Data from our meta-analyses confirm that the addition of one year of trastuzumab to anthracycline and taxane-containing adjuvant chemotherapy regimens provides substantial benefit for women with HER2-positive breast cancer, both in terms of disease recurrence and survival. The results from all of the trials incorporating one year of trastuzumab into the adjuvant regimen demonstrate a statistically significant increase in the incidence of symptomatic cardiac dysfunction and asymptomatic decreases in LVEF. Trastuzumab was first employed for metastatic breast cancer (MBC). The activity and safety of trastuzumab as a single agent were investigated in two phase II clinical trials in women with HER2-overexpressing MBC who had progressed after one or two chemotherapeutic regimens [15
]. The objective response rates were 11.6% and 15% in these two studies [15
]. Cardiac dysfunction was the most common adverse event, occurring in 5% of treated patients, many of whom had received doxorubicin prior to trastuzumab. In a study that was conducted to investigate the efficacy and safety of trastuzumab as a single agent in the first-line treatment of HER2-overexpressing MBC, the response rate was 26% [17
]. In that randomized phase II trial of first-line treatment, the patients were randomly assigned to one of two dose levels of trastuzumab (4 mg/kg initially followed by 2 mg/kg weekly, or 8 mg/kg to start, followed by 4 mg/kg weekly). The overall RR was 35% for women with 3+immunohistochemical (IHC) staining nearly double that reported for the previously treated patients. On the other hand, the overall RR was zero for those with 2+ IHC staining [17
]. This study concluded that single agent trastuzumab was active and well-tolerated as a first-line treatment for women with MBC with HER2 3+ overexpression, determined by either IHC or gene amplification by FISH [17
]. From these clinical trials, it has been shown that trastuzumab administered as a single agent is both active and well tolerated [15
]. The trastuzumab adjuvant trials have also provided valuable information on the efficacy and safety of combining trastuzumab with specific standard chemotherapy regimens. The NSABP B-31 and NCCTG N9831 trials have shown that trastuzumab can be combined with a standard AC-paclitaxel regimen, and the BCIRG 006 trial has shown that trastuzumab can be combined with a standard AC-docetaxel and a nonanthracycline regimen. Furthermore, there was a significantly longer overall survival time with 1 year of adjuvant Trastuzumab in the BCIR 006, B-31, N9831 and a clear trend in the other studies. Ours results based in these three and others two large powered studies assessing the role of Trastuzumab in addition to adjuvant chemotherapy for patients with HER2 positive tumors in reduced the mortality rate, recurrence and second tumors other that breast cancer. Together, these data present a variety of effective Trastuzumab-based treatment options for clinicians.
Another question observed in our review was the high incidence of brain metastases in patients who received adjuvant Trastuzumab. The causes of these trends are unknown. Bendell and colleagues [20
] retrospectively studied 122 women treated with trastuzumab alone or in combination with chemotherapy for Her-2-overexpressing metastatic breast cancer. Based on a median follow-up of 23 months, 34% of patients were diagnosed with CNS metastases, well above historical rates. At the time of diagnosis of CNS metastasis, 50% of patients were responding to therapy or had stable disease. That report was confirmed by the study of Clayton and colleagues [21
] which followed 93 metastatic breast cancer patients. Brain metastases occurred in 25% of patients during a median follow-up period of 10.8 months from the start of trastuzumab therapy. One theory suggests that Her-2 overexpression endows tumor cells with increased metastatic aggressiveness to sites such as the lungs and may similarly augment metastatic propensity to the CNS [22
]. Second, by allowing patients to live longer, trastuzumab may allow micrometastatic brain metastases to become symptomatic as a natural consequence of an extended life span. A nonexclusive, third theory posits that trastuzumab is effective against systemic metastases but relatively ineffective against CNS metastases due to its poor penetration of the blood-brain- barrier. That hypothesis may extend to cytotoxic chemotherapy as well as Trastuzumab [24
]. Limited pharmacokinetic data in support of this hypothesis suggest that systemic administration of trastuzumab results in drug levels in the CSF that are 300-fold lower than in the serum [25
]. Also, intrathecal administration of 4D5, the murine precursor of trastuzumab, shows efficacy against a human xenograft of Her-2-overexpressing cancer growing in the leptomeninges, suggesting that trastuzumab could be efficacious if it could penetrate the blood-brain- barrier [26
]. Based on our data and other studies [20
] we predict that brain metastases will become more prevalent as greater control over systemic metastases is achieved, particularly with regard to Her-2-positive tumors.
The incidence of cardiac events with trastuzumab in the EBC setting remained at an acceptable level and was similar across the adjuvant trials, with a reported overall incidence that was 0.6%–3.3% higher [11
]. Our results analyzing 9117 patients submitted to adjuvant trastuzumab by breast cancer suggest that sequencing the combination of trastuzumab and taxanes plus anthracycline-based chemotherapy increases the risk for class III or IV CHF (OR = 2.45, CI 95 1.89–3.16) However, in our analyses that result was associated with heterogeneity using random effect. Probably due to different definitions of cardiac events, evaluations for cardiac safety, analysis of cardiac end points, and duration of follow-up differed among the adjuvant trials and thus make comprehensive cross-trial conclusions difficult, as showed in Table . Comparisons regarding cardiac safety should therefore be approached with caution. Increasing evidence suggests that, in patients with metastatic breast cancer who experience a significant LVEF decline, management with beta-blockade and angiotensin-converting enzyme inhibition may allow careful reinitiation of trastuzumab therapy after assessment of the risk-benefit ratio [27
]. In the B-31 trial, 27 of the 31 patients in the trastuzumab arm have been followed for>6 months after diagnosis of a cardiac event; 26 were asymptomatic at last assessment and 18 remained on cardiac medication [11
]. In this way, the cardiac function of all patients who start treatment with trastuzumab should be monitored and with further follow-up, it will become clearer whether sequential or anthracycline-free regimens carry a lower risk of cardiac toxicity with equivalent efficacy. The mechanism of cardiac dysfunction associated with trastuzumab is not clearly understood, although several hypotheses have been proposed. These include the modification of anthracycline-induced cardiotoxicity, immunemediated destruction of cardiomyocytes, the effects on HER2 signaling pathways that are required for the maintenance of normal cardiac contractility, and the dependence on HER2 for myocyte survival, which is then impaired during trastuzumab treatment [27
]. There is increasing experimental evidence supporting a direct toxic effect of HER2 blockade on the heart. HER2 signaling appears to play an important role in embryonic cardiac development and cardioprotection, at least in rodents [28
]. Those data suggest that trastuzumab-related cardiotoxicity is not immune-mediated or due to effects outside the heart, and it does not result solely from the modification of anthracycline-induced cardiac toxicity. In contrast to anthracycline-related cardiotoxicity, trastuzumab-associated toxicity does not appear to be dose related, and it usually responds to standard medical treatment or the discontinuation of trastuzumab [30
]. Thus, in the adjuvant setting, continued treatment with trastuzumab is contraindicated if there is any evidence of cardiac dysfunction, and monitoring for early evidence of left ventricular dysfunction is important. In contrast, continuation of trastuzumab therapy or resumption of treatment after resolution of cardiac abnormalities may be safe in some women with metastatic breast cancer who develop early evidence of cardiac dysfunction.
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 have completed chemotherapy >6 months previously is unknown. However, in patients with HER-2/neu-positive breast cancer treated with AC followed by paclitaxel chemotherapy, 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. 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 (patients with estrogen receptor-positive and HER-2/neu-positive disease, patients with negative lymph nodes and tumors < 1 cm) and for whom trastuzumab alone might represent appropriate adjuvant therapy. Patients in the NSABP B-31, N9831, and BCIRG-006 trials received adjuvant radiation upon completion of chemotherapy during maintenance trastuzumab. Clinical trials should be designed to answer those questions.
Limitations of our study
One limitation in our study is the data source extracted from abstracted data or published studies and not individual patient data (IPD). Meta-analyses based on published data tend to overestimate treatment effects compared with individual patient data analyses. However, analyses using individual patient data may include fewer studies if all authors do not agree to submit their full databases to the analyzing group. In general, an IPD-based meta-analysis would give a more robust estimation for the association; therefore, we should interpret the results with care, especially for a positive result. Although the risk of publication bias exists in any meta-analysis, whether based on individual patient data or not, we feel that this was not an important aspect of our study, as many positive and negative trials were included in the analysis.