help button home button The Oncologist http://theoncologist.alphamedpress.org/subscriptions/etoc.dtl
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 13, No. 6, 620-630, June 2008; doi:10.1634/theoncologist.2008-0001
© 2008 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow CME: Take the course for this article:
 Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Syste...
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dahabreh, I. J.
Right arrow Articles by Murray, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dahabreh, I. J.
Right arrow Articles by Murray, S.

Breast Cancer

Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Issa J. Dahabreha,b, Helen Linardouc, Fotios Siannisd, George Fountzilase, Samuel Murrayf

aNational University of Athens, Medical School, Athens, Greece; bDepartment of Medical Oncology, Athens Medical Center, Athens, Greece; c1st Department of Oncology, Metropolitan Hospital, Athens, Greece; dDepartment of Mathematics, National University of Athens, Athens, Greece; eDepartment of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; fDepartment of Molecular Biology and Genetics, Metropolitan Hospital, Athens, Greece

Key Words. Trastuzumab • Adjuvant chemotherapy • Breast cancer • HER-2 • Systematic review • Meta-analysis

Correspondence: Samuel Murray, Ph.D., Department of Molecular Biology and Genetics, Metropolitan Hospital, 1, Ethnarhou Makariou & Venizelou Street, Piraeus, Greece. Telephone: +30-210-4809254/213; Fax: +30-210-4809257; e-mail: smurray{at}metropolitan-hospital.gr

Received January 2, 2008; accepted for publication April 2, 2008.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Summarize the main characteristics and findings of randomized controlled trials evaluating trastuzumab for the adjuvant treatment of early-stage breast cancer.
  2. Use combined-effect estimates provided by meta-analysis to appraise the risks and benefits of trastuzumab treatment in the adjuvant setting.
  3. Identify the links between basic science and drug development that led to the successful clinical use of trastuzumab, as well as the gaps in the existing evidence base regarding its use in breast cancer treatment.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Background. We performed a systematic review and meta-analysis to compare treatment outcomes for human epidermal growth factor receptor (HER)-2–positive breast cancer patients receiving adjuvant chemotherapy with or without trastuzumab.

Methods. We identified randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in patients with resectable breast cancer. Fixed-effects meta-analysis was used to combine data.

Results. Five eligible trials were identified, reporting outcomes on 13,493 women. Fixed-effects analysis showed disease-free survival to be superior for trastuzumab-treated patients (risk ratio [RR], 0.62; 95% confidence interval [CI], 0.56–0.68). Superiority was also observed for patients receiving trastuzumab with respect to mortality (RR, 0.66; 95% CI, 0.57–0.77), locoregional recurrence (RR, 0.58; 95% CI, 0.43–0.77), and distant recurrence (RR, 0.60; 95% CI, 0.52–0.68). Patients receiving trastuzumab with chemotherapy had a higher risk for congestive heart failure (RR, 7.60; 95% CI, 4.07–14.18) and left ventricular ejection fraction decline (RR, 2.09; 95% CI, 1.84–2.37). A higher risk for central nervous system metastasis as the first recurrence event (RR, 1.60; 95% CI, 1.06–2.40) was also noted in patients receiving trastuzumab.

Conclusions. The use of trastuzumab should be considered an integral part of the adjuvant therapy of HER-2–positive breast cancer patients.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Despite advances in early diagnosis and treatment, breast cancer remains a significant public health concern, with more than a million new cases diagnosed annually, resulting in >400,000 deaths worldwide [1]. In developed countries, most women diagnosed with invasive breast cancer have early-stage disease, which is treated with curative-intent surgery, with or without radiotherapy. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of randomized clinical trials with a 15-year follow-up established the efficacy of adjuvant chemotherapy, with anthracycline-based regimens demonstrating superiority [2]. However, even with optimal adjuvant therapy, a significant number of women develop recurrent disease [3]. This observation, combined with the significant toxicity of current chemotherapy regimens, offers a rationale for the development of agents against specific targets in the signaling pathways required for the survival and proliferation of breast cancer.

Among breast cancers diagnosed at any stage, 20%–30% are found to have amplification of the human epidermal growth factor receptor (HER)-2/neu gene by in situ hybridization (either fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) [4–7]. This amplification results in the overexpression of a 185-kDa transmembrane protein with tyrosine kinase activity that belongs to the ErbB family [8, 9]. Overexpression of this protein, usually demonstrated by immunohistochemistry (IHC), is associated with adverse disease prognosis and a worse response to treatment. In vitro and animal model experiments provided compelling evidence that targeting the signaling pathway activated by HER-2 could have significant antiproliferative effects on breast cancers and guided the clinical development of several anti-HER-2 antibodies [10, 11]. Among those, trastuzumab, a humanized monoclonal anti-HER-2 antibody, demonstrated significant activity in patients with heavily pretreated HER-2–positive metastatic breast cancer in early-phase studies [12, 13]. In a seminal phase III trial, the combination of trastuzumab with first-line chemotherapy resulted in a significant survival benefit when compared with chemotherapy alone. That study also revealed that trastuzumab, especially in combination with anthracyclines, was associated with significant cardiac toxicity [14]. These impressive results provided strong support for the conduct of several randomized controlled studies evaluating trastuzumab in combination with chemotherapy in the adjuvant setting. We conducted a systematic review and meta-analysis to estimate the benefits and risks of trastuzumab administration with or following chemotherapy for early-stage breast cancer.


   METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Trial Identification
We performed a computerized search of the MEDLINE database (last search, June 15, 2007), the Cochrane central register of controlled trials (Cochrane library, issue 2, 2007), the online proceedings of the American Society of Clinical Oncology (ASCO) Annual Meetings (years 1992–2007; last search, June 15, 2007), and the online proceedings of the San Antonio Breast Cancer Symposium (years 2004–2006; last search, June 15, 2007), using combinations of the following keywords: "adjuvant," "breast cancer," "adjuvant chemotherapy," "chemotherapy," "trastuzumab," "Herceptin," and "anti-HER-2." We manually searched oncology journals known to publish a large number of clinical trials and the reference lists of all articles we recovered and those of relevant review articles. We contacted experts in the field of breast cancer treatment to broaden our yield of potentially eligible trials. We did not apply any language restrictions.

Eligibility Criteria
All randomized controlled trials that evaluated the administration of trastuzumab with or following adjuvant chemotherapy versus chemotherapy alone were considered eligible for this analysis. All cytotoxic chemotherapy regimens were considered eligible for the systematic review, provided that the same drugs were given at the same dose in all study arms and that the arms differed systematically only regarding trastuzumab administration. Postchemotherapy radiotherapy and adjuvant hormonal treatment protocols, either with tamoxifen or aromatase inhibitors, were also not used for study selection. Trials testing the neoadjuvant administration of trastuzumab were excluded from this analysis, as were trials evaluating biologic or targeted agents other than trastuzumab. We included trials presented in abstract form only if they reported on at least one of the primary outcomes of our study (see below). When multiple reports on the same trial cohort were available, we used the one with the longest follow-up. We included results of interim analyses only if they represented the most recent available data.

Data Abstraction
The following information was recorded about each trial: first author, journal name and year of publication, follow-up period, number of patients assigned, excluded (for any reason), and analyzed per arm, chemotherapy and trastuzumab dosing and scheduling, and the number of outcome events and adverse events per arm.

The primary outcome was the disease-free survival (DFS) event rate, defined as disease progression or death from any cause. Secondary outcomes included mortality (death from any cause), locoregional recurrence, distant recurrence, and central nervous system (CNS) recurrence, class III/IV congestive heart failure (CHF), and significant decline in left ventricular ejection fraction (LVEF). CNS recurrence was defined as the development of CNS involvement as the initial metastatic event. A significant decrease in LVEF was defined according to each trial's monitoring protocol. Two investigators (IJD and SM) extracted the data. When there was a discrepancy on an outcome, a third investigator (FS) reviewed the data and consensus was reached. When data on the primary outcome were available from trials, we did not contact authors of the original trials.

Statistical Analysis
We used the number of events per arm to calculate risk ratios (RRs) and their 95% confidence intervals (CIs). We combined RRs using fixed-effects models to estimate pooled point estimates with their CIs using the Mantel-Haenszel method. Random-effects models were used in a sensitivity analysis. All analyses were performed according to the intention-to-treat principle, when appropriate data were available. For studies with zero total events in one arm, we used a continuity correction of 0.5 [15]. We tested between-study heterogeneity using the Q statistic and study consistency using the I2 statistic [16]. When extreme inconsistency was detected (I2 ≥75%), we did not present weighted summary estimates. We used formal statistical tests (Begg's and Egger's tests) to evaluate the presence of publication bias regarding our primary outcome (DFS). Heterogeneity was considered statistically significant at p < .1. For all other calculations, statistical significance was defined as p < .05. All tests were two-tailed. Fixed-effects metaregression analysis was used to explore potential sources of heterogeneity, whenever detected. Analyses were conducted using Comprehensive Meta-analysis (Version 2.2, Biostat, Englewood, NJ), StatsDirect (version 2.6.3, StatsDirect Ltd., Altrincham, UK) and SPSS (version 13.0, SPSS Inc, Chicago, IL).


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Trial Flow and Eligible Studies
The trial flow is summarized in Figure 1. We identified five eligible trials [17–23], reporting on 13,493 patients with HER-2–positive early breast cancer, 8,627 assigned to chemotherapy combined with trastuzumab and 4,866 assigned to chemotherapy alone. Characteristics of the included trials are summarized in Table 1. HER-2 positivity was assessed by IHC and FISH in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) 9831, and Herceptin® Adjuvant (HERA) trials, by IHC and CISH in the Finland Herceptin® (FinHer) trial, and by FISH only in the Breast Cancer International Group (BCIRG) 006 trial.


Figure 1
View larger version (29K):
[in this window]
[in a new window]

  		Figure 1. Results of searches for clinical trials comparing adjuvant chemotherapy with chemotherapy plus trastuzumab for early-stage breast cancer.

Abbreviation: RCTs, randomized controlled trials.

 


View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of eligible trials in this analysis

 
Patients at high risk for recurrence were enrolled in all studies, as demonstrated by the high prevalence of hormone receptor–negative disease and node-positive disease in the populations accrued. Three trials (the NASBP B-31, NCCTG N9831, and BCIRG 006 trials) evaluated the combination of doxorubicin and cyclophosphamide followed by an anthracycline, with or without trastuzumab. The HERA, BCIRG 006, and NCCTG N9831 trials were three-arm studies, while the FinHer trial was a 2 x 2 study (randomizing all patients to vinorelbine or docetaxel and then randomizing the HER-2–positive subgroup to trastuzumab or observation). From the FinHer study, we abstracted data regarding only the HER-2–positive subgroup of patients. The HERA trial was the only study that included a subgroup of patients treated with neoadjuvant chemotherapy. Because of the aggregate nature of the data, it was impossible to discriminate between patients treated with adjuvant chemotherapy and those treated with neoadjuvant chemotherapy. Thus, because this subgroup represented only about 10% of the total study population and these patients have been reported to have similar outcomes as the adjuvant subgroup, we chose to include the study in our analysis as a whole [17]. Data from the HERA study arm that evaluated the administration of 2 years of trastuzumab have not been reported and this arm was not included in our analysis. The NCCTG N9831 study had a control arm receiving doxorubicin and cyclophosphamide followed by paclitaxel and two arms receiving 52 weeks of trastuzumab, either concurrently or sequentially with paclitaxel. The most updated analysis focuses on the treatment arm receiving concurrent paclitaxel and trastuzumab, in which this arm of the NCCTG N9831 study together with the control arm were combined with the arms of the NSABP B-31 trial and treated as a single larger study [18, 19]. An analysis comparing the sequential paclitaxel–trastuzumab arm with the control arm of the NCCTG N9831 trial was presented at the ASCO 2005 Annual Meeting as an unplanned interim analysis with a small number of events [24]. Finally, we excluded the nonanthracycline, carboplatin-based arm of the BCIRG 006 trial because it did not have an appropriate unconfounded control [21, 22].

We found only one randomized trial evaluating trastuzumab exclusively in the neoadjuvant setting and we excluded it from our analysis [25]. Patient accrual in that study was stopped because of the emergence of a significant difference regarding pathologic complete response in favor of the trastuzumab arm. With only 42 randomized patients, the study has recently shown a survival benefit in favor of trastuzumab; given its small sample size its exclusion does not influence our results [26].

Overall, the study arms considered eligible for our analysis included 9,748 patients, 4,882 of whom were treated with chemotherapy combined with trastuzumab and 4,866 of whom were treated with chemotherapy alone.

Meta-Analysis of the Primary Outcome
There was no evidence of significant between-study heterogeneity or inconsistency for the primary outcome, DFS (I2 = 35,8%; Q = 4,67; p = .198), indicating that the trials were similar enough to be combined. DFS data were available from all trials (9,739 patients) and the pooled results were statistically significantly in favor of trastuzumab combined with adjuvant chemotherapy compared with chemotherapy alone (p < .0001). The RR of 0.62 (95% CI, 0.56–0.68) represents an overall 38% lower relative risk for disease progression or death from any cause with the use of trastuzumab. The forest plot for DFS is shown in Figure 2. Analysis using either a random- or fixed-effects model produced similar results.


Figure 2
View larger version (12K):
[in this window]
[in a new window]

  		Figure 2. Forest plot for DFS (primary outcome). Each study is shown by the point estimate of the risk ratio (square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines); the summary risk ratio and 95% confidence interval by fixed-effects calculations are shown by diamonds. For all figures, values lower than one indicate that trastuzumab has a beneficial effect when combined with chemotherapy.

Abbreviations: BCIRG, Breast Cancer International Group; DFS, disease-free survival; FinHer, Finland Herceptin® study; HERA, Herceptin® Adjuvant.

 
Meta-Analysis of Secondary Outcomes
Forest plots for selected secondary outcomes are presented in Figure 3 and Figure 4. Regarding overall survival, the combined results strongly favor the combination of trastuzumab with adjuvant chemotherapy over chemotherapy alone (p < .0001). The RR of 0.66 (data from all trials, 9,739 patients; 95% CI, 0.57–0.77) represents an overall 34% lower relative risk for death from any cause with the use of trastuzumab. The addition of trastuzumab to chemotherapy also resulted in a lower risk for developing locoregional recurrence (data from three trials [17, 19], 6,752 patients; RR, 0.58; 95% CI, 0.43–0.77; p = .0002) and distant recurrence (data from all trials [17, 19, 21, 23], 9,131 patients; RR, 0.60; 95% CI, 0.53–0.68; p < .0001).


Figure 3
View larger version (16K):
[in this window]
[in a new window]

  		Figure 3. Forest plots for mortality and distant recurrences (secondary outcomes). (A): Overall survival. (B): Distant recurrence.

Abbreviations: BCIRG, Breast Cancer International Group; FinHer, Finland Herceptin® study; HERA, Herceptin® Adjuvant; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project.

 


Figure 4
View larger version (14K):
[in this window]
[in a new window]

  		Figure 4. Forest plots for CNS recurrence, class III/IV CHF, and LVEF decline (secondary outcomes). (A): CNS recurrence as the first metastatic event. (B): Class III/IV CHF. (C): LVEF decline.

Abbreviations: BCIRG, Breast Cancer International Group; CHF, congestive heart failure; CNS, central nervous system; FinHer, Finland Herceptin® study; HERA, Herceptin® Adjuvant; LVEF, left ventricular ejection fraction; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project.

 
Interestingly, there was a higher risk for developing CNS disease as the first site of recurrence among patients receiving trastuzumab (data from three trials [18, 20], 6,752 patients; RR, 1.60; 95% CI, 1.06–2.40; p = .033).

Regarding cardiac function–related outcomes, there was evidence that combining trastuzumab with chemotherapy resulted in a higher risk for class III/IV CHF (data from four trials [27–30], 8,964 patients; RR, 7.60; 95% CI, 4.07–14.18; p < .0001). The CI for this outcome was somewhat wide because of the relatively low event rate. There was also evidence that trastuzumab was associated with LVEF decline (data from five trials [17, 23, 28, 31], 8,582 patients; RR, 2.09; 95% CI, 1.84–2.37; p < .0001). For all secondary outcomes, except LVEF decline, there was no indication of significant heterogeneity, although the small number of included trials makes this calculation somewhat unreliable. For LVEF decline, there was statistically significant between-study heterogeneity (I2 = 74.6%; Q = 15.72; p = .003), which was further explored by a fixed-effects meta-regression analysis. In general, for all secondary outcomes, analyses using either random- or fixed-effects models produced similar results (data not shown).

We used fixed-effects meta-regression analysis to investigate potential sources of heterogeneity regarding LVEF decline. The following variables were evaluated: date of patient enrolment initiation, date of study publication, control group event rate, median participant age, duration of trastuzumab administration (in weeks), cumulative trastuzumab dose, and percentage of patients receiving an anthracycline. Potential factors accounting for between-study heterogeneity included the duration of trastuzumab administration (p = .04) and the cumulative trastuzumab dose (p = .02). These results should be interpreted cautiously because of multiple comparisons.

Publication Bias
No evidence of publication bias was detectable for the primary outcome of this study, by either Begg's or Egger's test (Begg's test, p = .75; Egger's test, p = .67). However, because the number of trials included in this meta-analysis was less than the recommended arbitrary minimum number of 10 trials, statistical tests for publication bias are potentially unreliable [32, 33].


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Despite significant advances in the diagnosis and treatment of breast cancer, a substantial proportion of women diagnosed at an early stage are not cured and develop recurrent disease. This indicates a necessity for developing new, safer, and more effective therapies. HER-2 is a member of the ErbB family of transmembrane growth factor receptors with tyrosine kinase activity. Overexpression of HER-2 by breast cancer cells, usually via gene amplification, results in greater cell survival, proliferation, and resistance to apoptosis [34]. Patients with HER-2–positive disease demonstrate adverse disease characteristics at presentation (larger tumor size, higher tumor grade, and lymph node invasion), have shorter survival times, and have a higher risk for disease recurrence or progression. These features highlight the attractiveness of HER-2 as a potential treatment target [4, 35].

Trastuzumab, a humanized monoclonal anti-HER-2 antibody, has shown efficacy in the treatment of HER-2–positive metastatic breast cancer [14]. This has supported the investigation of its use in combination with anthracycline-based adjuvant chemotherapy in several large, randomized, controlled trials. We performed a systematic review of the published literature and abstracts presented at major oncology meetings to identify the most recent updates of these trials. By combining their results in a meta-analysis, we demonstrated a 38% lower DFS event rate and a similar 34% difference in overall survival favoring the administration of trastuzumab. Notably, the size of these benefits for patients with HER-2–positive tumors, traditionally considered to carry a negative prognosis, is comparable with those conferred by the use of adjuvant tamoxifen for patients with hormone receptor–positive disease, a subtype with a relatively good prognosis [36]. The beneficial effects of trastuzumab in terms of survival were also associated with a significantly lower risk for both locoregional and distant recurrence. In general, there was little evidence of heterogeneity or publication bias that may have influenced our results. The lack of heterogeneity is further supported by the consistency of results produced by random- and fixed-effects models.

There have been a number of concerns regarding the use of trastuzumab and the incidence of cardiotoxicity, including those raised by a meta-analysis presented concurrently with our work [37, 38]. Our analysis confirmed that benefits in disease control and survival came at the cost of serious cardiovascular adverse events, particularly heart failure accompanied by LVEF decline. The potential of trastuzumab to induce myocardial damage, especially when combined with anthracyclines, was initially observed in the metastatic setting [14]. We found the incidence of cardiotoxicity to be significantly higher among trastuzumab-treated patients than among controls. Specifically, the incidence of severe heart failure in the trastuzumab-treated arms was in the range of 0.5%–3.7%, compared with 0%–0.7% in the control arms. Several published studies suggest that trastuzumab-mediated cardiotoxicity is distinct from the more extensively studied cardiotoxicity of anthracyclines: trastuzumab-associated heart disease is probably idiosyncratic, is not dependent on the cumulative drug dose, does not involve the development of ultrastructural myocardial changes detectable by light microscopy, and, most importantly, is reported to be reversible in the majority of cases [39, 40]. When interpreting the results of adjuvant trastuzumab trials regarding cardiotoxicity, one has to remember that the available follow-up remains inadequate to fully assess the importance of cardiac involvement, particularly among patients who develop asymptomatic decreases in LVEF. Interpretation of our data is also complicated because of differences in the criteria for LVEF evaluation in each trial. Some reassurance is provided by data from the long-term use of trastuzumab in the metastatic setting, in which cardiac toxicity was found to be reversible in the majority of patients [41].

The substantial cardiotoxicity of anthracycline and trastuzumab coadministration has generated interest in nonanthracycline trastuzumab-based regimens, particularly now that evidence has emerged supporting the efficacy of nonanthracycline regimens in the adjuvant setting [42]. The BCIRG 006 trial will provide direct randomized evidence comparing carboplatin, docetaxel, and trastuzumab with the standard regimen of doxorubicin, cyclophosphamide, and docetaxel. At the trial's second interim analysis, the nonanthracycline arm had a low incidence of CHF (0.4%), equal to that in the doxorubicin, cyclophosphamide, and docetaxel arm, with superior efficacy [21, 31]. Longer follow-up is needed to establish the efficacy and safety of this regimen.

Another concern regarding the use of trastuzumab has been the association of its use with the development of metastatic CNS disease. A higher incidence of progression in the CNS has been observed in several retrospective studies of patients with HER-2–positive metastatic breast cancer treated with trastuzumab [43–45]. Our analysis demonstrated a higher incidence of CNS metastasis as the first recurrence event among patients treated with trastuzumab, which nonetheless was outweighed by the overall lower risk for distant recurrence (non-CNS visceral disease) and the impressive benefits in survival. The exact reasons for this phenomenon are unclear, but the etiology is probably multifactorial, involving a lower bioavailability of trastuzumab in the CNS because of poor blood–brain barrier penetration and its high effectiveness in preventing the development of non-CNS visceral disease. Although some investigators have suggested that HER-2–positive disease may preferentially involve the CNS, evidence from large retrospective datasets of nontrastuzumab-treated patients is inconclusive [46, 47].

Although not this study's primary focus, the methodology of HER-2 evaluation deserves a brief mention. The eligible trials used all three established methods of HER-2 detection (IHC, FISH, and CISH), and the criteria for positivity were rather homogeneous. IHC was considered positive when scored 3+ or when scored 2+ in combination with positive FISH. FISH positivity was uniformly defined as a HER-2:CEP17 ratio ≥2. The recently published ASCO/College of American Pathologists guidelines provide comprehensive information on integrating HER-2 assessment with clinical decision making [48].

Despite the large number of patients included in our analysis, there are several limitations to consider when interpreting our results. First, our approach was based on data abstracted from publications and not on individual patient data (IPD); thus, our results should be viewed as hypothesis-generating, and not as definitive evidence [49]. Although an IPD analysis of trastuzumab trials would be welcome, quantitative aggregation of data abstracted from publications is, for the time being, the best available summary of the evidence. Second, using the short-term results of randomized trials presented as interim analyses to estimate pooled point estimates may be a source of bias [50]. However, given the statistical power conferred by the large number of included patients and the adequate number of events that have accrued up to now, we believe our analysis detected actual treatment-related differences. Furthermore, the largely indisputable benefits in DFS seen with trastuzumab treatment can be expected to translate into a sustained long-term benefit in overall survival, an expectation well founded on similar observations made by the EBCTCG overview [2].


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 
Years of basic, clinical, and epidemiological investigations have led to the identification of HER-2 as a potential target for the treatment of breast cancer, facilitating the design of effective anti-HER-2 antibodies, culminating in the clinical testing of trastuzumab in the adjuvant setting. Our review demonstrates that combining trastuzumab with or following chemotherapy in the adjuvant setting results in benefits unparalleled by most available therapies for solid tumors. We believe that the combination of trastuzumab with or following chemotherapy should be strongly considered for HER-2–positive early-stage breast cancer, especially in patients at low risk for cardiovascular morbidity. Further research is needed to identify the most effective drug combination and treatment schedule, including clarification of the optimal duration of trastuzumab administration. Despite some open questions regarding the balance of trastuzumab's long-term benefits and risks, this monoclonal antibody is a bright example of how collaboration of basic, translational, and clinical research can lead to major breakthroughs in the treatment of cancer.


   NOTE ADDED IN PROOF
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
Author Contributions
 Acknowledgments
 References
 
After completion of the systematic review and conduct of the meta-analysis presented in this paper, the results of the PACS 04 trial, a randomized controlled trial of trastuzumab following adjuvant chemotherapy for operable node-positive breast cancer, were presented at the San Antonio Breast Cancer Symposium, in December 2007. The study reported on 528 HER-2–positive patients (by IHC or FISH), 260 of whom were randomized to receive trastuzumab and 268 of whom were randomized to observation following anthracycline-based chemotherapy (with or without docetaxel). For the sake of completeness, we repeated all calculations taking into account the results of this study. Given the study's small sample size, its influence on the pooled estimates was very small. The updated point estimates for all affected outcomes are listed in appendix Table A and represent a cumulative summary of the clinical trial evidence on adjuvant trastuzumab.


View this table:
[in this window]
[in a new window]

  		Table A. Updated pooled estimates for major outcomes

 

   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
Acknowledgments
 References
 
Conception/design: Issa J. Dahabreh, Samuel Murray

Administrative support: Issa J. Dahabreh, Fotios Siannis, George Fountzilas

Provision of study materials or patients: Issa J. Dahabreh, Helen Linardou, George Fountzilas

Collection/assembly of data: Issa J. Dahabreh

Data analysis and interpretation: Issa J. Dahabreh, Helen Linardou, Fotios Siannis, Samuel Murray

Manuscript writing: Issa J. Dahabreh, Helen Linardou, Samuel Murray

Final approval of manuscript: Issa J. Dahabreh, Helen Linardou, Fotios Siannis, George Fountzilas, Samuel Murray


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
References
 
Presented in part at the European Society of Medical Oncology Conference Lugano (ESMO Lugano, Lugano, Switzerland, July 5–8, 2007).

We would like to thank professor Michael Voulgarelis from the Department of Pathophysiology of the National University of Athens, Greece and Dr. Dimitrios Janinis from the Department of Medical Oncology of the Athens Medical Center, Athens, Greece for critically reviewing the manuscript and for providing an insightful clinical perspective.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Note Added in Proof
 Author Contributions
 Acknowledgments
 References
 

  1. Ferlay J, Bray F, Pisani P et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, Edition 2004, Volume IARC CancerBase No. 5, Version 2.0. 2004, IARC Press, Lyon, France, Available at http://www-dep.iarc.fr. Accessed December 27, 2007.
  2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687–1717.[CrossRef][Medline]
  3. Leyland-Jones B. Trastuzumab: Hopes and realities. Lancet Oncol 2002;3:137–144.[CrossRef][Medline]
  4. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.[Abstract/Free Full Text]
  5. Popescu NC, King CR, Kraus MH. Localization of the human erbB-2 gene on normal and rearranged chromosomes 17 to bands q12–21.32. Genomics 1989;4:362–366.[CrossRef][Medline]
  6. Schechter AL, Hung MC, Vaidyanathan L et al. The neu gene: An erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 1985;229:976–978.[Abstract/Free Full Text]
  7. Slamon DJ, Clark GM. Amplification of c-erbB-2 and aggressive human breast tumors? Science 1988;240:1795–1798.[Free Full Text]
  8. Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319:226–230.[CrossRef][Medline]
  9. Bargmann CI, Hung MC, Weinberg RA. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 1986;45:649–657.[CrossRef][Medline]
  10. Fendly BM, Kotts C, Vetterlein D et al. The extracellular domain of HER2/neu is a potential immunogen for active specific immunotherapy of breast cancer. J Biol Response Mod 1990;9:449–455.[Medline]
  11. Hudziak RM, Lewis GD, Winget M et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989;9:1165–1172.[Abstract/Free Full Text]
  12. Carter P, Presta L, Gorman CM et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 1992;89:4285–4289.[Abstract/Free Full Text]
  13. Shepard HM, Lewis GD, Sarup JC et al. Monoclonal antibody therapy of human cancer: Taking the HER2 protooncogene to the clinic. J Clin Immunol 1991;11:117–127.[CrossRef][Medline]
  14. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  15. Dahabreh IJ. Meta-analysis of rare events: An update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone. Clin Trials 2008;5:116–120.[Abstract/Free Full Text]
  16. Higgins JP, Thompson SG, Deeks JJ et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560.[Free Full Text]
  17. Smith I, Procter M, Gelber RD et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 2007;369:29–36.[CrossRef][Medline]
  18. Perez EA, Romond EH, Suman VJ et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. J Clin Oncol 2007;25:512.
  19. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.[Abstract/Free Full Text]
  20. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.[Abstract/Free Full Text]
  21. Slamon D, Eiermann W, Robert NJ et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in Her2neu positive early breast cancer patients. the 2006 San Antonio Breast Cancer Symposium; December 14–17, 2006; San Antonio, Texas, Presented at.
  22. Slamon D, Eiermann W, Robert NJ et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study. the 2005 San Antonio Breast Cancer Symposium; December 8–11, 2005; San Antonio, Texas, Presented at.
  23. Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820.[Abstract/Free Full Text]
  24. Perez EA, Suman VJ, Davidson N et al. Advances in monoclonal antibody therapy for breast cancer: Further analysis of NCCTG N9831. the 41st Annual Meeting of the American Society of Clinical Oncology; May 13–17, 2005; Orlando, Florida, Presented at.
  25. Buzdar AU, Ibrahim NK, Francis D et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676–3685.[Abstract/Free Full Text]
  26. Buzdar AU, Valero V, Ibrahim NK et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 2007;13:228–233.[Abstract/Free Full Text]
  27. Hind D, Pilgrim H, Ward S. Questions about adjuvant trastuzumab still remain. Lancet 2007;369:3–5.[CrossRef][Medline]
  28. Perez EA, Suman VJ, Davidson NE et al. Interim cardiac safety analysis of NCCTG N9831 Intergroup adjuvant trastuzumab trial. J Clin Oncol 2005;23:556.
  29. 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;23:7811–7819.[Abstract/Free Full Text]
  30. Geyer CE Jr, Bryant JL, Romond EH et al. Update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)->paclitaxel (T) vs. AC->T with trastuzumab (H). J Clin Oncol 2006;24:581.
  31. Robert NJ, Eirmann W, Pienkowski T et al. BCIRG 006: Docetaxel and trastuzumab-based regimens improve DFS and OS over AC-t in node positive and high risk node negative HER2 positive early breast cancer patients: Quality of life (QOL) at 36 months follow-up. J Clin Oncol 2007;23:556.
  32. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: Power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119–1129.[CrossRef][Medline]
  33. Lau J, Ioannidis JP, Terrin N et al. The case of the misleading funnel plot. BMJ 2006;333:597–600.[Free Full Text]
  34. Valabrega G, Montemurro F, Aglietta M. Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 2007;18:977–984.[Abstract/Free Full Text]
  35. Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–712.[Abstract/Free Full Text]
  36. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353:1734–1736.[Free Full Text]
  37. Bria E, Cuppone F, Fornier M et al. Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: The dark side of the moon? A meta-analysis of the randomized trials. Breast Cancer Res Treat. 2007 Jul 19 [Epub ahead of print].
  38. European Society of Medical Oncology. ESMO Conference Lugano, 2007. Dahabreh IJ, Economopoulos KP, Murray S. Trastuzumab with adjuvant chemotherapy for resectable breast cancer: A meta-analysis. Ann Oncol. 2007, 18, ix165, ix167, Available at http://annonc.oxfordjournals.org. Accessed December 27, 2007.[Free Full Text]
  39. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 2005;23:2900–2902.[Free Full Text]
  40. Ewer MS, Vooletich MT, Durand JB et al. Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820–7826.[Abstract/Free Full Text]
  41. Guarneri V, Lenihan DJ, Valero V et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center experience. J Clin Oncol 2006;24:4107–4115.[Abstract/Free Full Text]
  42. Jones SE, Savin MA, Holmes FA et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24:5381–5387.[Abstract/Free Full Text]
  43. Duchnowska R, Szczylik C. Central nervous system metastases in breast cancer patients administered trastuzumab. Cancer Treat Rev 2005;31:312–318.[CrossRef][Medline]
  44. Burstein HJ, Lieberman G, Slamon DJ et al. Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol 2005;16:1772–1777.[Abstract/Free Full Text]
  45. Yau T, Swanton C, Chua S et al. Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab. Acta Oncol 2006;45:196–201.[Medline]
  46. Tham YL, Sexton K, Kramer R et al. Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 2006;107:696–704.[CrossRef][Medline]
  47. Pestalozzi BC, Zahrieh D, Price KN et al. Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 2006;17:935–944.[Abstract/Free Full Text]
  48. Wolff AC, Hammond ME, Schwartz JN et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007;131:18.[Medline]
  49. Pignon JP, Hill C. Meta-analyses of randomised clinical trials in oncology. Lancet Oncol 2001;2:475–482.[CrossRef][Medline]
  50. Montori VM, Devereaux PJ, Adhikari NK et al. Randomized trials stopped early for benefit: A systematic review. JAMA 2005;294:2203–2209.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow CME: Take the course for this article:
 Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Syste...
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dahabreh, I. J.
Right arrow Articles by Murray, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dahabreh, I. J.
Right arrow Articles by Murray, S.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS
http://theoncologist.alphamedpress.org/misc/eLetters.shtml