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37Seminars in Oncology Nursing, Vol 23, No 1 (February), 2007: pp 37–45

BJECTIVES:o review the chemotherapy and tar-eted biologic options for treatment ofdvanced and metastatic breast can-er.

ATA SOURCES:linical and research articles and

extbook chapters.

ONCLUSION:ecent clinical research has led to these of novel targeted therapies in theanagement of locally advanced andetastatic breast cancer. Althoughetastatic breast cancer remains in-

urable, increases in disease-free andverall survival has been achieved.

MPLICATIONS FOR NURSING

RACTICE:ecent advances in the biological tar-eted therapies against Her2/neu,EGF, and EGFR are now either ap-roved therapies or are in the finaltages of clinical testing. Oncologyurses can help decrease toxicitiesnd maintain better QOL by fully un-erstanding the mechanism of actionf the drugs, expected side effects, andnticipated response to the novel regi-en.

EY WORDS:etastatic breast cancer, Targeted

herapy, CNS metastases, HER-2/eu, EGFR

Susan Moore, RN, MSN, ANP, AOCN®: On-ology Nurse Practitioner, Consultant, Can-er Expertise, Chicago, IL. Melody A.obleigh, MD, Professor of Medicine, Divi-ion of Hematology, Oncology and Stemell Transplant, Rush University Medicalenter, Chicago, IL.Address correspondence to Susan

oore, RN, MSN, ANP, AOCN®, 5437 W.arwick Ave, Chicago, IL 60641-3824;

-mail: smoore46@yahoo.com

2007 Elsevier Inc. All rights reserved.

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749-2081/07/2301-$30.00/0oi:10.1016/j.soncn.2006.11.007

TARGETING

METASTATIC AND

ADVANCED BREAST

CANCER

SUSAN MOORE AND MELODY A. COBLEIGH

VER THE past 10 years, breast cancer research hasyielded an amazing array of new diagnostic and treat-ment approaches, but an overall cure for and absolute

reventive method against breast cancer continue to elude scien-ists. In the United States, more than 40,000 women die frometastatic breast cancer (MBC) on an annual basis. When breast

ancer recurs, the focus shifts from cure to palliation of diseasend disease-related side effects, and maintaining quality of lifeQOL). A certain percentage of women have distant metastases athe time of original diagnosis; others are diagnosed with early stagereast cancer and experience distant recurrence months or yearsater, or are diagnosed with locally advanced stage III disease andre at high risk for recurrence. This article discusses targetedherapy for locally advanced and MBC, reviews treatment options,ighlights trends in treatment that have become standard of careecause of recent clinical research, and addresses nursing man-gement of metastatic and locally advanced breast cancer forhich targeted therapy is indicated.

SCOPE OF THE PROBLEM

reast cancer is a significant health problem in the UnitedStates, with more than 200,000 new diagnoses and more than

0,000 deaths attributed to breast cancer annually.1 Treatmentdvances have improved the survival of breast cancer but have notliminated death because of the disease. Despite earlier diagnosisnd better management of locally confined breast cancer, 20% to0% of patients will have recurrent disease in a distant organ.2 Forecades, chemotherapy and hormonal manipulation have been therimary means by which to manage locally advanced and MBC.ytotoxic chemotherapy can cause significant side effects. Treat-ent of advanced breast cancer with chemotherapy is a delicate

alancing act between finding an agent to which the tumor has not

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38 S. MOORE AND M.A. COBLEIGH

eveloped resistance, treating with sufficient doseo achieve response while, at the same time,voiding life-threatening side effects or decreasinghe QOL for women in whom the disease is noonger curable. Hormonal manipulations have lessoxicity but still include side effects such as hotashes, bone loss, or vaginal atrophy that maympair QOL.

TARGETED THERAPY

ell proliferation and differentiation are regu-lated by a number of hormones, growth fac-

ors, and cytokines that interact with cellular re-eptors and communicate with the nucleus of theell through a complicated network of intracellu-ar signaling pathways. Potential targets and theiroints of intervention include: ligands (neutraliza-ion before the ligand can associate with its recep-or); cellular receptors (prevention of binding ofrowth factors to receptors or by inhibiting kinasectivity in the receptor); and intracellular secondessengers and nuclear transcription factors (in-ibiting signaling).3 Increased understanding ofmall molecules and intracellular signal transduc-ion pathways has led to several pivotal discover-es in the pathogenesis of breast cancer. Defininghese targets has facilitated new treatments, col-ectively termed “targeted therapies.” The termargeted therapies has been used to describe a neweneration of small molecules and monoclonalntibodies (MAb) that have been rationally de-igned to inhibit very specific signal transductionnd transcription pathways found to be critical forancer cell growth and survival.4 Identification ofknown therapeutic target that is important to

he biology of the cancer cell allows researchers toevelop a specific agent to treat the disease byodifying the expression or activity of the target

n the growth and progression of the cancer.5,6

argeted Hormonal Therapy

ith the preceding definition in mind, a therapyhat has been used against breast cancer for de-ades can be considered the predecessor of mod-rn targeted therapy. In hormonal therapy, thearget is the hormone receptor; only womenhose breast cancer overexpresses the hormone

eceptor will benefit from targeted hormonal ther-py.5,7 The most important advance in targetedherapy for breast cancer is considered by some to

ave been the ability to target the estrogen recep- s

or.8 Hormonal manipulation as a treatment forreast cancer began before there was even annderstanding of the significance of estrogen orrogesterone receptors. It was known that oopho-ectomy, hypophysectomy, and adrenalectomyad a palliative effect on MBC, but it was not untilhe discovery of the estrogen receptor in the late960s9 that the development of targeted agentsuch as selective estrogen receptor modulators,romatase inhibitors, or estrogen receptor down-egulators to modulate the activity of the hor-onal pathway was possible. Resistance to endo-

rine therapy eventually develops in essentially allomen with advanced breast cancer.5

MONOCLONAL ANTIBODIES

er2-neu

he human epidermal growth factor receptorEGFR) is a group of transmembrane receptorsonsisting of four related members: HER1EGFR), HER2 (also known as c-erbB-2 and neu),ER3, and HER4. These receptors consist of anxtracellular ligand-binding domain, a transmem-rane domain, and an intracellular tyrosine ki-ase (TK) domain. Following ligand binding, HER

amily homodimers or heterodimers are formed,hich results in activation of the intracellular TKomain by phosphorylation. Activation of the TKseads to further downstream activation of intracel-ular pathways related to proliferation, angiogen-sis, and apoptosis.5,10 Ligands have been foundor HER1, HER3, and HER4, but no known naturaligands exist for HER2 (Fig 1).5 The associationetween overexpression of HER2, a proto-onco-ene overexpressed in approximately 20% of inva-ive breast cancers, and poor prognosis was pub-ished in 1987 by Reese and Slamon from UCLA.11

The recombinant humanized MAb trastuzumabas developed as an immunotherapeutic agentgainst the HER2 extracellular domain. It binds tohe HER2 receptor and reduces tumor cell prolif-ration by interrupting the cellular pathway. Fol-owing pivotal clinical trials, trastuzumab was ap-roved by the US Food and Drug AdministrationFDA) for use in the treatment of HER2-positiveBC in September 1998.12,13

Testing for HER2 status can be accomplished byither immunohistochemistry (IHC) or fluores-ent in situ hybridization (FISH). IHC testing isidely available and relatively inexpensive, but is

ubject to variability because of patient- and tu-

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TARGETING METASTATIC AND ADVANCED BREAST CANCER 39

or-specific factors, assay technique, and experi-nce of the observer.14,15 It is more accurate whenerformed on frozen tissue; most tissue specimensre preserved in formalin, which causes cross-inking of proteins. The longer the tissue is inormalin, the more cross-linking and masking ofhe epitope needed to detect the HER2 antibody.HC 3� results are generally considered to beER2-positive. Indeterminate IHC (1� or 2�)

esults warrant validation by FISH.16 FISH evalu-tes gene copy number, making it less subjectivehen performed in a validated laboratory. FISH isore expensive than IHC and currently repre-

ents the gold standard against which other assaysre measured. Automated IHC HER2 testing haseen developed, including the automated cellularmaging system (ACIS), which shows a 94% con-ordance rate between IHC-ACIS and FISH.14,17

he comparability of either assay with regard tohe ability to predict clinical benefit from trastu-umab therapy has not been prospectively stud-ed.18 Continued evaluation of the best method ofesting for HER2 status has resulted in a recom-endation that gene amplification demonstrated

y FISH is the preferred method for substantiationf true HER2 overexpression, especially when theHC result is questioned clinically.15,16,19 Whenatients are properly selected through an ap-roved standardized method, trastuzumab has ac-ivity as a single agent12 and increases theffectiveness of many chemotherapy agents inBC.20,21

IGURE 1. Human EGFR family. (Genentech, South Sanrancisco, CA. Reprinted with permission.)

Balancing efficacy and toxicity is a challenge r

hen treating patients with MBC. Trastuzumab assingle agent has few side effects affecting QOL orctivities of daily living. Hypersensitivity may oc-ur during the initial infusion but is exceedinglyare after treatment is established. An unexpectedoxicity of trastuzumab discovered during earlylinical trials was cardiotoxicity. During embry-nic development, HER2 appears to be critical tohe development of cardiac and neural systems. Indults, HER2 may still be important in cardiacemodeling under stress, which may explain whyhe incidence of trastuzumab-associated cardio-yopathy is increased in patients with anthracy-

line exposure, increased age, and a history ofypertension.22,23 The incidence of trastuzumab-ssociated cardiac toxicity was found to be ap-roximately 4% in the MBC setting when given assingle agent. When trastuzumab was combinedith doxorubicin and cyclophosphamide (AC),

he incidence of class III/IV cardiotoxicity was8% compared with 8% in those who received AClone.12 In routine practice, use of concurrentrastuzumab and anthracycline-based chemother-py should be avoided.24 When trastuzumab wasiven concurrently with paclitaxel, the incidencef cardiotoxicity was 11%, compared with 1%mong patients receiving paclitaxel alone.20 Car-iotoxicity during or following trastuzumab ther-py presents initially as a decrease in the leftentricular ejection fraction (LVEF) with a de-rease of 15% or more being considered clinicallyignificant. Prior treatment with an anthracyclinencreases the risk of cardiac toxicity with trastu-umab.25

The standard dosing of trastuzumab uses aeekly dosing schedule at 4 mg/kg for the first

loading) dose, followed by 2 mg/kg every week.eyland-Jones et al26 found that triple-dose ad-inistration every 3 weeks resulted in serum

rough concentrations comparable with the stan-ard weekly regimen with no increase in cardio-oxicity. This dosing schedule has not yet beenpproved by the FDA.Intrinsic trastuzumab resistance may be attrib-

ted to cellular mechanisms, signaling pathwayshat bypass the HER2 transmembrane receptor, orathways unrelated to HER2.27 Tumor progres-ion between treatment cycles may be caused byinetic resistance or problems secondary to vas-ular penetration because MAbs are large mole-ules affected by tumor vasculature, cellular ar-hitecture, and extracellular matrix. Acquired

esistance develops in any cancer where genomic

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40 S. MOORE AND M.A. COBLEIGH

nstability is high and multiple genetic variationsccur early in tumorigenesis. Although more com-licated and difficult to observe, the same mech-nisms (changes in drug metabolism enzymes andncreased drug efflux across the membrane) thatan cause acquired resistance to chemotherapygents can also affect MAb therapy. Lack of fullnderstanding of MAb drug resistance creates alinical dilemma of whether to continue the tar-eted component of therapy when progression iseen with trastuzumab plus chemotherapy.27,28

Progression of HER2-overexpressing MBC to theentral nervous system (CNS) is a significantroblem. Anecdotal experience has suggested thatatients with HER2-positive disease seem to bet increased risk for CNS metastases. Althoughot fully characterized, a retrospective chart re-iew points to a relationship between HER2 statusnd CNS metastases that may reflect a combina-ion of clinical and pathologic variables: (1) HER2-ositive tumors have a predilection for viscera,ncluding the brain; (2) trastuzumab does notross the blood-brain barrier, leaving the CNS as aelative sanctuary; and (3) the use of trastuzumabas altered the natural history of MBC in otherites, thereby allowing women to survive longernd be at greater risk for CNS spread.29 Overall,pproximately 20% of patients with MBC are diag-osed with brain metastases; autopsy data sug-ests a true incidence of nearly 30%. Amongomen with stage IV HER2-overexpressing breastancer, retrospective analyses have disclosed a5% to 43% incidence of brain metastases.29-32

Nursing implications during trastuzumabherapy. Because trastuzumab is a humanizedAb, true hypersensitivity reactions (HSR) are rare,ccurring in approximately 1% of infusions duringhe monotherapy clinical trial for MBC.18 The poten-ial for HSR exists and patients undergoing their firstr second infusion should be closely monitored fordverse effects during the infusion. Reactions wereost commonly reported in association with the

nitial infusion. Signs and symptoms include ana-hylaxis, urticaria, bronchospasm, angioedema,nd/or hypotension. The onset of symptoms gener-lly occurs during an infusion, but there have alsoeen reports of symptom onset up to 24 hours later.he appearance of any of these symptoms shouldlert the nurse to the possibility of a HSR. Thenfusion must be stopped immediately and the insti-ution’s protocol for management of HSRs should be

nitiated.18 The attending oncologist should be con- t

ulted regarding the safety of a trastuzumab chal-enge in the future.

During the first infusion with trastuzumab, aymptom complex consisting of chills and/or feveras observed in about 40% of patients in clinical

rials.13,18 The symptoms were usually mild tooderate in severity and were treated with acet-

minophen, diphenhydramine, and meperidinewith or without reduction in the rate of the infu-ion). Trastuzumab discontinuation is rarely re-uired. Other signs and/or symptoms may includeausea, vomiting, pain (in some cases at tumorites), rigors, headache, dizziness, dyspnea, hypo-ension, elevated blood pressure, rash, and asthe-ia. The symptoms occurred infrequently withubsequent trastuzumab infusions.18 The sensa-ion of pain at tumor sites during or in the first dayr two following the first several trastuzumab in-usions can be unsettling or frightening to womenith metastatic disease who experience pain in a

ite in which there has been no confirmation ofumor. Women with a high tumor burden areore likely to experience symptoms.Cardiac toxicity is a known side effect of tras-

uzumab. Nurses need to make certain that pre-reatment cardiac assessments have been com-leted. For most patients, a multi-gated acquisitionMUGA) scan or echocardiogram will provide suf-cient information to verify adequate cardiacunction by measuring the LVEF. In most institu-ions, an LVEF � 50% is considered normal. Pa-ients with significant history of hypertension,rrhythmias, or other cardiac problems may ben-fit from an evaluation by a cardiologist beforetarting trastuzumab therapy. There are no guide-ines to suggest that serial LVEF measurement isequired during or following trastuzumab therapyn asymptomatic patients; however, any patientith complaints of dyspnea, peripheral edema, ornexplained cough should undergo an LVEF mea-urement to determine if there has been a signif-cant decline in LVEF compared with the base-ine.13,22,28,33,34

ascular Endothelial Growth Factor (VEGF)eceptors

he role of angiogenesis in the development ofumors beyond 2 to 3 mm has been well-estab-ished35-38 and has led to a large-scale researchffort in an attempt to discover effective antian-iogenesis compounds. Normal human vascula-

ure is quiescent in healthy adults with each en-

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TARGETING METASTATIC AND ADVANCED BREAST CANCER 41

othelial cell dividing only once every 10 years.issue remodeling and angiogenesis are crucial for

he growth and metastasis of breast cancers.39

ngiogenesis is not only a pathologic process butlso is essential for homeostasis. Physiologic an-iogenesis is important in reproduction, woundealing, and menses, as well as a compensatoryesponse to ischemia in coronary artery and pe-ipheral vascular diseases. Thus, therapeutic effi-acy of antiangiogenic therapy requires a balancehere tumor angiogenesis is inhibited withoutisrupting physiologic angiogenesis.38 VEGF is airculating growth factor that correlates with re-ease of angiogenic factors by tumor cells, termedhe “angiogenic switch.” A primary trigger of thengiogenic switch is tumor hypoxia, which turnsn the VEGF tyrosine kinase signaling pathwayFig 2).38,40 In breast cancer, VEGF is upregulatedy activated HER1 and HER2 signaling. It is theost specific and powerful angiogenic factor41

nd, when activated, triggers cellular signalinghat alters endothelial cell survival, mitogenesis,igration, differentiation, vascular permeability,

nd mobilization of endothelial progenitor cellsrom the bone marrow into the peripheral circu-ation.5,42 One distinguishing factor of VEGF is itsbility to induce vascular permeability. In fact,his factor was originally named vascular perme-bility factor and was subsequently found to beomologous to VEGF. Inhibition of tumor angio-enesis provides an efficient strategy to slow downr block tumor growth.43

Bevacizumab is a recombinant humanized anti-EGF antibody that blocks binding of the ligand

IGURE 2. VEGF family and its receptors. (Genentech,outh San Francisco, CA. Reprinted with permission.)

EGF, impairing its ability to activate the receptor C

n endothelial cells, and inhibiting the formationf new blood vessels.44,45 A phase I/II study ofingle-agent bevacizumab (n � 75) in women withefractory MBC showed an objective response ratef 6.7% and stable disease in 17% of patients foreriods exceeding 6 months.46 A subsequent ran-omized phase III study of heavily pretreatedBC patients combining bevacizumab with cape-

itabine, an oral fluoropyrimidine pro-drug, ver-us capecitabine alone showed an increase inbjective response rate of 20% against 9% for cape-itabine alone but the primary endpoint of pro-ression-free survival was not met.47 A random-zed phase III study of weekly paclitaxel with orithout bevacizumab in previously untreatedBC patients has reported additive benefit to

he combination.48 Progression-free survival wasearly 11 months for patients receiving paclitaxelnd bevacizumab compared with slightly over 6onths for patients receiving paclitaxel alone.48

n FDA indication for the use of bevacizumab inBC is pending.Nursing implications during bevacizumab

herapy. Toxicities for bevacizumab include HSR,ypertension, proteinuria and nephrotic syndrome,hromboembolic events, poor wound healing, andemorrhage. The package insert for bevacizumab

ncludes a boxed warning for gastrointestinal perfo-ation and hemorrhage.49 As with all MAbs, the riskf a HSR is present during the first few infusions. Toeduce this risk, the first infusion should be givenver 90 minutes; if there are no signs of HSR, theecond infusion can be given over 60 minutes. Thehird and subsequent infusions can be given over 30inutes if no adverse effects were seen in the two

rior infusions.Hypertension was seen in the early studies of

evacizumab. In the study conducted by Hurwitzt al,50 hypertension was seen in 22% of partici-ants versus 8.3% in the control population. Gradehypertension (requiring therapy) was noted in

1% of the bevacizumab-treated group. In a phaseII study by Miller et al47 in MBC patients, grade 3ypertension was observed in 17.9% of those re-eiving capecitabine and bevacizumab. De novoypertension may develop over time or pre-exist-

ng hypertension may worsen in patients receivingevacizumab. The median interval from the firstose of bevacizumab to onset of hypertension was31 days (range, 7 to 316) in a study by Yangt al.51 The hypertension should be managed ac-ording to the 7th Report of the Joint National

ommission (JNC 7) on preventive medicine gen-

ew

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42 S. MOORE AND M.A. COBLEIGH

ral guidelines for hypertension available at http://ww.nhlbi.nih.gov/guidelines/hypertension/Proteinuria may appear concurrently with hyper-

ension or as a separate event. An association be-ween hypertension and proteinuria was noted inhe combination arm of an MBC study of capecitab-ne � bevacizumab. Patients who developed pro-einuria were more likely to become hypertensive47.1% vs 16.9%)47 and a statistically significant as-ociation between hypertension and proteinuria (P

.0006) was seen in a small (n � 40), nonrandom-zed post-marketing study by Martel et al.52 A urinepecimen should be assessed for protein before eachevacizumab infusion and treatment held if therine dipstick protein amount is � 1�, according toevacizumab prescribing information.49 Temporaryuspension of bevacizumab therapy is recom-ended in patients with evidence of moderate to

evere proteinuria and in patients with severe hy-ertension that is not controlled with medical man-gement. Failure to interrupt treatment duringrade 1 or 2 proteinuria may result in grade 3 pro-einuria/nephrotic syndrome necessitating termina-ion of treatment.49

Alterations in hemostasis secondary to the ad-inistration of antiangiogenesis therapy may in-

lude thrombosis, embolism, intracranial hemor-hage, epistaxis, hematemesis, hemoptysis, andleeding at tumor sites.53 In a bevacizumab MBChase I/II dose escalation study, two patients de-eloped subclavian/axillary vein thrombosis onhe same side as a central line; one case of super-cial thrombophlebitis was also observed.46 Thehase III colorectal trial reported thromboembolicvents at 19.3% of bevacizumab-treated patientsersus 16.1% in the control group.50 Patients whoevelop a serious arterial thrombotic event duringevacizumab therapy should permanently discon-inue bevacizumab.49

A study of bevacizumab in non–small cell lungancer, primarily in patients with squamous cellistology, reported significant bleeding at tumorites49,54 and subsequent colorectal studies of be-acizumab noted bowel perforation,50 which re-ulted in a boxed warning for the drug.49,55 Noimilar bleeding events were noted in the MBCrials. The problem of bowel perforation andleeding in cavitated lung lesions may be theesult of the drug’s ability to kill tumor cells thatave replaced healthy tissue, thus leading to ne-rosis and perforation. In the Hurwitz et al50 colo-ectal cancer trial, epistaxis was the most com-

only reported bleeding event (35.3%) in patients e

ho received bevacizumab. Blood is frequentlyoticed when patients blow their nose. Bevaci-umab administration should not follow or pre-ede major surgery by less than 6 to 8 weeks tovoid these complications.49 Bevacizumab shoulde permanently discontinued in patients who de-elop gastrointestinal perforation, wound dehis-ence requiring medical intervention, seriousleeding, nephrotic syndrome, or hypertensiverisis. Nurses administering bevacizumab shouldot ignore patient complaints of abdominal painut include possible gastrointestinal perforation inhe differential diagnosis.56

TARGETED THERAPY DRUGS IN THE

RESEARCH PIPELINE

GFR

relative of HER2, called HER1 (also calledGFR), may be overexpressed in 14% to 91% ofreast cancers.57 EGFR signal transduction occursn normal and abnormal cells as the result ofigand binding to a HER-family receptor, leading toimerization. Once dimerization occurs, the cir-uit is complete and the signal is relayed, resultingn activation of downstream targets that can stim-late tumor growth, angiogenesis, invasion, me-astasis, and inhibition of apoptosis. Most tyrosineinase inhibitors (TKIs) work by binding to andccupying the kinase pocket, thus robbing theinase of its phosphate source (preventing phos-horylation) and activation of the growth factoreceptors.45

Oral TKIs such as gefitinib and erlotinib haveeen studied as single agents in phase II MBC trialsith disappointing results.6,39 The lack of response

n these studies may have been because of the inac-ivity of EGFR inhibition alone, patient selectionadvanced stage, highly refractory disease), or in-bility to accurately identify tumors that are sensi-ive to EGFR inhibitors.39 Identification of EGFRandidates by cellular levels of EGFR may be flawedecause this method does not reflect the activatedorm of the receptor. High levels of serum EGFR areot predictive of response to therapy.45

Multiple signaling pathways contribute to theevelopment and growth of the cancer cell, so it isealistic to target more than one pathway whenesigning treatment. The dual approach, or pan-ER inhibitor methodology, showed a synergistic

ffect in earlier phase I trials for a variety of solid

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TARGETING METASTATIC AND ADVANCED BREAST CANCER 43

umors.58 Lapatinib (Tykerb; GlaxoSmithKline,esearch Triangle Park, NC), a dual kinase inhib-

tor showed a statistically significant increase inime to progression in combination with capecit-bine in Her2-overexpressing refractory, locallydvanced or MBC in a recently completed, openabel, phase III clinical trial (EGF100151).59 Lapa-inib targets both HER1 and HER2.60-62 A phase IIrial in women with relapsed or refractory inflam-atory breast cancer showed a 69% response

ate.63 Lapatinib is an oral therapy that showed a5% response rate as first-line treatment inomen with advanced breast cancer. The most

requently reported adverse events have been pruri-us, skin rash, diarrhea, acne, and dry skin.59,63,64

here is some evidence that lapatinib also crosseshe blood-brain barrier and is currently in phase IIesting for HER2-overexpressing breast cancerrain metastases.65 Further information is availablet http://www.gsk.com/ControllerServlet?appId�&pageId�402&newsid�703. An oral multi-tar-eted TKI investigational agent SU11248, alsonown generically as sorafenib (Sutent; Pfizer, Laolla CA), has shown both antiangiogenic and anti-umor activity by inhibiting VEGF-1, VEGF-2, plate-et derived growth factor receptor, and c-kit andlt-3 receptor tyrosine kinases.43,66 Sorafenib isDA-approved in the treatment of advanced renalell carcinoma and gastrointestinal stromal tumors.

he Future of Targeted Therapy

ledge and Miller39 suggested that future treatmentf breast cancer may involve a highly individualizedene chip technology that will design treatment spe-ifically targeted to the genetic and related charac-eristics of one person’s cancer. They also postulatedhat agents that have not shown activity in prior

linical trials may be studied again as methodologies i

REFEREN

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mO

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HU

cE

ecome available to identify a tightly defined sub-opulation that may show benefit.39

The discovery of a variety of genetic variationsn breast cancer has led researchers to the con-lusion that breast cancer is not a single, homog-nous disease, but rather a heterogeneous groupf diseases. Analysis of tissue samples from par-icipants in the National Adjuvant Surgical Breastnd Bowel Program B-31 clinical trial indicatedhat HER2-positive breast cancer patients maylso have amplification (extra copies) of the-MYC gene in addition to amplification of theER2 gene. Women with amplification of bothenes have a lower risk of recurrence followingreatment with chemotherapy and trastuzumabhan patients with amplified HER2 alone.67 De-ning new pathways that influence the develop-ent and progression of cancer and understand-

ng the crosstalk that occurs between theseathways will provide novel targeted pathwaysor the future. Gene therapy may be directedgainst cancer in the form of replacing nonfunc-ional or mutated tumor-suppressor genes.ther potential sources of targeted cancer drugs

nclude antisense and ribozyme therapeuticshat selectively target oncogenes for suppres-ion or destruction.The ultimate goal in the care of women with

ocally advanced and MBC is to find a cure. If cures not possible, then reducing this disease to aontrollable, chronic disease will only be possibley meeting three diagnostic and treatment chal-enges: (1) finding efficacious combinations of tar-eted therapies in such a way as to maximize theull synergistic potential; (2) identifying the pa-ients at the molecular level for whom these tar-eted therapy combinations will have the greatest

mpact; and (3) maintaining QOL.68

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herapy: wave of the future. J Clin Oncol 2005;23:1776-1781.9. Jensen E, DeSombre E, Jungblut P. Estrogen Receptors in

ormone Responsive Tissues and Tumors. Chicago, IL:niversity of Chicago Press: 1969.10. Yarden Y. The EGFR family and its ligands in human

ancer: signaling mechanisms and therapeutic opportunities.

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44 S. MOORE AND M.A. COBLEIGH

11. Reese DM, Slamon DJ, HER-2/neu signal transduction inuman breast and ovarian cancer. Stem Cells 1997;15:1-8.12. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational

tudy of the efficacy and safety of humanized anti-HER2 mono-lonal antibody in women who have HER2-overexpressingetastatic breast cancer that has progressed after chemother-

py for metastatic disease. J Clin Oncol 1999;28:2639-2648.13. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and

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TARGETING METASTATIC AND ADVANCED BREAST CANCER 45

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