tc 0 Tw [(Di)5.7(sc)6(us)5.2(si)5.7(on)]TJ /F4 1 Tf 9.24 0 0 9.24 315.3 303.66 Tm -0.0006 Tc -0.0431 Tw [(I)-5.4(n)0.9( this study, we)-5.6( )6.5(h)-5.6(a)-0.6(ve sho)-4.1(w)1.1(n )]TJ 12.1558 0 TD 0.0008 Tc -0.0445 Tw [(that )6.5(both sEGFR and s)5.8(H)-4(ER2 )6.5(lev-)]TJ -12.1558 -1.2727 TD -0.0002 Tc -0.0435 Tw [(e)-5.2(l)0(s ch)-5.2(ange significan)-5.2(tly betw)-5(een )-6.5(the )-6.5(times of )-6.5(pr)-5.4(imary )-6.5(and met-)]TJ T* 0.0022 Tc 0.045 Tw [(astati)2.4(c d)5.8(i)2.4(ag)5.8(n)3.7(o)-1.3(si)2.4(s,)3.9( al)2.4(be)3.7(i)2.4(t)2( i)2.4(n)-2.8( o)5.2(p)-0.7(p)5.8(o)-1.3(si)2.4(te)3.7( di)2.4(r)3.5(e)3.7(cti)2.4(o)5.2(ns)7.2(. W)3.7(e)3.7( hav)4.1(e)-2.8( al)2.4(so)]TJ 0 -1.2662 TD -0.0004 Tc 0.2749 Tw [(sh)-5.4(own)-5.4( that seru)-5.4(m EG)-6.6(FR levels are significan)-5.4(tly highe)-5.4(r)0.9( in)]TJ 0 -1.2727 TD 0 Tc 0.0991 Tw [(h)-5(e)1.5(althy)-4.6( individuals th)-5(an in)-5( PBC patients. )-6.5(Fina)-6.5(lly, w)-4.8(e)1.5( found a)]TJ T* 0.0006 Tc 0.079 Tw [(rise in )-6.5(serum HER2 expression )]TJ 13.7533 0 TD 0.0005 Tc [(to be associated with raised)]TJ -13.7533 -1.2727 TD 0.0011 Tc -0.0059 Tw [(tumour marker levels )-6.5(me)]TJ 10.3247 0 TD 0.0001 Tc 0.0016 Tw [(asur)-5.1(ed at metastasis.)]TJ -10.3247 -2.5455 TD -0.0005 Tc -0.0108 Tw [(Furth)-5.5(e)1(mor)-5.7(e)1(, our re)-5.5(sults sh)-5.5(ow)-5.3( that a chan)-5.5(g)3.1(e)-5.5( in sHER2 expres-)]TJ 0 -1.2662 TD -0.0004 Tc 0.0865 Tw [(sion is )6.5(a common fe)-5.4(ature)-5.4( )6.5(obser)-5.6(v)1.5(ed betw)-5.2(een)-5.4( )6.5(th)-5.4(e )6.5(ti)-6.7(me)-5.4( )6.4(of )6.4(pri-)]TJ 0 -1.2727 TD 0.0007 Tc 0.2153 Tw [(mar)-4.5(y)2.6( and metastatic diagnosi)]TJ 13.039 0 TD [(s. In our study, serum HER2)]TJ -13.039 -1.2727 TD -0.0004 Tc -0.0563 Tw [(e)-5.4(x)-0.5(pr)-5.6(ession )-6.5(chan)-5.4(g)3.2(ed in)-5.4( 32% of patien)-5.4(ts. There)-5.4( are)-5.4( seve)-5.4(ral pos-)]TJ T* -0.0006 Tc 0.0608 Tw [(sible e)-5.6(x)-0.7(plan)-5.6(ation)-5.6(s)4.4( )-6.5(for thi)-6.9(s)4.4(.)-5.4( It is inc)-5.6(r)0.7(easingly )-6.5(bei)-6.9(n)0.9(g )-6.5(recognized)]TJ T* 0.1712 Tw [(th)-5.6(at )6.5(in)-5.6(div)-5.2(i)-0.4(du)-5.6(al )6.5(brea)-7.1(st can)-5.6(cers are compose)-5.6(d)3( of biologic)-5.6(ally)]TJ T* -0.0011 Tc 0.0288 Tw [(an)-6.1(d ge)-6.1(netic)-6.1(ally differe)-6.1(nt )6.5(c)-6.1(l)-0.9(on)-6.1(es )6.5(of cel)-7.4(ls [16,17]. 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Spe)-4.6(c)1.9(ifi-)]TJ -12.9026 -1.2727 TD -0.0005 Tc 0.0542 Tw [(c)-5.5(a)-0.5(lly with r)-5.7(e)1(ga)-7(rds to u)-5.5(p)3.1(re)-5.5(gu)-5.5(lation)-5.5( of HER2, Sliche)-5.5(nmye)-5.5(r and)]TJ T* -0.0003 Tc -0.0045 Tw [(Fry )-6.5([21] an)-5.3(d )-6.5(Tan)-5.3(ner )-6.5(and coworkers [)-5.5(2)4.8(2])-5.5( demonstr)-5.5(ated this to)]TJ T* -0.0007 Tc 0.3401 Tw [(occu)-5.7(r in )6.5(bre)-5.7(a)-0.7(st )6.5(can)-5.7(cer)-5.9( )6.5(re)-5.7(lapsin)-5.7(g after adju)-5.7(vant hormon)-5.7(e)]TJ T* 0.0002 Tc 0 Tw (therapy.)Tj 0 -2.539 TD -0.0003 Tc -0.0629 Tw [(In this stu)-5.3(d)3.3(y we were)-5.3( able to obtain paire)-5.3(d)3.3( ti)-6.6(ssue)-5.3( sample)-5.3(s )-6.5(fr)-5.5(om)]TJ 0 -1.2727 TD 0.0005 Tc -0.0442 Tw [(eight patients and, in all, no )]TJ 11.6039 0 TD 0.0008 Tc -0.0445 Tw [(change in tissue HER2 expression)]TJ -11.6039 -1.2727 TD -0.0002 Tc 0.0214 Tw [(w)-5(a)-0.2(s )6.5(obser)-5.4(v)1.7(ed. Of )6.5(th)-5.2(ese, HER2 se)-5.2(rum expression)-5.2( )6.5(at metasta-)]TJ T* -0.0005 Tc 0.0282 Tw [(sis was n)-5.5(o)2.5(rmal in)-5.5( se)-5.5(ven)-5.5(,)1.2( although in one \()-5.7(w)1.2(hic)-5.5(h)1( exhi)-6.8(bite)-5.5(d tis-)]TJ T* 0.0006 Tc -0.0119 Tw [(sue over-expression at )-6.5(p)4.2(r)-4.6(imary\))]TJ 13.1818 0 TD -0.0006 Tc -0.0042 Tw [( )6.5(a chan)-5.6(g)3(e)-5.6( )6.5(in seru)-5.6(m expression)]TJ -13.1818 -1.2727 TD 0.0413 Tw [(w)-5.4(a)-0.6(s observ)-5.2(ed. This may )-6.5(su)-5.6(ggest an)-5.6( associa)-7.1(t)-0.8(ion )-6.5(be)-5.6(twee)-5.6(n tis-)]TJ 0 -1.2662 TD -0.0002 Tc 0.1902 Tw [(sue )6.5(expr)-5.4(ession at pr)-5.4(imary an)]TJ 12.8247 0 TD 0.0008 Tc 0.1827 Tw [(d serum )-6.5(expression at )-6.5(metas-)]TJ -12.8247 -1.2727 TD 0.0003 Tc -0.0505 Tw [(tases, although statistical analys)]TJ 13.4675 0 TD -0.0003 Tc -0.0499 Tw [(is on)-5.3( such)-5.3( a small gr)-5.5(oup is not)]TJ -13.4675 -1.2727 TD 0.0005 Tc -0.0118 Tw [(valid. Similar findings have been)]TJ 13.513 0 TD -0.0008 Tc -0.0105 Tw [( re)-5.8(ported by other)-6(s )-6.5(in a l)-7.1(a)-0.8(rge)-5.8(r)]TJ -13.513 -1.2727 TD -0.0006 Tc 0.1582 Tw [(c)-5.6(a)-0.6(se serie)-5.6(s)4.4( [)-5.8(2)-2(3])-5.8(. Howev)-5.2(e)0.9(r,)-5.4( the lite)-5.6(r)0.7(atur)-5.8(e reports conflicting)]TJ T* 0 Tc -0.0437 Tw [(findings on the expr)-5.2(ession )-6.5(of HER2 in )-6.5(pri)-6.3(m)4.8(ar)-5.2(y and )-6.5(metastastic)]TJ T* -0.0009 Tc 0.1455 Tw [(tissue)-5.9(;)3.9( some)-5.9( stu)-5.9(d)2.7(ie)-5.9(s h)-5.9(a)-0.9(ve identifie)-5.9(d no differe)-5.9(nce)-5.9(, whe)-5.9(r)0.4(eas)]TJ 0 -1.2662 TD -0.0003 Tc 0.3137 Tw [(other)-5.5(s )6.5(hav)-4.9(e)1.2( show)-5.1(n a )6.5(diffe)-5.3(r)1(en)-5.3(ce in up )6.5(to )6.5(26% of cases)]TJ 0 -1.2727 TD 0.0022 Tc 0.1229 Tw [([1)7.3(8,2)7.3(2)0.8(,2)7.3(4,2)7.3(5)0.8(]. Most of these )]TJ 13.0844 0 TD 0.0007 Tc 0.1309 Tw [(studies are sm)5.5(all )6.5(cas)5.7(e)-4.3( )6.5(series,)]TJ -13.0844 -1.2727 TD -0.0005 Tc 0.0087 Tw [(an)-5.5(d un)-5.5(de)-5.5(rstandably)-5.1( )6.5(so bec)-5.5(a)-0.5(use metastatic tissue for)-5.7( )6.5(a)-7(n)1(alysis)]TJ T* -0.0237 Tw [(in)-5.5( )6.5(breast canc)-5.5(er is not )6.5(re)-5.5(adily)-5.1( )6.5(av)-5.1(ailable. Indeed, this )6.5(is the on)-5.5(ly)]TJ T* 0 Tc 0.0082 Tw [(study, as far as we )6.5(ar)-5.2(e awar)-5.2(e,)]TJ 12.6169 0 TD 0.0003 Tc 0.0079 Tw [( whereby an )6.5(a)-6.2(ttempt is made )6.5(to)]TJ -12.6169 -1.2727 TD 0.0013 Tc -0.0061 Tw (analyze both serum and tissue of)Tj 13.8766 0 TD -0.0001 Tc 0.0018 Tw [( both the prima)-6.6(r)1.2(y and )6.5(metas-)]TJ -13.8766 -1.2662 TD 0.0008 Tc 0.0009 Tw [(tases)5.8( in the s)5.8(a)0.8(me )6.5(patient.)]TJ 0 -2.5455 TD -0.0007 Tc 0.1583 Tw [(Ser)-5.9(u)0.8(m EGFR le)-5.7(vels in)-5.7( our)-5.9( gr)-5.9(oup of brea)-7.2(st c)-5.7(a)-0.7(nce)-5.7(r pati)-7(ents)]TJ 0 -1.2727 TD 0.0088 Tw [(w)-5.4(e)0.9(re)-5.6( sign)-5.6(ificantly)-5.2( lower)-5.8( wh)-5.6(en )-6.5(compared w)-5.4(i)-0.4(th )-6.5(those )-6.5(in )-6.5(health)-5.6(y)]TJ T* -0.0002 Tc 0.0409 Tw [(c)-5.2(o)2.8(ntr)-5.4(o)2.8(l individuals. Alth)-5.2(ough this )6.5(obser)-5.4(v)1.7(ation )6.5(is su)-5.2(ppor)-5.4(ted )6.5(by)]TJ T* 0 Tc -0.0242 Tw [(other)-5.2(s )6.5([6],)-4.8( )6.5(it is note)-5(worthy that in our health)-5(y)1.9( control )6.5(group )6.5(20)]TJ T* -0.0001 Tc 0.281 Tw [(\()-5.3(4)5(0.)-4.9(8%)-6.7(\) had raise)-5.1(d)3.5( ser)-5.3(u)1.4(m EGFR leve)-5.1(ls. We)-5.1( would hav)-4.7(e)]TJ 0 -1.2662 TD -0.0003 Tc 0.002 Tw [(e)-5.3(x)-0.4(pe)-5.3(cted 95% of this group to fall w)-5.1(i)-0.1(thin th)-5.3(e re)-5.3(fe)-5.3(ren)-5.3(ce ran)-5.3(g)3.3(e)-5.3(,)]TJ 0 -1.2727 TD -0.0016 Tc 0.0553 Tw [(an)-6.6(d it m)-3.3(u)-6.6(st b)-4.5(e)-0.1( a)-8.1(s)3.4(s)-3.1(u)-0.1(m)-3.3(e)-6.6(d th)-6.6(at this)-3.1( is)-3.1( du)-6.6(e to)-5.1( dif)-3.3(f)-3.3(e)-0.1(re)-6.6(nce)-6.6(s i)-7.9(n)-0.1( ou)-6.6(r)]TJ T* 0.0014 Tc -0.0581 Tw [(co)4.4(ntro)4.4(l group and the co)4.4(ntro)4.4(l gr)]TJ 13.2532 0 TD 0.001 Tc -0.0577 Tw [(oup evaluated by Bayer to p)4.6(r)2.3(o-)]TJ -13.2532 -1.2727 TD -0.0003 Tc -0.0369 Tw [(duc)-5.3(e)1.2( the)-5.3( re)-5.3(fe)-5.3(renc)-5.3(e r)-5.5(a)-0.3(nge)-5.3(.)1.4( A 95% re)-5.3(feren)-5.3(ce )-6.5(range is based on)]TJ T* 0.0002 Tc 0.1379 Tw [(a normal distribution of the data, but )6.5(serum )6.5(EG)-6(FR \(as )6.5(with)]TJ T* -0.0007 Tc -0.0106 Tw [(tu)-5.7(mour)-5.9( )6.5(markers in ge)-5.7(nera)-7.2(l)-0.5(\) )6.5(w)-5.5(a)-0.7(s )6.5(n)-5.7(o)2.3(t normally distri)-7(bute)-5.7(d in ou)-5.7(r)]TJ 0 -1.2662 TD 0.0035 Tc -0.0083 Tw [(co)6.5(n)5(t)3.3(ro)6.5(l)3.7( g)7.1(r)-1.7(o)6.5(u)-1.5(p)7.1(.)5.2( Al)3.7(s)8.5(o)0(,)5.2( o)6.5(u)-1.5(r)4.8( )6.5(co)6.5(ntr)4.8(o)6.5(l)3.7( gr)4.8(o)6.5(u)-1.5(p)7.1( i)3.7(n)5(c)5(l)3.7(ud)7.1(ed)7.1( a )6.5(co)6.5(mbi)3.7(n)5(ati)3.7(o)0(n)]TJ 0 -1.2727 TD 0.0004 Tc 0.2935 Tw [(of women )-6.5(who had )-6.5(nor)-4.8(m)-1.3(al mammograms as part )-6.5(of the)]TJ T* -0.0009 Tc 0.087 Tw [(Na)-7.4(tional)-7.2( Health)-5.9( Servic)-5.9(e Bre)-5.9(a)-0.9(st Can)-5.9(cer )-6.5(Sc)-5.9(reee)-5.9(ning Pr)-6.1(ogram)]TJ T* -0.0003 Tc 0.041 Tw [(an)-5.3(d )-6.5(those )-6.5(who had atte)-5.3(nded )-6.5(a symptomatic )-6.5(bre)-5.3(a)-0.3(st clini)-6.6(c)1.2( but)]TJ T* -0.0006 Tc 0.1906 Tw [(h)-5.6(a)-0.6(d )-6.5(a normal a)-7.1(s)4.4(sessmen)-5.6(t. It)-7.3( may th)-5.6(ere)-5.6(f)4.2(ore )-6.5(be)-5.6( that )-6.5(be)-5.6(nign)]TJ T* -0.0004 Tc -0.0174 Tw [(brea)-6.9(st )-6.5(dise)-5.4(ases e)-5.4(f)4.4(fec)-5.4(t)-0.6( ser)-5.6(u)1.1(m EGFR le)-5.4(vels. )-6.5(Finally,)-5.2( diffe)-5.4(r)0.9(en)-5.4(ces)]TJ 0 -1.2662 TD -0.0006 Tc -0.0107 Tw [(in)-5.6( menopau)-5.6(s)4.4(al)-6.9( statu)-5.6(s)-2.1( betw)-5.4(een)-5.6( these tw)-5.4(o groups may)-5.2( have)-5.6( an)]TJ 0 -1.2727 TD -0.0013 Tc 0.1134 Tw [(in)-6.3(fl)-7.6(uenc)-6.3(e \()-6.5(s)3.7(e)-6.3(e)0.2( )-6.5(bel)-7.6(o)1.7(w\))-6.5(. H)-6.1(o)1.7(w)-6.1(e)0.2(ve)-6.3(r, )-6.5(we )-6.5(have)-6.3( not e)-6.3(v)0.6(aluate)-6.3(d )-6.5(this)]TJ T* 0 Tc 0 Tw [(specific)-5(a)0(lly.)]TJ 0 -2.5455 TD -0.0001 Tc 0.0668 Tw [(I)-4.9(n)1.4( addition)-5.1( to th)-5.1(ese fin)-5.1(d)3.5(in)-5.1(gs, )-6.5(a significan)-5.1(t decr)-5.3(ease )-6.5(in se)-5.1(rum)]TJ 0 -1.2727 TD -0.0008 Tc 0.0025 Tw [(e)-5.8(x)-0.9(pr)-6(essi)-7.1(on )-6.5(of EGF)-4.3(R)-2.6( was o)-4.3(b)2.8(se)]TJ 12.9026 0 TD -0.001 Tc 0.0027 Tw [(rved betwe)-6(en )-6.5(the diagnose)-6(s )-6.5(of)]TJ -12.9026 -1.2662 TD -0.0006 Tc -0.0171 Tw [(P)-5.5(B)-0.9(C )-6.4(and of )-6.4(me)-5.6(tastatic disease.)-5.4( This phen)-5.6(omen)-5.6(on,)-5.4( wh)-5.6(ere)-5.6(b)3(y)-5.2( a)]TJ 27.9675 68.6688 TD 0.0002 Tc 0.1574 Tw [(marker dec)-4.8(r)1.5(eases w)-4.6(i)0.4(th progr)-5(e)1.7(ssion )-6.5(of disease,)-4.6( is not com-)]TJ 0 -1.2727 TD -0.0004 Tc 0.0281 Tw [(mon)-5.4(l)-0.2(y )-6.5(seen)-5.4( an)-5.4(d )-6.5(sugge)-5.4(s)-1.9(ts )-6.5(tha)-6.9(t)-0.6( th)-5.4(is marker)-5.6( may)-5( provide )-6.5(differ)-5.6(-)]TJ T* 0.0008 Tc 0.0009 Tw [(ent information to tha)-5.7(t)0.6( from )]TJ 11.7468 0 TD 0.0001 Tc 0.0081 Tw [(CA15.3, CEA )6.5(and HER2. S)4.8(e)-4.9(veral)]TJ -11.7468 -1.2727 TD -0.0005 Tc 0.0542 Tw [(hy)-5.1(pothese)-5.5(s)4.5( )-6.5(for)-5.7( this )-6.5(observ)-5.1(ation)-5.5( h)-5.5(a)-0.5(ve )-6.5(been)-5.5( proposed.)-5.3( O)-6.7(ne )-6.5(is)]TJ 0 -1.2662 TD -0.0002 Tc 0.0019 Tw [(that the)-5.2( )6.5(proteolytic cle)-5.2(a)-0.2(vage of the ex)-6.8(tracell)-6.5(u)1.3(lar domain of the)]TJ 0 -1.2727 TD 0 Tc -0.0113 Tw [(EGFR re)-5(ceptor)-5.2( decr)-5.2(eases as )-6.5(normal c)-5(e)1.5(lls progr)-5.2(e)1.5(ss to ca)-6.5(ncer)]TJ T* 0.0011 Tc 0.0006 Tw [(cells. It has also been )-6.5(s)6.1(u)-3.9(g)4.7(g)-1.8(ested )]TJ 14.2143 0 TD 0.0002 Tc 0.008 Tw [(that that this may )6.5(be related)]TJ -14.2143 -1.2727 TD -0.0004 Tc 0.093 Tw [(to )6.5(the)-5.4( )6.5(assoc)-5.4(i)-0.2(ation)-5.4( )6.5(betwe)-5.4(en circ)-5.4(ulating se)-5.4(rum oestrogen and)]TJ T* -0.0007 Tc 0.0479 Tw [(seru)-5.7(m )-6.5(EGFR le)-5.7(vels sh)-5.7(own)-5.7( in )-6.5(se)-5.7(ver)-5.9(a)-0.7(l studies. In a study )-6.5(con)-5.7(-)]TJ T* 0.0001 Tc -0.0373 Tw [(ducte)-4.9(d)3.7( by Baron and col)-6.2(l)0.3(eag)]TJ 12.1299 0 TD -0.0003 Tc -0.0369 Tw [(ues postmenopau)-5.3(s)-1.8(al wome)-5.3(n had)]TJ -12.1299 -1.2662 TD -0.0005 Tc 0.3269 Tw [(sign)-5.5(ificantly lower )-6.5(sE)-6.9(GFR le)-5.5(vels th)-5.5(an did )-6.5(pre)-5.5(m)-2.2(enopau)-5.5(s)-2(al)]TJ 0 -1.2727 TD -0.0002 Tc 0.0863 Tw [(women )-6.5([13]. Also,)-5( in )-6.5(another)-5.4( study c)-5.2(o)2.8(nduc)-5.2(ted by L)-5.2(a)-0.2(fky )-6.5(and)]TJ T* 0 Tc 0.1186 Tw [(coworkers [)-5.2(2)5.1(6])-5.2( in )-6.5(metastatic )-6.5(breast c)-5(a)0(nce)-5(r patien)-5(ts tre)-5(a)0(ted)]TJ T* 0.0003 Tc 0.0988 Tw [(with an aromatase i)-6(nhibitor \(l)]TJ 12.5779 0 TD 0.0005 Tc 0.0986 Tw [(etrozole\), pos)]TJ 5.8571 0 TD (t-treatment serum)Tj -18.4351 -1.2727 TD -0.0004 Tc 0.0086 Tw [(EGFR )6.5(le)-5.4(vels \(me)-5.4(a)-0.4(su)-5.4(red at 1 )6.5(an)-5.4(d 3 mon)-5.4(t)-0.6(hs\) wer)-5.6(e)1.1( sign)-5.4(ificantly)]TJ T* -0.0007 Tc 0.0024 Tw [(lower th)-5.7(an pr)-5.9(etreatme)-5.7(nt leve)-5.7(ls.)]TJ 0 -2.539 TD -0.0009 Tc 0.0481 Tw [(In)-5.9( o)-4.4(u)0.6(r )-6.5(stu)-5.9(d)2.7(y)-5.5(,)0.8( patien)-5.9(ts wh)-5.9(o )-6.5(wer)-6.1(e)0.6( ER )-6.5(po)-4.4(sitive )-6.5(and o)-4.4(n)0.6( )-6.5(hor)-6.1(m)-2.6(one)]TJ 0 -1.2727 TD 0 Tc 0.1121 Tw [(treatment with tamoxi)]TJ 9.2468 0 TD 0.0006 Tc 0.1115 Tw [(fen )6.5(at the )6.5(time of metastatic diagnosis)]TJ -9.2468 -1.2727 TD -0.0002 Tc 0.1578 Tw [(we)-5.2(re )-6.5(signific)-5.2(antly )-6.5(less likely to exh)-5.2(i)0(bit )-6.5(a r)-5.4(e)1.3(du)-5.2(ction in)-5.2( ser)-5.4(u)1.3(m)]TJ T* 0 Tc 0.2355 Tw [(EGFR lev)-4.6(e)1.5(ls wh)-5(en )-6.5(compared w)-4.8(i)0.2(th patien)-5(ts who w)-4.8(e)1.5(re)-5( not)]TJ T* -0.0008 Tc -0.0299 Tw [(re)-5.8(ceiv)-5.4(i)-0.6(ng tre)-5.8(a)-0.8(tment \(Table)-5.8( )6.5(2\))-6(. 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Decisions on use)]TJ T* -0.001 Tc -0.0168 Tw [(of tar)-6.2(g)2.6(e)-6(t)-1.2(ed )-6.5(thera)-7.5(p)2.6(ie)-6(s )-6.5(in the)-6( me)]TJ 12.9286 0 TD 0.0008 Tc -0.0186 Tw [(tastatic )-6.5(setting are often bas)5.8(e)-4.2(d)]TJ -12.9286 -1.2662 TD -0.0006 Tc -0.0172 Tw [(on)-5.6( the)-5.6( oncogene )-6.5(expression )-6.5(of th)-5.6(e )-6.5(primar)-5.8(y tu)-5.6(mour)-5.8(. )-6.5(More)-5.6( c)-5.6(o)2.4(n-)]TJ 0 -1.2727 TD 0.3011 Tw [(troversial is whe)-5.7(t)-0.9(her elev)-5.3(ated )6.5(serum )6.5(H)-5.5(E)-0.6(R2 and/or)-5.9( )6.5(seru)-5.7(m)]TJ T* 0 Tc -0.0632 Tw [(EGFR )-6.5(leve)-5(ls might be )-6.5(used to sele)-5(ct patien)-5(ts for)-5.2( targeted )-6.5(ther-)]TJ T* -0.0005 Tc 0.0672 Tw [(apie)-5.5(s, e)-5.5(v)1.4(en)-5.5( if th)-5.5(e primar)-5.7(y tu)-5.5(mour)-5.7( tissue )-6.5(did )-6.5(not )-6.5(ov)-5.1(er-e)-5.5(xpre)-5.5(ss)]TJ T* 0.0001 Tc 0.1315 Tw [(these oncogenes.)-4.7( )6.5(This is an im)]TJ 13.7468 0 TD -0.0002 Tc 0.1318 Tw [(portant question that almost)]TJ -13.7468 -1.2727 TD 0 Tc 0.0017 Tw [(cer)-5.2(tainly will )6.5(r)-5.2(e)1.5(quire)-5( )6.5(a multi-in)-5(stitution)-5(a)0(l stu)-5(d)3.6(y to addre)-5(s)5(s.)]TJ /F2 1 Tf 10.98 0 0 10.98 56.82 346.74 Tm 0.0003 Tc 0.0019 Tw (Competing interests)Tj /F4 1 Tf 9.24 0 0 9.24 56.82 336.18 Tm -0.0003 Tc 0.002 Tw [(Th)-5.3(e authors de)-5.3(clare)-5.3( )6.5(th)-5.3(at )6.5(th)-5.3(ey hav)-4.9(e)1.2( no competing inter)-5.5(e)1.2(sts.)]TJ /F2 1 Tf 10.98 0 0 10.98 56.82 311.52 Tm 0.0023 Tc -0.0001 Tw [(A)5.4(u)-0.3(th)5.2(ors)4.2(')2.6( c)5(o)-1.1(n)5.2(t)1.1(ri)4.7(bu)5.2(tio)4.3(n)-0.3(s)]TJ /F4 1 Tf 9.24 0 0 9.24 56.82 300.9 Tm -0.0003 Tc 0.1449 Tw [(KSA )-6.5(was re)-5.3(sponsibl)-6.6(e for)-5.5( acquisition of data)-6.8(, with)-5.3( contribu-)]TJ T* -0.0007 Tc 0.0349 Tw [(tion)-5.7(s fro)-4.2(m)4.1( A)-4.1(A)2.4(, CA, A)-4.1(H)1( )6.5(an)-5.7(d CC. 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Tf 20.8872 0 TD -0.0029 Tc -0.035 Tw [(Ex)-6.7(pr)-9.8(es)-8.2(si)-8.5(on)-4.8( an)-4.8(d)]TJ -20.8872 -1.0677 TD 0.0017 Tc -0.0171 Tw [(c)5.5(o)-1.8(-exp)5.8(ressio)5.8(n)-0.2( of)6.4( th)5.8(e membe)7.3(r)-5.2(s o)5.8(f)-1.1( t)6.4(h)-1.8(e )7.5(epidermal g)5.8(r)-5.2(o)5.8(w)-0.2(th )7.5(facto)5.7(r)]TJ T* 0.0001 Tc 0.2026 Tw [(receptor)-6.8( \(EGFR\) )-7.5(fa)-6.8(mil)-5.5(y)-2.1( in i)-5.5(n)5.7(vas)-5.2(i)2(ve breas)-5.2(t)4.8( car)-6.8(c)3.9(inom)-4.6(a.)]TJ /F4 1 Tf 24.9549 0 TD 0.2027 Tc 0 Tw ( )Tj /F5 1 Tf 0.9474 0 TD 0.0008 Tc 0.2185 Tw [(Br J)]TJ -25.9023 -1.0602 TD 0.0025 Tc 0 Tw [(Ca)6.3(nce)4.7(r)]TJ /F4 1 Tf 3.1504 0 TD 0.003 Tc -0.0033 Tw [( 200)7.1(4, )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw (91:)Tj /F4 1 Tf 1.3759 0 TD 0.0035 Tc [(1)7.6(532-)9.8(1542)7.6(.)]TJ -9.8947 -1.0677 TD 0.0017 Tc 0.4867 Tw [(2)5.8(.)-1446(Tsutsui S, Ka)5.5(taoka A, Ohno S,)5.1( Mura)5.5(kami)6.7( S, Kinoshi)6.7(t)0.5(a J,)]TJ 2.2556 -1.0677 TD 0 Tc 0.1876 Tw [(Ha)-3.8(chita)-3.8(nda)-3.8( Y: )]TJ /F3 1 Tf 6.6767 0 TD 0.0023 Tc 0.1853 Tw [(Progno)6.4(s)-3(ti)4.2(c)6.1( and)6.4( predi)4.2(c)-1.5(t)7(i)-3.3(v)7.6(e)0.4( valu)6.4(e of e)7.9(p)-1.2(i)4.2(d)-1.2(ermal)]TJ -6.6767 -1.0602 TD 0.0022 Tc -0.0251 Tw [(g)6.3(r)-4.7(o)6.3(w)0.3(th fac)6(t)-0.6(or recept)6.9(or in rec)6(u)-1.3(rre)7.8(n)0.3(t breast)6.9( )-7.5(c)6(a)2.8(ncer.)]TJ /F4 1 Tf 22.1805 0 TD -0.0229 Tc 0 Tw ( )Tj /F5 1 Tf 0.5038 0 TD 0.0042 Tc -0.0255 Tw [(Cl)7.6(in Ca)8(nc)8(er)]TJ -22.6842 -1.0677 TD 0 Tc 0 Tw (Res)Tj /F4 1 Tf 1.6692 0 TD 0.0029 Tc -0.0032 Tw [( 20)7(02,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw (8:)Tj /F4 1 Tf 0.812 0 TD 0.0032 Tc [(3)7.3(454)7.3(-346)7.3(0.)]TJ -7.8496 -1.0677 TD 0.0015 Tc 0.0583 Tw [(3)5.6(.)-1446.2(Hudel)6.5(i)-1(st G,)4.9( Singer CF, )7.5(M)-6(a)5.3(na)5.3(vi M,)]TJ 16.8196 0 TD -0.0001 Tc 0.0599 Tw [( )7.5(P)-6.7(i)4.9(sc)-5.4(hinge)-5.4(r)4.6( K,)-4.2( Kubista E)-5.1(,)3.3( Cze)-5.4(r)4.6(-)]TJ -14.5639 -1.0602 TD -0.0006 Tc 0.1732 Tw (wenka K: )Tj /F3 1 Tf 4.5113 0 TD 0.0006 Tc 0.1645 Tw [(Co-)-6.3(e)6.2(xpress)-4.7(ion of Er)-6.3(bB-f)]TJ 11.3383 0 TD -0.0004 Tc 0.173 Tw [(am)-5.1(ily mem)-5.1(b)3.7(er)-7.3(s in )7.5(h)-3.9(u)-3.9(m)2.4(an)]TJ -15.8496 -1.0677 TD 0.0014 Tc 0.0208 Tw [(b)5.5(r)-5.5(east canc)5.2(er: Her-2/neu is th)]TJ 13.7594 0 TD [(e preferred d)5.5(i)-4.2(meriz)5.2(a)-5.5(t)6.1(i)-4.2(o)5.5(n)-0.5( candi-)]TJ -13.7594 -1.0677 TD 0.0026 Tc -0.0255 Tw [(d)6.7(a)-4.3(t)7.3(e)0.7( i)4.5(n)0.7( no)6.7(dal-p)6.7(o)-0.9(si)4.5(ti)4.5(ve )7.5(tum)5.4(ours)4.8(.)]TJ /F4 1 Tf 14.0075 0 TD -0.0229 Tc 0 Tw ( )Tj /F5 1 Tf 0.4962 0 TD 0.0032 Tc -0.032 Tw [(Br)7.9(ea)7(st )-7.5(C)7.3(a)-0.6(ncer Res Tr)7.9(ea)7(t)]TJ /F4 1 Tf 10.5639 0 TD 0.0035 Tc -0.0264 Tw [( 20)7.6(03,)]TJ /F3 1 Tf -25.0677 -1.0602 TD 0.0019 Tc 0 Tw (80:)Tj /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(35)7.3(3-36)7.3(1.)]TJ -3.6316 -1.0677 TD -0.0016 Tc -0.0288 Tw [(4.)-1449.3(S)-3.8(l)3.4(a)-5.4(m)-5(on )-7.5(DJ, )-7.5(God)-3.5(o)-1(l)-4.1(p)-3.5(hi)-4.1(n )-7.5(W, Jon)-6.9(e)0.6(s)-3.8( L)-6.9(A)-2.2(, )-7.5(Hol)-4.1(t)-2.8( JA, W)-10.7(o)-1(ng)-3.5( S)-3.8(G)-1.6(,)-5.7( Ke)-6.9(i)-4.1(t)4.7(h)-6.9( DE)-6.6(,)]TJ 2.2556 -1.0677 TD -0.0003 Tc 0.1353 Tw [(Le)-5.6(vin WJ,)-4.4( Stua)-4.1(rt SG, )-7.5(Udov)-6.9(e J,)-4.4( U)-4(l)4.7(lrich )-7.5(A,)]TJ /F5 1 Tf 17.9098 0 TD -0.0025 Tc 0.1541 Tw [( et al)-6.6(.)]TJ /F4 1 Tf 2.6316 0 TD -0.0003 Tc 0 Tw (: )Tj /F3 1 Tf 0.6767 0 TD 0.0028 Tc 0.1322 Tw [(St)7.5(udi)4.7(es)5( of th)6.9(e)]TJ -21.218 -1.0601 TD 0.0016 Tc 0.3289 Tw [(HER-2/neu prot)6.3(o-onc)5.4(ogene in)]TJ 14.4135 0 TD 0.0023 Tc 0.3357 Tw [( h)6.4(u)-1.2(man )7.5(breast)7( and )7.5(ovarian)]TJ -14.4135 -1.0677 TD 0.0013 Tc 0 Tw [(c)5.1(a)-5.6(nc)5.1(er.)]TJ /F4 1 Tf 3.2331 0 TD -0.0003 Tc ( )Tj /F5 1 Tf 0.5414 0 TD 0.0023 Tc [(Sci)5.7(e)-3(nce)]TJ /F4 1 Tf 3.4887 0 TD 0.0029 Tc -0.0032 Tw [( 19)7(89,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw [(244)7.5(:)]TJ /F4 1 Tf 1.9398 0 TD 0.0035 Tc [(707-)9.8(712.)]TJ -14.5714 -1.0677 TD -0.0009 Tc 0.1359 Tw [(5.)-1448.6(Gsch)-6.2(wan)-6.2(t)-2.1(ler-Ka)-4.7(ulic)-6.2(h D, Hude)-6.2(list)]TJ 16.3534 0 TD -0.0004 Tc 0.1279 Tw [( G,)-4.5( Ko)-7.3(estler WJ,)-4.5( Cze)-5.7(r)-3.2(wen)-5.7(k)-1(a )-7.5(K,)]TJ -14.0977 -1.0601 TD -0.0005 Tc 0.0754 Tw [(Mue)-5.8(l)-3(le)-5.8(r R,)-4.6( Helm)-3.9(y S, Ru)-5.8(eck)-8.7(linge)-5.8(r)4.2( E)-5.5(,)2.9( K)-7.1(u)1.7(bista)-4.3( E,)-4.6( Singer CF: )]TJ /F3 1 Tf 25.2857 0 TD 0.0012 Tc 0 Tw (EGFR)Tj 7.1053 80.609 TD 0.0023 Tc 0.1853 Tw [(ac)6.1(tivity in HER-2)7.9( )-7.6(ov)7.6(er-e)7.9(xpress)]TJ 14.203 0 TD 0.0015 Tc 0.1861 Tw [(ing me)7.1(tastatic)5.3( )-7.6(b)5.6(r)-5.4(east cancer:)]TJ -14.203 -1.0677 TD 0.0019 Tc 0.0128 Tw [(evidence)7.5( fo)6(r simultaneou)6(s)-3.4( )7.5(pho)6(sp)]TJ 15.1805 0 TD 0.0017 Tc 0.0055 Tw [(horylation of Her-2/)7(neu and)]TJ -15.1805 -1.0677 TD 0.0028 Tc 0 Tw (EGFR.)Tj /F4 1 Tf 2.797 0 TD -0.0003 Tc ( )Tj /F5 1 Tf 0.5414 0 TD -0.0008 Tc 0.002 Tw [(Onc)-4.6(o)-0.2(l)-4.9( Rep)]TJ /F4 1 Tf 4.6391 0 TD 0.003 Tc -0.0033 Tw [( 200)7.1(5, )]TJ /F3 1 Tf 3.1053 0 TD 0.0019 Tc 0 Tw (14:)Tj /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(30)7.3(5-31)7.3(1.)]TJ -14.7143 -1.0601 TD 0.0038 Tc -0.0267 Tw [(6.)-1436.4(M)6(lle)6(r V)6.3(,)-0.3( Witz)7.3(el)8.8( )-7.5(I)7.2(,)-0.3( P)4.7(a)0(n)6(t)2.6(el)8.8( K,)7.2( Kr)8.5(en)6(kel)8.8( )-7.5(S,)7.2( L)6(c)6(k)-4.4( HJ,)7.2( )-7.5(N)5(e)6(um)7.9(ann)6( R, K)4.7(e)6(lle)6(r)]TJ 2.2556 -1.0677 TD -0.0002 Tc 0.0751 Tw [(T)-7.1(,)3.2( Dittme)-5.5(r)4.5( J, J)-4(nicke)-5.5( )7.6(F,)-4.3( )7.6(T)-7.1(h)2(om)-3.6(ssen C: )]TJ /F3 1 Tf 16.1729 0 TD 0.0022 Tc 0.0727 Tw [(Prog)6.3(nos)4.4(t)-0.6(i)4.1(c)-1.6( and)6.3( pred)6.3(ic)6(ti)4.1(ve)]TJ -16.1729 -1.0677 TD 0.0021 Tc 0.0953 Tw [(impact o)6.2(f)-0.7( so)6.2(lu)6.2(ble epidermal gr)]TJ 14.2932 0 TD 0.0018 Tc 0.0956 Tw [(owt)6.5(h)-1.7( fact)6.5(or recep)5.9(t)-1(or \(sEGFR\))]TJ -14.2932 -1.0602 TD 0.002 Tc -0.0474 Tw [(protein in t)6.7(h)-1.5(e serum )7.6(of p)6.1(a)-4.9(t)6.7(i)-3.6(e)7.6(n)0.1(ts treated )7.6(wit)6.7(h)-1.5( ch)6.1(emo)6.1(t)-0.8(herapy )7.6(for)]TJ 0 -1.0677 TD 0.0012 Tc -0.0015 Tw (metastatic breast cancer.)Tj /F4 1 Tf 11.3985 0 TD 0.0072 Tc 0 Tw ( )Tj /F5 1 Tf 0.5414 0 TD 0.0019 Tc -0.0007 Tw [(Anti)5.3(cance)4.1(r R)]TJ /F4 1 Tf 5.5564 0 TD 0.0031 Tc -0.0034 Tw [( 2)7.2(006)7.2(, )]TJ /F3 1 Tf 3.1053 0 TD 0.0019 Tc 0 Tw (26:)Tj /F4 1 Tf 1.3759 0 TD 0.0033 Tc [(147)7.4(9-14)7.4(87.)]TJ -24.2331 -1.0677 TD -0.0001 Tc 0.1953 Tw [(7)-3.6(.)-1440.3(Ca)-3.9(rne)-5.4(y)0.8( )7.6(W)-9.2(P)0.8(, Ne)-5.4(um)-3.5(a)-3.9(nn R,)-4.2( )7.6(L)-5.4(i)4.9(pton)-5.4( A, Le)-5.4(itz)-4.2(e)2.1(l K, Ali )7.6(S,)-4.2( )7.6(P)-6.7(r)4.6(ic)-5.4(e CP:)]TJ /F3 1 Tf 2.2556 -1.0602 TD 0.0148 Tw [(P)-6.7(o)4(tential c)-3.9(l)1.8(i)-5.7(n)-2(ic)-3.9(al u)-3.6(t)4.6(i)-5.7(lity o)-3.6(f)4.6( s)-5.4(e)-2(rum)-4.8( HER)-8.2(-)0.5(2/)]TJ /F6 1 Tf 18.188 0 TD 0.0044 Tc 0 Tw [(neu)10( )]TJ /F3 1 Tf 1.9549 0 TD 0.0025 Tc 0.0122 Tw [(onco)6.5(prote)8.1(i)-3.1(n c)6.3(o)-1(n-)]TJ -20.1429 -1.0677 TD 0.0014 Tc 0.096 Tw [(centrations in patients wit)6.1(h)-2.1( breast)6.1( cancer.)]TJ /F4 1 Tf 19.3985 0 TD 0.0974 Tc 0 Tw ( )Tj /F5 1 Tf 0.7368 0 TD 0.0026 Tc 0.1039 Tw [(Cl)6(in C)6.7(h)-4.3(e)4.8(m)]TJ /F4 1 Tf 4.8045 0 TD 0.0035 Tc 0.0939 Tw [( 2)7.6(003,)]TJ /F3 1 Tf -24.9398 -1.0677 TD 0.0019 Tc 0 Tw (49:)Tj /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(1)7.3(579)7.3(-159)7.2(8.)]TJ -3.6316 -1.0602 TD 0.0021 Tc 0.0427 Tw [(8.)-1438.1(M)-5.4(a)5.9(nsour OA, Zekr)6.8(i AR, Har)6.8(v)3(ey )]TJ 15.8196 0 TD 0.0009 Tc 0.0439 Tw [(J, Teram)5(o)-6(to Y, el-Ahmady O: )]TJ /F3 1 Tf 12.6241 0 TD 0.0027 Tc 0 Tw (Tis-)Tj -26.188 -1.0677 TD 0.005 Tc -0.058 Tw [(sue)10.6( an)10.6(d s)7.2(e)3.1(ru)9.1(m c)8.8(-)-1.9(e)10.6(r)-1.9(b)9.1(B)1.3(-)5.6(2)3.1( a)5.6(n)3.1(d t)9.7(i)-0.6(s)7.2(s)]TJ 14.6165 0 TD 0.0014 Tc -0.0544 Tw [(u)5.5(e)-0.5( EGFR in breast)6.1( carcinoma:)]TJ -14.6165 -1.0677 TD 0.0007 Tc -0.001 Tw [(three years )-7.5(foll)-4.9(ow-up.)]TJ /F4 1 Tf 9.8496 0 TD -0.0003 Tc 0 Tw ( )Tj /F5 1 Tf 0.5414 0 TD 0.0009 Tc 0.0003 Tw [(Antic)4.7(a)-2.9(ncer Res)]TJ /F4 1 Tf 6.5564 0 TD 0.0029 Tc -0.0032 Tw [( 19)6.9(97,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw [(17)7.5(:)]TJ /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(3)7.3(101)7.3(-310)7.3(6.)]TJ -23.6917 -1.0602 TD 0.0037 Tc -0.0491 Tw [(9.)-1436.5(Na)7.5(rita)7.5( )-7.5(T)4.3(,)7.1( Fu)5.9(na)7.5(ha)7.5(shi)8.7( H,)7.1( Sato)4.3(h)5.9( )-7.5(Y)4.6(,)7.1( )-7.5(T)4.3(a)7.5(kagi H:)4( )]TJ /F3 1 Tf 19.812 0 TD 0.0017 Tc -0.0471 Tw [(C-erbB-2 pro)5.8(t)-1.1(ein in t)6.4(h)-1.8(e)]TJ -17.5564 -1.0677 TD 0.001 Tc 0.0137 Tw [(sera o)5.1(f)-1.8( b)5.1(r)-5.9(e)6.6(a)-5.9(st )7.5(cancer )7.5(patients.)]TJ /F4 1 Tf 13.7744 0 TD 0.0147 Tc 0 Tw ( )Tj /F5 1 Tf 0.5639 0 TD 0.0019 Tc 0.0069 Tw [(Brea)5.7(st )-7.5(C)6(a)-1.9(ncer Res Treat)]TJ /F4 1 Tf 10.6917 0 TD 0.0035 Tc 0.0112 Tw [( 1)7.6(992,)]TJ /F3 1 Tf -25.0301 -1.0677 TD 0.0019 Tc 0 Tw (24:)Tj /F4 1 Tf 1.3759 0 TD -0.0041 Tc [(97)-7.6(-)-5.3(1)-7.6(02)-7.6(.)]TJ 7.98 0 0 7.98 315.3 548.28 Tm 0.0027 Tc 0.0045 Tw [(10.)-851(Ma)6.5(zouni C,)6.1( Hall A,)6.1( Brogli)7.7(o K,)6.1( )-7.5(Fr)7.4(it)]TJ 16.2481 0 TD 0.0034 Tc 0.0038 Tw [(sc)5.6(he)5.6( H, Andr)8.1(e F)4(,)6.8( )-7.5(E)5.9(s)1.2(te)5.6(v)4.3(a)-0.4( F)4.1(J)2.5(, Ho)4(r-)]TJ -13.9925 -1.0677 TD 0.0022 Tc 0.208 Tw [(tob)7.8(a)-1.6(gyi GN, )7.5(Buz)5.7(d)0.3(ar)6.9( AU,)5.6( Pusz)5.7(tai)7.2( L,)5.6( Cr)6.9(istofanill)7.2(i M: )]TJ /F3 1 Tf 22.8647 0 TD 0.0005 Tc 0.2097 Tw [(Kinetics o)4.6(f)]TJ -22.8647 -1.0677 TD 0.0008 Tc 0.2019 Tw [(serum HER-2/neu)4.9( c)4.6(h)-2.7(anges in )7.5(patients )7.5(wit)5.5(h)-2.7( )7.5(H)-7(E)1.7(R-2-positive)]TJ 0 -1.0602 TD 0.0013 Tc -0.0618 Tw [(primary)6.6( breast c)5.1(a)1.9(ncer after init)]TJ 13.6617 0 TD 0.0032 Tc -0.0637 Tw [(i)5.1(a)-3.7(t)7.9(i)-2.4(o)7.3(n)1.3( of p)7.3(r)3.8(im)6(ary c)7(h)-0.3(em)6(othe)8.8(rap)7.3(y)1(.)]TJ /F5 1 Tf -13.6617 -1.0677 TD 0.0026 Tc 0 Tw [(Cance)4.8(r)]TJ /F4 1 Tf 3.1504 0 TD 0.0029 Tc -0.0032 Tw [( 20)7(07,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw [(109)7.5(:)]TJ /F4 1 Tf 1.9398 0 TD 0.0032 Tc [(496)7.3(-501)7.3(.)]TJ -10.4587 -1.0677 TD -0.0001 Tc 0.2028 Tw [(1)-3.6(1)-3.6(.)-853.8(H)-7.9(u)2.1(delist G, )-7.5(Kostler WJ,)-4.2( Gsch)-5.4(wa)-3.9(ntler-Ka)-3.9(ulic)-5.4(h )-7.5(D, )-7.5(Cze)-5.4(r)4.6(we)-5.4(nka)-3.9( K)-6.7(,)]TJ 2.2556 -1.0602 TD 0.0017 Tc 0.0205 Tw [(Kubista)5.5( E,)5.1( )-7.6(Muller R, Helmy S, Manavi M)-5.8(,)5.1( Zieli)6.7(n)-3.6(ski)6.7( )-7.6(CC,)5.1( Singer)6.4( )-7.5(CF:)]TJ /F3 1 Tf 0 -1.0677 TD 0.0021 Tc 0.0878 Tw [(Serum )7.5(EGFR leve)7.7(ls and ef)6.8(ficacy)]TJ 14.8647 0 TD -0.0034 Tc 0.0858 Tw [( o)-6.9(f)-6.2( )-7.5(tr)-10.3(ast)-6.2(u)-6.9(zu)-6.9(m)-8.1(a)-2.8(b-)-10.3(ba)-10.3(se)-5.3(d)-6.9( t)-6.2(h)-6.9(e)-5.3(r)-2.8(-)]TJ -14.8647 -1.0677 TD 0.0021 Tc 0.1179 Tw [(ap)6.2(y in)7.7( patients wit)6.8(h)-1.4( met)6.8(a)-4.8(static b)6.2(r)2.7(east c)5.9(a)-4.8(nc)5.9(er.)]TJ /F4 1 Tf 21.1729 0 TD 0.12 Tc 0 Tw ( )Tj /F5 1 Tf 0.782 0 TD -0.0013 Tc 0.1304 Tw [(Eu)-8.2(r J)-7.9( Cancer)]TJ /F4 1 Tf -21.9549 -1.0602 TD 0.0037 Tc 0 Tw [(2006)7.8(, )]TJ /F3 1 Tf 2.8346 0 TD 0.0019 Tc (42:)Tj /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(18)7.3(6-19)7.3(2.)]TJ -6.4662 -1.0677 TD 0.0034 Tc 0.1015 Tw [(12.)-850.3(Ma)7.2(ih)5.6(le N)4.6(J)2.5(, La)7.2(fky JM, Bar)8.1(o)4(n AT,)6.8( )-7.6(B)7.2(o)4(ardm)7.5(an CH, Gre)5.6(e)-1.9(n)5.6(w)3.1(ood TM,)]TJ 2.2556 -1.0677 TD -0.0009 Tc -0.0596 Tw [(Ch)-6.2(risten)-6.2(sen)-6.2( )7.5(TA,)-5( Re)-6.2(iter )7.5(JL)-6.2(, Cora EM)-8.4(, Le)-6.2(e H, Sum)-4.3(a)-4.7(n VJ: )]TJ /F3 1 Tf 22.8045 0 TD 0.0016 Tc -0.0621 Tw [(EGF rec)5.4(e)-0.3(p-)]TJ -22.8045 -1.0602 TD 0.0029 Tc -0.0183 Tw [(tor/ErbB i)4.8(s)5.1(ofo)6.9(r)-4(m)5.7(s)-2.4( )7.5(as)5.1( s)5.1(e)1(rum b)7(i)]TJ 13.8195 0 TD -0.0007 Tc -0.0147 Tw [(om)-5.4(ark)-7.6(er)-7.6(s in breast and ovar)-7.6(ian)]TJ -13.8195 -1.0677 TD 0.0017 Tc 0 Tw (cancer.)Tj /F4 1 Tf 3.2331 0 TD -0.0003 Tc ( )Tj /F5 1 Tf 0.5414 0 TD 0.0008 Tc 0.0004 Tw (J Clin Ligand Assay)Tj /F4 1 Tf 8.6015 0 TD 0.0029 Tc -0.0032 Tw [( 20)7(02,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw [(25)7.5(:)]TJ /F4 1 Tf 1.3759 0 TD 0.0027 Tc [(57-6)6.7(0)-0.8(.)]TJ -19.1203 -1.0677 TD -0.0181 Tw [(13.)-851(Bar)7.4(o)-4.2(n)4.9( AT,)6.1( Cora)6.5( E)5.2(M)2.7(, )7.5(La)6.5(fky )7.5(JM, )7.5(Board)8.3(m)-0.7(an)4.9( CH,)6.1( B)6.5(u)-2.6(e)4.9(n)-2.6(a)6.5(f)3(e )7.5(MC, )7.5(Rade)4.9(-)]TJ 2.2556 -1.0602 TD 0.0014 Tc -0.0092 Tw [(maker A, Liu )7.6(D)-4.9(,)4.8( Fishman DA, )7.6(P)-5.2(o)2(dr)6.1(atz )7.6(K)-5.2(C)-0.5(, Mai)6.4(h)-3.9(l)6.4(e)-3.9( NJ: )]TJ /F3 1 Tf 22.3759 0 TD 0.0019 Tc -0.0098 Tw [(So)6(lu)6(ble epi-)]TJ -22.3759 -1.0677 TD 0.0015 Tc 0.2764 Tw [(dermal)3.4( growt)6.2(h)-2( fac)5.3(t)-1.3(or \(s)3.7(EGF)7.1(R)-6.6(/)6.8(s)-3.8(ErbB1\) as)3.7( a po)5.6(tenti)3.4(a)2.1(l)3.4( ris)3.7(k)2.1(,)]TJ T* 0.0027 Tc 0.0271 Tw [(sc)6.5(ree)8.3(n)0.8(ing)6.8( and di)4.6(agno)6.8(sti)4.6(c)-1.1( s)4.9(e)0.8(rum)5.5( bi)4.6(omarker of ep)6.8(it)7.4(hel)4.6(i)4.6(a)-4.2(l)4.6( ov)8(ar-)]TJ 0 -1.0602 TD 0.0017 Tc 0.622 Tw [(ian c)5.5(a)-5.2(n)7.3(c)-2.1(er.)]TJ /F4 1 Tf 5.4812 0 TD 0.6237 Tc 0 Tw ( )Tj /F5 1 Tf 1.7895 0 TD -0.0005 Tc 0.6709 Tw [(C)-3.9(a)-4.3(nc)-4.3(er Epi)-4.6(d)-2.4(em)-5.5(iol)-4.6( Bi)-4.6(om)-5.5(arkers Prev)]TJ /F4 1 Tf 17.1429 0 TD 0.0035 Tc 0.6202 Tw [( 2)7.6(003,)]TJ /F3 1 Tf -24.4135 -1.0677 TD 0.0019 Tc 0 Tw (12:)Tj /F4 1 Tf 1.3759 0 TD 0.0031 Tc [(1)7.2(03-1)7.2(13.)]TJ -3.6316 -1.0677 TD 0.0029 Tc 0.1171 Tw [(14.)-850.8(Na)6.7(hta)6.7( R,)6.3( E)5.4(s)0.7(te)5.1(va)6.7( FJ: )]TJ /F3 1 Tf 11.2556 0 TD 0.0014 Tc 0.1111 Tw [(HER-2-target)6.1(ed therap)]TJ 10.4286 0 TD 0.0023 Tc 0.1102 Tw [(y: lesso)6.4(n)0.4(s learn)7.9(e)0.4(d)]TJ -19.4286 -1.0602 TD 0.0039 Tc -0.0042 Tw [(and)7.9( fut)8.6(u)0.4(r)4.5(e)2( di)5.8(re)9.5(cti)5.8(o)0.4(ns)6.1(.)]TJ /F4 1 Tf 9.6391 0 TD -0.0003 Tc 0 Tw ( )Tj /F5 1 Tf 0.5414 0 TD 0.0037 Tc -0.0025 Tw [(Cl)7.1(in Ca)7.5(nc)7.5(er)8.4( Res)]TJ /F4 1 Tf 7.188 0 TD 0.0043 Tc 0.0029 Tw [( 2)8.4(003)8.4(, )]TJ /F3 1 Tf 3.1053 0 TD 0.0019 Tc 0 Tw (9:)Tj /F4 1 Tf 0.812 0 TD 0.0033 Tc [(507)7.4(8-50)7.4(84.)]TJ -23.5414 -1.0677 TD 0.0035 Tc 0.0864 Tw [(15.)-850.2(Els)8.8(t)2.3(on)5.7( CW, Ell)8.5(i)1(s IO:)3.8( )]TJ /F3 1 Tf 11.391 0 TD -0.0025 Tc 0.0924 Tw [(Pat)-5.3(h)-6(ol)-8.1(og)-6(ic)-6.3(al )-7.5(p)-6(r)-1.9(og)-6(n)-4.4(o)-6(st)-5.3(ic)-6.3( f)-5.3(a)-1.9(c)-6.3(t)-5.3(ors)-7.8( i)-8.1(n)3.1( )-7.5(b)-6(r)-1.9(e)-4.4(a)-1.9(st)]TJ -9.1353 -1.0677 TD 0.0016 Tc 0.171 Tw [(cancer. 1. The value of histo)5.7(l)-4(o)5.7(g)-1.9(ical )-7.5(grade in )-7.5(b)5.7(r)-5.3(e)7.2(a)-5.3(st cancer:)]TJ 0 -1.0602 TD 0.0433 Tw [(experienc)5.3(e from a large stu)5.6(d)-2(y with)5.6( lo)5.6(ng-term follow-up.)]TJ /F4 1 Tf 25.4737 0 TD 0.0448 Tc 0 Tw ( )Tj /F5 1 Tf 0.6241 0 TD 0.003 Tc [(His)8.3(-)]TJ -26.0977 -1.0677 TD 0.0003 Tc [(t)-6.9(opathology)]TJ /F4 1 Tf 4.9925 0 TD 0.003 Tc -0.0033 Tw [( 199)7.1(1, )]TJ /F3 1 Tf 3.1053 0 TD 0.0019 Tc 0 Tw (19:)Tj /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(40)7.2(3-41)7.3(0.)]TJ -11.7293 -1.0677 TD 0.0018 Tc 0.0204 Tw [(16.)-851.9(G)-5.7(o)2.4(ing JJ, Abd El)6.8(-M)-5.7(onem)5.9( )-7.6(HM, Cr)6.5(aft JA)-6.3(: )]TJ /F3 1 Tf 19.203 0 TD 0.0032 Tc 0.019 Tw [(Cl)5.1(onal)5.1( orig)7.3(in)8.8(s of hu)7.3(man)]TJ -16.9474 -1.0602 TD 0.0015 Tc -0.0018 Tw [(breast c)5.3(a)-5.4(n)7.1(c)-2.3(er.)]TJ /F4 1 Tf 6.3835 0 TD -0.0003 Tc 0 Tw ( )Tj /F5 1 Tf 0.5414 0 TD 0.0003 Tc 0.0009 Tw [(J Patho)-6.6(l)]TJ /F4 1 Tf 3.4662 0 TD 0.0029 Tc -0.0032 Tw [( 200)7(1,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD -0.0056 Tc 0 Tw [(19)-7.5(4)-15(:)]TJ /F4 1 Tf 1.9398 0 TD 0.0031 Tc [(4)7.2(06-4)7.2(12.)]TJ -17.6993 -1.0677 TD 0.0043 Tc -0.0197 Tw [(17.)-849.4(Kl)9.3(eiv)5.2(i)1.8( )7.5(K,)7.7( Lo)4.9(th)6.5(e R)9.6(A)-3.8(,)7.7( Hei)9.3(m)0.9( S,)7.7( Ts)9.6(aro)4.9(u)6.5(ha )7.5(H,)7.7( K)5.2(r)1.5(agg)9.9(e)-1(ru)6.5(d SM)4.3(, )7.5(Pa)8.1(ndi)9.3(s)2.1( N,)]TJ 2.2556 -1.0677 TD 0.0023 Tc -0.0553 Tw [(Pa)6.1(padopoul)7.3(ou A, )7.5(A)-5.8(n)4.5(dersen J,)]TJ 12.4286 0 TD -0.053 Tc 0 Tw [( J)-53.9(a)-56.8(k)-53.6(o)-52.4(b)-54.9(s)-55.2(e)-50.8(n)-58.3( K)-52.1(S)-55.2(,)-49.6( T)-59.9(e)-50.8(i)-55.5(x)-48(e)-58.3(i)-55.5(r)-48.3(a)-56.8( M)-53(R)-55.2(:)-52.7( )]TJ /F3 1 Tf 11.5414 0 TD 0.0006 Tc (Genome)Tj -23.9699 -1.0601 TD 0.0026 Tc -0.018 Tw [(profi)4.5(l)4.5(i)-3(ng)6.7( of breas)4.8(t)-0.2( cance)8.2(r)-4.3( c)6.4(e)0.7(ll)4.5(s)4.8( sel)4.5(e)0.7(ct)7.3(ed again)8.2(s)-2.7(t i)4.5(n)0.7( vi)4.5(tro s)4.8(hows)]TJ 0 -1.0677 TD 0.003 Tc 0.1771 Tw [(cop)7.1(y)0.8( number ch)7.1(ang)7.1(e)1.1(s.)]TJ /F4 1 Tf 10.6466 0 TD 0.1801 Tc 0 Tw ( )Tj /F5 1 Tf 0.9023 0 TD 0.0035 Tc 0.1857 Tw [(Ge)5.7(n)4.1(e)-1.8(s Ch)4.1(ro)4.1(mo)4.1(so)4.1(me)5.7(s Can)4.1(c)-0.3(e)5.7(r)]TJ /F4 1 Tf 13.3083 0 TD 0.1766 Tw [( 2)7.6(002,)]TJ /F3 1 Tf -24.8571 -1.0677 TD 0.0019 Tc 0 Tw (33:)Tj /F4 1 Tf 1.3759 0 TD 0.0031 Tc [(3)7.2(04-3)7.2(09.)]TJ -3.6316 -1.0601 TD 0.0022 Tc 0.2681 Tw [(18.)-851.5(Zida)6(n J,)5.6( )-7.6(Dashkovsky I)5.6(,)-1.9( Stayerma)6(n C, Ba)6(sher W, Coza)6(cov )-7.6(C,)]TJ 2.2556 -1.0677 TD 0.0078 Tc 0.1874 Tw [(Ha)11.6(d)5.9(a)4(r)12.5(y)1.2( A)7.2(:)8.1( )]TJ /F3 1 Tf 4.9023 0 TD 0.0024 Tc 0.2003 Tw [(Co)6.5(mpari)4.3(s)-2.9(on)8( of)7.1( HER-2 )7.5(ove)8(r)-4.5(ex)6.2(pres)4.6(si)4.3(on )7.5(in)8( pri)4.3(m)-2.3(ary)]TJ -4.9023 -1.0677 TD 0.0014 Tc -0.0017 Tw [(breast cancer )-7.5(and metastatic )-7.5(si)]TJ 14.218 0 TD 0.0037 Tc 0.0035 Tw [(tes)5.9( an)9.3(d i)5.6(t)0.9(s)5.9( effec)7.5(t)0.9( o)7.8(n)1.8( bi)5.6(ol)5.6(ogi)5.6(cal)]TJ -14.218 -1.0602 TD 0.0019 Tc 0.1406 Tw [(targ)5.9(eting th)6(erap)6(y )-7.6(o)6(f)-0.9( metastatic disease.)]TJ /F4 1 Tf 18.5489 0 TD 0.1425 Tc 0 Tw ( )Tj /F5 1 Tf 0.8346 0 TD 0.005 Tc 0.1466 Tw [(Br J)5.9( )-7.5(Ca)8.8(nc)8.8(er)]TJ /F4 1 Tf 5.5113 0 TD 0.0035 Tc [( 2)7.6(005,)]TJ /F3 1 Tf -24.8947 -1.0677 TD 0.0019 Tc 0 Tw (93:)Tj /F4 1 Tf 1.3759 0 TD 0.0031 Tc [(5)7.2(52-5)7.2(56.)]TJ -3.6316 -1.0677 TD 0.0016 Tc 0.2387 Tw [(19.)-852.1(M)-5.9(eng S,)5( Tri)6.6(p)-0.3(athy )7.5(D, )7.5(Shete )7.5(S,)5( Ashfaq )7.5(R, )7.5(Haley B,)5( Perkins S,)]TJ 2.2556 -1.0602 TD 0.0037 Tc 0.1915 Tw [(Bei)8.7(t)2.5(sc)5.9(h P)4.6(,)-0.4( )7.6(Kh)5.9(an)5.9( A, )7.6(Eu)5.9(hu)5.9(s D)4.9(,)-0.4( O)3.7(s)1.5(bo)4.3(rn)5.9(e)5.9( C,)]TJ /F5 1 Tf 18.7218 0 TD 0.0053 Tc 0.1989 Tw [( et)5.6( )-7.6(a)9.1(l)1.2(.)]TJ /F4 1 Tf 2.7594 0 TD -0.0003 Tc 0 Tw (: )Tj /F3 1 Tf 0.7368 0 TD 0.0018 Tc 0.1934 Tw [(HER-2 g)5.9(ene)]TJ -22.218 -1.0677 TD 0.0023 Tc 0.1628 Tw [(amplif)7(ic)6.1(atio)6.4(n )7.5(can b)6.4(e)0.4( ac)6.1(quired )]TJ 14.2481 0 TD 0.002 Tc 0.1556 Tw [(as breast canc)]TJ 6.9173 0 TD 0.0008 Tc 0.1643 Tw [(er pro)4.9(g)-2.7(resses.)]TJ /F5 1 Tf -21.1654 -1.0677 TD 0.0023 Tc -0.0011 Tw [(P)-5.8(r)7(oc Natl)5.7( Aca)6.1(d)0.4( Sci)5.7( US)7.6(A)]TJ /F4 1 Tf 10.5865 0 TD 0.0031 Tc -0.0034 Tw [( 2004)7.2(, )]TJ /F3 1 Tf 7.98 0 0 7.98 442.56 199.7401 Tm 0.0019 Tc 0 Tw (101:)Tj /F4 1 Tf 1.9398 0 TD 0.0032 Tc [(93)7.3(93-9)7.3(398)7.2(.)]TJ -17.8872 -1.0602 TD -0.0002 Tc 0.045 Tw [(2)-3.7(0)-3.7(.)-853.9(K)-6.8(u)2(u)-5.5(k)-0.8(asjarvi T,)-4.3( Ka)-4(rhu R,)-4.3( Ta)-4(nn)-5.5(er M, K)-6.8(a)3.6(h)-5.5(k)-0.9(one)-5.5(n)2( M)-7.7(,)3.2( Sch)-5.5(a)3.6(f)-7.4(f)0.1(er A, N)-6.5(u)2(p-)]TJ 2.2556 -1.0677 TD 0.0023 Tc 0.268 Tw [(ponen N,)5.7( Pennanen S, Kall)7.3(ioni)7.3(emi)7.3( )-7.6(A,)5.7( )-7.6(Kal)7.3(lioniem)6.4(i O)-5.3(P)3.2(,)5.7( )-7.6(I)5.7(s)0.1(ola J:)]TJ /F3 1 Tf T* 0.0017 Tc 0.0506 Tw [(Genetic het)6.4(e)-0.2(ro)5.8(geneity and clonal )-7.5(evo)5.8(l)-3.9(u)5.8(t)-1.1(ion underlying devel-)]TJ T* 0.0005 Tc 0.0217 Tw [(opment of )-7.6(asynchronous)-4.8( m)-4.2(e)6.1(tas)-4.8(t)-2.3(as)]TJ 15.8496 0 TD 0.0018 Tc 0.0204 Tw [(is in human b)5.9(r)2.4(east canc)5.6(er.)]TJ /F5 1 Tf -15.8496 -1.0602 TD 0.0023 Tc -0.0011 Tw [(Cance)4.5(r)-0.5( Re)4.5(s)]TJ /F4 1 Tf 5.1128 0 TD 0.0029 Tc -0.0032 Tw [( 19)7(97,)6.3( )]TJ /F3 1 Tf 3.1128 0 TD 0.0019 Tc 0 Tw [(57)7.5(:)]TJ /F4 1 Tf 1.3759 0 TD 0.0032 Tc [(1)7.3(597)7.3(-160)7.3(4.)]TJ -11.8572 -1.0677 TD 0.0009 Tc 0.1191 Tw [(21.)-852.8(Slich)-4.4(enmye)-4.4(r )7.5(W)-8.2(,)4.3( Fry D: )]TJ /F3 1 Tf 12.5639 0 TD 0.002 Tc 0.118 Tw [(Anticancer t)6.7(h)-1.5(erapy target)6.7(in)7.6(g th)6.1(e Erb)6.1(B)]TJ -10.3083 -1.0677 TD -0.0028 Tc 0.3709 Tw [(f)-5.6(a)-2.2(m)-7.5(i)-0.9(l)-8.4(y)2.5( )-7.5(of)-5.6( re)-4.7(c)-6.6(e)-4.7(pt)-5.6(o)-6.3(r)-2.2( t)-5.6(y)2.5(r)-9.7(o)1.2(s)-8.1(i)-0.9(n)-4.7(e)-4.7( ki)-8.4(na)-9.7(se)-4.7(s.)]TJ /F4 1 Tf 17.3308 0 TD 0.3681 Tc 0 Tw 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