Phase II Study of Weekly Intravenous Trastuzumab (Herceptin)
`in Patients With HER2/neu-Overexpressing
`Metastatic Breast Cancer
`
`Jose Baselga, Debasish Tripathy, John Mendelsohn, Sharon Baughman, Christopher C. Benz, Lucy Dantis,
`Nancy T. Sklarin, Andrew D. Seidman, Clifford A Hudis, Jackie Moore, Paul P. Rosen,
`Thomas Twaddell, I. Craig Henderson, and Larry Norton
`
`The HER2/neu proto-oncogene is overexpressed in 25%
`to 30% of patients with breast cancer. Trastuzumab
`(Herceptin; Genentech, San Francisco, CA), a recom(cid:173)
`binant humanized monoclonal antibody with high affin(cid:173)
`ity for the HER2 protein, inhibits the growth of breast
`cancer cells overexpressing HER2. In this phase II study
`the efficacy and toxicity of weekly administration of
`trastuzumab was evaluated in 46 patients with meta(cid:173)
`static breast cancer whose tumors overexpressed
`HER2. A loading dose of 250 mg trastuzumab was
`administered intravenously, which was followed by I 0
`weekly doses of I 00 mg each. Upon completion of this
`treatment period, patients with no disease progression
`could receive a weekly maintenance dose of I 00 mg.
`Patients in this trial had extensive metastatic disease,
`and most had received prior anticancer therapy.
`Ninety percent of patients achieved adequate serum
`levels of trastuzumab. Toxicity was minimal, and no
`antibodies against trastuzumab could be detected. Ob(cid:173)
`jective responses were observed in 5 of the 43 evalu(cid:173)
`able patients, which included I complete remission and
`4 partial remissions, for an overall response rate of
`I 1.6%. Responses were seen in mediastinum, lymph
`nodes, liver, and chest wall lesions. Minor responses
`(seen in 2 patients) and stable disease (14 patients)
`lasted for a median of 5.1 months. These results dem(cid:173)
`onstrate that trastuzumab is well tolerated and clini(cid:173)
`cally active in patients with HER2-overexpressing met(cid:173)
`astatic breast cancers who have received extensive
`prior therapy. The regression of human cancer through
`the targeting of putative growth factor. receptors such
`as HER2 warrants further evaluation ot trastuzumab in
`the treatment of breast cancer.
`
`From the Department of Medicine, Services of Breast and Gy(cid:173)
`necological Cancer Medicine and Clinical Immunology, Department
`of Pathology, Memorial Sloan-Kettering Cancer Center, New York,
`NY; Division of Oncology, University of California, San Francisco,
`CA; and Pharmacol<inetics and Metabolism and Clinical Research,
`Genentech, Inc, South San Francisco, CA.
`Dr Baselga has received research grant support from Genentech,
`Inc.
`Supported in part by an American Society of CUnical Oncology
`Career Development Award (J.B.), an S.P.O.R.E. grant (p50-
`CA58207) from the National Cancer Institute, and Genentech,
`Inc.
`Address reprint requests to Jose Baselga, MD, Department of
`Medical Oncology, Vall d'Hebron University Hospital, Paseo Vall
`d' Hebron 119', 129, 08035 Barcelona, Spain.
`Copyright© 1999 by W.B. Saunders Company
`0093-7754/99/2604-1201
`
`Semin Onco/ 26 (suppl 12):78-83. Copyright© 1999 by
`W.B. Saunders Company.
`
`D URING the last decade, proto-oncogenes
`
`encoding growth factors and growth factor
`receptors have been found to play important roles
`in the pathogenesis of several human malignan,
`. cies, including breast cancer .1 The HER2 gene
`(also known as neu and c-erbB-2) encodes a
`185-kd
`transmembrane glycoprotein
`receptor
`(p185HERZ) that has partial homology with the
`epidermal growth factor receptor. Both receptor
`molecules have intrinsic tyrosine kinase activ,
`ity. 2-4 Overexpression of HER2, which occurs in
`25% to 30% of human breast cancers, 5•6 is an
`independent predictor of poor prognosis in pa,
`tients with primary disease involving axillary
`lymph nodes. 5,7,s Several lines of evidence support
`a direct role for HER2 in the pathogenesis and
`clinical aggressiveness of HER2-overexpressing tu,
`mors: (1) the introduction of HER2 into nonneo,
`plastic cells causes their malignant transforma(cid:173)
`tion,9,10 (2) transgenic mice expressing HER2
`develop mammary tumors, 11 (3) HER2 overex(cid:173)
`pression is common in ductal carcinoma in situ
`and in associated invasive cancers, 1Z,l3 and ( 4)
`antibodies directed at pl85HERZ can inhibit the
`growth of tumors and transform cells that express
`high levels of this receptor. 14-18 The latter obser(cid:173)
`vation suggests that pl85HERZ may be a potential
`target for the treatment of breast cancer or prein(cid:173)
`vasive breast lesions because these cells commonly
`overexpress HER2.
`The murine monoclonal antibody (MoAb)
`4D5, directed against the extracellular domain of
`pl85HERZ (ECDHER2), is a potent inhibitor of
`growth in vitro and in xenograft models of human
`breast cancer cells overexpressing HER2.19-21 Mu(cid:173)
`rine antibodies, however, are limited clinically be(cid:173)
`cause they are immunogenic. To facilitate further
`clinical investigations, MoAb 4D5 was human(cid:173)
`ized. Monoclonal antibody 4D5 was initially de(cid:173)
`rived by immunizing mice with cells expressing
`high levels of the HER2 gene product, plSSHERZ.19
`Recombinant humanized anti-pl85HERZ MoAb
`
`78
`
`Seminars in Oncology, Vol 26, No 4, Suppl 12 (August), I 999: pp 78-83
`
`AVENTIS EXHIBIT 2049
`Mylan v. Aventis, IPR2016-00712
`
`

`
`WEEKLY INTRAVENOUS TRASTUZUMAB
`
`79
`
`trastuzumab (Herceptin; Genentech, San Fran(cid:173)
`cisco, CA) was engineered by
`inserting
`the
`complementarity-determining regions of MoAb
`4D5 into the framework of a consensus human
`lgG 1 :22 The resulting MoA):, has high affinity for
`pl85HERZ (Kd = 0.1 nmol/L), markedly inhibits in
`vitro and in human xenografts the growth of breast
`cancer cells containing high levels of pl85HERZ
`(Fig 1), and induces antibody-dependent cellular
`cytotoxicity. 22,23 Trastuzumab was found to be safe
`and to have dose-dependent pharmacokinetics in
`two prior phase I clinical trials.
`We conducted a phase II study of trastuzumab in
`patients with metastatic breast cancer. The objec(cid:173)
`tives of the trial were to determine the antitumor
`activity of trastuzumab in this patient population
`as well as to further define the toxicity profile and
`the pharmacokinetics of trastuzumab.
`
`PATIENTS AND METHODS
`
`Patients
`Patients eligible for this study were adult women whose
`metastatic breast carcinomas overexpressed HER2 (see below).
`All patients had measurable disease, a Karnofsky performance
`status of at least 60%, and preserved hematologic, liver, renal,
`and pulmonary function. Patients with lymphangitic pulmo(cid:173)
`nary metastases, history of brain metastases, or bone metastases
`as the only site of measurable disease were excluded. Chemo(cid:173)
`therapy or additive hormonal therapy within 3 weeks before
`study entry (6 weeks for mitomycin C or nitrosoureas) was not
`permitted. Informed consent was obtained and documented in
`writing before patient entry into the study.
`
`Tumor expression of HER2 was determined by immunohis(cid:173)
`tochemical analysis, as previously described, 5•6 using a set of
`thin sections prepared from the patient's paraffin-archived tu(cid:173)
`mor blocks. The primary detecting antibody used was murine
`MoAb 4D5, which has the same complementarity-determining
`regions as trastuzumab. Tumors were considered to overexpress
`HER2 if at least 25% of the tumor cells exhibited characteristic
`membrane staining for pl85HERZ.
`
`Antibody Administration
`to achieve trastuzumab
`The pharmacokinetic goal was
`trough serum concentrations exceeding 10 µ,g/mL, a level as(cid:173)
`sociated with optimal inhibition of cell growth in a preclinical
`model.22 The optimal dose and schedule of trastuzumab was
`based on two prior phase I clinical trials, conducted at the
`University of California, Los Angeles, and at Memorial Sloan(cid:173)
`Kettering Cancer Center (New York, NY), which had docu(cid:173)
`mented dose-dependent pharmacokinetics. In the current trial,
`trastuzumab was given intravenously over a period of 90 min,
`utes in the outpatient setting. Each patient received a loading
`dose of 250 mg trastuzumab on day 0, and beginning on day 7,
`100 mg of trastuzumab weekly for a total of 10 doses. At the
`completion of this treatment period, patients having stable
`disease or minor, partial, or complete responses were entered on
`a maintenance phase of weekly trastuzumab administration
`until disease progression.
`
`Pharmacol<inetics, Determination of Extracellular
`Domain of p185HER2 Levels, and Antibodies
`Directed Against Recombinant Human
`Monoclonal Antibody HER2
`Blood samples for pharmacokinetic analysis were collected
`just before each treatment with trastuzumab and within the first
`hour following the end of each trastuzumab infusion. Serum
`concentrations of trastuzumab were determined in an assay that
`detects binding to ECDHERZ. The nominal limit of detection
`for trastuzumab in serum samples was 156 ng/mL. The presence
`of antibodies to trastuzumab was determined with a bridging(cid:173)
`type titer enzyme-linked immunoassay. Circulating concentra(cid:173)
`tions of ECDHERZ shed by the patient's tumors were also
`determined using enzyme-linked immunoassay.24 The pair of
`antibodies used for the assay were 7C2, as capture antibody,
`and 2C4, as horseradish peroxidase-conjugated antibody to
`detect the bound complex; the lower limit of detection for this
`assay ranged from 2.8 to 8.3 ng/mL.
`Serum levels of trastuzumab as a function of time were
`analyzed for each patient using a one-compartment model.
`Model parameters (volume and the elimination rate constant,
`Ke) were estimated for each patient using a maximum likeli(cid:173)
`hood estimation procedure.25 Trastuzumab half-life (t112 ) was
`calculated by dividing ln2 by Ke.
`
`Evaluation of Toxicity and Response
`Toxicity was scored based on modified National Cancer
`Institute Common Toxicity Criteria. Complete blood cell
`count, urinalysis, coagulation profile, and hepatic enzyme, re,
`nal, and electrolyte studies were performed weekly while on the
`study.
`·
`Tumor response was determined at the completion of the
`initial 11,week treatment period. All responses were confirmed
`
`Doses of Trastuzumab
`
`''''' ''' Control
`
`.,.
`E
`-2. 4
`E
`::::J
`
`5
`
`3
`
`Q)
`
`~ ... 0
`E
`i=
`
`2
`
`....................
`
`10
`
`20
`Days of Growth
`
`Trastuzumab
`
`········
`
`30
`
`40
`
`Fig I, Activity of trastuzumab against well-established BT-
`474 tumor xenografts, Trastuzumab was given intraperitone(cid:173)
`ally twice a week for 4 weeks at doses of I, 10, and 30 mg/kg.
`The data from the group treated with a dose level of IO mg/kg
`is shown here. The control group was treated with a nonspe(cid:173)
`cific humanized immunoglobulin G MoAb at a dose of 30 mg/
`kg. Trastuzumab doses ;;,, I mg/kg markedly suppressed the
`growth of the HER2-overexpressing BT-474 xenografts,
`
`

`
`80
`
`BASELGA ET AL
`
`by an independent extramu_ral evaluation committee composed
`of an oncologist and a radiologist. A complete response was
`defined as disappearan~e of all radiographically and/or visually
`apparent tumor; partial response as a reduction of at least 50%
`in the sum pf the products of the perpendicular diameters of all
`measurable lesions; minimal response as a reduction of at least
`25% and less than 50% in the diameters; stable disease as no
`change of greater than 25% in the size of measurable lesions;
`and progressive disease as an increase of 25% or more in any
`measurable lesion or the appearance of any new lesion. Al(cid:173)
`though bone metastases were not considered measurable for
`response, patients were required to have at least stable bone
`lesions to be considered responders. Patients who had entered
`the maintenance phase of the study had their tumor responses
`evaluated every 11 weeks or earlier if clinically indicated. Time
`to tumor progression was calculated from the beginning of
`therapy to disease progression. The confidence limits for re(cid:173)
`sponse rates were calculated using the exact method for a single
`proportion. 26
`
`RESULTS
`
`Forty-six patients were enrolled in the study.
`Patient characteristics are shown in Table 1. Their
`level of tumor overexpression of HER2 was rela(cid:173)
`tively high, with more than 80% of the tumors
`exhibiting positive membrane staining in more
`than half of the cells. Our patient population had
`extensive metastatic disease: 34.5% of the patients
`had three or more metastatic sites. Dominant sites
`of metastases were visceral in 80% of cases (lung in
`18 cases, liver in 13 cases, both liver and lung in
`five cases, and ovary in one case). Only 17.4% of
`cases had dominant metastases in soft tissues (skin,
`lymph nodes), and one patient had bone as the
`dominant site of disease. The total number of
`patients with bone disease was 18 (39%). All but
`one of the patients had received prior chemother(cid:173)
`apy, with 82.6% having received at least one reg,
`imen for metastatic disease and 63% having re(cid:173)
`ceived two or more regimens. Of this latter group,
`four patients had previously received high-dose
`chemotherapy with hematopoietic stem cell sup,
`port.
`trastuzumab pharmacokinetics are
`Data on
`available from 45 patients (Table 2). Over 90% of
`the examined population ( 41 patients) had trastu(cid:173)
`zumab trough levels above the targeted 10 µ,g/mL
`level. The mean serum half-life of trastuzumab was
`8.3 ± 5.0 days (mean± S.D.). As shown in Table
`2, trastuzumab serum half-life was found to depend
`on the presence of circulating ECDHERl released
`from the tumor into the serum. Antibodies against
`trastuzumab (human antihuman antibodies) were
`not detected in any patients.
`Treatment with trastuzumab was remarkably
`
`Table I. Patient Characteristics
`
`Level of HER2 expression*
`25% to 50% of cells
`>50% of cells
`Receptor status
`Estrogen receptor-positive (n = 40)
`Progesterone receptor-positive (n = 39)
`No. of metastatic sites
`I
`2
`;,,3
`Dominant site of metastasis
`Viscera
`Skeleton
`Soft tissues
`Prior therapy
`Chemotherapy
`Adjuvant chemotherapy
`Neoadjuvant chemotherapy
`Metastatic diseaset
`None
`I regimen
`2 regimens
`>2 ~egimens
`Hormonal therapy
`Adjuvant tamoxifen
`Metastatic disease
`
`Patients,
`n=46(%}
`
`7 (15.2)
`39 (84.8)
`
`17 (42.5)
`15 (38.5)
`
`16 (34.5)
`14 (30.4)
`16 (34.5)
`
`37 (80.4)
`I (2.2)
`8 (17.4)
`
`45 (97.8)
`26 (56.5)
`4(8.7)
`
`8 (17.4)
`9 (19.6)
`9 (19.6)
`20 (43.5)
`
`7 (15.2)
`21 (45.6)
`
`NOTE. The median patient age was SO years (range, 30 to 65
`years). The median Karnofsky performance status was 90
`(range, 60 to I 00).
`* Percent of tumor cells with cytoplasmic membrane staining.
`t Median, 2; range, 0 to 7.
`
`well tolerated (Table 3). Of768 administrations of
`trastuzumab, only 11 events occurred that were
`considered to be related to the use of the antibody.
`Fever and chills occurred on five occasions after
`administration of the first dose of trastuzumab. The
`fever lasted less than 8 hours in all cases and did
`not recur on subsequent administrations of the
`antibody. Three patients experienced chest pain in
`areas of tumor involvement shortly after infusion
`of the first dose of trastuzumab, requiring an over(cid:173)
`night admission to the hospital for pain control in
`one case. The pain did not recur on successive
`administrations of the antibody. None of the pa,
`tients whose cancer regression met the formal cri,
`teria for complete or partial response had pain at a
`tumor site after administration of trastuzumab.
`The number of patients evaluable for treatment
`response on evaluation day 77 was 43 (Table 4).
`
`

`
`WEEKLY INTRA VENOUS TRASTUZUMAB
`
`81
`
`Table 2: ECDHER2.oependent Pharmacokinetics
`of Trastuzumab
`
`Table 4, Response Rate Obtained With Trastuzumab
`in 43 Evaluable Patients
`
`N
`
`45
`
`40
`
`5
`
`Patient Grnup
`
`All patients
`Circulating ECDHER2
`<500 ng/ml
`Circulating ECDHER2
`>500 ng/ml
`
`Herceptin t 11; (d),
`Me'an ± SD
`
`8.3 ± 5.0
`
`9.1 ±4.7
`
`1.8 ± 1.0
`
`Abbreviations: t 112, serum half-life; ECD, extracellular do-
`main.
`
`Among the 43 evaluable patients, five had tumor
`responses: one patient had a complete remission
`and four had partial remissions. Therefore, the
`overall response rate (complete plus partial remis(cid:173)
`sions) for evaluable patients was 11.6% (95% con(cid:173)
`fidence interval, 4.36% to 25.9%). Two patients
`had minor responses and 14 patients had stable
`disease at day 77. These patients entered a main(cid:173)
`tenance phase of weekly antibody administration
`until progression of disease. The median time to
`progression for patients with either minor or stable
`disease was 5.1 months. After 2 weeks of treat(cid:173)
`ment, an additional patient had a greater than
`50% reduction iri the size of metastatic disease on
`the mediastinum and chest wall. While the dura(cid:173)
`tion of response was greater than 4 weeks, by
`evaluation day 77, the lesion had begun to regrow
`from the size of maximal response to therapy. Per
`protocol guidelines, this patient was therefore con(cid:173)
`sidered not to have responded to therapy but
`rather to have had progression of disease.
`
`DISCUSSION
`
`During the last decade, overexpression of the
`HER2 gene has been shown to play an important
`
`Table 3, Trastuzumab-Related Toxicity
`
`Moderate
`(Grade 2)
`
`Severe
`(Grade 3)
`
`Fever and chills
`Pain at tumor site
`Diarrhea
`Nausea and emesis
`
`5
`2
`2
`I
`
`I
`
`NOTE: Administrations of trastuzumab = 768.
`
`Complete response
`Partial response
`Overall response
`Minor response
`Stable disease
`Progression of disease
`
`N (%)
`
`I (2.3)
`4 (9.3)
`5 (11.6)
`2 (4.6)
`14 (32.6)
`22 (51.2)
`
`role in the pathogenesis and poor prognosis of
`breast cancer. As a consequence, strategies di(cid:173)
`rected at interfering with HER2 expression or the
`function of its protein, pl85HERZ, have been an(cid:173)
`ticipated to have therapeutic value. Extensive pre(cid:173)
`clinical studies have shown that certain monoclo(cid:173)
`nal antibodies directed against pl85HERZ can
`inhibit growth of HER2-overexpressing tumor
`cells.15-19 This study provides the first clinical ev(cid:173)
`idence of the antitumor activity of one of these
`agents, trastuzumab.
`Of 4 3 patients with p 185HERZ -positive tumors
`evaluable for response after treatment with trastu(cid:173)
`zumab, five experienced a complete or partial re(cid:173)
`mission, for an overall response rate of 11.6%. One
`additional patient had a greater than 50% reduc(cid:173)
`tion of cancer lasting over 1 month, but was not
`considered a responder by our protocol definition.
`The objective antitumor responses observed were
`of clinical importance since two patients had re(cid:173)
`gression of cancers in their livers and one patient
`achieved a pathologically proven complete re(cid:173)
`sponse of her chest-wall disease, which has per(cid:173)
`sisted for over 48 months. Our patients had many
`sites of metastatic involvement, which is one of
`the worst prognostic characteristics regarding re(cid:173)
`sponse to therapy. This selection was a conse(cid:173)
`quence of entry criteria, which specified that pa(cid:173)
`tients with disease involving only their bones were
`ineligible for accrual because bone is the solitary
`site of initial metastatic involvement in up to 60%
`of cases.27 It will be of interest to determine in
`follow-up studies whether the response rate to
`trastuzumab will be higher if patients with less(cid:173)
`extensive breast cancer are treated, since labora(cid:173)
`tory studies have shown that the response to anti(cid:173)
`receptor antibodies is greater with lower tumor
`burden.28 Another relevant question is whether
`the response rate to trastuzumab will be higher in
`
`

`
`82
`
`BASELGA ET AL
`
`a patient popiilation with less prior chemotherapy
`for stage IV disease, since prior experience has
`shown that untreated patients usually respond bet(cid:173)
`trr to new anticancer drugs. 29 This issue is cur(cid:173)
`rently being addressed in an ongoing clinical trial
`in which W1stuzumab is being givJn as first-line
`therapy for metastatic disease (see report by Shak
`et al in this supplement, pp 71-77).
`It is important to note that while not achieving
`a complete or partial response, 37% of patients in
`this trial achieved minimal responses or stable
`disease. In clinical trials of many anticancer drugs,
`particularly chemotherapy, the achievement of
`stable disease is not considered a reliable measure
`of anticancer activity. With trastuzumab, however,
`stable disease may be an authentic reflection of the
`biological action of the drug, which differs mark(cid:173)
`edly from conventional anticancer agents. In the
`laboratory, trastuzumab has been noted to be cy(cid:173)
`tostatic, causing growth arrest, rather than cyto(cid:173)
`cidal, causing cell death. The unusually long du(cid:173)
`rations of minimal responses and stable disease
`seen in our trial may relate to this distinction.
`These data are especially interesting in light of the
`absence of significant toxicity observed here, since
`in a setting in which palliation is a main objective,
`quality of life while on treatment should be a main
`end point.
`The dose and schedule of trastuzumab adminis(cid:173)
`tration used in this protocol provided adequate
`serum concentrations in all patients, except in
`those with circulating
`levels of
`tumor-shed
`ECDHERZ at serum concentrations greater than
`500 ng/mL. ECDHERZ is known to be released
`by some breast cancer cells that overexpress
`HER230-32 and elevated ECDHERZ serum levels
`have been reported previously in patients with
`breast cancer.31 ,33,34 Our initial explanation for the
`short serum half-lives and subtherapeutic trough
`levels of trastuzumab in this group of patients was
`that in the presenGe of ECDHERZ in the serum,
`antigen-antibody complexes form and are rapidly
`cleared from the circulation. An alternative expla(cid:173)
`nation is that a higher level of ECDHERZ in the
`serum may correlate with a higher tumor burden.
`However, it is important to notice when analyzing
`the data presented that our sample population was
`small and patients had large tumor burdens.
`Hence, the effects of elevated serum ECDHERZ
`levels on trastuzumab pharmacokinetics and re(cid:173)
`sponse to therapy must be further defined in larger
`follow-up studies.
`
`There are several possible mechanisms, which are
`not mutually exclusive, that could explain the
`clinical results observed. The first is based on the
`observation that trastuzumab induces a marked
`d~wnreguhJ.tion of pl85HER2
`.19 Antibody-induced
`downregulation of pl85HERZ has been shown to in(cid:173)
`duce reversion of the transformed phenotype in
`HER2-transformed cells.14 By a similar mechanism,
`the continuous exposure to trastuzumab at adequate
`concentrations achieved in our trial could be revers(cid:173)
`ing the malignant phenotype of the clinical cancers
`by downregulating their level of pl85HERZ. Another
`possible mechanism of action concerns the observa(cid:173)
`tion that trastuzumab is a potent inducer of antibody(cid:173)
`dependent cellular cytotoxicity.22 However, while
`this immune-mediated mechanism might play a role
`in the observed clinical responses, antibody-depen(cid:173)
`dent cellular cytotoxicity is obviously not involved
`in the pronounced growth-inhibitory effects of the
`antibody in vitro.
`The observed activity of trastuzumab against ad(cid:173)
`vanced breast cancers overexpressing HER2 provides
`the first clinical evidence that anti-growth factor
`receptor-directed strategies may be useful in the
`treatment of human breast cancer. Therefore, con(cid:173)
`tinued research with this agent and other HER2-
`targeted treatment strategies appears warranted. In
`preclinical studies both in vitro and in human tumor
`xenografts, trastuzumab markedly potentiates the an(cid:173)
`titumor effects of several chemotherapeutic agents,
`including cisplatin, doxorubicin, and paclitaxel,23,35
`without increasing their toxicity. A recently com(cid:173)
`pleted phase III trial has confirmed clinically that the
`addition of trastuzumab markedly enhances the an(cid:173)
`titumor activity of doxorubicin and paclitaxel com(cid:173)
`pared with the activity of these agents alone (see
`Shak et al, pp 71-77). Taken together, these results
`support the concept that trastuzumab, given alone or
`in combination with chemotherapy, will be a useful
`tool for the treatment of patients with HER2-over,
`expressing breast cancer. Further studies will be
`needed to establish whether trastuzumab also may be
`of therapeutic benefit in the adjuvant setting or in
`patients with a lower degree of HER2 overex(cid:173)
`pression.
`
`REFERENCES
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`2. Coussens L, Yang,feng TL, Liao Y,C, et al: Tyrosine
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`
`

`
`WEEKLY INTRA VENOUS TRASTUZUMAB
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