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

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1 The Oncologist Breast Cancer Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials ISSA J. DAHABREH, a,b HELEN LINARDOU, c FOTIOS SIANNIS, d GEORGE FOUNTZILAS, e SAMUEL MURRAY f a National University of Athens, Medical School, Athens, Greece; b Department of Medical Oncology, Athens Medical Center, Athens, Greece; c 1 st Department of Oncology, Metropolitan Hospital, Athens, Greece; d Department of Mathematics, National University of Athens, Athens, Greece; e Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; f Department of Molecular Biology and Genetics, Metropolitan Hospital, Athens, Greece Key Words. Trastuzumab Adjuvant chemotherapy Breast cancer HER-2 Systematic review Meta-analysis Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. LEARNING OBJECTIVES 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. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT 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 trastuzumabtreated patients (risk ratio [RR], 0.62; 95% confidence interval [CI], ). Superiority was also observed for patients receiving trastuzumab with respect to mortality (RR, 0.66; 95% CI, ), locoregional recurrence (RR, 0.58; 95% CI, ), and distant recurrence (RR, 0.60; 95% CI, ). Patients receiving trastuzumab with Correspondence: Samuel Murray, Ph.D., Department of Molecular Biology and Genetics, Metropolitan Hospital, 1, Ethnarhou Makariou & Venizelou Street, Piraeus, Greece. Telephone: /213; Fax: ; smurray@metropolitan-hospital. gr Received January 2, 2008; accepted for publication April 2, AlphaMed Press /2008/$30.00/0 doi: / theoncologist The Oncologist 2008;13:

2 Dahabreh, Linardou, Siannis et al. 621 chemotherapy had a higher risk for congestive heart failure (RR, 7.60; 95% CI, ) and left ventricular ejection fraction decline (RR, 2.09; 95% CI, ). A higher risk for central nervous system metastasis as the first recurrence event (RR, 1.60; 95% CI, ) was also noted in patients receiving trastuzumab. Conclusion. The use of trastuzumab should be considered an integral part of the adjuvant therapy of HER- 2 positive breast cancer patients. The Oncologist 2008; 13: INTRODUCTION 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 curativeintent 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 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 ; last search, June 15, 2007), and the online proceedings of the San Antonio Breast Cancer Symposium (years ; 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

3 622 Trastuzumab in the Adjuvant Treatment of Breast Cancer 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 I 2 statistic [16]. When extreme inconsistency was detected (I 2 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 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. was defined as p.05. All tests were two-tailed. Fixedeffects 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 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. 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

4 Dahabreh, Linardou, Siannis et al. 623 Table 1. Characteristics of eligible trials in this analysis Median follow-up Node positive HR positive Study (years) a Tumor characteristics Treatment regimens per arm n patients of (%) (%) HERA b 2 Early-stage invasive Arm A CT RT 3 observation 1, (56.8) 855 (50.4) breast cancer, node Arm B CT RT 3 H 12 mos 1, (56.7) 860 (50.5) positive or high-risk node negative (tumor 1 cm) Arm C CT RT 3 H 24 mos 1,689 NR NR NCCTG N9831 c 2.9 Early-stage invasive Arm A AC 3 P (86.9) 426 g (52.8) breast cancer, node Arm B AC 3 P H (89) 414 g (51.2) positive or high-risk node negative (tumor 1cmif HR negative or 2cmif HR positive) Arm C AC 3 P 3 H 981 NR NR NSABP B-31 d 2.9 Early-stage, node-positive Arm A AC 3 P (100) 460 g (52.8) invasive breast cancer Arm B AC 3 P H (100) 448 g (51.9) BCIRG 006 e 3 Node positive or high-risk Arm A AC 3 D 1, (71) 579 (54) node negative Arm B AC 3 D H 3 H 1, (71) 580 (54) Arm C D Carbo H 1, (72) 581 (54) or node-negative breast Arm B D or V H 3 CEF (89.7) 58 g (50) FinHER f 3 Early-stage, node-positive Arm A D or V 3 CEF (78.4) 51 g (44) cancer ( 2 cm and PgR negative) Arrows denote the sequential administration of drugs. a Trial follow-up is that of the most recent efficacy analysis. b The HERA trial allowed the administration of several alternative chemotherapy regimens; chemotherapy was anthracycline based in 94% of patients; 26% received a taxane and 76% received radiotherapy. Patients had to have received at least four cycles of an approved chemotherapy regimen. In all cases, the maximum cumulative dose of doxorubicin was 360 mg/m 2 and the maximum cumulative dose of epirubicin was 720 mg/m 2. For trastuzumab, a loading dose of 8 mg/kg i.v. was followed by 6 mg/kg every 3 weeks for 1 or 2 years (data on 2 years administration not available). c NCCTG N9831: 60 mg/m 2 doxorubicin and 600 mg/m 2 cyclophosphamide every 3 weeks for four cycles followed by 12 weekly doses of 80 mg/m 2 paclitaxel was compared with the same regimen plus a 4-mg/m 2 loading dose of trastuzumab followed by weekly doses of 2 mg/kg for 51 weeks. d NSABP B-31: 60 mg/m 2 doxorubicin and 600 mg/m 2 cyclophosphamide every 3 weeks for four cycles followed by 175 mg/m 2 paclitaxel every 3 weeks for four cycles was compared with the same regimen plus a 4-mg/kg loading dose of trastuzumab followed by weekly doses of 2 mg/kg for 51 weeks. e BCIRG 006: 60 mg/m 2 doxorubicin and 600 mg/m 2 cyclophosphamide every 3 weeks for four cycles followed by 100 mg/ m 2 docetaxel on day 1 of each 21-day cycle was compared with the same regimen plus a 4-mg/kg concurrent loading dose of trastuzumab followed by 2 mg/kg weekly for 12 weeks subsequently followed by 6 mg/kg every 3 weeks for 14 cycles. f FinHER: 100 mg/m 2 docetaxel on day 1 of each 21-day cycle or 25 mg/m 2 vinorelbine on days 1, 8, and 15 of the 21-day cycle and 600 mg/m 2 fluorouracil, 60 mg/m 2 epirubicin, and 600 mg/m 2 cyclophosphamide on day 1 of each 21-day cycle was compared with the same regimen plus a 4-mg/kg loading dose of trastuzumab followed by weekly doses of 2 mg/kg for 9 weeks. g Estrogen receptor positive patients. Abbreviations: AC, doxorubicin and cyclophosphamide; BCIRG, Breast Cancer International Group; Carbo, carboplatin; CEF, cyclophosphamide, epirubicin, and fluorouracil; CT, chemotherapy; D, docetaxel; FinHER, Finland Herceptin study; H, trastuzumab; HERA, Herceptin Adjuvant trial; HR, hormone receptor; NCCTG, North Central Cancer Treatment Group; NR, not reported; P, paclitaxel; NSABP, National Surgical Adjuvant Breast and Bowel Project; PgR, progesterone receptor; RT, radiotherapy; V, vinorelbine. trastuzumab. The HERA, BCIRG 006, and NCCTG N9831 trials were three-arm studies, while the FinHer trial was a 2 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

5 624 Trastuzumab in the Adjuvant Treatment of Breast Cancer 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. 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 (I 2 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, ) 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. 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, ) 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, ; p.0002) and dis-

6 Dahabreh, Linardou, Siannis et al. 625 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. tant recurrence (data from all trials [17, 19, 21, 23], 9,131 patients; RR, 0.60; 95% CI, ; p.0001). 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, ; 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, ; 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, ; 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 (I %; Q 15.72; p.003), which was further explored by a fixed-effects metaregression analysis. In general, for all secondary outcomes, analyses using either random- or fixed-effects models produced similar results (data not shown).

7 626 Trastuzumab in the Adjuvant Treatment of Breast Cancer 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. 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. We used fixed-effects meta-regression analysis to investigate potential sources of heterogeneity regarding LVEF decline. The following variables were evaluated: 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 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 metaanalysis, 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

8 Dahabreh, Linardou, Siannis et al. 627 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 fixedeffects 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,

9 628 Trastuzumab in the Adjuvant Treatment of Breast Cancer 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 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 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 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 Table A. Updated pooled estimates for major outcomes Outcome RR (95% CI) p-value DFS 0.63 ( ).0001 Mortality 0.66 ( ).0001 Locoregional recurrence 0.60 ( ).0002 Distant metastasis 0.62 ( ).0001 CHF 7.32 ( ).0001 LVEF decline 2.09 ( ).0001 Data from the PACS 04 study presented at the 2007 San Antonio Breast Cancer Symposium have been included into the primary analysis. Abbreviations: CHF, congestive heart failure; CI, confidence interval; DFS, disease-free survival; LVEF, left ventricular ejection fraction; RR, risk ratio. 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. ACKNOWLEDGMENTS 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. AUTHOR CONTRIBUTIONS 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 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. Lyon, France: IARC Press, Available at www-dep.iarc.fr. Accessed December 27, 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: Leyland-Jones B. Trastuzumab: Hopes and realities. Lancet Oncol 2002;3: 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: Popescu NC, King CR, Kraus MH. Localization of the human erbb-2 gene on normal and rearranged chromosomes 17 to bands q Genomics 1989;4: Schechter AL, Hung MC, Vaidyanathan L et al. The neu gene: An erbb-

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12 Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Issa J. Dahabreh, Helen Linardou, Fotios Oncologist Murray Siannis, George Fountzilas and Samuel 2008;13; DOI: /theoncologist This information is current as of July 15, 2008 Updated Information & Services including high-resolution figures, can be found at: