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009doiected to survive 10 years after diagnosis.1 The manage-nt of patients with MBC continues to evolve, but thereains considerable room for improvement. In recent years,ny new chemotherapeutic agents (such as platinum com-unds, taxanes, capecitabine, gemcitabine, and ABI-007)ve become available that have improved the efficacy anderability of chemotherapy. Additionally, a better under-nding of the fundamental biology of breast cancer has ledthe identification of cellular pathways that may be amena-to targeted intervention. In this article, we present an

erview of recent developments in breast cancer treatment.

ormonal Therapyrmonal therapy is the first consideration for patients withrogen- or progesterone-receptor-positive MBC, particu-

tamoxifen, which had been the benchmark for first-line treat-ment of hormonal-responsive MBC.2 Fulvestrant, a differenttype of antiestrogen drug that acts by down-regulating theexpression of estrogen receptors, is often used as a third-linehormonal agent. In this setting (after tamoxifen and AI), ful-vestrant can benefit 20% to 30% of patients (stable disease orbetter) for 6 to 26 months.3 The optimal dosing and scheduleof fulvestrant is being investigated further. With standarddosing of 250 mg intramuscularly once a month, it takes 3 to6 months for the blood levels to reach steady state, whereasthat can be achieved in significantly less time if a loading doseis used. In ongoing clinical trials, the Southwest OncologyGroup and others have used a schedule of 500 mg intramus-cularly on day 0 followed by 250 mg on days 14, 28, andmonthly intervals thereafter.

Even though hormonal therapy can control disease, some-times for an extended period, most patients will eventuallyprogress. Thus, there is interest in exploring novel agents orcombinations that can re-establish hormone responsiveness.Data from animal models suggest that a combination of an AIplus fulvestrant might be more efficacious than either agent

yo Clinic, Jacksonville, FL.Roy has received research grant support from Sanofi-Aventis, Celgene,and Cephalon. Dr Perez has received research grant support from Ge-nentech, Pfizer, Eli Lilly and Company, and AstraZeneca.ress reprint requests to Edith A. Perez, MD, Hematology-Oncology De-ew Therapies in the Treatvek Roy and Edith A. Perez

Systemic therapy for breast cancer is undeyears, a better understanding of the underlyition of several opportunities to target cellulmonal therapy is often chosen as the first lintolerated. However, most patients eventuallylation. Improved understanding of the mechanibetween hormone receptors and cellular growthsignal transduction inhibitors and hormonal afrom preclinical studies suggest that this goagenic therapy has shown efficacy in colorecbreast cancer, although improved overall surbeen advances in cytotoxic chemotherapy. Roil-free albumin nanoparticles (ABI-007) has adrug delivery with associated improvementnisms of action are also in development andresistant to currently available agents.Semin Oncol 33(suppl 9):S3-S8 2006 Else

espite advances in early detection and adjuvant treat-ment of early stage disease, breast cancer remains a sig-alosug

partment, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224.E-mail: perez.edith@mayo.edu

3-7754/06/$-see front matter 2006 Elsevier Inc. All rights reserved.:10.1053/j.seminoncol.2006.03.018nt of Breast Cancer

many interesting advances. In recentlogy of cancer has led to the identifica-hways for therapeutic advantage. Hor-erapy because it is generally very wellme unresponsive to endocrine manipu-hormonal resistance, and of the interplayays, provides the rationale for combiningto overcome resistance. Emerging datat be achievable in the clinic. Antiangio-lung cancer and appears promising in

as not yet been shown. There have alsoulation of paclitaxel in polyoxy-castor-d more convenient, safer, and enhancedcomes. New agents with novel mecha-r to have activity in cancer cells that are

c. All rights reserved.

ly if the disease is limited to the bones or there is onlynimal visceral organ involvement. Aromatase inhibitorsne or in sequence.4 In vitro and animal model data alsogest that the combination of an AI plus a small-molecule

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Epidermal growth factor receptor (EGFR) expression isociated with acquired resistance to antiestrogen therapy.ongoing phase II trial is assessing the clinical benefit of theFR inhibitor erlotinib in combination with the AI letrozolepatients with estrogen- or progesterone-positive MBC. Iner examples of this approach, letrozole has been com-ed with the tyrosine kinase (TK) inhibitor imatinib,4 withibitors of themammalian target of rapamycin pathway (CI9 or RAD 001),6 and with the small-molecule dual-kinaseibitor lapatinib.7 These agents are discussed inmore detailer.

hemotherapyemotherapy remains the mainstay of treatment for thejority of patients with MBC. Newer agents and combina-ns are being developed to improve response and survivales. An important consideration is whether to use combi-tion or single-agent chemotherapy. Clinical trials havewn that, compared with single-agent chemotherapy,binations have a better response rate and greater chance

significant tumor reduction, which is often associated withproved symptom control, quality of life, and functionaltus. Superior survival was shown with a combination ofecitabine plus docetaxel compared with capecitabinene in anthracycline-pretreated patients.8 More recently, anefit in overall survival was seen with a combination ofcitabine plus paclitaxel compared with paclitaxel alone

first-line treatment of MBC.9 However, there is no proofm randomized clinical trials that combination chemother-y is superior in terms of overall survival compared with thee agents used singly in sequence.

The last few years have seen the introduction of new che-therapeutic agents for the treatment of breast cancer;se include taxanes, platinum compounds, and gemcitab-. Taxanes (paclitaxel and docetaxel) are some of the mostive agents against breast cancer. These have different spec-of side effects (eg, hypersensitivity and neurotoxicity arest commonly described with paclitaxel, while fatigue, as-nia, and fluid retention are more often associated withcetaxel). Direct comparison of these agents in a recentdomized clinical trial found docetaxel to be superior toclitaxel in terms of overall survival and time to progression,t associated with significantly more toxicity, althoughbal quality-of-life scores were similar.10

Platinum compounds (cisplatin and carboplatin) are alky-ing agents with significant activity in breast cancer. Be-se of different mechanisms of action and nonoverlappingicity, platinum compounds are often combined with tax-es11,12 or other agents such as gemcitabine. Gemcitabine isantimetabolite nucleoside analog originally introduced fortreatment of metastatic pancreatic cancer. It has subse-

ently shown activity against a variety of cancers, alone or inbination. Its role in the treatment of breast cancer is

lving. Because anthracycline- and taxane-based regimensincreasingly used in adjuvant or early MBC settings, plat-

usiintm compounds and gemcitabine offer new treatment op-ns for patients who have received prior therapy with thesents.13,14

wer Chemotherapy Agentshough paclitaxel has significant activity in MBC, it hassiderable toxicity. The poor solubility of paclitaxel re-ires the use of the lipid-based solvent polyoxyl castor oilremophor EL; BASF, Ludwigshafen, Germany) as a vehi-, which can cause histamine-mediated hypersensitivity re-ions. Despite slow infusion and premedication with corti-teroids and antihistamines, severe or fatal reactions canl occur.15 Abraxane (Abraxis Oncology, Schaumburg, IL)polyoxyl-castor-oil-free formulation inwhich paclitaxel islivered as a suspension of albumin nanoparticles (averagee, 130 nm). This eliminates the need for premedicationd special infusion sets, and permits infusion over 30 min-s. Additionally, drug transport into tumors may be en-nced by albumin-receptor-mediated transport across en-thelial cells.16 A phase II study testing an albumin-boundmulation of paclitaxel (ABI-007) showed the safety of ah dose of 300 mg/m2 infused over 30 minutes withoutmedication. Response rates (complete and partial re-nses) of 64% and 21% were seen in first-line and subse-ent-line treatment of MBC, respectively.17 A phase III trialpared ABI-007 (260 mg/m2) givenwithout premedicationr 30minutes every 3weeks with paclitaxel (175mg/m2). Nopersensitivity reactions occurred with ABI-007. A signifi-tly higher response rate, time to progression, and loweridence of grade 4 neutropenia were seen with ABI-007.18

phase II study by the North Central Cancer Treatmentoup (NCCTG) is evaluating a weekly regimen (125 mg/) in combination with gemcitabine as first-line therapyMBC.Ixabepilone, a novel semisynthetic analog of epothelone B,tubulin-polymerizing agent in development for the treat-nt of breast and other cancers. It binds to the same bindingon tubulin as paclitaxel, and leads to microtubule stabi-

ation, causing cell-cycle arrest and apoptosis.19 It haswn activity against breast cancer, including in patientsth taxane-refractory disease. Objective response was seen22% of previously taxane-treated MBC patients in a phaserial.20 The activity of ixabepilone in taxane-refractory dis-e makes it an attractive alternative to paclitaxel in combi-tion with other agents such as trastuzumab or carboplatin.e NCCTG has an ongoing phase II trial of trastuzumabth weekly carboplatin and ixabepilone in patients withman epidermal growth factor receptor (HER)2-overex-ssing MBC. A multicenter, multinational phase III trialnsored by Bristol-Myers Squibb (New York, NY) compar-ixabepilone plus capecitabine versus capecitabine alone iso in progress. Accrual of approximately 1,200 patients isnned, with overall survival as the primary endpoint.Vinflunine is a new tubulin-targeted third-generationca alkaloid. It was developed by a semisynthetic process

ng superacidic chemistry to introduce two fluorine atomso the vinorelbine molecule.21 Vinflunine is freely water

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New therapies in the treatment of breast cancer S5uble, obviating the need for polyoxyl castor oil or othervents, as well as the need for steroid premedication. Inl-line experiments, it showed increased activity over itsrent compound vinorelbine. Activity was also seen in hu-n tumor xenograft models bearing small-cell lung cancer,al carcinoma, and colorectal, prostate, or breast cancerfts. Myelosuppression and constipation were the mainicities noted in phase I studies; neuropathy was uncom-n. Phase II studies showed activity in second- and third-e treatment of MBC (response rate, 30%; stable disease,%; N 60).22 Further evaluation of this drug with largerfinitive studies is being planned.

argeted Therapiesditional chemotherapy agents achieve their desired effectsdisrupting cellular functions that are common to malig-nt as well as normal cells, and consequently have a rela-ely narrow therapeutic index. Greater understanding ofmolecular biology of cancer has identified cellular path-ys that are uniquely or predominantly altered in cancerls and that can potentially be targeted for therapy. Thisproach offers the prospect of enhancing anticancer efficacythout causing significant damage to normal cells (toxicity).ere is also emerging evidence that various cellular path-ys can influence each other via cross-pathway phosphor-tion. Thus, targeted therapies may be able to synergizeth other targeted agents or traditional chemotherapeuticgs.

giogenesisgiogenesis is a critical factor in tumor progression. Vascu-endothelial growth factor (VEGF) is an important angio-ic growth factor that has been implicated in the pathogen-s of a number of diseases, including breast cancer. Higherels of tumor VEGF expression correlate with a worse prog-sis in breast cancer. The angiogenic growth factor family,mprised of five isoforms of VEGF (VEGF-A, -B, -C, -D,d -E) and placental growth factor, acts through three TKeptors:VEGF receptor (VEGFR)-1,VEGFR-2, andVEGFR-3.addition to angiogenic activity, VEGF also has a powerfulrmeability-increasing effect on vasculature, which mighttribute to tumor progression by enhancing nutrient ex-

ange and easier intravasation of tumor cells during metas-is.Bevacizumab, a recombinant humanized antibody, inhib-angiogenesis by binding to VEGF and preventing it fromding to the receptor. The ability of antiangiogenic agentsenhance the anticancer efficacy of conventional chemo-rapeutic agents has been shown in randomized clinicalls in metastatic colorectal cancer and advanced nonsmalll lung cancer, where the use of bevacizumab is associatedth increased survival.23 A large randomized clinical trial inast cancer also showed a better response rate (19.8%)withombination of bevacizumab plus capecitabine compared

th capecitabine alone (9.1%; P .001), but without anociated survival benefit.24 An interim planned analysis of a

agativase III randomized, controlled, multicenter trial (E2100)722 women with previously untreated MBC showedrked improvement in progression-free survival in the be-izumab-plus-paclitaxel arm compared with paclitaxelne (11 v 6 months, respectively).25

VEGF-trap is a chimeric, entirely human, dimeric glycop-ein that consists of a high-affinity VEGF-binding domainked to the biologically more active VEGFR-2 domain andimmunoglobulin (Ig)-G1 Fc domain. Because of the veryh binding affinity for VEGF, VEGF-trap prevents theGFVEGFR interaction and causes marked inhibition ofgiogenesis and tumor growth in animal models. Responseta are limited at this time, but completed phase I studiesve shown an acceptable safety profile and encouragingts of activity. One patient with renal cancer had stableease for over 6 months.26,27 Phase II studies are currentlying developed.Other small molecules that inhibit angiogenesis by dis-ting VEGF signaling pathways are under investigation. Intrast to bevacizumab, they are orally active and some havepotential additional benefit of targeting multiple cellular

thways. Sunitinib (SU11248) is a multitargeted oral TKibitor with activity against VEGF, platelet-derived growthtor (PDGF), c-kit, and Flt3. A phase II study (N 51) ofitinib 50 mg a day for 28 days in a 42-day cycle in heavilytreated patients with MBC showed encouraging activityrtial response in 14%, stable disease in 2% of patients).proximately half the patients required dose reduction be-se of toxicity.28 GW786034 is a novel, multitargeted,all-molecule inhibitor of human VEGFR-1, -2, -3, PDGFeptor- and -, and c-kit TKs, with showed antitumord antiangiogenic activity in in vitro angiogenesis models asll as human tumor xenografts in mice.29 Limited humanerience in phase I trials shows the drug to be well toler-d.29 Hypertension was the most frequent adverse effect,d was easily controlled with antihypertensive medications.e maximum tolerated dose was not reached in humanls. Phase II studies to further evaluate this agent are beingnned.

FRe EGFR family of transmembrane TK receptors is impor-t for the growth and survival of epithelial cells. Receptorivation leads to dimerization followed by sequentialosphorylation of downstream messenger molecules,lminating in transcription of the genes responsible forl proliferation. In several human cancers, includingast, overexpression of the EGFR gene has been shown toassociated with poor prognosis. Four members of theFR family are described (HER1, HER2 (neu/ErbB2),R3, and HER4).30 Expression of HER2, the most recog-ed receptor in breast cancer, is amplified in 25% to 30% ofasive breast cancers (termed HER2-positive) and confersadverse prognosis.Trastuzumab, a humanized monoclonal antibody directed

inst the extracellular domain of HER2, is biologically ac-e and has been shown to improve the survival of patients

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S6 V. Roy and E.A. Perezth HER2-positive MBC as evaluated by protein expressiongene amplification.31,32 Accurate assessment of HER2 statusall patients is critical to provide themwith the opportunity toefit from this life-prolonging therapy. It is important that thisperformed in an appropriately experienced laboratory.33

stuzumab is approved for weekly administration in theited States, but pharmacokinetic data and clinical experi-ce suggest that a 3-weekly schedule, which may be moresirable for patients, is safe and effective.34 Multiple phase IIls have shown that trastuzumab can be effectively com-ed with other chemotherapeutic agents, such as vinorel-e,35 gemcitabine,36 carboplatin, or paclitaxel.37 Despitesuccess of trastuzumab, less than 50% of patients who

erexpress HER2 respond, and almost all eventuallygress. Newer small-molecule or antibody inhibitors ofR2 are in development.Pertuzumab is a humanized antibody directed against aferent epitope on HER2 than is targeted by trastuzumab,d which blocks EGFR dimerization.38 Thus, pertuzumabibits not only HER2, but other EGFR pathways as well.ase I and II trials show that an every-3-week schedule wasll tolerated, but only limited activity (6 of 78 patients hadponse or stable disease for at least 5 months) was seen ins cohort ofMBC patients with low expression of HER2.39,40

Lapatinib is an orally active small-molecule inhibitor ofR1- and HER2-associated TK. It has shown efficacy, aloned with conventional chemotherapy, in patients withR2-positive breast cancer who had progressed duringstuzumab treatment.41 A phase II trial of lapatinib as first-e treatment of HER2-positive metastatic or locally ad-ced breast cancer showed a 35% response rate.42 Thisnt is being actively investigated in several phase III trials.randomized controlled trial of letrozole with or withoutatinib in estrogen receptor-positive MBC has started ac-al. Seven hundred sixty patients will be enrolled to allowficient power to detect a 30% improvement in time togression as the primary endpoint. Two large, multina-nal, randomized controlled trials of lapatinib and chemo-rapy are also in progress: one studying capecitabine withwithout lapatinib for HER2-positive previously treatedC patients is planning to enroll 528 patients, with pro-ssion-free survival as the primary endpoint, and the other570-patient trial of paclitaxel with or without lapatinib ast-line treatment of HER2-negative, untested MBC, withe to progression as primary endpoint.Erlotinib is an orally active EGFR inhibitor that is ap-ved in the United States for the treatment of nonsmalll lung cancer. Ongoing studies are evaluating the efficacyerlotinib, alone or in combination with chemotherapy, forariety of malignancies, including breast cancer. A recentlyorted phase III National Cancer Institute of Canada-Clin-l Trials Group study showed improved overall survivalth erlotinib plus gemcitabine compared with gemcitabinene (hazard ratio for death, 0.81) in patients with advancedncreatic cancer.43 An NCCTG phase II study of a combi-tion of gemcitabine plus erlotinib as first- or second-line

atment of MBC showed a 14% response rate and a medianvival time of 4.6 months.44 A phase II trial of erlotinib plus

ageprerozole in women with estrogen- or progesterone-receptor-sitive MBC is ongoing at Vanderbilt University (Nashville,), with an expected enrollment of 150 patients. EGFRression will be assessed retrospectively in a subset of pa-

nts. Another phase II study is evaluating a combination ofotinib plus docetaxel for MBC. Accrual is expected to bepleted in 2007.

s/Raf/MEK/ERK Pathwaytivation of the Ras signaling pathway is considered an im-rtant mechanism of human oncogenesis. Ras regulates sev-l pathways, including the Raf/mitogen-activated proteinase (MAPK) and extracellular signal-regulated kinaseK) kinase (MEK)/ERK cascade, which synergistically in-ces cellular transformation. Ras-mediated activation of Rafds to sequential phosphorylation and activation of MEKd ERK, which translocates from the cytoplasm to the nu-us and modulates the expression of growth-regulatinges. Therefore, inhibition of the Ras/Raf/MEK/ERK signal-pathway in tumors may be of clinical benefit.

The enzyme farnesyltransferase causes post-translationaldification of Ras, allowing it to associate with the plasmambrane and be involved in signal transduction. Inhibitionthis enzyme can thus block Ras-mediated signaling andve broad antitumor effects. Tipifarnib is a farnesyltrans-ase inhibitor that has broad activity against a variety ofcers in preclinical models. A phase II trial of two differentedules of tipifarnib (300 or 400mg twice a day, or 300mgice a day for 21 days in a 28 day cycle) in MBC showedponse rates of 10% and 14%, and stable disease for 4 to 12nths in 15% and 9% of patients, respectively.45 Fatigue,utropenia, thrombocytopenia, and neurotoxicity were thein adverse effects. Preclinical studies show synergy withoxifen and letrozole,46,47 and a phase I study found that abination with tamoxifen was well tolerated.48 Cancer and

ukemia Group B is conducting a randomized phase IIdy of letrozole with or without tipifarnib in over 100 pa-nts, with overall response rate as the primary endpoint.Raf is a family of serine-threonine kinases that act as down-eam effectors of the Ras pathway. BAY43-9006 is a Rafase inhibitor with activity in a broad spectrum of preclin-l tumor models. It also inhibits several receptor TKs thatinvolved in tumor progression, including VEGFR-2 and -3,GFR-, Flt3, c-kit, and p38 (a member of the MAPKily).49 The NCCTG is currently conducting a phase II

nical trial of this compound in patients with previouslyated MBC. Initial accrual has been completed and the re-ts of a planned analysis are awaited.

ammalian Target of Rapamycinmmalian target of rapamycin is a serine-threonine kinaseolved in the regulation of several proteins important forl-cycle regulation. In breast cancer, this pathway can beivated by the estrogen receptor, insulin-like growth fac--1 receptor, and EGFR. Rapamycin is the best-known

nt in this class and is in clinical use as an immunosup-ssive agent. However, analogs of rapamycin (CCI-779 and

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New therapies in the treatment of breast cancer S7D001) have been developed that have better stability andin clinical trials for a variety of malignancies. CCI-779 haswn considerable activity in breast cancer cell lines, par-ularly estrogen receptor-positive and HER2-positive tu-rs.50 Encouraging synergy with tamoxifen and letrozoles seen in preclinical studies.51 A phase II study of CCI-779anthracycline- or taxane-refractory patients with MBCwed a partial response in 11% and stable disease in 33%patients.52 A large phase III, randomized, placebo-con-lled, double-blind study is comparing oral CCI-779 ad-nistered in combination with letrozole as first-line hor-nal therapy in postmenopausal women with locallyvanced or MBC. An accrual of 1,200 patients is planned.gression-free survival will be assessed as the primary end-int.

onclusione last few years have seen many encouraging develop-nts in the treatment of breast cancer, and there is reason tooptimistic about continued progress in the future. There iso a better understanding of the underlying biology and aater appreciation for the heterogeneity of the disease. It isped that this understanding, along with the developmentpredictive markers of response (such as by molecular pro-ng), will allow therapeutic agents to be used with morecision tomaximize the chance of benefit andminimize theelihood of toxicity. To realize this potential, it is criticalt patients are encouraged to enroll in well-designed clin-l trials whenever possible.

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32. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvantchemotherapy for operable HER2-positive breast cancer. N Engl J Med353:1673-1684, 2005

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New Therapies in the Treatment of Breast CancerHormonal TherapyChemotherapyNewer Chemotherapy Agents

Targeted TherapiesAngiogenesisEGFRRas/Raf/MEK/ERK PathwayMammalian Target of Rapamycin

ConclusionReferences