Targeted Therapiesin Early-StageBreast Cancer:Achievementsand Promises

George W. Sledge Jr, MD*, Aparna C. Jotwani, MD, Lida Mina, MD

KEYWORDS

� Breast cancer � Targeted therapy � HER2 � Chemotherapy

One of the most impressive changes in the therapeutic landscape of breast cancer in thepast decade has been the advent of targeted therapies for specific subtypes. This articlediscusses the meaning of targeted therapy and examines the genomic basis for targetedtherapyas it hasemergedover thepast decade. Humanepidermalgrowth factor receptor2 (HER2)–targeted therapy, the principle example of targeted therapy to enter the adju-vant arena in the past decade, is described in depth. Novel targeted therapies underdevelopment, many currently being examined in the adjuvant setting, are also explored,including anti–vascular endothelial growth factor therapy, poly (ADP ribose) polymerase(PARP) inhibition for triple-negative breast cancers, and agents targeting site-specificmetastasis to the bone (receptor activator of NF-kB [RANK] ligand [RANKL] inhibition).Chemotherapy, the epitome of nonspecific anticancer therapy, is in the process ofbecoming targeted therapy as understanding of breast cancer biology improves.

WHAT IS MEANT BY TARGETED THERAPY?

The meaning of the term targeted therapy is open to wide interpretation. At its mostbasic level, targeted therapy might simply imply that a drug has a specific moleculartarget, but this is a very low-level definition, because all therapeutic agents havemolecular targets.1 Saying that a taxane targets microtubules and is therefore targetedtherapy renders the concept essentially trivial and meaningless.

Indiana University, Simon Cancer Center, Indiana Cancer Pavilion, RT-473, 535 Barnhill Drive,Indianapolis, IN 46202, USA* Corresponding author.E-mail address: gsledge@iupui.edu

Surg Oncol Clin N Am 19 (2010) 669–679doi:10.1016/j.soc.2010.04.005 surgonc.theclinics.com1055-3207/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

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Instead, the authors previously suggested that targeted therapy should havea broader and more inclusive meaning.1 Useful elements in defining targeted therapymight include the following:

1. The drug has a specific molecular target, which is the lowest level of meaning fortargeted therapy. However, the idea is implied that the target should be a relativelyspecific one (ie, the more promiscuous the agent in its molecular targets, the less itshould be considered a targeted therapy.

2. The target is biologically relevant (eg, part of the malignant phenotype) for specificcancers. The estrogen receptor (ER) is biologically relevant to the growth of specifichuman breast cancers, as is HER2. Replicating DNA is relevant to the malignantphenotype but is nonspecific (rendering most chemotherapeutics poor examplesof targeted therapy).

3. The target is reproducibly measurable in individual patients. Tamoxifen is usefulbecause estrogen receptor can be measured. Trastuzumab is useful becauseHER2 can be measured with some reliability using immunohistochemistry orfluorescence in situ hybridization. The robustness of the ability to assay a targettherefore becomes of crucial importance. However, this does not necessarilyimply that the target must always be measured. For instance, the presenceof a B-cell lymphoma or of a chronic myelogenous leukemia routinely indicatesthe presence of the molecular target for these tumors.

4. The presence of that measurable target correlates with clinical benefit whenthe therapy is used. A targeted therapy used for every patient with breastcancer by definition cannot be targeted in any meaningful sense. Hormonaltherapy only benefits patients who are estrogen receptor–positive, and trastu-zumab’s real benefits are (probably) confined to patients with HER2-positivecancers.

TARGETED THERAPY IN THE CONTEXT OF GENOMICS

One of the profound revolutions in the understanding of breast cancer occurred in thepast decade, with the realization that breast cancer was not a single disease but ratherseveral diseases that happened to arise from the same organ.2,3 The new technologyof cDNA microarrays allowed the examination of large numbers of expressed genes inhuman breast cancer. Bioinformatic exploration of relatively large patient cohorts foroutcome end points such as disease-free and overall survival in the context of geneexpression followed rapidly.4

It became obvious breast cancer was, from a genetic standpoint, a collection ofdiseases. Unsupervised cluster analysis defined luminal, basal, cerbB21, and‘‘normal’’ breast subtypes (though the ‘‘normal’’ subtype may prove to have been arti-factual).2 The luminal cancers (so called because their expression profile resembledthat of luminal cells of milk ducts) were further divisible into A and B subtypes. Thesesubtypes paralleled clinical subtypes long recognized by physicians. Luminal cancersshow substantial overlap with ER-positive tumors, and, in their A and B subtypes, rela-tively hormone-sensitive and -insensitive ER-positive breast cancers. Basal cancers,in contrast, overlap with what so-called triple-negative’’ breast cancers (ER-, proges-terone receptor [PR]–, and HER2-negative), and c-erbB2– (HER2) positive tumorswere self-explanatory. Although clinicians might believe that unsupervised clusteranalysis ‘‘told us what we already knew,’’ when these studies first became availablephysicians rarely considered basal tumors a biologically distinct subset, nor werethey aware of distinct genomic subsets within the luminal (ER-positive) subgroup.

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From a therapeutic standpoint, and for the point of this article, this genomic clus-tering offers an underlying biologic rationale for the basic approaches to systemictherapies in breast cancer, and more specifically for targeted therapy of breast cancer.We will not focus on hormonal therapy as a targeted therapy (although ER-targetedtherapies are arguably the first targeted therapy in all of cancer medicine), but willinstead focus on other existing and novel molecular targets with potential adjuvantbenefits for early-stage breast cancer.

HER2-TARGETED THERAPY

The HER family of receptor tyrosine kinases plays an important role in breast cancerbiology. These transmembrane receptor tyrosine kinases have a standard motifcomprising an external (ligand-binding) domain, a transmembrane domain, and aninternal tyrosine kinase domain.5 HER2 particularly has long attracted the attentionof scientists because of its profound effect on tumor biology in the tumors in whichit is amplified (approximately 15%–20% of patients with breast cancer). HER2 drivesgrowth, invasion, and metastasis of breast cancers, and in the past its presence ina primary breast cancer was associated with increased risk for, and early deathfrom, breast cancer.6–8

In the mid-1990s, the concurrent development of reliable assays for HER2 overex-pression (using immunohistochemistry) and amplification (using fluorescence in situhybridization), and the development of the first agent targeting HER2 (the humanizedmonoclonal antibody trastuzumab), led to the first clinical trials specifically targetingHER2 in the metastatic setting. In a pivotal phase III trial in the front-line metastaticbreast cancer setting, Slamon and colleagues9 showed that addition of trastuzumabto standard chemotherapy regimens improved both progression-free and overallsurvival.

This demonstration of the benefits of targeted therapy for HER2-positive metastaticdisease led rapidly to the development of adjuvant therapy trials for HER2-positiveearly-stage breast cancer. Several large trials testing HER2-targeted therapy in theadjuvant setting have been presented, and provide stunning confirmation for thebenefits of targeted therapy in the context of HER2-positive breast cancer. Two NorthAmerican studies, the National Surgical Adjuvant Breast and Bowel Project (NSABP)B-31 trial and the North Central Cancer Treatment Group (NCCTG)–coordinated Inter-group trial N9831, merged their chemotherapy control arms (doxorubicin and cyclo-phosphamide followed by paclitaxel) in a comparison with the same regimens plusa year of trastuzumab for a joint analysis. They reported a highly significant 49%reduction in the risk for disease recurrence with sequential trastuzumab (4-yeardisease-free survival, 86% vs 73%; hazard ratio [HR], 0.51) and a 37% reduction inthe risk of death (4-year overall survival, 93% vs 89%; HR, 0.63).10

These results were confirmed by the Herceptin Adjuvant (HERA) trial, in which 5090women with HER2-positive (node-negative or -positive) early breast cancer under-went standard adjuvant chemotherapy and then were randomly assigned to eitherobservation or the addition of trastuzumab for 1 or 2 years after completion of thecytotoxic chemotherapy regimen chosen by their oncologist. A significant reductionin disease-free survival (36%) and a significant improvement in overall survival(34%) was reported.11

Subsequently, the BCIRG 006 study examined the role of non–anthracycline-basedchemotherapy in combination with trastuzumab. Patients receiving trastuzumab inthe context of anthracycline-based chemotherapy clearly experience an increasedrisk for congestive heart failure, and preclinical studies have suggested that

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non–anthracycline-based combinations had significant activity. The Breast CancerInternational Research Group (BCIRG) 006 trial compared two anthracycline-containing regimens (doxorubicin/cyclophosphamide [AC] followed by docetaxelwith or without trastuzumab) versus a non–anthracycline trastuzumab combination(carboplatin plus docetaxel and trastuzumab [CTH]) in 3222 women with HER2-positive early breast cancer. Both trastuzumab-containing arms were superior tothe non-trastuzumab arm, and no significant efficacy difference between the 2trastuzumab-containing arms was observed (with an HR for disease-free survival of0.67 and 0.61 for AC/docetaxel/trastuzumab and TCH, respectively).12

The debate regarding the benefit of anthracyclines in HER2-positive breast cancercontinues to vex oncologists. It was first hypothesized that HER2-positive tumors aremore sensitive to anthracyclines. However this was not confirmed in the preclinicalsetting. Pegram and colleagues13 tested the sensitivity of HER2-overexpressing celllines to doxorubicin and found that HER2 overexpression alone did not predict for doxo-rubicin sensitivity. More recently, the topoisomerase II alpha gene amplification wasalso studied, given anthracyclines’ principle role as topoisomerase II alpha inhibitors.The topoisomerase II alpha gene is located on the long arm of chromosome 17 nearthe HER2 gene. Topoisomerase II alpha amplification correlates strongly with HER2overexpression.12 Several retrospective studies in the metastatic setting suggestedthat topoisomerase II alpha amplification is a predictor of anthracycline response,and results of the control arm of the BCIRG 006 adjuvant trial (ie, in the absence of tras-tuzumab) seemed to confirm this.12 Because BCIRG 006 was not powered to compareanthracycline and non–anthracycline trastuzumab-containing regimens, no solidprospective data show which approach (if either) is preferred. Both anthracycline andnon-anthracycline approaches fall within the current standard of care.

The proper duration of treatment in the adjuvant setting remains unanswered. Thefour larger clinical trials (NSABP B-31, N9831, HERA, and BCIRG 006) have used atleast 1 year of adjuvant trastuzumab. The results of the HERA trial arms of 1 versus2 years of adjuvant trastuzumab are awaited. In contrast, the smaller FinHer trial sug-gested that as little as 9 weeks might provide the same efficacy with less toxicity,which in turn has led to trials examining a shorter duration of therapy.14 Current prac-tice uses a standard 1-year regimen.

Although trastuzumab-based regimens remain the standard of care in the adjuvantHER2 setting, newer agents have entered the HER2 arena. Lapatinib is an oral smallmolecule receptor tyrosine kinase inhibitor of both epidermal growth factor receptorand HER2. Preclinical data suggest that it is synergistic with trastuzumab againstHER2-positive breast cancer. It was recently approved for advanced HER2-positivemetastatic breast cancer, because it showed activity in trastuzumab-refractory meta-static disease in combination with capecitabine in a large phase III randomized trial.15

Lapatinib’s role is currently being examined in the adjuvant setting in the international,multi-group Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO)trial, which randomizes patients undergoing standard chemotherapy approaches toreceive either trastuzumab, lapatinib, the combination of the two drugs, or theirsequential use.

NOVEL APPROACHES: ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY

Evidence for a role of angiogenesis (new blood vessel formation) in breast cancer isderived from several independent lines of evidence. Beginning in the early 1990s,evidence emerged that tumor microvessel density in human breast cancers was asso-ciated with an increased risk for relapse and death. Proangiogenic factors are readily

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measurable in early breast cancers, and vascular endothelial growth factor (VEGF) inparticular is associated with an increased risk for recurrence and death in patients withearly-stage breast cancer.16 Increased VEGF production by breast cancers is alsoassociated with an increased risk for brain and visceral metastasis. HER2 amplifica-tion is also associated with increased VEGF production in human breast cancers, sug-gesting this important breast cancer subtype as a particular target of interest.17,18

The improved understanding of VEGF biology suggested several potential means oftargeting the VEGF system.19,20 The VEGFs are a family of five related glycoproteins(VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor) that act through threetype III receptor tyrosine kinases (VEGFR-1, VEGFR2, VEGFR-3); in addition the neu-ropilins (NP1 and NP2) act as coreceptors for the VEGFRs, increasing the bindingaffinity of VEGF to VEGFR tyrosine kinase receptor. The functional effects of VEGFdepend on which ligand-receptor complex is activated.

The VEGF axis may be attacked in multiple ways, including (among FDA-approvedagents) ligand-binding agents (eg, bevacizumab), agents interfering with the VEGFreceptor tyrosine kinase (eg, sunitinib, sorafenib), agents interfering with downstreameffectors of VEGF activity (eg, mammalian target of rapamycin [mTOR] inhibitors), andagents that indirectly affect angiogenesis through modulation of VEGF production(eg, HER2-targeting agents).

Of these approaches, ligand inhibition with bevacizumab is currently the only FDA-and European Medicines Agency (EMEA)–approved agent for metastatic breastcancer. This approval is based on two randomized controlled trials. E2100 randomizedwomen to receive paclitaxel alone or in combination with bevacizumab as front-linetherapy for HER2-negative metastatic disease,21 and the AVADO trial randomizeda similar patient population to receive docetaxel alone or in combination with bevaci-zumab at one of two doses.22 Both trials showed a statistically significant improve-ment in progression-free survival. Neither showed a significant improvement inoverall survival, although both were relatively poorly powered to show a survivaladvantage. Other phase II metastatic trials have suggested that patients HER2-positive advanced breast cancer might benefit from the combination of anti-VEGFtherapies with anti-HER2 therapies.23,24

Based on the results in advanced disease, adjuvant trials have been initiated in bothHER2-negative and HER2-positive populations. E5103 randomizes women withlymph node–positive and high-risk lymph node–negative disease to receive eithera backbone chemotherapy regimen (AC followed by paclitaxel) alone or in combina-tion with bevacizumab (administered either for the duration of chemotherapy or fora total of a year of therapy). The BEvacizumab and Trastuzumab Adjuvant Therapyin HER2-positive Breast Cancer (BETH) trial randomizes patients with HER2-positive breast cancer to undergo either a standard chemotherapy/trastuzumabcombination or the same with bevacizumab. Both are large, well-powered trials withprimary disease-free survival end points and secondary overall survival end points.

Whether bevacizumab (or other VEGF-targeting agents) can legitimately be calledtargeted therapy is currently uncertain. Although the molecular target (VEGF) is welldefined and readily measurable, a specific subpopulation benefiting from anti-VEGFtherapy cannot currently be defined. Early investigations suggested that specificsingle nucleotide polymorphism variants of VEGF may be associated with clinicalbenefit in the metastatic setting, an observation that is currently being examined aspart of the large E5103 adjuvant bevacizumab proof-of-concept trial.25

Concerns have been raised regarding the potential benefits of anti-VEGF therapy in theadjuvant setting. The vasculature of micrometastases and overt metastases may differsignificantly, and therefore benefits seen in the overt metastatic setting may not translate

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to the adjuvant setting. Preclinical studies in some animal models of micrometastaticdisease have suggested that anti-VEGF therapy may actually promote the developmentof metastases, although these models are open to question on several grounds.26 Finally,the adjuvant colorectal NSABP C-08 trial failed to show a statistically significant clinicalbenefit regarding its primary disease-free survival end point. The results of ongoingadjuvant bevacizumab trials are therefore awaited with some trepidation.

NOVEL APPROACHES: CHEMOTHERAPY AS TARGETED THERAPY

Although chemotherapeutic agents have specific molecular targets (typically DNA ormicrotubules), their relative nonspecificity has argued against defining them as tar-geted agents. Modern genomic analyses are well on their way to changing thisperception. The identification of genomic subgroups within the luminal breast cancersallows subpopulations with specifically greater or lesser benefit with adjuvant chemo-therapy to be defined. In general, patients with ER-positive breast cancer experiencingbenefit (across several genomic classification platforms) are characterized by rela-tively high proliferation rates and relatively lower ER concentrations.27 This findinghas allowed clinicians (using commercially available assays such as Oncotype DXand Mammaprint) to offer adjuvant chemotherapy as targeted therapy for early-stage disease and, more importantly, to avoid toxic therapies when the therapeutictarget (rapidly proliferating cancer cells) is not present.28 More recently, the initialobservations seen in lymph node–negative breast cancer have been extended tothe lymph node–positive, ER-positive setting.29

The first-generation genomic tests (eg, Oncotype DX, Mammaprint) define the roleof relatively generic chemotherapy regimens as targeted therapy. Future develop-ments in this arena will undoubtedly identify individual chemotherapy agents as tar-geted therapies based on their genomic or proteomic characteristics.

NOVEL APPROACHES: PARP INHIBITION FOR TRIPLE-NEGATIVE (BASAL)BREAST CANCER

Genomic analyses showed the existence of a genomically distinct subpopulation ofbreast cancers now called basal or triple-negative breast cancer (the latter basedon the lack of ER, ER, and HER2). This population of patients constitutes approxi-mately 15% of those with newly diagnosed breast cancer, and is clinically significantboth because of its relative aggressiveness and the lack of available targeted thera-pies.30 This subpopulation represents the common ‘‘home’’ for BRCA-1 mutatedbreast cancers. In addition, many non–BRCA-mutated breast cancers havea BRCA-like phenotype.

These observations have led to the development of the first targeted therapeutics fortriple-negative breast cancers. The most promising targeted therapy currently beingexamined is PARP inhibition in triple-negative and BRCA-mutated cancers. PARPsare DNA-binding proteins involved in detection and repair of single-stranded DNAbreaks. Triple-negative and BRCA-deficient cancers have impaired homologousdouble-stranded DNA repair mechanisms. In this setting, a compensatory pathwayof DNA repair known as base excision repair (BER), which is dependent on the functionof PARP, allows the cancer cell to recover from DNA damage by upregulation ofPARP.31,32

Multiple PARP inhibitors are under development, two of which (BSI-201 and ola-parib) have shown promising results in phase II studies presented at the 2010 Amer-ican Society of Clinical Oncology meetings. O’Shaughnessy and colleagues33

reported the results of a randomized phase II trial of chemotherapy (carboplatin/

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gemcitabine) with or without BSI-201 in 123 women with triple-negative metastaticbreast cancer. The overall response rate was 16% in the group of patients treatedwith chemotherapy alone and 48% among those who underwent chemotherapyplus BSI-201 (P 5 .002). A striking improvement was also seen in progression-freeand overall survivals in patients treated with BSI-201 (progression-free survival, 3.3vs 6.3 months, P<.0001; overall survival, 5.7 vs 9.2 months; P 5 .0005). Surprisingly,the addition of BSI-201 was not reported to be associated with additional toxicity.

Tutt and colleagues34 reported a single-arm phase II study of olaparib in 54 patientswith metastatic breast cancer carrying a BRCA mutation. Impressive results werereported, with response rates as high as 41% and median progression-free survivalof 5.7 months when olaparib was given at a dose of 400 mg orally twice daily. Again,toxicity was very tolerable. These remarkable results are currently being confirmed inongoing phase III trials.

If the results of the first phase III trials with PARP inhibition in metastatic diseaseconfirm earlier phase II findings, they will be followed with phase III trials in the adju-vant setting for patients with triple-negative breast cancers. Pilot trials examiningnovel combinations and schedules in the adjuvant setting are underway. The presenceof distinct molecular targets (BRCA mutations) that are clinically measurable suggeststhe possibility that PARP inhibition my also find a place in the breast cancer preventionsetting, a concept being examined in pilot studies currently being developed under theauspices of the National Cancer Institute.

NOVEL APPROACHES: TARGETING SITE-SPECIFIC BONE METASTASIS

Breast cancer has long been characterized by the presence of site-specific metastasis,with bone metastasis being the most common specific site. In patients with metastaticbreast cancer, the incidence of bone metastases is 73%.35,36 In addition, bone healthand maintenance of bone integrity are important issues for clinicians treating breastcancer patients.37 Treatment considerations include local (eg, surgery, radiation) andsystemic disease control (eg, chemotherapy; biologic and endocrine therapy).

Systemic therapies can be associated with late effects that impact bone health. Anestimated 50% to 70% of premenopausal women who have undergone adjuvantchemotherapy will develop permanent ovarian failure or early menopause.Chemotherapy-induced ovarian failure is considered a high-risk factor for boneloss.38 Adjuvant hormonal therapies that decrease circulating estrogen levels alsoplace breast cancer patients at increased risk for osteoporosis. Recently, aromataseinhibitors have been found to improve progression-free survival and have feweradverse effects compared with tamoxifen, the historical standard, in postmenopausalwomen with hormone receptor–positive, early-stage breast cancer.

Bone is a dynamic tissue that is continually undergoing formation through osteo-blastic activity and resorption through osteoclastic activity. This system is tightlycontrolled and balanced by many factors, but the dominant pathway that controlsnormal bone remodeling is the RANK/RANKL/osteoprotegerin (OPG) signaling triad.39

Osteoblasts and bone marrow stromal cells secrete RANKL and OPG. Binding ofRANKL to its receptor RANK on the surface of osteoclast precursors stimulates osteo-clastogenesis. OPG is a soluble decoy receptor for RANKL. Through binding toRANKL, OPG prevents the interaction between RANKL and RANK to regulate exces-sive bone resorption.40 Estrogen effects bone through decreasing osteoclasts andstimulating osteoblastic activity.41 Thus, estrogen deficiency leads to increasedbone resorption and rapid bone loss.41

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The mechanism of bone metastases involves bone destruction, which is mediatedby osteoclasts. Osteoclasts require the RANKL for their maturation, function, andsurvival.42–44 Binding of RANKL to the osteoclasts stimulate increased bone resorp-tion and the release of other growth factors that trigger a cycle of bone destructionand tumor cell proliferation, in addition to the migration of tumor cells to thebone.45,46

Denosumab is a fully human monoclonal antibody that specifically inhibits RANKLand therefore inhibits osteoclast function and bone resorption.47–50 Given subcutane-ously, a single dose was shown to suppress bone turnover for up to 6 months in post-menopausal women with low bone mass.47 In a small, randomized, double-blind studyto determine the safety and efficacy of denosumab in patients with radiologicallyconfirmed bone metastases from either breast cancer (n 5 29) or multiple myeloma(n 5 25), denosumab was found to suppress bone turnover for up to 84 days andwas well tolerated.49

Promising results in phase II trials of denosumab led to a larger phase III studyinvolving more than 2000 patients.51 This trial randomized patients with metastaticbreast cancer to either subcutaneous denosumab and intravenous placebo (n 51026) or subcutaneous placebo and intravenous zoledronic acid (n 5 1020). Prelimi-nary reports indicate that denosumab was superior to zoledronic acid in delayingthe time to first on-study skeletal-related event (SRE), and overall survival and timeto progression were similar in both arms.

Although denosumab is not yet approved for use in the United States for themanagement of bone metastases from breast cancer, these studies define it asa potential new targeted therapy for metastatic breast cancer. In the near future, deno-sumab will be studied in the adjuvant setting for patients with breast cancer. Denosu-mab is also under investigation for the treatment of bone loss associated witharomatase inhibitors. A randomized, double-bind, placebo-controlled phase III trialin postmenopausal women with ER-positive breast cancer undergoing adjuvanthormonal therapy with an aromatase inhibitor plus calcium and vitamin D supplemen-tation compared placebo (n 5 125) with subcutaneous denosumab (n 5 127) every 6months.52 The twice-yearly administration of denosumab led to significant increasesin bone mineral density, with similar overall adverse effect rates.

Although denosumab is arguably the first therapy for site-specific bone metastasiswith a specific molecular target, it is not the first approach to site-specific bone metas-tasis. Several phase III trials have examined the role of bisphosphonate therapies forbone metastasis in breast cancer, and several of these trials indicate that the use ofbisphosphonates may reduce the incidence of bone (and other) metastases.

SUMMARY

Targeted therapy in the adjuvant setting is now a clinical reality. Targeted therapieshave a basis in the underlying genomics of breast cancer, with genomic subpopula-tions of breast cancer paralleling (to greater or lesser extent) existing therapeutic cate-gories for the disease. Although targeting of ER and HER2 have led the way, newertargeted therapies are rapidly advancing toward the clinic in the adjuvant setting.Although not all of these may arrive, the future certainly seems promising. The abilityto identify specific lesions at the molecular and cellular levels, together with theincreasing availability of agents targeting these specific lesions, will increasingly domi-nate breast cancer therapeutics. These agents should improve outcomes of allpatients with early-stage breast cancer, and simultaneously diminish the toxicityexperienced.

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