APR 2 4 1997
`
`MARCH 1997
`
`VOL 11 • NO 3 (SUPPLEMENT NO 2)
`
`Update on the Taxanes in Breast Cancer
`A symposium held in co11j1111ctio11 ll'ilh 1he
`191'1 Ammnl San A111011io Breast Cancer Co11fere11ce
`
`Sponsored by:
`Cancer Therapy and Research Cell/er
`San All/onio Cancer lns1i1111e
`The UniFersicv of Texas Health Science Ce11ter at San Antonio
`
`The Taxanes: Dosing and
`Scheduling Considerations
`
`Paclitaxel for Breast Cancer:
`The Memorial Sloan(cid:173)
`Kenering Experience
`
`Eric K. Rowinsky
`University of Texas
`Heahh Science Center
`
`Andrew D.
`Seidman, et al
`Memorial Sloan-Kettering
`Cancer Center
`
`Paclitaxel-Based
`Combination Chemotherapy
`
`Gabriel Hortobagyi
`M.D. Anderson Cancer Center
`
`The International Expe1ience Peter M. Ravdin
`With Docetaxe] in the
`Univer..iiyofTcxas
`Treatment of Breast Cancer Health Science Center
`
`HER2 Overexpression and
`Paclitaxel Sensitivity in
`Breast Cancer
`
`Jose Baselga. et al
`Hospital General Universitari
`Vall d' Hebron. Barcelona
`
`EXHIBIT
`6
`
`Oesmoncl-HeUmann
`
`3/23/2018 CAR
`
`HOSPIRA EX. 1006
`Page 1
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`Update on the Taxanes
`in Breast Cancer
`
`A symposium hell/ in conjunction w ith the
`J 9thAmmal San Antonio Breast Cancer Conference
`
`ponsored by:
`Cancer Therapy a nll Research Center
`San Antonio Cancer Institute
`Tile University of Texas I leaf ch Science Center at &an Antonio
`
`Supported by an unresuic1ed educational gram from Bristol-M yers Squibb Oncology
`
`SUPPl...E.'1E.''T NO 2 • MARCii 1997 • ONCOLOGY
`
`HOSPIRA EX. 1006
`Page 2
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`2 of 12
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`Publishing Staff
`
`\ll"C'ARTllY
`JAME.SI
`Edoton:il 0.mctor
`
`ROSSA '\'l:E S/(71 PA '\OWSKI
`"''"'"'"t M•n•i!'"ll l-.dot.,..
`
`JEA..'\l"l'\E COROl\lloi\
`Produe11on Dimc'lor
`
`A'"TllO"Y CITTROl\E
`'\:uoon:il S•IC> RcprCS<"nWJ\t
`
`CARA fl. GI '/I.I\
`A"'"""t t:d1ttlfl•I Oorttt<>r
`
`ELLEN OKI!\ l'()WJ,RS
`Mnnui;oni: Edoh>r
`
`HDWIN S. OEffNER
`Con,ulun; E.d11nr
`
`A 'IJ>Rl·W NASll
`Jl "E SKl,NER
`Scnittir Lduor'
`
`GAIL VA' KOOT
`&11tonal C0<1<d1nJtor
`
`CHRISTINA FEM•f,sSEY
`LOIS FRlclJMAN
`A,,i,lant l.:.d1to"
`
`NANCY M. f'INN
`MADELINE McCAltTllY
`STACE' Zl:.UROWSKI
`Cc.l1hx1JI A'"''""""'
`
`LISA KATI.
`AnDomct<>r
`
`JOAS OETI:RS
`Ad,cn'""l! Coonhnah>t
`
`EVELYN A. FOSEl.I A
`AJminhtratii.·i: A~'''cun1
`
`JOHN J. CORONNA
`Oortttor or Sale'
`
`GLRAl.Dl"E GE.'"TIU:
`Dita:t<1f of ()pcnitlOll.•
`
`ROBERT C. CA'ALE
`Pubh.-hcr
`
`FAY SYMONS
`01.....-tor.
`Educ•tion31 l'rogruon'
`
`TRACEY MADIO
`Bu.!ot1nc:>s Mllnagcr
`
`MIA I IPP
`l'nK>fr..-adc:r
`
`\lt\R) SC"lll LO'i-R
`1'allonal Sak, \l•n•fcr
`
`JOH'I A. GE.,'TILF.. JR.
`f>n-.,odcnt
`
`Chnoal or1n1110\ C\J'R°''Cd on anock"' MC thll\C of the •Uthclf\ ""'' do "'" ""'"'''JTll) ren..,t the opomon' .. r thc '"''"""· .kl\cttl>tt>. edot\lr\ or the
`publi,hcr•nJ nlfi.c""' PRR.111< 0-.l"OLOG\ wi'c' to -elc.i l.no"'lcdi;c•hlc. c•pcricn.:ed .iutbo" iltl<I re' "'"'c" tor 11r11dn.Ukl to:llbv.ttchn1<."3l qllm<'
`from reader. I lo"<' er. neither the editors nor P"l>l"her an ~uonntet the chnoc:il :idncc oITcrro
`R~ nlU.\I t:tlc onto olLXOUnt tlclt an'"'c" to chm.::il 'l""'"on'...., lormul.icd ... ithout t-rnclit or pciwnal cumon.uon o(thc p;>tlC1lt •nJ ore N....cl
`
`onl} on the: 1nform.111on '"l'Phcd b) the: ph)'1>JC..,, malins the 1n<jUlf) '' our reoJct' mu.<t ~urel) appm:o•IC. our cdocun•I ;,J\ ''°"' ron<ulW>l<. ~
`re\ ic"'c"' c•nnot d1:1j100\C or ~ .... he ro. ~ panocular pallcnt "'""""t :><:tuoll) «<mg the p:l11t"11t ThU>. the ~(ll<"nll ronimcnu '" thl\ JO<lmal at< b.'l\cd ('e
`the chnoal c'pcocncc ol the author<.. re< ocw<T'S. and <'On<ultont< and 'h<>UIJ n<M he con,trucd a.< .1 lorm:il con<uh.llo<ln ,.,. ,pccific rcrornmctl<fuut>n '"'a
`p:&r11.-ular p•llCnl
`The aumor-. cdll!"'· JnJ pul>l"her t:».c C.\tremc .::.re to hc ccnaoo that drug' :ind d~gc rC\'OOll11<"nd.1tmn' '"" pr«1\C and occurnu:. llo"'""'·
`t)l'Oi:t"r>hocul Cm.>f\ C1111 OC\:ur. ·n,.,refore. be 'ure to doublc·chccl nil du'3J;C "'licdul<s on an1clc, 111;ain,t tl1C manuf.H.tu~r·, packOJ1C inform:iuon dola
`Al..,. do...,gc< and mctho1h of 0Jmon1>irnuon or phtum.1ccut1cal pmducl\ mcnuoned by autl10r< r»O) not nci:c,-anl) hc the'"""'._, 1ho;c li\tcd on tho
`p:oc\.agc inwn. Su~h d<l\Oj;C' Ulld dcli»CI') mcthoc.I\ lllJO)' re0cct the dmocnl C~pcflcllCC Of the nuthor or llUltK"' and/or ll\O) rCOcet the C~pencn..-c Of other
`chnu .. 'ti1 Ill\ c'Ug!ilUr"'I
`O~C'OL .. om CISSN OS90·'Xl'JH- Otntcnt> copyrighted 1997 t>y PRR. Inc .. 17 Pro>pcct Street. lluntonl!tun. 'IV 11743. Jim>e' F. McC•nh). Vi«
`l'Tc>iJcnt- Eduonul J>1rcc111r: C:tra II. Glynn. A"'"""' l;;Jotunal l)orc.:tur: Ellen Olin Power.. Manu~ona hd1111t, Ed"'" S O.,ITner. Vice l'Tc\lcknt
`Con~ultonl? Eduoc Rol>en C Con•k. Vic:c l'rc>1dcn1- Pubh,hcr: Jnhn J Coronno. faccutnc Vtec ~1Jcnt Otract('t' of S~lc-. John A G<nulc. Jr~
`l'rc'ldcnL All n~ht' fC\Cr\cJ Spcc1•I Pnticnt lnfonna11un Aid< "13) l>c reproJuccd b) "" 1ndl\1du:il rh>,•<••n lur do,tnbuuoo on hos"' her"''" prw:ticc
`"ilhout 'pccoli.: miu<"I m the P\lbh<hcr One or t"'u COi>''"' of :utoclc- h.lf pcN>rUI or intcmal U>C 1113) be~ :>t no ch:u'Jc Copying bc)ond tlw numbcf
`for pc:1\00:il ,,.. 1ntcm:il U\C ,, p:uited b) PRR. Inc .. JlfO\odcd lh;c • rec of 9~ pct p:ll!C per Cop) ~' f"'ld th~tly to the Cop) right C1=ncc Center. 27
`Con~ Strett. SJlcm. \1 \ 01 1>70 ttdcpllonr !iQb. 7.U.l.lSO) Sikh ~'''""'<loo not C\knd to '°"''"It f\)t ~ncr.&l d1\lnbuuon. ror a1f\cruuna"'
`rrornot1(1D;ll U\C. 11t for re~k. "'ht<h miuirc 'i""'r"' v.nttcn pcm11"""' from the P"bli>hcr O'C'Ot.om "indi>Jcd 1n lode\ ~1edicu<. &capt;a Meda.
`E.\IR..SE. and the Con<'ttl..Jt :ind Cnnccr Linc <bub"'O mt the: l\•toorul Con..-cr ln\lotutc.
`Chcoi.tJ<" "pubh'hcd rnonthl) b} PRR. Inc .. v.11h pubhcJllOfl alflcc, >I Hunongton. ' ' 11741 ltrlcphMc. Slt>-12-1-l>!lOOJ. Subscnpoon nll4"'
`domc..uc imd Can.>da. Sl!S per )"'1r: fomi:n. SU17 per )Car: 'tlklcnl\. S75 per )c:tr: single copon of thl\ \Ul'Pkmcnt. Sil ca.:h. Plc:i.se nolll)' Pl'S McJi.-.J
`lll"rl<1ini: Group. 111<. prompt!) or chBni:t of addrc>' ('Cnd old m:i1hng lnhcl And new :>Cidre'''· Scron~I•" l""tll$C p>od >I Hun1in1?tOn. NY 11743 o.ncl .i
`:idd1uon•I m•ohni; nffttt, l'O\t""1.'>lcr: Pia."' "'nd l>Lklrc>' l'h•n~c' (fonn 3579) 10 Osc·ot ocn. c/o PPS Medical /\1Drl.cung Group. Inc .• 26-i P:t.\..a.1<
`t\\cnuc. Foor1icld. NJ 071Ml-l·!S95.
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`ONCOLOGY~
`
`ROBERT f WITlTS. Mil
`M<d1<1n< Rr>nd>
`N1110ft>IC......,l1t..Ulllk
`l:do10<-ln·Chr<f
`
`Associate Editors
`
`NEIL K. AARONSO!'-. PllD
`()rpuunrru of ~>'~"''I Jk\('.ltt.h
`~ Nrthctlan..h Cancer ln\.11tu1c:
`
`MARTIN D. ABtLOtr. MO
`On'""" .,r M~-.1 On<i~<'J)
`Joblb llop&.in> Oncul<'S) ('<nlrr
`
`IX>l'AU> I. All RA \IS. \II)
`AIDS Profr.un
`S.... F.-"1~" Gcocr.aJ 11•"1"00
`
`RJC"llAJU) BARAKAT. \11)
`G)~Sc:"""
`~lcmonlLI Sk\;&n· l.r11mn1 C""'a C<nitt
`
`RO"\AU> BLUM, \1()
`°'"-''"" u( Mnl1<•I On.:O~'S)
`Sc• Yc1d;. Un1\it:Nl) MtJh.'.11 Ctnltt
`
`BARRIE CAS.~tumt. 1'111)
`l'nhc-f'H) ol Noirth C".utlllna omJ DuL.t Unl\C"t\11)
`
`DA\ ID F. CEUA.1'110
`Om"°'1 ttl l'>)<ll<><o,.,11 \<n k""
`Ru-iic~c.., .....
`Ru-ii ~ll<n"" SI l"l<"• \l<J1,,J C<nl<'f
`
`BRUCE D. CllCSO"\. Ml>
`t11"".l 1o ..... ,........, o._i.. c ...... Th<np)
`fa'11""""" l'\-os11Un-0.>1•K., u(Canccr rn:otmcnl
`'.tiLun.:iJ ~"Cf lR\hfU(t
`
`1.AWllE.'-CF. R. COIA, MD
`U.'1 rw-.& R:kh.tttJ(lfl ~okll) A'\\X1'1.1ron
`Tnm .. R1\f'r. Ne-. Jtof\Cy
`
`E. DAVID CRAWFORD. Ml)
`0.> '"""of linJ!os)
`l Coko.lo llulth x1<n«• C<ni<"r
`
`WARRL\ L E.\Kl.11. Ml>
`Oud. o .... .,."' cu1om.....i ~Uls<")
`Rctb l;nrl \l<dl<M C<n1tt °'"' YotL
`
`BL'RTOS L USE."\ULR(,. \ID
`
`°'""""""'"' ot S1UJ•ul o ... ,~.'Sl
`""' °'""' c ..... .., c· ..... ,
`
`KATHl.&.'1 M. f-011 V, Ml)
`P.un Sc:nKt
`\kmonaJ SI0'9n·l\.C'lttnnr t"~n<t"r ('cmc1
`
`,\USON FRHl+.LI>. \Ill
`Oud. Chnk.:.J ln(«luJu' 1)1\of'Ol"-c"\
`l\::tliOrW C:anr..er 1n .. u1utr
`
`DANlloL G. llAl.I FR. MO
`llcm;omloll}·On..-.•~) ~"'"'
`Unl\C"•I) or Ptnn\.)h<an)OI
`
`I. CRA ICO 111·.M>t;KSOJ\. Mll
`D<p.mm<nl ol \l<Jo<al Ono.""'it)
`U •11 C.ahihrma. ~ l·r.vt\:t\4..0
`
`JIMMll C 11()1.t.,\ \I). \II>
`~)~h1.all)~h.C'
`\\tmon.J Sk'Mn· l.;<'<1<nn1 C"11<n C<nl<t
`
`\\ IU.IA\1 J. llOSt.;IJ\S, \II>
`C)n«vk,;) S<r..,,..-
`M<,.,..,•J Sh.,.,,·l.<ll<linr (...,.n Ccal<t
`
`\ . C-RAICO JORDA1'. l'hl>. DSC
`8~"' Ct.n.."tr M~1f\:h Pn.>srum
`Nunhv.C",tcm Vnh·cnn>
`
`Bl'RNARD U·VIN. MD
`Vttc Prc,itknt fof Catk:~I l'rt,\'nhon
`MD Andc<Ntn ('.mu·• c.·cn•cr
`
`\ 1(-rOR It\ l'I. MD
`Dcponmrn1 of Stum-On"•k>i>
`\J D An.l<N., C-.-.r t"cnl<r
`
`.\U !;."\ S. l.ICH n.K. \JO
`Dcponmrn1 of R..J'""•"' Onn""')
`UAl\cn.11) u( \hdu1 .. n
`
`MARY MCCAll!l. R'I
`llt\ ,,K>n of r_., ..... rr, ~;im~fit
`N:iu~1 CarM:n ln4.lll11tc
`
`RODNl!Y R. Mii.i ION. MD
`lkp.&11nW'nt or RIJIJ.llOO Ork:UIUl}
`Unl\c"U) of l1'•1tb. Oa11'1C',,11fc
`
`\IOSICA \IORKO\\. \10
`l>i~-uw. (\llfnf'R'htn'l'C' Brei.\! P'n'Sr.un
`'Mh•r4em L'nl\fT'U~ Mnl*':.I Cc-ntcr
`
`Jl OD I'.. \IOOl- \ti)
`D<p.nmrnt ol Sursa)
`lin11,.......i s.n,..-
`t.. ft1\m1I) uf IN I ko1lth Sl.ll'nt."C':\
`
`'I. \I\ LKS, Ml)
`LUG1"'11
`Dcr.Y1•ll<nl 11I Oonl"')••"'"ll>
`l 'nl\C1'11)' nf P1thburi:h
`
`RIC"HARIJ l'A1T. Ml>
`Anc-\lhn1~ t'.un '<'r\1lt
`\I I) An.kr- Can."<r < ·<n1<t
`
`RICHARD l'Al.l)VR. ~ID
`Ot1Ji1Lnmrnt ,,, MC'd1~1I <>n..:,.-ol)
`M 0 ;\nJrNH'I COJK."Cr ("('ntcr
`
`l>A \I ll>CL llOPL.ACK. MD
`ll<m.a1<•k>lll"~ Scm<e:
`le"'•"' C'"tultJrrn·\ fl\)'l..ptl;al llUlhCt"1
`
`l>ll Vt" 1 ROSL.S. \ID
`\l<d"al On«>l<JJY l>«toon
`'unh .. Ncrn l 0 n1\CNt)' C.an-.n Center
`
`RKl;.."\l)A Ml.\ \K. MD. PllD
`0.f"'lrll<nr 1>1 R:ldr .. Klll OikoJo&)
`Ml Su'UI McJK:;,tl CC'nCCr. i-.:vc
`
`TllO.\IA.\ J. ~.\IITll. MU
`~kJ1 ... 2l \olk-s;c "' V1rs1nra
`M"""'> C111".er \cnt~r. R1..:hmunJ. V1r;1n1:a
`
`N SIMO'I rCl l!>KMW>YIAN. MD
`P.a.:1(1" \ht;"'r' \tcd11;'1I Group
`Ll>n tk .. h. ( •l1lum11
`
`l!ll,\l>RA..~,\I\ \ IKRA..\I. MD
`l>q>utm<nl <•I lbJl1"""° 0...~l'J)
`Al~ lJn\tc1n(\~krc=,tf \trJ1c:1nc. '\C
`
`l.Al'.IU :-.n. 0. \\AGMA'I. MO
`l>t\l\ .. lft ot ~UflC')
`t11) ol lk~ '"''ocu.I \teJh.-al Center
`
`JANh \\ l·hK\, Ml>
`l)C'fQf1111("nl ~'I Mf'dH.·1nr
`D.ln.i·hubcr CancC'r ln...'411u1c
`
`Sll>Nrv WINAWLR. Mr>
`G.a\.lmC'nlcfok.,.) ~nd !\utnl)IJO Scntcc
`\kmlt\&I ~ktiln·~C'llt'n"t C'anco Ccntn
`
`RODGLR J. \\ ll\N, \II>
`C"ommurut> On..:''"'I~ Prosr•m
`
`\I D '""'°""" c.,,...., C<"01<1
`
`\TASI 1.Y A. \\l\OKl.R. MO
`C.,"ll,. Ot"''""')nknu11))1>s) t11rut. All..u
`
`fRl'~l WYM>l·R. \11)
`AnlCrtUl'l lft .. llh l:OUnJ;JllOO
`
`SUPPLEMENTN02 • MARCii 1997 • O'ICOLOGY
`
`3
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`HOSPIRA EX. 1006
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`A Supplement to
`
`ONCOLOGY®
`
`CONTENTS
`
`MARCH 1997 (SUPPLEMENT NO 2)
`
`SPEC IAL ISSl lE
`
`Update on the Taxancs in Breast Cancer
`• \ s:-·1111x>.•i11111 /1c/1/ i11 ('l>11i1111t•rio n wic/i the
`19 111 . \11111111/ 8 1111 A 1111111it> /Jrca.,1 Gmwcr Go11Jcn:mcc
`
`T he Taxanes: Dosing and
`Schedulin~ Considerations
`
`Paclitaxel for Breast
`Cancer: The Memorial
`~ loan-Kettering Cancer
`Center Experience
`
`Pnclit:1xcl-Based
`Combination Chemotherapy
`for Breast Cancer
`
`T he International
`Experience With Docetaxel
`iJl the Treatment of Breast
`Cancer
`
`1 IER2 Overcxpression and
`PacHtaxel Sensitivity in
`Breast Cancer:
`Thempeutic Implications
`
`7
`
`20
`
`29
`
`38
`
`43
`
`Eric K. Rowinsky, MD
`Uni ver.;ity of Texas I lealth
`Science Center at San A ntonio
`
`Andrew O. Seidman, MD
`Clifford A. Hudis, MO
`George Raptis, MO
`Jose Baselga, \10
`DaYid Fennelly, Mil. MRCPI
`Larry Norton. MO
`M emorial Sloan-Kettering Cancer Center
`
`Gabriel N. Hortobagyi, J\10
`The Uni ver,,ity of Texas
`M .D . Anderi.on Cancer Center
`
`Peter M. Ravdin, MO, PhD
`Uni versity of Texas Health
`Science Center at Sun Antonio
`
`J ose Baselga, MD
`Hospital General Univcrsitari Vall d' Hebron
`Barcelona. Spain
`Andrew D. eidman, MO
`P. Peter Rosen, MO
`Larry Norton. MO
`M emorial Sloan-Kettering Cancer Center
`
`SUPl'LEMENT NO 2 • MARCii 1997 • ONCOLOGY
`
`5
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`JOSE BASELGA. \10
`Oncology Service
`HospirnJ General Univcr.;ir:iri
`Vall d'Hebron
`Barcelona. Spain
`
`ANDREW 0 . SEIDMAN. MD
`Breast Medicine Service
`Depanment of Medicine
`
`P. PETER ROSEN, MD
`Depanment of Pmhology
`
`HER2 Overexpression and
`Paclitaxel Sensitivity in
`Breast Cancer: Therapeutic
`Implications
`
`ABSTRACT
`
`LARRY NORTO'll. MD
`Brcru.t Medicine Scmice
`Depanmcnt of Medicine
`Memorial Slo.1n-Kcttering
`Cancer Center
`New Yori... NC\\ Yori..
`
`T he mxanc.' nre an imponant new
`
`0 1•erexpression by the HER2 gene plays a signifteant role in breast
`cancer patliogeuesis, and tlle phenom enon is commonly regarded as a
`predictor of a poor prognosis. HER2 01·erexpressio11 has been linked to
`se11siti11ity and/or resistance to llom1011e therapy and cliemotherapelllic
`class of anticancer agents with a
`regimens, inc/riding CMF (cy clopllospliamide, m etliotrexate, and jluoro(cid:173)
`unique mechnni~m of action.[ I]
`Paclitnxel (Tuxol). the first taxane used
`uracil) and ant/iracyclilles. Studies of patients with adl'011ced disease dem-
`in clinical trials, was l)riginally isolated
`OTIS/rate that, despite the association of HE R2 o ~erexpression wiJ/i poor
`in 1971 from the barl.. of the Pacific
`prognosis, tl1e odds of HE R2-positi1•e patients responding cli11ically to
`yew. Ta.m.\ bre1•if11/ia. It w:c. selected
`taxanes •••ere greaJer than three times those of llER2-negalfre patie111s.
`for clinical de,clopment b:c.ed on im-
`F11rtlterst11die:. u1prttlinicalmodelsu.sedcombi1101io11t/1errrp)tforbreastcanur
`pressi\ e anti tumor acti' Hy against the
`cells tllaJ 01·eruprus HER2. and the use of agm ts that i111etfere wiJJ1 HER2
`implanted B 16 melanoma and the hu-
`fi111cti011 plus paclilaxel (Taxol) resu/Jed in sig11i[1Cant antilumor effeas.
`man MX-1 mammary tumor xenogr:ift. ' - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - '
`Since then, paclitaxel has been
`shown to have a high degree of anti tu(cid:173)
`mor actfrity in women "ith met:u.taLic
`breast cancer. as well :u. a lack of cross(cid:173)
`rcsisumce with nnthr:.1cyclinc!>. Current
`clinical research with paclitaxel in breast
`cancer is focused on several aspects.
`including: optimal doi.ing and schedul(cid:173)
`ing: the agent'!; role in the treatment of
`early brc.1\t cancer: its u..c in high-dose
`inteni.ity therapy of breast cancer: and
`combination therapy of pachta'tel with
`other antineopl35tic agent~.
`An area ofincrc~ing interest in clin(cid:173)
`ical research on ta>tanc~ i\ the possible
`role of oncogenes. such ~ HER2. in
`dc1cm1ining clinical rc'pon~ to padi-
`
`taxel. Studies have examined whether
`~tnuegies can be de:.igncd to incre:bC
`the agent·~ efficacy (or curb ~ist:mcc
`to it) in breast com:ers that overcxprc(cid:173)
`sess HER2. A\•ailablc data that will be
`presented in this review suggest Lhat
`HER2 ovcrcxprc~'ion may innuence Lhc
`respon~e to pacliLaJlcl in patients with
`mct:t'>tatic brca't cancer and tha1 amj(cid:173)
`HER2 monoclon:.11 antibodie:. signifi(cid:173)
`cantly increase the anLitumor activity
`of paclitaxel in vi1ro and in vivo.
`
`H ER2/c-erbB-2b 1eu
`in Breast Cancer
`
`One or 1w11 copoc< of 1hi' 11111clc for personal
`or nucmnl u-.c m•y he mad• a1 no drnrgc. Copie.~
`beyond 11101 number rrqui"' lh31 3 9r per p;igc per
`copy f« Ix- p;11d 10 the C"fl> nt:Ji1 Ct=ncc C<n·
`lcr. 212 Ro\Cwood Dmc. D:in•cr>.. MA 01970.
`Specify ISSN Oll<J0.\1091 For funhcr infonn:i·
`1ion.·cont:1C11hc ('("(' ai ~'1-7~. Write
`rubh\hcr '"" hutL 'l""""llC\
`
`During the lru.1 decade. proto-onco(cid:173)
`genes encoding growth foctors and
`g.rowth factor rccepton. have been found
`to piny impon:1111 role~ in the pathogen(cid:173)
`c!>is of :.ever.ii human mnlignancie.'>. in(cid:173)
`cluding bl"ClL't canccr.121111e HER2 gene
`(also known a.\ 11e11 and as t-erbB-2)
`encodes a 185-1..D tran~mcmbrane gly-
`
`coprotcin l\.'Ccptor (pl8511au) 1ha1 h:c.
`panial homology with the epidermal
`growth factor (EGF) rccep1or: the gene
`~hnrc.' intrin\ic tyrosine kinase activity
`with the rcceptor.(3-5] The EGF recep(cid:173)
`tor and p 185111 1t.1 belong to a superfami(cid:173)
`ly of receptor.. known ai. type I tyro~inc
`kina~ receptors. which have nn extra(cid:173)
`cellular ligand-binding domain. a tr.ms(cid:173)
`mcmbrJne hpophilic 'egment. and an
`intracellular protein tyrosine kina.">C do(cid:173)
`main with a regulatory carboxyl termi(cid:173)
`nal -..:gmcnt.161
`HER:? h overcxprcs:.ed in 25CK to
`J()<k> of human brca.~t cancersP.81 and
`indicates a worse prognosis in patients
`who have positive axillary lymph
`nodcs.16.7.91 T he observation that
`HER2 ovcrexprcssion ii. associated with
`a poor prognosb could imply th:u HER2
`b wlcly a marker event. On the other
`hand. HER2 could be a progno:.tie fac(cid:173)
`tor that playi. a role in the pathogenesi~
`of brca't cancer.
`
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`Role of Monoclonal Antibodies
`Several lines of evidence suppon a
`direct role for HER2 in 1hc pathogenesis
`and clinical nggrc,~ivenc.'~ of ovcrcx(cid:173)
`pressing lumor..: (I) The introduction of
`HER2 into nonneoplaMic cells causes
`their malignant transfonna1ion.( I 0.11)
`(2) Transgenic mice e~prcssing HER2
`develop mammary tumors.( 12( (3)
`HER1 ovcrcxprc.~ion i' common in duc(cid:173)
`tal carcinoma~ in si1u and in their asso(cid:173)
`ciated invai.ive cancers.( 13.141 (4) The
`mechani~ms responsible for this growth
`ad,•antagc an: thought 10 be related 10
`1he fact thm p 185111.111 m•crcxprcssion re(cid:173)
`sults in activation nfn series of signaling
`pathway!> (PLC-gan11n;u'phosphatidyli(cid:173)
`nositol: Pl(3)~na.<;e: STAT91/1SGF-3:
`ras/r::if/MAP-k111a.'i<! pn1hwny: ~re: fami(cid:173)
`ly). and that ac1ivmion of these path(cid:173)
`ways rcsull!> in gene ac1iva1ion 1ha1
`ultimatcl} rc.'uhs in cell prolifcralion.[6)
`(5) Anlibodies directed again~ pl8511au
`can inhibit the grow1h of tumors and of
`transfonned cclli> 1hn1 express high lev(cid:173)
`els of this receptor.( 15-191
`The lauer Ob\crvaiion suggesb that
`p l8511uu may be n po1cn1inl target for
`the trcntmenl of breast cancer or prein(cid:173)
`vasive breast lesion~ bccnusc 1hesc cells
`commonly overexpress HER2. The
`murinc monoclonal an1ibody (MoAb)
`405. directed again't lhe ex1rneellular
`domain of p 1 s511t1t1 CECD1"AZ). is a po(cid:173)
`tent inhibi1or of in vilro gro" lh and. in
`xenogrnfl modeh. of human breast c:in(cid:173)
`cer cclb ovcrexprcs,ing HER2.(20-22)
`Murine MoAbs. however. arc limi1ed
`clinically because they arc immunogen(cid:173)
`ic. Therefore. 10 faciliu11c funher clini(cid:173)
`cal invcstig:uions. MoAb 405 wa~
`humanized. The re~ulting recombinant
`humanized anti-p I R511m MoAb (rlrn(cid:173)
`MoAb HER2) wa.-. found 10 be safe and
`10 have do~c-dcpcndl"nt phann:icokine1-
`ics in two prior phase I clinical trials.
`
`HER2 Ovcrexpression as a
`Predictor of Response to Taxanes
`Since HER2 plays a role in breast
`cancer pa1hogcnc,ii. :ind HER2 ovcreit(cid:173)
`pre.,sion corrcla1es wilh more aggres(cid:173)
`sive clinical behavior. several studies
`have auemptcd 10 correlate whe1hcr
`HER2 ovcrexpression is a predictor for
`response to :.ys1cmic therapy. Studies
`10 date have shown I hat HER2 overeit(cid:173)
`pression predicts a worse re.~ponse to
`honnonnl therapy with 1an1oxifcn (Nol(cid:173)
`vadex) in advanced discasc(23.24) and
`in early-stage brca.~t cnncer patients.(25)
`
`Dose-Response EITccls
`to Anlhrncyclim'S
`The rel:llion~hip between HER2
`overexprcssion nnd response 10 chemo(cid:173)
`therapy appean. 10 be more complex.
`Data indic:11e 1ha1 HER2-positive tu(cid:173)
`mors have increased resistance 10
`adjuvan1 CMF (cyclophosph:imide.
`methotrcitatc. 3Jld nuorouracil1-bru.ed
`thcrapy[26.27( and. conver~cly. in(cid:173)
`creru.ed doi.c-rc:.ponsc cffcrti. 10 an an·
`1hrncyclinc-con1;aining regimen.PSI
`In Intergroup Study 0011.126) pa(cid:173)
`tients with primary breast cunccr tu·
`mors larger 1han 3 cm or with estrogen
`receptor-negative 1umon. were rnndom(cid:173)
`i1cd 10 receive ci1hcr CMF chemother(cid:173)
`apy or oh1>erva11on. P:i1ien1s with
`HER2-ncgative tumor. \\ho received
`adjuvanl chemo1hcrnp) ~howed signif(cid:173)
`icantly improved discn...c-free sun•ival
`when compared "ith untreaied patient~.
`In contra~1. patient~ with HER1-po,i-
`1ivc 1umllr. ~hllwed no bcnelit from
`:idjuvant thcrJpy.
`Jn the International Breast Cancer
`Study Group trial. patienLS with nodc(cid:173)
`po~itive curly hreast cancer were run(cid:173)
`domi1.cd to rct:civc either one cycle of
`pcrioperu1ive chcmo1herapy or pro(cid:173)
`longed adjuvnnt chemotherapy. dclined
`as ~ix cycle.' of CMF-based chemothcr(cid:173)
`apy.[27 J In thti. ... 1ud}, lhe effect of pro(cid:173)
`longed chemotherapy was gre:uer in
`p:11icnl\ with HER2-negaiivc tumor...
`The po'>-\ible predic1ive role of HER1
`ovcrexpl'C.!',ion ha.' alM> been analyzed
`in paticnh wi1h earl) breast cancer
`tre:lled with anthracyclinc-containing ad·
`juvan1 1hcrnpy. In a well-known ran·
`domi1.ed ~udy by 1he Cancc.r and l..;:ukcrnia
`Group B (CALGB). three doses (high.
`modcrme, ruld low) of cyclophosphamidc.
`cloxoruhicin. ruld nuorourocil were com(cid:173)
`pared in women wilh nodc·posiLive bn:a:.1
`canccr.(28) P:11ien1s randomly assigned
`10 the high-do-.c regimen of adjuvant
`chemotherapy had -.ignilicantly longer
`dise;isc-frcc and O\erall survival if their
`tumor..o,·crc:1.pl"C.'>>Cd HER1. Thisd~­
`w..poni.c effect wu.\ not ~n·ed in pa(cid:173)
`ticnl\ w~ tumors had minimal or no
`HER2 expre.,.\ion.
`Thu.\, lindingl> from lhc CALGB
`Mudy ~uggeM that there is a significant
`dosc-re.\ponsc cf'fcc1 of adjuvan1 thcr:i(cid:173)
`py with an anthrncycline-containing
`regimen in pmienls wi1h HER2 overex·
`pression but not in p:itients with no or
`minimal HER2 ex pres., ion. The group· s
`linal conclu3iOn wa~ that HER2 O\Cr·
`
`expre~sion may be a useful marl.er for
`identifying pa1icnti. who arc most like(cid:173)
`ly to bcnelil from high doses or adju·
`van1 doxorubicin-bascd chcmothcmpy.
`
`HER2 Overexpression
`and Taxone Sensiti\'il)
`Bccau~ taxancl> arc becoming" 1dc·
`I) ui.cd m the management of ad\anccd
`brc:131 cancer. ''e decided 10 anal)lc
`whether there i<. 11 relaiionship bet\\ccn
`HER2 cxpre,,ion and clinical ~en,itiv·
`i1y 10 1axanc,. In a Mudy performed at
`Memorial Sloan-Kcnering Cancer Ccn·
`1cr. the pos,ihlc rela1ionship between
`HER2 ovcrcxpres,ion and rcspon~ 10
`1axanc' wru. analy1ed in pnticnts with
`mc1:1,1111ic breaM canccr.[291 HER2 C.\·
`prc"ion " "" 'tudied in palicnll> 1rca1cd
`"ith one of eight protocoll> of sin!? le·
`agen1 l:l\anc therapy over the p:!!>I 5
`year... All patient.\ hnd bidimens1onall)
`mcai.urable di\Ca\e :ind his1oloI?1c:ill)
`confim1ed 111e1:ma1ic breast cancer.
`Archi\cd pamflin-cmbcdded 1umur
`tii.,ue wa' nvnilablc for immunohis-
`1ochcmiMry in 122 patients ou1 of 1hc
`total of 212 patients treated: of the!.C.
`102 (84%) received pacliwxel and 20
`( 16%). doce1:1Xel (Taxotcrc). Gt.'Ographic
`conl>idcrotion~ were the most frcque111
`obstuclc in lack of tiS3uc availabilitv
`for HER2 anal}l>i,.
`·
`Twnor expres:.ion or HER2 \\as clctcr(cid:173)
`mincd by immunohistochemical anal) i~
`of :i -cl of lhin ....xtions prepared fmm
`paucnL,. pat:1ffin-an:hi\ed 1umor blocl.'
`(u.~ previou,ly dcscrihcd(7.8]). The pri(cid:173)
`mary dctcc1ing antibody used W:l!> mu(cid:173)
`rinc MoAb 405. directed at lheexu-.n:llu!Jr
`domuin of pl g51ioo. TulllOI~ were comid(cid:173)
`cn.'Cl 10 ovcrcxprcss HER2 if Ill least I ()C;l
`of the tumor cells cithihired char:ictcrilolic
`mcmbmnc staining for pl851ruu.
`Seven progno,1ic foc1ors were ru.(cid:173)
`sc:.~ for ru.!>Oeiation with tumor rc(cid:173)
`l>JX>n-c: HER2 ovcrcxpn:ssion. ~on:d
`a.' po'> Hive or ncgaiive: ~trogen-reccp­
`tor siaiu~: e:1.1en1 of disease, divided
`into one 10 two invohed organ S}i>!Cm~
`v~ 1hrce or mon: involved systems: e>.(cid:173)
`tcnt of prior chemotherapy. categori1ed
`~one 10 1wo courses or more than 1wo
`course.\; presence of visceral disea)>C;
`prior therapy with doxorubicin: and
`Kamofsky perfom1:1nce s1uius. Slr.1li(cid:173)
`lied a.' 60 10 80 or 90 10100.
`Jn 37.7% of p:uien1s. tumon. ''ere
`po\iti\·c by immunohistochemistry with
`the 405 anti bod). The O\erall rcspon-.c
`10 l:t~anc.~ for all pa1ienlS in lhil. analy-
`
`44
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`MS \\3S 46.7~. Remarkably. 65.2'k of
`patients with HER2-po,iti\e tumors
`re'ponded vi. 35.5'k of pauenu. with
`HER2-negntive tumors. Usi ng a
`Muntcl-Hi1enszel test. the P value for
`this difference was signilicru11 m .002.
`Visceral dominance (P = .011). low
`pcrfonnancc suuu~ {P = .057). und ex(cid:173)
`teMivc prior therapy correlmcd with
`poor clinical response. Among these.
`HER2 overexprcssion was positively
`corrclau:d with low pcrfommncc ,tmus
`( P = .002). and low perfom1ancc Matus
`with extensive prior therapy.
`ll1cse correlations should bi11' against
`re.-.pon!>C in HER2-positivc c:isc~. which
`wa\ not observed. Indeed. Mmtificd anal(cid:173)
`Y'i' controlling for confounding vari(cid:173)
`able' demonstrated the vulue of HER2
`Matus in predicting taxane respon..c. lbe
`odd\ mtios of re!>pon..e for HER2-posi(cid:173)
`tive vs HER2-negative 1umon. were 3.95
`nni:r udjusting for visceml disca..c. 3.17
`nftcr ndjusting for number of prior ther(cid:173)
`apic.,. and 3.06 aficr adjui.1i11g for pcr(cid:173)
`fonnance ~1u1us. Thus. despite u poi.i1ivc
`correlation of HER2 expression and poor
`prog~tic feawrcs. the odd'> of l IER2-
`po~itive patients re_,ponding clinic:illy
`to t:mlll~ were grc:ucr thnn three timei.
`tho~ of HER2-nesaiive pa11en1s.
`
`Tentative Results
`With Polyclonal Antibody
`Tumor specimen~ were nlsoanalyzed
`\\ nh a rabbit polyclonal :inti bod) direct(cid:173)
`ed at the cytopl~mic c-tenni nu\ epitopc
`of pl 85'~. lmmunoh1stochcm1calcval(cid:173)
`ua1ion with this antibody rei.ullctl in a
`higher proponion of HER2 po~itivit)
`(57%). Patients who were shown 1ohavc
`llER2-positive tumors using this anti(cid:173)
`bod) were more likely tOrc\pond to tax(cid:173)
`anci.. nlthough 1hc difference wa~ not
`'tatistically ~ignilicant (P = 3).
`Resul~ with I.hi~ polyclonal antibody
`ha\e 10 be vie"ed with caution because
`57~ of the tumors stained po~itive for
`HER2 overexprcssion- a higher propor-
`1ion than with the MoAb. ;ind higher
`than has been rcponcd prc\liously. Fur-
`1hcr confinnatory ~tudie~ 11rc needed to
`vcnfy our results, which 4.-0uld have sig(cid:173)
`mticant implication~ for the treatment
`of p:uicnts "ilh ad\'anced brea.'1 cancer.
`
`Puclitaxcl and the Signal
`T n1nsductioo Pathway
`The possible meclrnnbm~ underly(cid:173)
`ing the interaction between HER2 over(cid:173)
`c\prc.,:.ion and laJCanc sen~i1ivi1y are
`
`erbB-2 A
`erbB-1,
`• 2,3,4
`
`RAS-GTP -~ p
`
`;
`
`I RAF I\ IGRB2 (•
`~I P_a_c_l-it_a_x_e~, , e p IGRB201sHc 0
`t ~ sos
`"' · l e p
`
`p
`
`p
`
`I Nuclear Transcription I
`
`Figure 1: Interaction of Paelltaxel with pl 85_.. Slgnal Transduction Path(cid:173)
`way-Paclitaxel activates c-raf-1 and MAP kinase in breast cancer cells.
`
`unknO\\ n. Paclita.xel stabili1c:. micro(cid:173)
`tubulc,. prevents tubulin depolymeriw(cid:173)
`tion. and promotc.s tubulin bundling. In
`nddi1io1110 thi~ well-documented mech(cid:173)
`anism of action. some evidence ~ug­
`ge~h thal paelitaxcl activate~ key
`clemenL<. of the HER2 signal trnnsduc(cid:173)
`tion pathwa) (Figure 1).(30-32(
`The mitogen-stimulatcd protein
`scrin\.'llhrconine kinase c-mf-1 functions
`as a ccntml component of the mi1ogen(cid:173)
`ac1iva1ed protein kinase ( M AP kinu!>C)
`signal 1ransduc1ion paihway.(331 In
`MCF-7 brc;~I cancer cell~. paclita>.el
`treatment leads to activaiion of c-rof-1.
`documented by a reduced c-rof-1 clcc(cid:173)
`trophorctic mobility after paclita,cl ex(cid:173)
`po~urc.130) Furthermore. paclitaxel
`therapy induces a do~- and 1ime-de(cid:173)
`pcnden1 accumul::ttion of the cyclin in(cid:173)
`hibitor of p21 "'An, and c-raf-1 depiction
`prevents this activation. In addition to
`c-m/- 1 m:tivation. tyroi.ine phosphory(cid:173)
`lation 1>f MAP kinase is a well-docu(cid:173)
`mented response lo paclitaxcl. and it
`probabl) rcprc.'>CnL~ a funcuonally im(cid:173)
`ponan1 event by the agent.130.32)
`The acuvatiom of the HER2 .-.isnal
`1 rnn ~duc1ion pn1hway by pachrnxel
`could al~<> n:suh in activation of pucli(cid:173)
`taxel-induced apopto~i~.131 I Thus.
`HER2 overexpression would provide
`
`an incrcn.-.cd opponuni1y to enhance the
`cy101oxic effect~ of paclitaxel.
`
`Combined J'hergpy With Amj(cid:173)
`HER2 Meats and Cltemq1lterap.J.
`
`rep(cid:173)
`As already mentioned. pl8510"
`resent~ a potential target for tumors that
`ovcrcxprci.-. HER2. A novel approach
`tha1 is currently bemg explored is the
`combined u'IC of them pies directed ut
`p 185""Jt2, such a~ MoAbs given alone or in
`combin:uiun with conventional chcmo·
`1hempcu1ic ngcnlS. including paclitaxcl.
`Seveml group:. ha~e produced anti(cid:173)
`bodies directed again~t lite pl 851111u re(cid:173)
`ceptor protein on human cells. Some of
`these antibodic' can iohibi1 the gro\\ 1h
`of monoln}er cuhu~ ofbre3SI and 1>vn(cid:173)
`riao tumor cell.-. that overexprc.-.~
`p I 85111:it2. ( 15-18.20.34,35) In extensive
`studie1> conducted at Gcnentcch, Inc, a
`clear relatiunship between the level of
`HER2 proio-oncogene expression and
`sensiti\'ity 10 the growth-inhibitory
`effect~ of 1he antibodies \\as ob(cid:173)
`sened.120.21.34)
`Brc~t earcinomacdls with liule e~ -
`
`Thi, rl:>C:in:h ho' hecn •upponcd by nn ASCO
`Cnrccr Dcvclopmcnl A"unl und by the IA>n Shu(cid:173)
`la Found:ninn
`
`SUPPi 1-.Mlil\'T ~O:? • MARCii 1997 • ONCOLOGY
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`prc~ion ofplSSlllJ<z (cg, MCF7. MDA(cid:173)
`MB-231, ZR-75- 1, and MDA-MB-436)
`were not inhibited by MoAbs. Cell lines
`with higher levels of pl8511'" (MDA(cid:173)
`MB-175. MDA-MB-453, MDA-MB-
`361) were increasingly more sensitive
`to antibody-mediated growth inhibition.
`SK-BR-3 and BT-474. the highest ex(cid:173)
`pressors of p I 8511~R? of t11e cell lines
`studied. were the mo::.t :.ensitivc to the
`antiprolifcrative effects (showing ap(cid:173)
`proximately 70'1f growth inhibition).
`The most potent growth inhibitory
`anti-p 185111.11 2 MoAb was 4D5. The ac(cid:173)
`tivity of MoAb 405 and a humanized
`version of this MoAb against human
`breast adenocarcinomu cells bearing
`HER2k-erbB-2 has been evalumccl in
`the nude mouse xenograft model. Lnhi(cid:173)
`bition of tumor growth has been ob(cid:173)
`servedl 36.37 I with eradicalion of
`w.:11-cstablisbcd tumors.I'.\?] Thus.
`MoAb 405 apperu-s to have potential
`therapeutic applicatiOnl> for tumors
`ovcrcxprc.~sing pl 8511!00.
`
`A " Humanized" Antibody
`ln an :utcmpt to circumvent an anti(cid:173)
`globulin response during therapy, a "hu(cid:173)
`manized'' antibody was constructed by
`Gcnentech scicntiM.s.[38) Denoted
`rhuMoAb HER2. 1his antibody con(cid:173)
`tained the antigen-binding portions of
`murine MoAb 405 (discussed above)
`and a human immunoglobulin variable
`region framework. rhuMoAb HER2 has
`potency comparable LO murine 405 in
`blocking the proliferation of breast car(cid:173)
`cinoma cells in vitro. Funhermore,
`rhuMoAb HER2 lgGI is much more
`eflic:ie111 in supponing antibody-depen(cid:173)
`dent cellular cytotoxicity. which could
`increase its antitumor ac1ivity.
`Initial phase I studies were conduct(cid:173)
`ed, and a phase JI study has rcctntly
`been completed in patients with meta(cid:173)
`stntic brea\t carcinomas O\crcxprcs.~ing
`HER2.j391 Forty-sL' patienL~ were Ln:<lt·
`ed with a loading dose of250 mg of IV
`rhuMoAb HER2. then with 10 '~eckJy
`dOSC!- of 100 mg each. Patient::. with no
`progression of disease at 1he completion
`of thi~ treauncnt period were offered a
`weekly maintenance phase of 100 mg.
`The study patients had extensive
`metastatic disease. and most had re-
`
`Add!'C'> :ill com:i.pondcncc 10:
`Jos~ B2>c:lga. MD
`Ho;pilnt Ge~rol Unh·c"it:iri Vall d'Hebron
`Pg. Vllll d'Hcbron 119-129
`080.15 Borcclona, SJ>'lm
`
`ceived extensive prior anticancer thera(cid:173)
`py. Adequate :serum levels of rhuMo(cid:173)
`Ab HER2 were obtained in 90% of the
`patients. The mean serum half-life of
`rhuMoAb HER2 was 8.3 ± 5.0 days.
`Interestingly, rhuMoAb HER2 serum
`half-life was found to be dependent on
`the presence of circulating p I 85111 ... 1 rc(cid:173)
`ceptor extracellular domain ECD"ER!re(cid:173)
`lcascd from the tumor into t