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Emerging Agents in the Treatment ofAnthracycline- and Taxane-Refractory Metastatic

Breast Cancer

Windy Dean-Colomb and Francisco J. Esteva

Despite the recent trend toward treatment of early stage breast cancer aggressively with anthra-cyclines and taxanes, nearly half of those women will have metastatic recurrence. Moreover,because of the increasing prior exposure to these drugs, far more women facing first-line therapyfor recurrent disease will now have developed anthracycline- and taxane-refractory metastaticbreast cancer (ATRMBC), presenting a major therapeutic challenge. A number of established drugsare showing promise in this setting: capecitabine alone or combined with lapatinib; gemcitabine;vinorelbine; and oxaliplatin. At the same time, a variety of new drugs are emerging for potential usein ATRMBC. Among the drugs in clinical development that have shown promising activity includenovel classes of compounds (camptothecins and epothilones), newer members of establishedclasses (pemetrexed and vinflunine), and agents with novel mechanisms of action (the mitosisinhibitor E7389 and the ascidian-derived anticancer compound trabectedin). Several molecularlytargeted agents are also being evaluated in ATRMBC, including interleukin-2 receptor–bindingdenileukin diftitox, and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which inhibits theprotein chaperone heat shock protein 90.Semin Oncol 35 (Suppl 2):S31-S38 © 2008 Elsevier Inc. All rights reserved.

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reast cancer accounts for approximately 25% ofall new cancer cases diagnosed in the UnitedStates each year, with an estimated incidence of

82,460 for 2008.1 Over the past several years, thereas been a shift in the treatment of early stage breastancer, with much more aggressive treatment adminis-ered in the neoadjuvant and adjuvant settings. Adju-ant chemotherapy can decrease the risk of relapseoth in node-positive and node-negative breast cancer.nthracycline- and taxane-based chemotherapy (either

n combination or sequentially) are the mainstay for thereatment of these patients in the adjuvant setting.

Despite the appropriate use of effective local anddjuvant systemic treatments, approximately 40% ofomen with stage II/III breast cancer develop meta-

tatic disease. Many of these patients have already re-eived adjuvant anthracycline and taxane chemother-py, resulting in presentation of more patients with

he University of Texas MD Anderson Cancer Center, Houston, TX.rs Dean-Colomb and Esteva have no relevant relationships with com-mercial interests to disclose.

ddress correspondence to Francisco J. Esteva, MD, The University ofTexas MD Anderson Cancer Center, Houston, TX 77030; e-mail:festeva@mdanderson.org

270-9295/08/$ - see front matter2008 Elsevier Inc. All rights reserved.

(oi:10.1053/j.seminoncol.2008.02.008

eminars in Oncology, Vol 35, No 2, Suppl 2, April 2008, pp S31-S

nthracycline- and taxane-refractory/resistant meta-tatic breast cancer (ATRMBC). This has created a greathallenge for oncologists, as these patients have fewreatment options, particularly if the tumor is negativeor estrogen receptor, progesterone receptor, and hu-an epidermal growth factor receptor (HER)2 (the

o-called “triple negative” subtype). Significant effortsave been focused on the development of new agentso treat patients who have developed ATRMBC. Numer-us studies have evaluated various agents in eithernthracycline-refractory or taxane-refractory metastaticreast cancer, but only a few have involved patientsith both. As the survival of patients with metastaticreast cancer continues to improve,2 the developmentf novel agents for patients with ATRMBC will be

ncreasingly important.

GENTS CURRENTLY IN USE IN THEREATMENT OF ANTHRACYCLINE- ANDAXANE-REFRACTORY METASTATIC BREASTANCER

apecitabine

Capecitabine (Xeloda; Roche, Nutley, NJ) is an oraluoropyrimidine prodrug that is enzymatically con-erted to 5-fluorouracil (5FU) in a three-step process

Fig 1). The final conversion requires thymidine phos-

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horylase, an enzyme that is highly active in cancerells, thus permitting preferential accumulation of 5FUn these cells. Capecitabine was approved by the USood and Drug Administration (FDA) for the treatmentf metastatic breast cancer on the basis of phase II trialshat showed objective responses in patients withTRMBC.

The pivotal study conducted in the United Statesncluded 135 women with advanced breast cancer whoad received prior anthracycline and taxane chemo-herapy. An overall response rate (ORR) of 20% wasbserved with a median overall survival (OS) of 12.8onths and median time to disease progression (TTP)

f 93 days.3 These results were supported by a similarulticenter, phase II study involving 126 patients with

igure 1. Chemical structure of some common chemo-herapeutic agents used in the treatment of ATRMBC.

nthracycline- and taxane-pretreated metastatic breast n

ancer treated with capecitabine (1,250 mg/m2 twiceaily for 14 days followed by 7 days of rest). An ORR of8% was observed with a median OS of 15.2 months.4

n both of these studies, capecitabine was well toler-ted, with the most common treatment-related adversevent being hand-foot syndrome, followed by diarrhea,ausea, and vomiting. Based on these results, in anffort to improve upon the activity seen with capecit-bine monotherapy, capecitabine has been used inombination with multiple other agents that have pre-iously shown at least modest activity as single agentsn the treatment of metastatic breast cancer.5-7

A randomized phase III clinical trial showed that aombination of capecitabine and lapatinib (Tykerb;laxoSmithKline, Philadelphia, PA) was superior toapecitabine alone in patients with HER2-overex-ressing metastatic breast cancer who had beenreviously treated with an anthracycline, a taxane,nd trastuzumab.8 This study led to the approval ofapatinib for patients with HER2-overexpressingTRMBC. A similar approach was taken with bevaci-umab (Avastin; Genentech, San Francisco, CA), aonoclonal antibody that targets vascular endothe-

ial growth factor. However, the addition of bevaci-umab to capecitabine did not improve TTP com-ared with capecitabine alone in patients withTRMBC.9

Overall, capecitabine has shown remarkable efficacyn a patient population with relatively poor prognosis.ts favorable toxicity profile, as noted by minimal my-losuppression and alopecia, along with its synergisticctions with a wide range of other antitumor agents,as cemented its use as first-line therapy for ATRMBC.

emcitabine

Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) is ayrimidine antimetabolite that interferes with DNAynthesis (Fig 1). It requires intracellular metabolism toorm its active metabolite. Several studies have shownts utility in the treatment of metastatic breast cancer,oth as a single agent and in combination with othergents. Overall, almost 90 clinical trials have been per-ormed assessing the efficacy of gemcitabine in meta-tatic breast cancer, including four randomized phaseII trials.10 However, only six clinical trials have evalu-ted gemcitabine alone or in combination therapy forse in ATRMBC.

Three phase II studies have evaluated gemcitabineonotherapy in ATRMBC. Two of the studies, involv-

ng 64 patients, showed favorable results, with ORRsanging between 17% and 20%, median duration ofesponse of 9 months, and median OS of 9.5 and 11onths.11,12 However, in one study, no objective re-

ponse was observed.13 Favorable responses have alsoeen reported when gemcitabine was used in combi-

ation with other chemotherapeutic agents such as

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isplatin, vinorelbine, and 5FU in patients withTRMBC.14-16

A randomized phase III trial involving 252 womenith ATRMBC showed an improved TTP with the com-ination of gemcitabine plus vinorelbine versus vi-orelbine alone. In this study, patients were randomlyssigned gemcitabine (1,200 mg/m2) plus vinorelbine30 mg/m2), both on days 1 and 8, or single-agentinorelbine (30 mg/m2, days 1 and 8). ORRs were 36%or patients assigned gemcitabine plus vinorelbine and6% for those assigned vinorelbine (P � .093), withedian progression-free survival (PFS) of 6.0 months

nd 4.0 months, respectively (P � .0028). However,hese findings did not translate into a difference inedian OS (15.9 v 16.4 months, respectively; P �

8046). Grade 3/4 neutropenia was reported in 61% ofhe patients receiving gemcitabine plus vinorelbine,ompared with 55% of those assigned vinorelbinelone (P � .0074).16

inorelbine

Vinorelbine (Navelbine; GlaxoSmithKline) is a semi-ynthetic vinca alkaloid (Fig 1). It induces cytotoxicityy inhibiting microtubule assembly. Its efficacy inTRMBC has been documented in several phase IItudies as a single agent. In one phase II trial, patientsith metastatic breast carcinoma who had experi-

nced progression despite anthracyclines and taxanesere treated with vinorelbine (initial dose 30 mg/m2/eek with decrease to 25 mg/m2 if needed). Objective

esponses were observed in 10 of 40 patients (25%),ith a median TTP of 6 months for responding patients

nd median OS of 6 months.17 Because of its modestyelotoxic effects, vinorelbine is most often used in

ombination with other agents with less myelotoxicity.everal small clinical trials showed objective responsessing a combination of vinorelbine with cisplatin inatients with ATRMBC.18,19 However, this combination

s associated with significant toxicity.

latinum Compounds

The efficacy of cisplatin and carboplatin in patientsith unselected ATRMBC is less than 10%.20 Interest-

ngly, however, platinum compounds may have a rolen specific types of breast cancer. In the first phase IIrial of trastuzumab in combination with chemother-py, cisplatin was chosen based on preclinical datandicating that cisplatin with HER2 monoclonal anti-ody resulted in synergistic response in the treatmentf patients with refractory metastatic breast cancer thatverexpressed HER2/neu.21 However, a randomizedhase III trial recently showed that a combination ofocetaxel, trastuzumab, and carboplatin was not supe-ior to the doublet docetaxel/trastuzumab.22

Nevertheless, a role for platinum compounds has

lso been postulated in the treatment of triple-negative e

reast cancer, particularly in patients with BRCA1/2utations. This is based on the premise that patientsith BRCA1/2 mutations already have impaired DNA

epair, thus the use of DNA-damaging agents (such aslatinum compounds) should result in more effectiveilling of these breast cancer cells. Carboplatin is cur-ently being studied in patients with triple-negativeTRMBC in combination with the anti-epidermalrowth factor receptor (EGFR) monoclonal antibodyetuximab.

Newer platinum agents are also being evaluated forse in the treatment of breast cancer. Oxaliplatin is aiaminocyclohexane platinum compound that binds toNA, halting replication and transcription, resulting inventual cell death (Fig 1). As with other agents, it haseen studied as both a single agent and in combinationith other cytotoxic agents in the treatment ofTRMBC. Additive or synergistic effects have been re-orted when it has been used in combination regi-ens. Four phase II trials have examined the efficacy of

xaliplatin in patients with ATRMBC.Two trials examined oxaliplatin with 5FU (N �

10), with ORRs ranging from 27% to 34%, a medianTP of 4.8 to 5.3 months, and median OS of 11.9 to2.3 months.23,24 When oxaliplatin (130 mg/m2, day 1)as combined with only vinorelbine (24 mg/m2 day 1

nd 8, N � 41), an ORR of 26.8% was observed. Medianollow-up was 15.9 months, median TTP was 3.4onths, and estimated OS was 12.7 months. Thirty-

hree patients (79%) developed grade 3/4 neutropenia,nd three patients had severe constipation requiringospitalization.25 When oxaliplatin was used in tripleherapy with 5FU and vinorelbine (N � 46), slightlyigher results were observed, with an ORR of 34.8%,edian TTP of 5.7 months, and estimated OS of 18.8onths.26

Based on these studies, oxaliplatin when used inombination with other chemotherapeutic agentseems to provide favorable efficacy in the treatmentf ATRMBC. However, randomized trials confirminghese findings are needed to support the addition ofxaliplatin to standard therapeutic regimens for thisopulation.

Agents currently in use in the treatment of ATRMBCre summarized in Table 1.3-7,9,11-19,23-26

MERGING AGENTS IN THE TREATMENT OFNTHRACYCLINE- AND TAXANE-REFRACTORYETASTATIC BREAST CANCER

amptothecins

Irinotecan (CPT-11), a camptothecin derivative, is arodrug that is metabolized by carboxylesterase to

orm SN-38, its active metabolite. SN-38 then binds toopoisomerase 1-DNA complex thereby stabilizing it,

ventually resulting in permanent single- and double-

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S34 W. Dean-Colomb and F.J. Esteva

tranded DNA breaks and thus cell death. Irinotecanas been shown in three clinical trials to have efficacy

n ATRMBC when used either as monotherapy or inombination with other agents.

Antitumor activity of single-agent irinotecan inTRMBC was first shown in a phase II study in whichatients with refractory breast cancer (N � 103)eceived irinotecan at 100 mg/m2 weekly for 4 weeksith a 2-week rest or 240 mg/m2 every 3 weeks forweeks. Mean ORR was 18.5% with a mean durationf response of 4.6 months and mean OS of 9.2onths.27 In a phase II study with epirubicin- andaclitaxel-pretreated breast cancer patients (N �0), irinotecan (100 mg/m2) given biweekly withocetaxel (80 mg/m2) with filgrastim supporthowed an ORR of 64% with median PFS and OS at 10nd 23 months, respectively.28 More recently, irino-ecan (80 mg/m2 days 1, 8, 22, and 29) was evaluateds an S-phase modulator and studied in combinationith capecitabine (1,500 mg/m2/day in dividedoses days 2 to 15 and 23 to 36) in a phase I study ofeavily pretreated metastatic breast cancer patients.s shown in preclinical studies, even at this lowerodulatory dose, irinotecan did increase the number

f tumor cells in S-phase, thus presumably increasingheir vulnerability to action by capecitabine.29

Exatecan mesylate, a synthetic camptothecin deriv-

Table 1. Established Agents Used in the Treatme

Agent Study

C only Blum et al, 19993

C only Fumoleau et al, 20044

C � VN Ahn et al, 20045

C � CP Donadio et al, 20056

C ¡ VN�CP Lin et al, 20067

C � BVC Miller et al, 20059

GC only Modi et al, 200511

GC only Rha et al, 200512

GC only Smorenburg et al, 200113

GC � CP Sánchez-Escribano et al, 2007GC � CY � 5FU Frasci et al, 200215

VN only Zelek et al, 200117

VN � C Ray-Coquard et al, 199818

VN � C Vassilomanolakis et al, 20031

VN � GC Martin et al, 200716

OX � 5FU Pectasides et al, 200323

OX � 5FU Zelek et al, 200224

OX � VN Petit et al, 200625

OX � VN � 5FU Delozier et al, 200626

Abbreviations: ORR, overall response rate; OS, overall survivalcisplatin; BVC, bevacizumab; GC, gemcitabine; CY, cyclophos

*Median.

tive, has also been studied in ATRMBC. In a phase II e

tudy, 39 patients were given exatecan either at 0.3g/m2 or 0.5 mg/m2 per day depending on prior che-otherapy regimen. Exatecan was shown to have mod-

rate activity, with an ORR of 18%, a median TTP of 3onths, and median OS of 14 months. The most fre-

uent grade 3/4 nonhematologic toxicities were fa-igue (28%) followed by nausea and headache (both at0%).30 Another topoisomerase inhibitor in develop-ent, edotecarin, has not shown promising antitumor

ctivity in ATRMBC (A.D. Seidman, personal communi-ation, November 11, 2007).

pothilones

Over the past several decades, antimicrotubulegents such as the taxanes paclitaxel and docetaxelave become an important part of the arsenal for thereatment of metastatic breast cancer. However, these of these agents has been affected by multiple fac-ors, including issues related to formulation, neurotox-city, and the emergence of drug resistance. This pre-ents a unique challenge, not only in the use of thesegents as first-line therapy for locally advanced breastancer, but also for recurrent and/or metastatic breastancer. As a result, newer agents are being developedo address these issues.

One class of recently developed compounds is the

ATRMBC

N ORR (%) OS (mo)* PFS (mo)*

135 20 12.8 3.3126 28 15.2 4.944 50 17.0 5.339 36 10.9 5.237 32 9.5 5.9

462 19 15.1 4.8622 17 9.5 NR38 20 11 923 0 7.8 1.922 9 8 469 38 13 640 25 6 612 58 5.6 NR36 47 9 4

252 26/36 16.4/15.9 4/650 34 12.3 5.360 27 11.9 4.841 27 12.7 3.446 35 18.8 5.7

rogression-free survival; C, capecitabine; VN, vinorelbine; CP,e; 5FU, 5-fluorouracil; OX, oxaliplatin; NR, not reported.

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hat, like taxanes, have antimicrotubule activity. How-ver, these compounds and derived analogs havehown significant antitumor activity even in cells pre-iously resistant to taxanes.31 Three epothilone ana-ogs, ixabepilone (BMS-247550), patupilone, and KOS-62, are in phase II or III clinical investigation for thereatment of metastatic breast cancer. While severaltudies have reported activity with these analogs in thereatment of breast cancer following prior treatmentith taxanes32-34 or anthracyclines,35 there is currentlynly one published phase II study that has evaluatedpothilones in ATRMBC.

In this multicenter, phase II study, 126 women withetastatic breast cancer resistant to anthracyclines,

axanes, and capecitabine, were administered ixabepi-one (40 mg/m2) as a 3-hour intravenous infusion onay 1 of a 21-day cycle.36 With 113 patients assessableor response, ORR reached 18.3% for all treated pa-ients, and 50% of patients achieved stable disease.edian duration of response and PFS were 5.7 and 3.1onths, respectively, with an OS of 8.6 months. Grade

/4 treatment-related adverse events included periph-ral sensory neuropathy (14%), fatigue (13%), myalgia8%), and stomatitis (6%). As a result of these findings,tudies are under way or planned to evaluate the ben-fit of epothilones in combination with other chemo-herapeutic agents in the neoadjuvant and metastaticreast cancer settings.

emetrexed

Pemetrexed is a multitargeted antifolate that inhibitseveral enzymes in the de novo synthesis of purinesnd pyrimidines. Two phase II trials have evaluated itsfficacy in patients with ATRMBC. In a multicenterhase II trial, an interim analysis of a subset of patientsn � 31) previously treated with anthracyclines andaxanes who then received pemetrexed (600 mg/m2)nce every 21 days had an ORR of 26% with a medianisease response of 5.4 months and a median OS of2.8 months.37 In another phase II study, patients witheavily pretreated breast cancer (with regimens con-aining anthracyclines, taxanes, and capecitabine) weredministered pemetrexed (500 mg/m2) on day 1 of a1-day treatment cycle. The ORR was 8%, with stableisease exhibited in 36% of patients. Median TTP was.9 months, and median OS was 8.2 months. Patientseported symptom improvement, such as decreasedain intensity (16%) and decreased nausea (32%). Theost common toxicities were hematologic, with gradeneutropenia in 10% of patients.38

influnine

Vinflunine is a fluorinated vinca alkaloid. It is aicrotubule inhibitor agent and exerts its cytotoxic

ffects by preventing microtubule assembly during mi-

osis, resulting in eventual apoptosis. However, unlike m

ther vinca alkaloids, like vinorelbine, vinflunine bindseakly to tubulin at the vinca-binding site. This iselieved to result in less neurotoxicity with the use ofinflunine.39,40

Vinflunine was initially shown to inhibit the growthf MX-1 breast cancer xenografts. In this preclinicaltudy, vinflunine showed superiority over vinorelbineith regard to prolonged survival and tumor growth

nhibition.39 In a phase I study, two out of three heavilyretreated metastatic breast cancer patients achieved aartial response, thus warranting further investiga-ion.41 Similar promising results have been seen in ahase II study in ATRMBC in which 60 patients werereated with vinflunine (320 mg/m2) every 21 days. AnRR of 30% was observed, with a median PFS of 3.7onths and median OS of 14.3 months. The most

requent adverse event was neutropenia (grade 3 in8.3%, grade 4 in 36.7% of patients).42 These resultsonfirm that vinflunine is an active agent in ATRMBCnd thus merits further investigation.

7389

Halichondrin B is a highly potent anticancer agentriginally found in marine sponges. The scarcity of thisatural product has made it difficult to carry out theecessary clinical trials to assess its efficacy as an anti-ancer drug. However, processes have been developedhat have allowed synthesis of structurally simpler an-logs of that product that have retained the potency ofhe parent compound.43 E7389 is a synthetic macrocy-lic ketone analog of halichondrin B. E7389, like hali-hondrin B, induces G2-M cell cycle arrest and disrup-ion of mitotic spindles, consistent with the tubulin-ased antimitotic mechanism. However, when E7389as studied with purified microtubules and in living

ells, its primary antimitotic mechanism was found toe related to its ability to suppress microtubule growthut not shortening.44 This results in formation of ab-ormal mitotic spindles that cannot pass the meta-hase/anaphase checkpoint, thus resulting in celleath. This is unlike other antimitotic drugs, such asinblastine and paclitaxel, which mainly act by sup-ressing both the shortening and growth phases oficrotubule dynamic instability.In MCF-7 breast cancer cells in vitro, E7389 has been

hown to block mitosis in concert with inhibition ofroliferation as well. Additionally, it was shown toignificantly suppress the rate and extent of microtu-ule growth. In light of these encouraging results, twohase III clinical trials are currently recruiting patientso evaluate the efficacy of E7389 in the treatment ofatients with metastatic breast cancer. In one study,7389 will be compared with capecitabine in patientsith locally advanced or metastatic breast cancer re-

ractory to previous anthracycline and taxane treat-

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rabectedin

Trabectedin (ET-743, Yondelis; Johnson & Johnson,ew Brunswick, NJ) is a novel marine-derived antican-er compound found in the ascidian Ecteinascidia tur-inate. A small phase II trial showed a response rate of2% in patients with ATRMBC.45 This agent is currentlynder phase II/III development in breast cancer, hor-one-refractory prostate cancer, sarcomas, and ovarian

ancer. One of the ongoing phase II trials in patientsith ATRMBC is evaluating the efficacy and safety of

rabectedin in combination with capecitabine.

enileukin Diftitox

Biologic therapies targeting surface proteins are be-oming important in the treatment of cancer. Thispproach is based on the fundamental principle thatancer cells express antigens or proteins on the surfacehat enable the malignant phenotype, and that theseroteins can be targets of monoclonal antibodies orecombinant hybrids of toxin/receptor ligands. Theersistence of these surface markers even in chemo- oradioresistant tumor cells allows for the developmentf agents for use in patients with refractory disease. Infforts to increase the efficacy of surface-targeted bio-ogic therapy, protein toxins capable of inducing celleath by a single molecule have been connected to

igands that can bind to receptors of cancer cells. Thentitumor effects are achieved once these agents bindo a particular receptor, undergo receptor-mediatedndocytosis, and then release their toxins inside theell.46

Denileukin diftitox (Ontak; Ligand Pharmaceuticals,an Diego, CA) represents an example of this modalityhat has been approved by the FDA. In this preparation,acteria-derived truncated diphtheria toxin is fused to ainding subunit for the interleukin (IL)-2 receptor (IL-R). The fused IL-2/diphtheria toxin complex binds toL-2R, is internalized via receptor-mediated endocytosisn an acidified vesicle, and then is cleaved within thendosome to release the active fusion protein DTA.TA is then released into the cytosol where it inhibitsrotein synthesis, leading to eventual cell death.47 This

Table 2. Emerging Agents Used in the Treatmen

Agent Study

Irinotecan (q1wk/q3wk) Perez et al, 200427

Irinotecan � docetaxel Frasci et al, 200528

Exatecan Esteva et al, 200330

Pemetrexed Spielmann et al, 200137

Pemetrexed O’Shaughnessy et al, 200Abbreviations: ORR, overall response rate; OS, overall survival; P*Median.

esults in delivery of the cytotoxic agent directly to theumor cell. Initial clinical work with denileukin diftitoxas been performed in lymphoid-derived malignancies,nd it is currently FDA-approved only for use in cuta-eous T-cell lymphoma. However, a phase I/II clinicalrial is currently recruiting patients with advancedreast cancer who did not respond to previous treat-ents.

argeted Therapy

The ideal therapy for metastatic breast cancerhould block pathways critical to the survival of cancerells. Examples include trastuzumab and lapatinib foratients with HER2-overexpressing tumors, and endo-rine therapy for patients with estrogen receptor-pos-tive tumors. Heat shock protein 90 (Hsp90) is a mo-ecular chaperone for many signaling proteinsecessary to promote cancer proliferation and resis-ance to therapy. Several Hsp90 client proteins inreast cancer include the estrogen receptor, the recep-or tyrosine kinase HER2, and the serine-threonine ki-ases Raf-1 and Akt. These proteins are important tohe growth and survival of breast cancer cells becausef the cross-talk that occurs between them. Thus, in-ibitors of Hsp90 can have tremendous anticancer ac-ivity. Several inhibitors of Hsp90 have been identifiedhat can simultaneously deplete levels of multiple on-ogenic proteins by enhancing their degradation.

17-(allylamino)-17-demethoxygeldanamycin (17-AAG)s an ansamycin antibiotic that binds to Hsp90 and in-uces the degradation of proteins that require this chap-rone, thus promoting tumor cell death. In one study,nhibition of Hsp90 function downregulated Akt kinasend sensitized tumor cells to paclitaxel-induced apopto-is.48 In another study, 17-AAG was found to downregu-ate HER2 in trastuzumab-resistant breast cancer cells,hus suggesting its potential usefulness in trastuzumab-esistant HER2-overexpressing tumors.49 In light of theseromising results, a phase II clinical trial is currentlynder way to evaluate the efficacy of 17-AAG in patientsith chemo-refractory metastatic breast cancer.

TRMBC

N ORR (%) OS (mo)* PFS (mo)*

3 (52/51) 19 (23/14) 9.2 (9.7/8.6) 4.5 (4.9/4.2)50 64 23 1039 18 14 331 26 12.8 5.480 8 8.2 3

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Emerging agents used in the treatment of ATRMBCre summarized in Table 2.27,28,30,37,38

ONCLUSION

Significant progress has been made in the develop-ent of novel chemotherapeutic agents for metastatic

reast cancer. Anthracyclines and taxanes are the mostffective chemotherapies for breast cancer and areommonly used in the adjuvant and neoadjuvant set-ings. Novel chemotherapies are needed for the man-gement of patients who develop metastatic diseaseespite adjuvant treatment with anthracyclines and tax-nes, and for patients who receive these agents in theetastatic setting. In addition to the agents discussed

n this supplement, a large number of novel chemo-herapeutics are under development in phase I trials.opefully, some of them will have activity in patientsith metastatic breast cancer in the setting of anthra-

ycline and taxane resistance.

EFERENCES1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008.

CA Cancer J Clin 58:71-96, 20082. Giordano SH, Buzdar AU, Smith TL, et al: Is breast cancer

survival improving? Cancer 100:44-52, 20043. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II

study of capecitabine in paclitaxel-refractory metastaticbreast cancer. J Clin Oncol 17:485-493, 1999

4. Fumoleau P, Largillier R, Clippe C, et al: Multicentre,phase II study evaluating capecitabine monotherapy inpatients with anthracycline- and taxane-pretreated met-astatic breast cancer. Eur J Cancer 40:536-542, 2004

5. Ahn JH, Kim SB, Kim TW, et al: Capecitabine and vinorel-bine in patients with metastatic breast cancer previouslytreated with anthracycline and taxane. J Korean Med Sci19:547-553, 2004

6. Donadio M, Ardine M, Berruti A, et al: Weekly cisplatinplus capecitabine in metastatic breast cancer patientsheavily pretreated with both anthracycline and taxanes.Oncology 69:408-413, 2005

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