The Oncologist, Vol. 11, No. 8, 857-867, September 2006; doi:10.1634/theoncologist.11-8-857 © 2006 AlphaMed Press
Adjuvant Therapy with Trastuzumab for HER-2/neu-Positive Breast CancerDepartment of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Key Words. HER-2/neu-positive breast cancer • Trastuzumab • Adjuvant therapy • Antibody • Targeted therapy Correspondence: Ana Maria Gonzalez-Angulo, M.D., Department of Breast Medical Oncology, The University of Texas M. D. Ander-son Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: agonzalez{at}mdanderson.org Received February 2, 2006; accepted for publication June 14, 2006.
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Breast cancer is the most common cancer in women in the U.S. and western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. In experimental models, transfection of the her-2/neu gene results in transformation of mammary epithelial cells. In human breast cancer, amplification of the her-2/neu gene results in protein over expression and poor prognosis. Patients whose tumors have her-2/neu gene amplification have a shorter disease-free survival time than patients whose tumors exhibit a normal her-2/neu gene copy number. her-2/ neu gene amplification identifies a biologically unique subset of aggressive breast tumors that are sensitive to growth inhibition and apoptosis induced by anti-HER-2/neu-targeted therapies. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastatic HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. However, potential cardiotoxicity requires careful patient selection. Here, we review the recently completed clinical trials of adjuvant trastuzumab in the adjuvant setting. HER-2/neu testing, patient selection, cardiotoxicity, duration of therapy, and directions for future research are discussed.
Breast cancer is the most common cancer in women in the U.S. and western Europe. More than 210,000 women were predicted to be diagnosed, and more than 40,000 were predicted to die from the disease in 2005 in the U.S. [1]. HER-2/neu belongs to a family of four transmembrane receptor tyrosine kinases that mediate cell growth, differentiation, and survival [2, 3]. Overexpression of the HER-2/neu protein, amplification of the her-2/neu gene, or both occur in 20%25% of breast cancers [4, 5]. HER-2/neu-positive breast cancer is an aggressive type that has a high rate of recurrence and short disease-free intervals after adjuvant (postoperative) chemotherapy [4]. Until recently, the most effective adjuvant systemic therapy for these patients consisted of combination chemotherapy that included an anthracycline-based regimen and a taxane-based regimen [6]. Trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA), a humanized monoclonal antibody against the extracellular domain (ECD) of HER-2/neu, has been shown to benefit patients with HER-2/neu-positive metastatic breast cancer [710]. Trastuzumab is not associated with the typical side effects of chemotherapy, such as cytopenias, nausea, vomiting, or alopecia, and hypersensitivity reactions are rare [11]. The most clinically important side effect is cardiotoxicity, which is reported in 2.6%4.5% of patients receiving trastuzumab alone, and in as many as 27% of patients when trastuzumab is combined with an anthracycline in metastatic disease [11]. Cardiotoxicity can be manifested as asymptomatic decreases in left ventricular ejection fraction (LVEF) or symptomatic congestive heart failure (CHF) [11, 12]. Randomized phase III clinical trials recently showed that trastuzumab significantly improves disease-free survival (DFS) and overall survival when used weekly or every 3 weeks for 1 year in patients with early HER-2/neu-positive breast cancer [1316].
Search Strategy The MEDLINE and EMBASE (Via Ovid) databases were searched from 1995 through September 2005 using PubMed (National Library of Medicine). The search included all articles and abstracts that included at least one of the following text words (tw) or medical subject headings (MeSH) in their titles, their abstracts, or their key word lists: trastuzumab (including all MeSH terms) OR Herceptin (tw), disease-free survival (including all MeSH terms) OR overall survival (including all MeSH terms), adjuvant (including all MeSH terms), breast cancer (including all MeSH terms), erbB-2 (including all MeSH terms)ORHer2-neu(including al lMeSH terms)ORHER2 (tw) OR Her2/neu (tw), trastuzumab (including all MeSH terms) OR Herceptin (tw) AND Cardiotoxicity (tw). To supplement the strategy, the abstracts presented at the 2004 and 2005 meetings of the American Society of Clinical Oncology, the European Society of Medical Oncology, and the San Antonio Breast Cancer Symposium also were searched. The principal investigators of the leading abstracts were contacted to obtain the complete data presented at the meeting or, if possible, the in-press manuscript accepted by the journals.
Search Results The U.S. Preventive Task Force (USPTF) review process was used to evaluate the quality of the evidence. The USPTF systematically searches multiple bibliographic research databases to help ensure an unbiased identification of the relevant literature. Predetermined selection criteria minimize bias and improve the efficiency of reviewing that literature. It uses quality criteria developed by methodologists to guide judgments of weaknesses and strengths of individual research studies, and models explicitly define methods for rating and integrating multiple pieces of heterogeneous evidence [17]. After reviewing the 38 documents, and taking into consideration the specific criteria of population (women with HER-2/neu-positive breast cancer), intervention (trastuzumab administered i.v. at any dose and for any duration in the adjuvant setting), methodology (randomized controlled trials), and outcome (differences in survival and toxicities), three full manuscripts and four meeting presentation were selected for the basis of this literature review.
Because the only currently available predictor of responsiveness to trastuzumab is HER-2/neu status, the American Society of Clinical Oncology recommends evaluation of all primary breast tumors for HER-2/neu status [18]. Currently, two methods of measuring HER-2/neu are approved by the U.S. Food and Drug Administration for selecting patients for trastuzumab-based therapy: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC allows determination of HER-2/neu protein expression in paraffin-embedded tissue samples using a HER-2/neu-specific antibody. Two commercially available kits, the HercepTest® (Dako, Carpinteria, CA) and PathwayTM HER-2, (Ventana, Tucson, AZ), can be used to stain breast tumors on a semiquantitative scale from 0 (no detectable HER-2/neu protein) to 3+ (high HER-2/neu protein expression). Tumors with a score of 3+ are most likely to respond to trastuzumab and those with a score of 01+ are least likely to respond [7, 9, 19]. The disadvantages of IHC are subjective interpretation and semiquantitative results. Another important issue is that there are at least a dozen other antibodies against HER-2/neu that different labs use for IHC. The binding affinity, specificity, and receiver operating characteristic (ROC) curve vary substantially from antibody to antibody, making comparison of different series challenging at best. FISH allows quantification of gene copy number to determine whether an invasive carcinoma is driven by her-2/neu gene amplification. This method is more specific and sensitive than IHC [20]. Although the concordance rate between IHC and FISH is approximately 80% [2123], FISH should be routinely performed on tumors scored 2+ by IHC because FISH improves upon the ability of IHC to predict a response to trastuzumab in this subset of patients [24]. Again, both IHC and, to a lesser extent, FISH vary from laboratory to laboratory, being more reproducible in high-volume reference laboratories than in smaller laboratories, as shown by the National Surgical Adjuvant Breast and Bowel Project (NSABP), which found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest® IHC or FISH by a central testing facility [25]. The Intergroup also reviewed the tumor specimens from the first 119 patients enrolled in trial N9831; 74% were found to be HercepTest® 3+, and 66% were found to have her-2/neu gene amplification. Only six of nine (67%) specimens submitted by local laboratories as HER-2/neu positive by FISH could be confirmed by central assays. The poor concordance (74%) between local and central testing for HER-2/neu status led to modifications in the eligibility criteria for N9831 [26]. New investigational methods of measuring HER-2/ neu include the use of chromogenic in situ hybridization (CISH), which has a 100% concordance with FISH and a good concordance with IHC in the 01+ and 3+ categories, while it has a poor agreement with weak protein overexpression (2+), making CISH a useful tool to evaluate breast cancer HER-2/neu status that can be implemented in a surgical pathology laboratory [27].
Four large, randomized, clinical trials and one smaller randomized Finnish trial of trastuzumab as adjuvant therapy for operable breast cancer have been completed and their initial results reported: the NSABP B-31 [13], Intergroup N9831 [13], Breast International Group (BIG) Herceptin® Adjuvant (HERA) [14], Breast Cancer International Research Group (BCIRG)-006 [15], and Finnish FinHer trial [16] (Table 1
NSABP B-31 and Intergroup N9831 The NSABP B-31 trial [13] compared four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of every-3-week paclitaxel (P) (AC P, arm 1) with AC P plus 52 weeks of trastuzumab (H) beginning with the first cycle of P (arm 2). The N9831 trial [13] was a three-arm study that compared four cycles of AC followed by 12 weekly doses of paclitaxel (AC P, arm A) with AC P followed by 52 weeks of H beginning after P (arm B) and with AC P plus 52 weeks of H beginning with the first P cycle (arm C). Because arm 1 and arm 2 of the B-31 trial are similar to arms A and C of the N9831 trial, the studies were amended to include a joint statistical analysis combining arm 1 and arm A for comparison with arm 2 and arm C. Arm B was excluded from the analysis because H was not given concurrently with P. At the first planned interim analysis, there were 394 events (recurrent, second primary cancer, or death before recurrent cancer) reported in 3,351 patients, with a median follow-up of 2 years. There were 261 events in the control arms (arms 1 and A) and 133 in the investigational arms (arms 2 and C), (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.390.59; p = 2 x 10-12). This result crossed the early-reporting boundary. The absolute difference in DFS rate was 12% at 3 years and 18% at 4 years. There was a 33% lower mortality hazard (p = .015) with the addition of trastuzumab. However, there was a higher incidence of CHF in patients who received trastuzumab [13]. For the B-31 trial, cardiac monitoring was done with cardiac history forms submitted at entry, every 6 months for the first 5 years, and yearly thereafter. Multigated acquisition (MUGA) scans were required in both treatment arms before entry, after AC, and at 6, 9, and 18 months; additional scans could be performed at the investigators discretion. Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed cardiac events (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7%4.9%). CHF was more frequent in older patients and in patients with marginal post-AC LVEF. The cumulative incidence of MUGA results meeting the Cardiac Review and Evaluation Committee criteria for asymptomatic decline in LVEF by 10% to <55% at least once during the 52 weeks was 17% (95% CI, 15%20%) in arm 1 and 34% (95% CI, 31%38%) in arm 2 (HR, 2.1; 95% CI, 1.72.6; p < .0001). Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. [28]. In the N9831 trial, LVEF was evaluated by MUGA scan or echocardiogram at trial entry (pre-AC therapy), post-AC therapy, and at 6, 9, and 1821 months following registration. Reported cardiac event (class III or IV CHF and cardiac death) rates for the control arm, arm B, and arm C were 0.3%, 2.5%, and 3.5%, respectively. A higher proportion of patients experienced a 15% decrease in LVEF at any time point in the trastuzumab-containing arms compared with the nontrastuzumab-containing arm (arm A, 6.7%; arm B, 14.2%; arm C, 17.3%). There was a trend toward a higher risk for cardiac toxicity with increasing age: the 2-year cumulative incidence was 3.8% versus 2.3% for patients aged 60 years versus <50 years in arm B, and the 2-year cumulative incidence was 8.8% versus 1.7% for patients aged 60 years versus <50 years in arm C [29]. Several important issues are not addressed by this analysis. The interpretation of the reported results must take into account the very short follow-up (median of 2.0 years, 2.4 years for the B-31 trial and 1.5 years for the N9831 trial). However, the effect of trastuzumab was substantial in both trials despite differences in the paclitaxel schedule and initiation of hormonal therapy, and benefit of trastuzumab was evident at both locoregional and distant sites. Because node-negative patients became eligible for the N9831 trial just 18 months prior to the analysis, only 191 node-negative patients were included. Only three events had occurred in this subset at the time of the analysis, so the specific benefit of trastuzumab in node-negative patients cannot be addressed. The N9831 trial was also designed to address the efficacy of trastuzumab initiated concurrently with paclitaxel versus sequentially (arm B vs. arm C), but this comparison requires substantially longer follow-up than was needed to address the issue of concurrent trastuzumab versus no trastuzumab in the joint analysis. However, an unplanned comparison of arms B and C was approved, and the comparison suggested that delayed administration of trastuzumab may be less effective than concurrent administration [30].
HERA The interpretation of the reported results of this trial must also take into account the very short follow-up (median, 12 months; maximum, 36 months). However, the pattern of early and largely distant relapse in patients with HER-2/neu-positive breast cancer, and the clinically and statistically significant reduction in the risk for relapse achieved with trastuzumab justified release of the results of this interim efficacy analysis. The results of the HERA trial could be widely applicable to women with HER-2/neu-positive breast cancer for the following reasons: different types of neoadjuvant and adjuvant chemotherapy were allowed before initiation of trastuzumab; trastuzumab was given every 3 weeks, which was shown in the metastatic disease setting to have similar efficacy, side effects, and pharmaco-kinetics as the weekly schedule[31]; and patients with node-negative disease were included. It appears that trastuzumab is effective regardless of the type of prior chemotherapeutic regimen received and the extent of nodal involvement. The cardiotoxicity rate was low, but it could change with longer follow-up.
BCIRG-006 The efficacy data from the two trastuzumab-containing regimens are not sufficiently mature to reliably determine differences at this time, and the number of events required for analysis of overall survival has not yet been reached.
FinHer
Trastuzumab-induced cardiotoxicity was noted in the initial trials of this agent for metastatic disease and was evident in a randomized phase III trial of chemotherapy with or without trastuzumab. The rates of cardiac dysfunction, usually defined as New York Heart Association class III or IV CHF, cardiomyopathy, or a decrease in LVEF (>10%), were 3%7% with trastuzumab alone, 13% with concurrent paclitaxel, and 27% with concurrent anthracyclines. An independent cardiac review committee performed a retrospective analysis of seven phase II/III trials for metastatic breast cancer and found greater age and the combination of trastuzumab with anthracyclines to be associated with a higher risk for cardiotoxicity [33]. Several pathophysiologic hypotheses have been proposed to explain trastuzumab-induced cardiotoxicity. These include drugdrug interactions, the induction of immune-mediated destruction of cardiomyocytes, and the requirement of HER-2/neu signaling for myocyte survival [3436]. The association between cardiac dysfunction and trastuzumab influenced the design of the clinical trials of adjuvant trastuzumab for early breast cancer. The importance of obtaining a baseline measurement of LVEF before initiating trastuzumab therapy became obvious; abnormal cardiac function, high levels of previous anthracycline exposure, and pre-existing heart disease were considered relative contraindications to trastuzumab therapy. Cardiac function was also to be monitored during therapy by echo-cardiography or nuclear cardiac scanning upon completion of anthracyclines, at 12 weeks of trastuzumab therapy, and at least at 6, 9, and 18 months after randomization [1315]. The safety results of the large trials of adjuvant trastuzumab in breast cancer suggest that sequencing the combination of trastuzumab and taxanes immediately following the administration of anthracycline-based chemotherapy increases the risk for class III or IV CHF (4.1% in trastuzumab-treated patients vs. 0.8% in the control group of the B-31 trial compared with only 1.73% of patients treated with trastuzumab vs. 0.06% in the control group of HERA) [1315, 28]. The B-31 trial has also reported that older age (>50 years) and marginal postanthracycline LVEF are major risk factors for trastuzumab-induced cardiotoxicity [28]. On the other hand, in the N9831 trial, cardiotoxicity was also associated with older age but not with a history of prior radiotherapy [29].
However, most patients who develop cardiac dysfunction as a result of trastuzumab therapy remain asymptomatic and improve with treatment. Trastuzumab should be discontinued if CHF is detected and temporarily suspended if a patient has a decline in LVEF of 15% or any decline that results in an LVEF
The pivotal trial for metastatic breast cancer by Slamon et al. [9] clearly demonstrated the significant activity of the combination of doxorubicin and trastuzumab; thus, clinical trials are currently assessing safer ways to combine trastuzumab with an anthracycline. A major strategy is to use fewer cardiotoxic anthracyclines. Preliminary evidence suggests that the combination of trastuzumab with liposomal doxorubicin is safe and effective, and this approach is currently being assessed by the Eastern Cooperative Oncology Group (E3198 trial) and others [3840]. Table 2
Buzdar and colleagues [41,42]showed that concomitant administration of trastuzumab and paclitaxel followed by CEF is safe and highly effective in the neoadjuvant therapy setting. The pathologic complete response rate was 65.2%, the rate of grade 1 or 2 cardiotoxicity was 10%, and only one patient developed symptomatic heart failure.
her-2/neu amplification/HER-2/neu overexpression identifies a biologically aggressive subset of breast cancers with marked sensitivity to growth inhibition and apoptosis induced by anti-HER-2/neu therapies. However, the clinical benefit of anti-HER-2/neu agents is not observed in all patients with HER-2/neu-positive tumors: single-agent trastuzumab produces objective responses in approximately one third of patients with HER-2/neu-positive disease [7], but the response rate may be as high as 50% when trastuzumab is combined with chemotherapy. It is important to understand the mechanisms that confer sensitivity to trastuzumab so that patients with disease that will not respond to the agent can be spared its potential adverse effects. The NSABP, continuing its effort to identify amplified genes in breast cancer that correlate with prognosis, analyzed 27 genetic loci for the presence of amplified genes in 1,900 cases of node-positive breast cancer from study B-28 [43]. Multivariate analysis of these data revealed that the c-myc, her-2/neu, and HTPAT amplicons were associated with a poor prognosis and that the coamplification of c-myc and her-2/neu was correlated with worse outcome than when only her-2/neu or c-myc was amplified. The researchers then analyzed the data from 1,736 patients from trial B-31 [13] and found that 30% of the cases had c-myc amplification. Interestingly, patients who had c-myc coamplification had a worse outcome if they were treated with chemotherapy alone, but they had a 4-year recurrence-free survival rate of 90% when treated with chemotherapy and trastuzumab. The researchers suggested that indirect targeting of dys-regulated c-myc may be possible if cooperating genes that provide antiapoptotic signaling are identified [44].
The topoisomerase-II alpha (topo-II The her-2/neu gene product is composed of a cytoplasmic domain with tyrosine kinase activity, a transmembrane domain, and an ECD. The HER-2/neu ECD may be cleaved and shed from the surface of breast cancer cells, and serum HER-2/neu ECD levels can be detected by enzyme-linked immunosorbent assay (ELISA). Serum HER-2/neu ECD testing does not show any significant crossreactivity with other members of the epidermal growth factor receptor family [46]. The HER-2/neu ECD can be detected in the serum of 15%30% of early-stage breast cancer patients at the time of diagnosis, and in up to 50% of patients with metastatic breast cancer [47, 48]. Among 250 primary breast cancer patients, Molina et al. [49] showed that 28.4% had abnormal serum HER-2/neu ECD levels prior to diagnosis of a recurrence. These secreted soluble isoforms of the HER-2/neu receptor are currently being examined as bio-markers for detecting early recurrence or metastasis and for predicting response to therapy [19, 50, 51]. Recent studies suggest that a decrease in HER-2/neu concentration in serum 24 weeks after the start of trastuzumab therapy is correlated with progression-free survival [52]. High serum concentrations of HER-2/neu ECD have also been correlated with higher relapse rates, and elevated pretreatment levels of HER-2/neu ECD have been associated with poor clinical response to hormone therapy and chemotherapy in metastatic breast cancer patients [53, 54].
The success of trastuzumab has made it mandatory for oncologists to check HER-2/neu status in all patients with breast cancer. The clinical development of this monoclonal antibody uncovered cardiotoicity as a potential adverse event, and careful patient selection is important to minimize it. The results of adjuvant nonanthracycline-containing chemotherapy in the BCIRG-006 trial, particularly in patients whose tumors did not possess coamplification of the her-2/neu and topo-II genes, reflect how cancer therapy has the potential to become refined through a better understanding of important molecular events in cancer cells. While the sequential administration of trastuzumab after chemotherapy appears to be effective, longer follow-up is needed to determine whether simultaneous and sequential administration with other chemotherapy agents are equally effective and whether there is a population of patients in whom chemotherapy is not necessary (e.g., patients with negative lymph nodes and tumors no larger than 1 cm, or patients with estrogen receptor-positive and HER-2/neu-positive disease) and for whom trastuzumab alone might represent appropriate adjuvant therapy. Clinical trials should be designed to answer these questions. The optimal timing of initiation of trastuzumab in patients with early-stage HER-2/neu-positive breast cancer who have completed adjuvant chemotherapy also has not been defined. The HERA trial allowed patients to begin trastuzumab up to 6 months after local treatment and chemotherapy had been completed. Whether trastuzumab would benefit patients who had completed chemotherapy >6 months previously is unknown. However, in patients with HER-2/neu-positive breast cancer treated with AC followed by paclitaxel chemotherapy (control group in the NSABP B-31 trial), the hazard rate for recurrence increased significantly the first year and remained high in the second year after surgery. This would suggest that trastuzumab therapy is beneficial, although this situation has not been tested in randomized clinical trials. The small FinHer study, while not practice-changing, suggests that the administration of adjuvant trastuzumab for a full year may not be necessary. If the HERA trial demonstrates no benefit to trastuzumab administration for 2 years compared with 1 year, it will then be necessary to study shorter durations of therapy to minimize potential cardiotoxicity. Furthermore, the updated data of the M.D. Anderson neoadjuvant therapy study showed that, at median follow-up of 3 years (original cohort) and 2 years (additional cohort), all patients who received chemotherapy and trastuzumab remained free of disease without any clinically evident cardiac dysfunction [41]. There are not enough clinical data about sequencing or combining trastuzumab with radiation therapy and/ or hormone therapy in the adjuvant treatment setting. Patients in the NSABP B-31, N9831, and BCIRG-006 trials received adjuvant radiation upon completion of chemotherapy during maintenance trastuzumab. Hormonal therapy for patients with hormone receptor-positive disease was begun at the completion of either chemotherapy or radiation therapy as per investigator. Until new data appear discussing this matter, the recommendation is to follow these protocols.
Trastuzumab resistance is another area requiring further study. Several approaches are being explored to overcome trastuzumab resistance. Current data suggest that an understanding of the phosphatidylinositol 3' kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in individual tumors will help identify tumors unlikely to respond to trastuzumab-based therapy. However, the data regarding topo-II
With all these data in hand, it is apparent that the critical component of the treatment of patients with HER-2/neu-positive breast cancer is trastuzumab; other treatments (chemotherapy, hormone therapy) are adjuvant to trastuzumab. Adequate assessment of HER-2/neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Finally, clinical trial design and participation are critical to continue to answer important unsolved questions.
F.J.E. has acted as a consultant for Genentech.
This work was supported by the Nellie B. Connally Breast Cancer Research Fund.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:16591672. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809820. Tan-Chiu E, Yothers G, Romond E et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:78117819. This article has been cited by other articles:
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