The role of h e r2-targeted therapies in women with

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1 PRACTICE GUIDELINE SERIES The role of h e r2-trgeted therpies in women with h e r2-overexpressing metsttic brest cncer S. Dent b s c m d,* Sh. Verm m d,* J. Ltreille m d, D. Ryson m d, M. Clemons m b b s m d, J. Mckey m d, Su. Verm m s e d m d, # J. Lemieux m s c m d,** L. Provencher m m d, S. Chi m d, B. Wng m s c, nd K. Pritchrd m d # ABSTRACT The role of trgeted therpies in the tretment of women with brest cncer hs been rpidly evolving. Trstuzumb, monoclonl ntibody ginst the humn epiderml growth fctor receptor 2 (h e r 2), ws the first h e r 2-trgeted therpy tht clerly demonstrted significnt clinicl benefit for women with h e r 2-overexpressing metsttic brest cncer (m b c). However, in recent yers it hs become incresingly pprent tht, when trstuzumb is used in the firstline setting in combintion with chemotherpy, most women eventully develop progressive disese. Determining the tretment options vilble to women who hve progressed while on trstuzumb therpy hs been hmpered by pucity of high-qulity published dt. In ddition, with the stndrd use of trstuzumb in the djuvnt setting (for eligible h e r 2-positive ptients), the role of nti-h e r 2 gents for ptients who experience brest cncer relpse hs become cliniclly relevnt question. This mnuscript reviews current vilble dt nd outlines suggestions from pnel of Cndin oncologists bout the use of trstuzumb nd other h e r 2-trgeted gents in two key m b c indictions: Tretment for women with h e r2-positive m b c progressing on trstuzumb (tht is, tretment beyond progression) Tretment for women with h e r2-positive m b c recurring following djuvnt trstuzumb (tht is, re-tretment) The suggestions set out here will continue to evolve s dt nd future trils with trstuzumb nd other h e r2-trgeted gents emerge. KEY WORDS Metsttic brest cncer, trstuzumb, tretment beyond progression, re-tretment, h e r2-trgeted therpy 1. INTRODUCTION The humn epiderml growth fctor receptor 2 (h e r 2) is trnsmembrne tyrosine kinse receptor protein tht is prt of the he r fmily of growth fctor receptors (h e r1 to h e r4). The h e r 2 receptor is involved in cell cell nd cell strom communiction, primrily through signl trnsduction involving the Rs/mitogen-ctivted protein kinse nd phosphtidylinositol 3 kinse (pi3k)/akt pthwys 1. These signls ultimtely promote cell prolifertion, survivl, nd motility. Amplifiction of the h e r 2/neu gene nd resulting overexpression of the h e r 2 protein occurs in pproximtely 20% of invsive primry brest cncers 2. The h e r 2 ltertion in erly-stge brest cncer is ssocited with more ggressive disese nd higher risk of relpse thn is seen with h e r 2-negtive cncers 3 7. Trstuzumb is monoclonl ntibody tht binds to the extrcellulr domin of h e r2. Severl mechnisms of ction underlie the ntitumour effects of trstuzumb. Trstuzumb blocks h e r2-ctivted cell signlling, thereby reducing cell prolifertion nd restoring bility to undergo poptosis by inhibiting the pi3k/akt pthwy 1,8,9,. The result is incresed cellulr sensitivity to chemotherpy nd rdiotherpy 10. Trstuzumb hs been shown to inhibit h e r 2- regulted ngiogenesis 8,11 13 nd, in preclinicl models, to recruit the immune system through ntibodydependent cellulr cytotoxicity, triggering ctivtion of nturl killer cell medited poptosis Trstuzumb hs lso been shown to prevent the formtion of p95 h e r 2 ( truncted ctive form of h e r 2), which my led to inhibition of tumour development 8,17. Migliccio I, Gutierrez MC, Wu MF, et l. PI3 kinse ctivtion nd response to trstuzumb or lptinib in h e r-2 overexpressing loclly dvnced brest cncer (l b c). Presented t the 31st Annul Sn Antonio Brest Cncer Symposium; Sn Antonio, TX; December 10 14, Copyright 2009 Multimed Inc. 25

2 DENT et l. In pivotl first-line metsttic brest cncer (m b c) trils (Tble i), the ddition of trstuzumb to stndrd systemic chemotherpy tretment resulted in significntly improved time to disese progression, improved response rtes, nd n overll survivl benefit (s compred with chemotherpy lone) Consequently, single-gent trstuzumb following chemotherpy or trstuzumb in combintion with chemotherpy is now considered stndrd tretment for m b c ptients who overexpress h e r 2. In clinicl prctice, trstuzumb is usully continued until disese progression. There is considerble controversy regrding the potentil clinicl benefit of continuing trstuzumb fter relpse tht is, therpy beyond disese progression s component of second nd subsequent lines of systemic therpy. As well, with the pprovl nd widespred incorportion of trstuzumb s component of djuvnt systemic therpy for h e r2-positive erly-stge brest cncers (stges i iii), uncertinty remins regrding the potentil role of trstuzumbbsed therpy upon relpse. Dt regrding these two clinicl questions remin limited nd primrily consist of nonrndomized retrospective (Level 3) evidence. The gol of the present pper is to review the current evidence nd to outline suggestions from pnel of Cndin oncologists regrding the use of trstuzumb nd other h e r 2-trgeted therpies in two key m b c ptient indictions: Tretment for women with h e r2-positive m b c progressing on trstuzumb (tht is, tretment beyond progression) Tretment for women with h e r2-positive m b c recurring following djuvnt trstuzumb (tht is, re-tretment) 2. DEVELOPMENT OF PANEL SUGGESTIONS The uthors of this pper met in Toronto for one-dy conference in June The pnel reviewed results of the ltest trils evluting trstuzumb nd other h e r2-trgeted gents in the neodjuvnt, djuvnt, nd metsttic settings. Bsed on tril informtion, suggestions were formulted for ech setting. For m b c, drft mnuscript reviewing the current vilble dt nd outlining the suggestions from the pnel ws initilly written by medicl writer (BW) nd ws reviewed nd revised by four min pnel members (SD, KP, ShV, nd JL). The finl mnuscript ws pproved by the remining seven pnel members (JM, SuV, DR, SC, MC, JL, nd LP). Published nd presented clinicl trils results (vilble s of Mrch 2009) were incorported into the present document. Support for the initil meeting of the Cndin dvisory pnel nd the development of the present mnuscript ws provided by n unrestricted eductionl grnt from Hoffmnn L Roche Cnd. The uthors received n honorrium for ttending the meeting, but not for writing the mnuscript. The uthors re solely responsible for the content of the mnuscript, with no restrictions set by the sponsor. 3. TRIALS IN MBC Two mjor pivotl trils involving more thn 650 women with h e r2-positive m b c hve exmined the t b l e i Efficcy results from pivotl first-line metsttic brest cncer trils Clinicl endpoint Trstuzumb AND [pclitxel OR (nthrcycline AND cyclophosphmide)] Tril rms Slmon et l., (n=469) Pclitxel OR (nthrcycline AND cyclophosphmide) Tril rms Mrty et l., 2005 nd ,20 (n=186) Trstuzumb AND docetxel Medin o r r (%) p<0.001 p= Docetxel lone Medin d r (months) p<0.001 p=0.009 Medin t t p (months) p<0.001 p= Medin o s (months) p=0.046 p= Tril survivl results were updted t the 2006 Sn Antonio Brest Cncer Symposium. The superior survivl benefit for trstuzumb plus docetxel over docetxel lone ws mintined (31.2 months vs months); however, the survivl difference ws no longer significnt (p = ), perhps becuse most of the ptients rndomized to docetxel lone (57%) subsequently crossed over to receive trstuzumb. o r r = objective response rte; d r = durtion of response; t t p = time to progression; o s = overll survivl. 26

3 role of trstuzumb in combintion with systemic chemotherpy s compred with chemotherpy lone in the first-line setting In both studies, lthough different chemotherpeutic regimens were used, the ddition of trstuzumb, s compred with chemotherpy lone, significntly prolonged time to disese progression, incresed response rte, prolonged durtion of response, nd incresed overll survivl benefit (Tble i). Severl smll, retrospective cse cohort studies hve exmined the role of continuing trstuzumb beyond progression in second- nd subsequent-line therpy with vrious chemotherpy prtners. Overll response rtes rnged from 18% to 50% in the second line, 14.3% to 38.1% in the third line, 19.2% to 20% in the fourth line, nd less thn 10% in fifth-line trstuzumb-bsed regimens. Time to progression ws reported s months in the second line, months in the third line, months in the fourth line, nd pproximtely 4 months in fifth-line trstuzumb-bsed regimens (Tble ii) Similr results of continuing trstuzumb with vrious chemotherpy prtners beyond progression in women with mbc hve been observed in prospective phse ii trils, lthough dt remin limited. Across studies, overll response rtes of 11% 50% tble ii Response rtes of trstuzumb in combintion with chemotherpy in women with metsttic brest cncer progressing on trstuzumb: retrospective nd cse cohort studies Reference Ptients Therpy line (n) Second Third Fourth Fifth o r r ttp o r r ttp o r r ttp o r r ttp (%) (months) (%) (months) (%) (months) (%) (months) Tokjuk et l., (docetxel, vinorelbine, cispltin, cpecitbine, etoposide, gemcitbine, nd trstuzumb) Stemmler et l., (txne, vinorelbine, or other chemotherpy, nd trstuzumb) Gelmon et l., (txne, or vinorelbine nd trstuzumb, or trstuzumb lone) Grcí-Sénz et l., (2nd line) b n r 21 (3rd line) 10 (4th line) (chemotherpy nd trstuzumb) Metro et l., (2nd line) (3rd line) 9 (4th line) (chemotherpy nd trstuzumb) Fountzils et l., (2nd line) (3rd line) 26 (4th line) 12 (5th line) (vinorelbine or gemcitbine nd trstuzumb) Admo et l., (2nd line) c 9 (3rd line) (vinorelbine, txne, pegylted liposoml doxorubicin, or gemcitbine nd trstuzumb) Montemurro et l., (vinorelbine, txnes, liposoml doxorubicin, cpecitbine, letrozole, or tmoxifen nd trstuzumb) Fbi et l., (chemotherpy nd trstuzumb) Those who received trstuzumb tretment beyond progression (in the second line, unless otherwise stted). b Stble disese 60%. c Reported for third-line tretment nd beyond. o r r = overll response rte; t t p = time to progression; n r = not reported. 27

4 DENT et l. were observed fter second-line trstuzumb-bsed regimen, with greter thn 60% response rte observed with one third-line trstuzumb-bsed regimen (Tble iii). Time to progression rnged from 6 months to 8 months in second-line nd 9 months in third-line trstuzumb-bsed regimens (Tble iii) The French Hermine tril, prospective observtionl study in women who hd h e r2-positive m b c, contributed intriguing survivl dt in the setting of progression 37,38. A totl of 623 ptients were enrolled, of whom 221 (cohort A) received first-line trstuzumb-bsed therpy (tht is, with pclitxel, docetxel, vinorelbine, or cpecitbine) nd 117 (cohort B) received trstuzumb-bsed therpy s prt of second-line tretment 38. After 2 yers of follow-up, significntly longer overll survivl ws observed in ptients treted with first-line trstuzumb (cohort A) s compred with those who discontinued trstuzumb fter initil progression (Tble iv). For ptients who continued trstuzumb s component of second-line therpy (cohort B), overll survivl from the first trstuzumb tretment ws gin longer thn it ws in ptients who discontinued trstuzumb (Tble iv). Given the nonrndomized nture of the t b l e iii Response rtes for trstuzumb in combintion with chemotherpy in women with metsttic brest cncer progressing on trstuzumb, prospective phse ii trils Reference Ptients Therpy line (n) Second Third o r r ttp o r r ttp (%) (months) (%) (months) Tripthy et l., (chemotherpy nd trstuzumb) Morbito et l., (vinorelbine, gemcitbine, nd trstuzumb) Orlndo et l., (cyclophosphmide, methotrexte, nd trstuzumb) Del Binco et l., (2nd line) (3rd line) (chemotherpy nd trstuzumb) Brtsch et l., b 8 b (cpecitbine nd trstuzumb) Bchelot et l., (vinorelbine nd trstuzumb) Modi et l., (tnespimycin nd trstuzumb) Those who received trstuzumb tretment beyond progression (in the second line, unless otherwise stted). b Reported for second-line tretment nd beyond. o r r = overll response rte; t t p = time to progression. t b l e iv Summry of efficcy dt from French Hermine cohort study 38 Efficcy endpoint Continued trstuzumb (n=107) First (n=177 ) Discontinued trstuzumb (n=70) Therpy line Continued trstuzumb (n=87) Second (n=117) Discontinued trstuzumb (n=30) Medin o s (months) From initition of trstuzumb Not reched b From dte of progression o s t 2 yers (%) From initition of trstuzumb Follow-up dt re vilble for only 177 of the 221 ptients who received first-line trstuzumb-bsed therpy. b After medin follow-up of 27.8 months. o s = overll survivl. 28

5 study nd the potentil bises involved in the selection of ptients who received second-line therpy, the foregoing results must be interpreted with cution. It is fesible tht underlying ptient chrcteristics could hve contributed to the observed improvement in overll survivl in ptients who were ble to continue to receive trstuzumb therpy t the time of disese progression. 3.1 Rndomized Clinicl Trils A recently published study ddressed the question of continuing trstuzumb beyond progression fter first-line tretment 39 (Tble V). This prospective phse iii tril compred cpecitbine plus trstuzumb with cpecitbine lone in ptients with loclly dvnced or metsttic brest cncer with disese progression during trstuzumb tretment. Ptients could hve received up to one prior chemotherpy regimen for m b c. Ptients were required to be trstuzumb-free for fewer thn 6 weeks, to hve been tking trstuzumb for t lest 12 weeks, nd to hve bseline left ventriculr ejection frction of 50% or better. A totl of 156 (of plnned 482) ptients were ccrued. During the recruitment phse of the study, lptinib ws registered by the U.S. Food nd Drug Administrtion for the indictions being tested, nd on the dvice of the Independent Dt Monitoring Committee, this study ws terminted premturely. The primry objective ws time to progression; secondry objectives were sfety, objective response rtes, clinicl benefit rtes, nd overll survivl 39. Ptients received cpecitbine (2500 mg/m 2 ) for 14 dys of 21-dy cycle, nd trstuzumb (6 mg/kg) ws dministered in 3-week cycles. Compred with cpecitbine lone, the ddition of trstuzumb to cpecitbine resulted in significnt improvements in time to progression (8.2 months vs. 5.6 months; hzrd rtio: 0.69; 95% confidence intervl: 0.48 to 0.9; p = ), with significnt improvements in overll response rtes (48.1% vs. 27.0%, p = ) nd clinicl benefit rte (75.3% vs. 54.0%, p = ). Medin overll survivl ws not sttisticlly different (25.5 months vs months, p = 0.257). No unexpected toxicities were observed. In the trstuzumb-contining rm, single cses of congestive hert filure, tchyrrhythmi, hypertension, nd drop to below 40% or 10% decline from bseline in left ventriculr ejection frction were observed. 3.2 Other Trgeted Strtegies for Tretment Beyond Progression A number of other gents trgeting h e r2 nd other members of the epiderml growth fctor receptor fmily hve been evluted s single gents or in combintion with other chemotherpy prtners. These include lptinib nd pertuzumb. The role of lptinib, tyrosine kinse inhibitor tht inhibits both h e r1 nd h e r2, ws investigted in prospective rndomized phse iii clinicl tril. Women with her2-positive mbc who hd progressed on trstuzumb (n = 324) nd who hd received nthrcyclines nd txnes, were rndomized to receive cpecitbine lone (2500 mg/m 2 dys 1 14, every 3 weeks) or cpecitbine (2000 mg/m 2 dys 1 14, every 3 weeks) with lptinib (1250 mg/m 2 twice dily, dys 1 14, every 3 weeks) 40,41. The primry endpoint ws time to progression. Secondry endpoints included progression-free survivl, overll survivl, clinicl benefit, prtil response rte, nd sfety. Women ssigned to the combintion rm experienced significntly longer time to progression (27 weeks vs. 19 weeks, p = ) thn did those tking cpecitbine lone. Overll response rtes were higher in the combintion rm (24% vs. 14%, p = 0.017). The hzrd rtio for overll survivl in the combintion rm (versus cpecitbine lone) ws 0.78 (95% confidence intervl: 0.55 to 1.12; p = 0.177; Tble v i). Bsed on these dt, the combintion of lptinib with cpecitbine ws t b l e v Summry of efficcy dt from the Germn Brest Group 26 tril Clinicl endpoint Tril rms von Minckwitz et l., (n=152) Trstuzumb AND cpecitbine Cpecitbine lone ttp (months) 8.2 p= o r r (%) 48.1 p= c b r (%) 75.3 p= os (months) 25.5 p= t t p = time to progression; o r r = overll response rte; c b r = clinicl benefit rte; o s = overll survivl. t b l e v i Summry of efficcy dt from trils by Geyer et l. Clinicl endpoint Tril rms Geyer et l., 2006 nd ,41 (n=324) Lptinib AND cpecitbine Cpecitbine lone t t p (weeks) p= pfs (%) 8.4 p< o r r (%) 24 p= c b r (%) n r os (months) nr nr p=0.177 Bsed on updted dt presented in t t p = time to progression; pfs = progression-free survivl; o r r = objective response rte; c b r = clinicl benefit rte; n r = not reported; o s = overll survivl. 29

6 DENT et l. pproved by the U.S. Food nd Drug Administrtion for ptients with dvnced or metsttic h e r2-positive brest cncer who hve received prior therpy with n nthrcycline, txne, nd trstuzumb. Lptinib ws recently pproved by Helth Cnd (My 14, 2009) nd is indicted in combintion with cpecitbine for the tretment of ptients with dvnced or metsttic brest cncer whose tumours overexpress h e r2. Eligible ptients should hve progressed on txnes, nthrcyclines, nd trstuzumb before the strt of the lptinib nd cpecitbine combintion. Helth Cnd pprovl ws bsed on improvement in time to progression; no significnt improvement in overll survivl ws observed. O Shughnessy et l. exmined trstuzumb nd lptinib combintions versus lptinib lone in women with hevily pretreted h e r2-positive m b c (n = 296) progressing on trstuzumb therpy. The primry endpoint ws progression-free survivl; the secondry endpoints were clinicl benefit rte t 24 weeks, response rte, nd overll survivl. Ptients in the intent-to-tret popultion who received combintion therpy experienced significntly longer medin progression-free survivl (12.0 weeks vs. 8.4 weeks, p = 0.029) nd significntly better clinicl benefit rte (25.2% vs. 13.2%, p = 0.02). The differences in response rte (10.3% vs. 6.9%, p = 0.46) nd medin overll survivl time (51.6 weeks vs weeks, p = 0.106) were not sttisticlly significnt 42. Pertuzumb, nother humnized monoclonl ntibody developed to trget different domin of the h e r2 receptor, hs been studied in combintion with trstuzumb for ptients with h e r2-positive m b c nd disese progression on, or subsequent to, trstuzumb therpy with two or more prior chemotherpy regimens In phse ii open-lbel single-rm study, clinicl benefit rte of 50.0% nd n objective response rte of 24.2% (including 16.7% prtil response nd 7.6% complete response) were observed in 66 evluble ptients 46. No cliniclly significnt crdic events were observed. 3.3 MBC After Adjuvnt Trstuzumb (Re-tretment) There re currently no published clinicl trils to guide clinicins in the mngement of women with h e r2- positive mbc who relpse fter receiving djuvnt trstuzumb. A number of ctively recruiting phse ii nd iii studies re ddressing this importnt clinicl issue. The r h e (Retretment After Herceptin Adjuvnt) study is nonrndomized phse ii tril tht is exmining the efficcy of trstuzumb therpy lone (cohort A) or with docetxel or pclitxel (cohort B) in ptients who hve relpsed 6 months or more fter completion of t lest 10 months of djuvnt trstuzumb. The choice of cohort will be mde for ech ptient by the investigtor, in ccordnce with the investigtor s clinicl prctice. The plnned size for ech cohort is 40 ptients 47. Three ongoing phse iii trils re evluting first-line systemic therpy regimens for women with h e r2-positive m b c who my or my not hve received djuvnt trstuzumb. Although these trils do not specificlly ddress the potentil benefit of the ddition of trstuzumb to the chemotherpy regimen (versus the bsence of trstuzumb), the results of such studies my provide some insight into the role of trgeted therpy in this setting. The cleoptr tril is exmining the efficcy nd sfety of trstuzumb nd docetxel with or without pertuzumb s first-line chemo-biologic therpy in ptients with h e r2-positive m b c, with disese-free intervl of 12 months or more fter djuvnt trstuzumb. The primry endpoint is progression-free survivl; secondry endpoints re overll survivl, response rte, nd sfety. The trgeted smple size is The v e r e l tril is designed to ssess the efficcy nd sfety of first-line trstuzumb nd docetxel with or without bevcizumb in ptients with h e r2-positive loclly recurrent or metsttic brest cncer who hve not received prior chemotherpy or rdiotherpy for their metsttic disese. Ptients will be strtified by prior djuvnt nd neodjuvnt txne chemotherpy nd prior djuvnt trstuzumb therpy. Ptients will be strtified by prior djuvnt or neodjuvnt txne chemotherpy nd prior djuvnt trstuzumb therpy. Ptients must hve completed djuvnt trstuzumb therpy 6 months or more before enrolment. The primry endpoint is progression-free survivl; secondry endpoints re overll survivl, overll response, durtion of response, time to tretment filure, qulity of life, nd sfety. The trget smple size is The m.31 (c o m p l e t e) tril being undertken by the Ntionl Cncer Institute of Cnd Clinicl Trils Group is n interntionl phse iii tril exmining the efficcy nd sfety of first-line txne-bsed chemotherpy combined with lptinib (or trstuzumb) in ptients with h e r2-positive metsttic disese. Ptients re required to hve hd t lest 12-month intervl from prior chemotherpy or h e r2-trgeted therpy in the djuvnt or neodjuvnt setting. The primry endpoint is progression-free survivl; secondry endpoints include overll survivl, incidence rtes of nd time to centrl nervous system metstses t the time of progression, overll response rte, clinicl benefit response rte, dverse event profile, qulity of life, clinicl outcomes using biomrkers, nd helth economics (including helthcre utiliztion nd helth utilities). The trget smple size is Other Trgeted Therpies A vriety of other novel trgeted therpies re currently under investigtion in women with h e r2-overexpressing m b c who my hve received djuvnt trstuzumb-bsed therpy (tht is, those who present with de novo metsttic disese) or for women who hve progressed while receiving trstuzumb-bsed therpy 30

7 for metsttic disese (second- or subsequent-line setting). In phse ii tril, trstuzumb-mcc -dm1, toxinconjugted version of trstuzumb 51, ppers to offer improved efficcy nd reduced toxicity over unconjugted trstuzumb in hevily pre-treted ptients 52. An ongoing phse iii tril is currently evluting trstuzumb-m c c -d m1 in comprison with the combintion of cpecitbine nd lptinib in ptients with h e r2- positive loclly dvnced or metsttic brest cncer who hve received prior trstuzumb-bsed therpy 53. The mmmlin trget of rpmycin, mt o r, is centrl regultor of G1 cell-cycle protein synthesis tht precedes commitment to norml cellulr repliction. Inhibition of mt o r hs been shown to hve ntiprolifertive ctivity in brest cncer by deregultion of the pi3k/akt pthwy One mt o r inhibitor, deforolimus, is now being tested in combintion with trstuzumb in single-rm phse ii tril involving h e r 2-positive trstuzumb-refrctory m b c ptients. For eligible ptients, t lest 4 weeks must hve elpsed since erlier investigtionl therpy, chemotherpy, or rdiotherpy 57. The t r io-018 interntionl phse iii study is evluting the ddition of everolimus (or plcebo) to stndrd trstuzumb nd weekly pclitxel in the tretment of h e r 2-positive dvnced brest cncer 58. Histone decetylse is nother nticncer trget tht controls gene expression through trnscription regultion 59,60. Pnobinostt, n inhibitor of histone decetylse 61, is being studied in single-rm phse iib/ii tril in combintion with trstuzumb for h e r 2-positive m b c ptients who hve progressed during or fter trstuzumb tretment 62. Pnobinostt is lso being studied s monotherpy in the t r io-016 study 63. Het shock protein 90 (Hsp90) is chperone protein tht enbles cncer cell survivl 64. The Hsp90 inhibitor IPI-504 is being investigted in singlerm phse ii tril in combintion with trstuzumb for ptients with pretreted, loclly dvnced, or metsttic h e r2-positive brest cncer. Ptients must hve received t lest two erlier regimens, with trstuzumb being component in t lest one (not including djuvnt regimens, unless progression on djuvnt tretment occurred) 65. The selective ngiopoietin 1 nd 2 neutrlizing peptibody AMG 386 inhibits ngiogenesis by preventing interction of ngiopoietins with Tie2 receptors 66. This gent is currently being studied in phse i setting combining esclting doses of AMG 386 with pclitxel nd trstuzumb, nd esclting doses of AMG 386 with cpecitbine nd lptinib DISCUSSION 4.1 Tretment Beyond Progression Although retrospective cse cohort nd prospective phse ii clinicl trils (Level 3 evidence) hve demonstrted sfety nd suggested possible clinicl benefit from the continution of trstuzumb beyond progression fter first-line therpy in women with h e r 2-positive m b c, it hs been impossible to support the use of this strtegy without higher qulity (Level 1) evidence. The uncertinty of this therpeutic pproch hs been compounded by lck of understnding of the mechnism of resistnce to trgeted therpies in h e r 2-positive m b c. At the present time, good definition of resistnce from mechnistic point of view is not vilble, leving prctitioners to rely on clinicl definition bsed on disese progression in reltion to the trgeted therpy. This re remins one of ctive, ongoing reserch. The prospective rndomized controlled tril conducted by the Germn Brest Group (g b g 26) demonstrted the clinicl benefit of continuing trstuzumb with nother chemotherpy prtner (time to progression: 8.2 months vs. 5.6 months) 39. The bsence of n overll survivl dvntge should not be deterrent to the use of trstuzumb beyond first-line progression, becuse time to progression is n endpoint worthy of considertion. In ddition, given tht g b g 26 ws premturely stopped nd tht the trgeted smple size ws not reched, it is possible tht the study ws underpowered to detect survivl difference. Two rndomized phse iii trils hve exmined the role of combining (lptinib trstuzumb) or switching (trstuzumb to lptinib plus cpecitbine) trgeted therpies in women with h e r 2-positive m b c. Although these two studies do not directly ddress the question of continuing trstuzumb beyond progression (no rm without trstuzumb), the results support the contention tht, in this popultion, continuing n nti-h e r 2 trgeted therpy my be resonble. Pnel Suggestion: It is highly unlikely tht dditionl studies exmining the specific role of trstuzumb combined with second-line chemotherpy will be forthcoming for women with h e r2-positive m b c who hve progressed on trstuzumb. The vilble evidence, including dt from prospective rndomized controlled trils, seems to support the continution of h e r2-trgeted therpy with trstuzumb or with lptinib in combintion with cpecitbine. Despite these pnel suggestions, the modest clinicl benefits observed with this pproch should encourge further reserch nd prticiption in clinicl trils for this ptient popultion. 4.2 Re-tretment No rndomized clinicl dt support the use of trstuzumb or other nti-h e r2 therpies in women with h e r2-positive m b c who hve received trstuzumb in the djuvnt setting. Severl clinicl trils re currently ddressing this importnt clinicl issue. 31

8 DENT et l. Pnel Suggestion: In the bsence of dt, nd given the benefits seen in mbc ptients who continue trstuzumb beyond progression, it would seem resonble to consider re-tretment for ptients exposed to djuvnt trstuzumb who hve relpsed 6 months or more fter djuvnt therpy. Prticiption in clinicl trils for this ptient popultion is encourged. 5. CONCLUSIONS The uthors of this mnuscript developed tretment suggestions bsed on review of the literture regrding tretment options for women with h e r2-positive m b c. The role of trgeted therpies in this ptient popultion will continue to evolve with the completion nd publiction of ongoing clinicl trils. 5.1 Dte of Author Suggestions The pnel suggestions were completed in Mrch REFERENCES 1. Ykes FM, Chinrtnlb W, Ritter CA, King W, Seelig S, Arteg CL. Herceptin-induced inhibition of phosphtidylinositol-3 kinse nd Akt is required for ntibody-medited effects on p27, cyclin D1, nd ntitumor ction. 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Proc Am Soc Clin Oncol 2007;25:. [Avilble online t: org/ascov2/meetings/abstrcts?&vmview=bst_detil_view &confid=47&bstrctid=32524; cited June 30, 2009] 67. United Sttes, Ntionl Institutes of Helth, CliniclTrils.gov. Sfety study of AMG 386 to tret h e r2-positive loclly recurrent or metsttic brest cncer [Web pge]. Bethesd, MD: CliniclTrils.gov; [Avilble t: ct2/show/nct ; cited: My 6, 2009] Correspondence to: Susn Dent, The Ottw Hospitl Cncer Centre, Generl Division, 501 Smyth Rod, Ottw, Ontrio K1H 8L6. E-mil: [email protected] * The Ottw Hospitl Cncer Centre nd University of Ottw, Ottw, ON. Réseu Cncer Montérégie nd Université de Sherbrooke, Longueuil, QC. Atlntic Clinicl Cncer Reserch Unit nd QEII Cncer Cre Progrm, Hlifx, NS. Princess Mrgret Hospitl, Toronto, ON. Cross Cncer Institute, University of Albert, Edmonton, AB. 34

11 # Sunnybrook Odette Cncer Centre nd University of Toronto, Toronto, ON. ** Centre de Recherche du Centre Hospitlier ffilié universitire de Québec, Quebec City, QC. Hôpitl du Sint-Screment, Quebec City, QC. British Columbi Cncer Agency Vncouver Centre, Vncouver, BC. Remedy Communictions Limited, Toronto, ON. 35