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Abstract

Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18–23% of invasive breast carcinomas and is associated with a worse prognosis. This novel transforming gene was identified in 1985, and in 1987 HER2 amplification was demonstrated to be central to the aggressive, malignant phenotype of these cancers and a significant predictor of both time to relapse and overall survival. These observations led to the development of the first monoclonal antibody targeting the extracellular domain of HER2, trastuzumab (Herceptin®, Genentech and Hoffman LaRoche, Switzerland), which was approved by the US FDA for metastatic breast cancer in 1998. In 2005, results from four major trastuzumab adjuvant trials demonstrated a marked reduction in risk of recurrence, and trastuzumab is now an essential component of the adjuvant treatment of H ER2-positive early breast cancer. Concerns regarding cardiac safety and mechanisms of resistance to trastuzumab remain important issues and are being addressed in ongoing research efforts.

Keywords

adjuvant therapy anthracyclines breast cancer cardiotoxicity HER2 positive trastuzumab

After nonmelanoma skin cancer, breast cancer remains the most common cancer diagnosis among women in the USA. The annual incidence of breast cancer increased through 2001 but then began to decrease annually by 3%. Mortality from breast cancer has been declining by 2.2% since 1990, presumably owing to the broad acceptance of screening mammography and the improved efficacy of treatments for early-stage disease [101]. Advances in understanding of molecular and cellular biology have accelerated the development of improved therapies by identifying critical pathways related to cell-cycle progression, proliferation and cell survival. Specific aberrations in these pathways have been identified that play a critical role in the development of the malignant phenotype. One of the most significant of these is the amplification of the gene for the human epidermal growth factor receptor (HER)2 protein, a member of the HER family of cell surface receptors.

HER-receptor family

The HER family of transmembrane protein receptors consists of four related members: HER1 (also termed EGF receptor [EGFR]), HER2, HER3 and HER4, or ErbB-1, −2, −3 or −4, respectively [1,2]. They share a common structural motif: an extracellular binding domain, a transmembrane lipophilic segment and an intracellular tyrosine kinase (TK) domain. Following ligand binding, the members of the HER family, except for HER2, undergo conformational changes that allow for dimerization, which is necessary for activation of the TK domain. HER2 does not have an identified ligand and exists in a fixed conformation resembling the ligand-activated state of the other HER family receptors, allowing dimerization in the absence of ligand binding [3]. HER3 lacks a TK domain, so heterodimerization with HER2 or either ligand-bound HER1 or HER4 is necessary for downstream signaling through this receptor. The normal function of HER2 is to form heterodimers with other activated members of the HER family, which initiate a cascade of downstream signaling through multiple intracellular pathways. As a result, cell-cycle activation, cell proliferation and increased cell survival through inhibition of apoptosis occur [4].

HER2 gene amplification occurs in 18–23% of breast cancers [5,6], and is associated with a worse prognosis and more aggressive behavior in both early and metastatic breast cancer [7]. Amplification results in marked elevations of protein expression, giving rise to extensive HER2 homodimerization, which results in ligand-independent activation of the phosphoinositide-3 kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) downstream pathways. Activation of these critical pathways results in cell proliferation, cell-cycle progression and survival, and the sustained, inappropriate activation of these pathways play a central role in the behavior of these cancers. Heterodimerization of overexpressed HER2 protein with other HER family members may also contribute to the inappropriate activation of these pathways (Figure 1).

Figure 1.

HER family activation pathways.

Trastuzumab in metastatic breast cancer

The first successful therapy developed to specifically target HER2 gene amplification was trastuzumab (Herceptin®, Genentech and Hoffman LaRoche, Switzerland), a humanized monoclonal antibody directed against an epitope on the extracellular domain of HER2 [8]. Trastuzumab monotherapy demonstrated response rates of 26% as first-line therapy for HER2-positive metastatic breast cancer [9], and 15% in patients previously treated with chemotherapy [10]. When combined as first-line therapy with a number of different chemotherapeutic agents, trastuzumab has resulted in response rates ranging from 40–70% [11 –13]. In the pivotal Phase III trial, which combined trastuzumab with doxorubicin plus cyclophosphamide (AC) or paclitaxel, 469 women with previously untreated metastatic breast cancer were randomly assigned to chemotherapy alone versus chemotherapy with trastuzumab. The addition of trastuzumab led to an improved response rate (50 vs 32%; p < 0.001), improved median duration of response (9.1 vs 6.1 months; p < 0.001), and prolonged overall survival (OS) (median 25.1 vs 20.3 months; p = 0.046) [11]. Results of these trials led to the approval of trastuzumab for the treatment of HER2-positive metastatic breast cancer (Table 1) [102].

Table 1.

Trastuzumab with chemotherapy as first-line therapy for metastatic disease.

Agent(s) administered with trastuzumab	Response rate (%)	Median response duration (months)	Median TTF (months)	Median survival (months)	Ref.
Doxorubucin plus cyclophosphamide	56	9.1	7.2	26.8	[11]
Paclitaxel	41	10.5	5.8	22.1	[11]
Docetaxel	61	11.7	9.8	31.2	[12]
Vinorelbine	68	N/P	5.6	N/P	[13]

N/P: Not provided; TTF: Time to failure.

Trastuzumab & cardiac dysfunction in metastatic breast cancer trials

The most important adverse event in the pivotal Phase III trial of trastuzumab was cardiac dysfunction. Asymptomatic or symptomatic left ventricular dysfunction was identified in 27% of patients who received AC plus trastuzumab, 8% of those who received AC alone, 13% of the group given paclitaxel and trastuzumab and 1% of those receiving paclitaxel alone. The rates of New York Heart Association (NYHA) Class III or IV symptomatic heart failure were 16, 3, 2 and 1%, respectively. Patients receiving paclitaxel had previously received an anthracycline as a component of their adjuvant therapy [11].

While the inhibition of HER2 signaling is presumed to be the central mechanism of trastuzumab-related cardiotoxicity, the exact pathophysiologic mechanism is unknown.

A knockout mouse model with a cardiac-restricted, conditional HER2 deletion mutant developed dilated cardiomyopathy [14] and showed enhanced susceptibility to anthracycline-induced cardiotoxicity [15]. These and other data suggest that the inhibition of HER2 receptor-dependent myocyte survival pathways may increase susceptibility to heart failure following the known cardiotoxicity associated with anthracycline treatment.

Randomized trials of adjuvant trastuzumab

Treatment for HER2-positive metastatic breast cancer has been greatly improved by the addition of HER2-targeted therapy, and some patients treated with trastuzumab remain free of progressive disease for years, even though most eventually succumb to their disease. Since HER2-targeted therapy provided important benefits in the metastatic setting, clinical trials were developed to evaluate trastuzumab in the adjuvant setting. Many early-stage HER2-positive breast cancer patients can be treated successfully by surgery, chemotherapy, endocrine therapy and radiotherapy and, as such, incremental cardiotoxicity was a critical design issue in adjuvant trastuzumab trials. Since the rates of cardiac dysfunction that occurred in those who received concomitant anthracyclines and trastuzumab were unacceptable, adjuvant trials were designed to give anthracyclines and trastuzumab sequentially rather than concomitantly. One trial also evaluated an important nonanthracycline regimen [16].

Design of adjuvant trials of trastuzumab

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of randomized trials of polychemotherapy in early-stage breast cancer demonstrated that anthracycline-based regimens were superior to nonanthracycline-based regimens with respect to recurrence (p = 0.00001) and breast cancer mortality (p < 0.00001) [17]. Retrospective data conducted on tumor specimens from a subset of patients from Cancer and Leukemia Group B (CALGB) trial 8541, which compared three dose levels (standard, moderate and low) of cyclophosphamide, doxorubicin and fluorouracil (CAF) in 1572 women with node-positive breast cancer suggested that a benefit from standard-dose CAF over lower-dose levels of CAF was limited to patients with HER2-positive tumors [18]. A recent meta-analysis of a series of retrospective studies of specimens from trials that showed the superiority of anthracycline-containing regimens relative to non-anthracycline regimens demonstrated that the incremental benefits of anthracyclines appeared to be limited to women with HER2-positive breast cancer. Among these patients (n = 1536) the hazard ratio (HR) was 0.71 (95% CI: 0.61–0.83; p < 0.001) for disease-free survival (DFS) and 0.73 (95% CI: 0.62–0.85; p < 0.001) for OS. No benefit was apparent for anthracycline regimens for women with HER2-negative disease. The test for interaction between HER2 status and receipt of anthracyclines was significant for both DFS (χ² = 13.7; p < 0.001) and OS (χ² = 12.6; p < 0.001) [19].

The inclusion of anthracyclines in the chemotherapy regimens used in the adjuvant trastuzumab trials was an important issue because of the cardiotoxicity associated with anthracycline–trastuzumab combinations. Three trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) had established four cycles of AC as a standard of care for women with both node-positive (trials B-15 and B-16) [20,21] and node-negative (trial B-23) breast cancer [22]. Subsequent trials conducted by CALGB (9344) [23] and the NSABP (trials B-27 and B-28) [24,25] demonstrated improved outcomes with the administration of paclitaxel or docetaxel for four cycles following AC. These sequential regimens were chosen as the control chemotherapy regimens in B-31, North Central Cancer Treatment Group (NCCTG) N9831 [26], and Breast Cancer International Research Group (BCIRG) 006 [16]. In these trials, patients completed AC before they received trastuzumab in combination with a taxane. It was thought that the sequential administration of the anthracycline followed by trastuzumab would lower the risk of cardiotoxicity to a level that would be acceptable in the adjuvant setting. The Herceptin Adjuvant (HERA) trial also used the sequential approach by having all chemotherapy completed before random assignment to 1 or 2 years of trastuzumab or observation.

NSABP B-31, NCCTG N9831, BCIRG 006 & the HERA trial

The NSABP B-31 trial compared four cycles of AC followed by four cycles every 3 weeks of paclitaxel (AC→P, arm 1) with AC→P plus 52 weeks of trastuzumab beginning with the first cycle of paclitaxel (AC→PH→H, arm 2). The NCCTG N8931 trial was a three-arm study that compared four cycles of AC followed by 12 weekly doses of paclitaxel (AC→WP, arm A) with AC→WP followed by 52 weeks of trastuzumab beginning after paclitaxel (AC→ WP→ H, arm B) and with AC→ WP plus 52 weeks of trastuzumab beginning with the first week of paclitaxel (AC→WPH→H, arm C). Since arms 1 and 2 of B-31 were similar to arms A and C of N9831, the studies were amended before any interim analyses to provide for a joint statistical analysis comparing the control arms with the concurrent arms of the two studies (Figure 2).

Figure 2.

Major adjuvant trastuzumab trials.

The BCIRG 006 trial employed four cycles of AC followed by four cycles of docetaxel (AC→ T) as the control chemotherapy regimen. One investigational arm initiated 52 weeks of trastuzumab concurrently with docetaxel (AC→ TH→ H). The study included a third arm evaluating a novel nonanthracycline regimen consisting of six cycles of carboplatin plus docetaxel initiated concurrently with 52 weeks of trastuzumab (TCH→ H) [25]. The regimen was based on preclinical observations of synergy between platinum-based chemotherapy and trastuzumab and supported by data from trials conducted in women with metastatic breast cancer [27,28].

The HERA trial required eligible patients to have received at least four cycles of neoadjuvant or adjuvant chemotherapy from a list of approved regimens before entry and random assignment. Most patients received an anthracycline-based chemotherapy regimen (94%), while a minority (26%) received a taxane [29].

Cardiac eligibility criteria & cardiac monitoring

All of the trials were limited to patients in good health without pre-existing cardiac disease. B-31 and N9831 required entry left ventricular ejection fraction (LVEF) to be in the normal range for the institution [26]. BCIRG 006 required entry LVEF to be 50% or greater [16]. HERA required patients to have a LVEF of 55% or greater following chemotherapy and radiotherapy [29]. Similar guidelines for the initiation and continuation of trastuzumab were employed, with mandatory discontinuation of trastuzumab in the event of confirmed substantive asymptomatic declines in LVEF or symptomatic cardiac dysfunction.

NSABP B-31 and NCCTG N9831 used the same end point for severe cardiac toxicity, referred to as a cardiac event (CE) [26]. A CE was defined as confirmed congestive heart failure (CHF) with NYHA Class III or IV symptoms or definite or probable cardiac death. The definition of a CE in BCIRG 006 was broader than that in B-31 and N9831 [16]. Any symptomatic left ventricular dysfunction (NHYA Class II, III or IV symptoms), grade 3 or 4 cardiac ischemia/infarction, grade 3 or 4 cardiac arrhythmias, and cardiac-related deaths were all included in the end point in BCIRG 006.

The HERA trial also employed different definitions for cardiac toxicities [29]. Cardiac death was defined as death definitely due to heart failure, myocardial infarction or documented arrhythmia, or sudden unexpected death within 24 h of a definite or probable CE. Severe CHF was defined as a patient having NYHA class III or IV symptoms, confirmed by a cardiologist, with a significant LVEF decline. A significant LVEF decline was defined as an absolute decline of at least 10% from baseline LVEF, and to below 50% identified by multiple gated acquisition (MUGA) scan or echocardiogram. Symptomatic CHF included the patients identified as having severe CHF and was defined as any degree of CHF considered symptomatic by a cardiologist with a significant LVEF decline.

Efficacy results of adjuvant trastuzumab trials

NSABP B-31/NCCTG N9831

The first interim analysis of B-31/N9831 was conducted with a combined median follow-up of 2 years and demonstrated a striking benefit for patients randomized to receive trastuzumab [26]. The primary end point of DFS was improved with trastuzumab (HR: 0.48; 95% CI: 0.39–0.59; p < 0.001) and was observed in all subsets. Overall survival was also improved (HR: 0.67; 95% CI: 0.48–0.93; p = 0.015). A subsequent analysis with a median follow-up of 2.9 years demonstrated that the reduction in HR for DFS events was maintained at 0.49 (95% CI: 0.41–0.58; p < 0.001) as was the reduction in risk of death at 0.63 (95% CI: 0.49–0.81; p = 0.0004). The 4-year DFS was improved from 73.1 to 85.9% (Table 2) [30].

Table 2.

Adjuvant trastuzumab trials: recent reports of primary end point analyses.

Trials	Events (median follow-up; months)	3-year DFS control (%)	3-year DFS trastuzumab (%)	DFS hazard (95% CI)	p-value#	Ref.
NSABP B-31/NCCTG N9831	619(34.8)	78	88	0.48(0.41–0.57)	<0.0001	[30]
BCIRG 006AC/TH vs AC/T	320(36)	81	87	0.61(0.48–0.76)	<0.0001	[31]
BCIRG 006TCH vs AC/T	334(36)	81	86	0.67(0.54–0.83)	0.0003	[31]
HERA	539(23.5)	74	81	0.64(0.54–0.76)	<0.0001	[32]

AC: Doxorubicin plus cyclophosphamide; BCIRG: Breast Cancer International Research Group; DFS: Disease-free survival; H: Trastuzumab; HERA: Herceptin Adjuvant trial; NCCTG: North Central Cancer Treatment Group; NSABP: National Surgical Adjuvant Breast and Bowel Project; T: Docetaxel; TCH: Docetaxel, carboplatin and Herceptin®.

BCIRG-006

The first interim analysis of BCIRG 006 was conducted with a median follow-up of 23 months. The HR for DFS events of AC→TH→H relative to AC→T was 0.49 (95% CI: 0.37–0.65; p < 0.0001) and 0.61 (95% CI: 0.47–0.79; p = 0.0003) for TCH→H relative to AC→T [16]. There were an insufficient number of deaths to analyze survival at the initial report. A follow-up analysis was conducted with a median follow-up of 36 months [31]. The HR for DFS events of AC→TH→H relative to AC→T was 0.61 (95% CI: 0.48–0.76; p < 0.0001) and 0.67 (95% CI: 0.54–0.83; p = 0.0002) for TCH→H relative to AC→T. Survival was improved with a HR for death of 0.59 (95% CI: 0.42–0.85; p = 0.004) with AC→TH→H relative to AC→T and 0.66 (95% CI: 0.47–0.93; p = 0.017) with TCH→H relative to AC→TH→H. The 4-year DFS was improved from 77% in the control arm to 83% with AC→TH→H and to 82% with TCH→H. No statistical difference was evident between the two investigational arms, but the study was underpowered for this comparison. However, the CI around the point estimates for the DFS HRs overlapped widely, suggesting similar clinical activity.

HERA trial

The interim analysis of the HERA trial was conducted with 1 year of median follow-up [29]. The unadjusted HR for a DFS event in the group that received trastuzumab for 1 year relative to the observation group was 0.54 (95% CI: 0.43–0.67; p < 0.0001). Differences in OS were not statistically significant. A subsequent analysis was reported after a median follow-up of 23.5 months [32]. The unadjusted HR for the risk of a DFS event with trastuzumab compared with observation was 0.64 (95% CI: 0.54–0.76; p < 0.0001). An improvement in OS was also demonstrated with an unadjusted HR for the risk of death of 0.66 (95% CI: 0.47–0.91; p = 0.0115). Results comparing 1 versus 2 years of trastuzumab have not been reported.

Cardiac toxicity data from adjuvant trials

NSABP B-31

A formal cardiac safety analysis with 3 years of median follow-up was reported shortly after the joint efficacy analysis was published [33]. The cumulative incidence of CEs was 4.1% in the trastuzumab-treated patients versus 0.8% in control patients, giving an absolute difference of 3.3% (95% CI: 1.7–4.9). Trastuzumab was discontinued early owing to cardiac effects (asymptomatic decline in LVEF, symptoms of cardiac dysfunction or other cardiac symptoms) in 19% of patients. Approximately 14% of these were due to confirmed, substantive, asymptomatic declines in LVEF. Potential predictors for an increased risk of a CE were also evaluated. Age of over 50 years (p = 0.03), need for hypertension medication at entry (p = 0.07), and baseline LVEF below 55% (p = 0.0001) were predictive. Women aged younger than 50 years had a 2% risk of developing a CE, while women aged 50 years and older had a risk of 5.3–5.4%. A need for hypertension medication resulted in a risk of 5.2%. Women with a baseline LVEF within the normal range but less than 55% had a 3-year cumulative incidence of 14.5% for a CE. Other potential risk factors such as left-sided radiation therapy, smoking history, family history, diabetes or hyperlipidemia were not predictive. A 5-year update of cardiac dysfunction in NSABP-31 was recently reported, demonstrating that the cumulative incidence of CEs in this study remained unchanged at 3.9% [34].

NCCTG N9831

The 3-year cumulative incidence of CHF was 0.3% in the control arm and 3.3% in the concurrent trastuzumab arm [35]. Factors associated with an increased risk of a CE with trastuzumab were evaluated. Women aged 60 years or younger had a risk of 6.6%, women aged 50–59 years had a 2.8% risk, and women younger than 50 years had a 2.1% risk (p < 0.003). Prior or current use of antihypertensive agents increased the risk to 6.6% (p = 0.005). Baseline LVEF less than 55% also increased the risk to 5.6% (p = 0.033), which was less pronounced than what was reported in the B-31 trial. No other risk factors were identified. Overall, the risk factor analysis of N9831 supports the findings of B-31.

BCIRG 006

The definition of a CE in BCIRG 006 was broader than that in B-31 and N9831. At the time of the initial efficacy report, the rate of CE by the 006 criteria was 0.95% (95% CI: 0.46–1.74) with AC→T compared with 2.34% (95% CI: 1.52–3.44) with AC→TH→H (p = 0.016), and 1.33% (95% CI: 0.72–2.21) with TCH→H (p = 0.54) [16]. At the updated efficacy analysis, cardiac toxicity was reported using criteria similar to those used in B-31 and N9831 [31]. No cardiac deaths had occurred on BCIRG 006, so the number of patients with symptomatic LV dysfunction was 4/1050 (0.38%) with AC→T, 20/1068 (1.87%) with AC→TH→H, and 4/1056 (0.38%) with TCH→H. The difference between the rates in the trastuzumab arms was statistically significant (p = 0.0015). The percentages of patients with a relative decline from a baseline of 10% or over were 10, 18 and 9%, respectively, for the three regimens.

HERA

The HERA trial had a number of important design differences from the other large trials [29]. Patients had to complete chemotherapy and radiotherapy before random assignment and had to have a postchemotherapy LVEF of 55% or over. With a median follow-up of 12 months, the cumulative risk of severe CHF was 0.6% in the trastuzumab arm and 0% in the observation arm [36]; this corresponds to the definition of a CE in both B-31 and N9831. The rate of symptomatic CHF was 2.15% in the trastuzumab arm and 0.12% in the observation arm; this corresponds to the definition of cardiac dysfunction in BCIRG 006. Patients with a screening LVEF of 55–59% had a significantly higher incidence of one of the HERA cardiac end points of 6.90 versus 2.72% for higher LVEF values. Patients with potential risk factors for hypertension (e.g., aged over 60 years, smoking history, diabetes or hypothyroidism) also had a nonsignificant trend toward a higher incidence.

Future perspective

Efficacy and safety results from these four large adjuvant trials have established trastuzumab as an essential component of systemic therapy for operable, HER2-positive breast cancer. However, questions regarding the optimal use of trastuzumab remain. Perhaps the most important of these involves the impact that the inclusion of anthracyclines has on the efficacy and cardiac toxicity of trastuzumab when used in combination with chemotherapy in the adjuvant setting. The decision to complete the anthracycline-based portion of chemotherapy before the initiation of trastuzumab was successful in keeping the rate of severe cardiac toxicity low enough for the adjuvant setting, in view of the marked reduction in risk for recurrence and death with the introduction of trastuzumab. However, the data from BCIRG 006 clearly demonstrate that the risk of cardiotoxicity with trastuzumab in the absence of anthracyclines (TCH→H) is negligible and the regimen has substantial activity [16,31]. Unfortunately, BCIRG 006 was not powered to determine small differences in efficacy, so uncertainty remains regarding the activity of TCH→H relative to AC→TH→H. While the confidence intervals around the point estimates overlapped widely, the HRs for improved DFS and OS for AC→TH→H relative to control (AC→T) have been slightly better numerically than for TCH→H, relative to the same control. It is unlikely that a study adequately powered to address this question will ever be conducted, or that additional follow-up will provide sufficient events to demonstrate small differences, given the efficacy of both trastuzumab regimens.

Concordant data from NSABP B-31 and NCCTG N9831 clearly identify patients with an elevated degree of risk for severe cardiac toxicity associated with the sequential AC-followed-by-paclitaxel-plus-trastuzumab regimens [33,34]. Women aged over 55–60 years, those on anti-hypertensive medication, and particularly those with LVEF values below 55% appear to have a degree of risk that does not justify treatment with an anthracycline-containing regimen, given the activity and negligible cardiac risk with TCH→H. Women without these risk factors were still at increased risk for severe CEs with sequential regimens relative to TCH→H and should be presented with the efficacy and safety data from both approaches to allow them to make an informed risk–benefit decision regarding adjuvant systemic therapy.

Other unanswered questions will ultimately be addressed with additional follow-up of N9831 and HERA. N9831 had two investigational arms that only differed by the timing of the initiation of trastuzumab; the unreported arm (arm B) from the study initiated trastuzumab after the completion of paclitaxel; the other investigational arm (arm C), combined with NSABP B-31 in the joint efficacy analysis, began trastuzumab concurrently with paclitaxel. After additional follow-up, both arms will be compared with the control arm, and the study is reported to be sufficiently powered to detect clinically relevant differences in efficacy end points between the two approaches. The comparison of 1 year of trastuzumab with the unreported arm of HERA, in which patients received 2 years of trastuzumab, will provide important information regarding duration when trastuzumab is initiated following completion of chemotherapy. The FinHer study, which randomized 1010 women with early breast cancer to receive three cycles of either docetaxel or vinorelbine followed by three cycles of fluorouracil, epirubicin and cyclophosphamide (FEC), included a subset of 232 patients with HER2-positive breast cancer who were also randomized to receive trastuzumab for 9 weeks with their docetaxel or vinorelbine. Trastuzumab, administered for this brief period concurrently with chemotherapy, was found to improve recurrence-free survival (HR: 0.42; 95% CI: 0.21–0.83; p = 0.01), with a trend toward improved OS (HR: 0.41; 95% CI: 0.16–1.08; p = 0.07) [37]. These results suggest that a shorter duration of trastuzumab might be sufficient when it is administered concurrently with chemotherapy. A shorter duration of trastuzumab could decrease the incidence of cardiac toxicity and would substantially lower the considerable costs relative to a full year of therapy. However, the results need to be verified by larger trials, and an ongoing French study is comparing 6–12 months of trastuzumab [103].

In spite of the remarkable improvement in outcome for women with early-stage HER2- positive breast cancer, some of these women still develop recurrence [29]. The second generation of adjuvant trials for HER2-positive breast cancer is evaluating methods to overcome the resistance demonstrated in patients who develop recurrent disease. Amplification of HER2 is associated with the production of VEGF, which promotes angiogenesis and contributes to the malignant phenotype of HER2-amplified breast cancer [38]. Preclinical models [39] and data from a Phase I/II trial in which trastuzumab was combined with another monoclonal antibody that binds to VEGF [40,41], bevacizumab, indicate that important potential synergy exists for the simultaneous inhibition of HER2 and VEGF. The NSABP, CIRG and other international collaborators are conducting a global adjuvant trial (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-positive Breast Cancer [BETH]) (Figure 3) [104], where women with operable HER2-positive breast cancer are randomized to receive chemotherapy with trastuzumab or chemotherapy with trastuzumab plus bevacizumab. The two trial groups and some of the international investigators are using TCH→H as the control regimen in the trial. Other international investigators are using a regimen of docetaxel plus trastuzumab for three cycles followed by a regimen of FEC for three cycles followed by completion of 52 weeks of trastuzumab as their control regimen. In both investigational arms, bevacizumab is administered concurrently with trastuzumab.

Figure 3.

New trials.

The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial (Figure 3) [105] is another international trial being conducted jointly by the Breast International Group and the North American Breast Cancer Intergroup to evaluate the potential role of lapatinib (Tykerb®, GlaxoSmithKline, UK), a small-molecule, dual TK inhibitor of HER2 and HER1 (EGFR) [42] in the adjuvant therapy of HER2-positive breast cancer. Lapatinib plus capecitabine has been shown to be superior to capecitabine alone in women with heavily pretreated metastatic breast cancer that had progressed following therapy with regimens containing trastuzumab, an anthracycline and a taxane [43]. All patients in ALTTO receive an anthracycline-based chemotherapy regimen and then begin HER2-targeted therapy. Paclitaxel may be administered concurrently with targeted therapy at the investigator's discretion. Patients are randomized to receive one of four targeted therapy regimens for 1 year: trastuzumab; lapatinib; trastuzumab for 3 months followed by lapatinib for 9 months; or trastuzumab in combination with lapatinib.

Understanding and overcoming trastuzumab resistance is a major focus of academia and the pharmaceutical industry. Lapatinib was the first drug developed and approved to address this issue. Other agents such as pan-HER inhibitors [44,45], heat-shock protein inhibitors [46], insulin-like growth factor (IGF) inhibitors [47], and other HER2-targeted monoclonal antibodies, such as pertuzumab [48 –51], are being developed and evaluated in patients with metastatic HER2-positive breast cancer. The wealth of potential agents to overcome trastuzumab resistance offers hope that effective treatment will ultimately be available for all women who develop HER2-positive breast cancer.

Executive summary

Human epidermal growth factor receptor family

Human epidermal growth factor receptor (HER) family of transmembrane proteins consists of four related members: HER1, HER2, HER3 and HER4.

HER2 gene amplification occurs in 18–23% of invasive breast carcinomas and is associated with a worse prognosis and more aggressive behavior.

Ligand-independent activation of downstream pathways plays a central role in the behavior of these cancers.

Trastuzumab in metastatic breast cancer

Trastuzumab is a monoclonal antibody directed against an epitope on the extracellular domain of HER2.

It is the first successful targeted therapy developed specifically to treat HER2-positive breast cancer.

Trastuzumab monotherapy has been shown to be active as first-line as well as second-line therapy in metastatic HER2-positive breast cancer.

Combinations of trastuzumab with various chemotherapeutic agents as first-line therapy resulted in response rates ranging from 40 to 70%.

Trastuzumab & cardiac function

An important adverse effect of trastuzumab in the pivotal Phase III trial was cardiac dysfunction.

Incidence of cardiotoxicity was higher in patients who received anthracycline and trastuzumab concurrently.

The exact pathophysiologic mechanism of trastuzumab-related cardiotoxicity is unknown.

Preclinical data suggest that inhibition of HER2 receptor-dependent myocyte survival pathways may increase susceptibility to heart failure following the known cardiotoxicity associated with anthracycline treatment.

Executive summary

Design of adjuvant trastuzumab trials

Since the majority of women with early-stage breast cancer can be effectively treated with a combination of locoregional therapy (surgery and radiation) and systemic therapy (chemotherapy and endocrine therapy), trastuzumab-related cardiotoxicity was a major concern of the investigators designing the adjuvant trastuzumab trials.

Adjuvant trials were designed to give trastuzumab sequentially after anthracycline-based chemotherapy regimens rather than concomitantly because of the results in the metastatic setting that demonstrated higher rates of cardiotoxicity with concomitant anthracycline and trastuzumab therapy.

The BCIRG 006 trial included a nonanthracycline regimen.

All four major adjuvant trastuzumab trials defined cardiac eligibility criteria as well as protocols for cardiac monitoring.

Efficacy results of adjuvant trastuzumab trials

NSABP B-31 and NCCTG N9831 studies had similar arms, hence, a joint statistical analysis comparing the control arms with the concurrent weekly paclitaxel and trastuzumab arms of the two studies was conducted.

At 2.9 years of median follow-up of NSABP B-31/N9831, addition of trastuzumab to adjuvant chemotherapy showed a significant benefit for disease-free survival (DFS) and overall survival (OS).

The first interim analysis of BCIRG 006 reported improved DFS in both the anthracycline and the nonanthracycline arms with the incorporation of trastuzumab. The second interim analysis demonstrated improvement in both DFS and OS.

The initial results of the Herceptin Adjuvant (HERA) trial with 1 year of follow-up demonstrated improvement in DFS but not OS. However, a subsequent analysis with longer follow-up showed an increased OS as well.

Cardiac toxicity data from adjuvant trials

Data on the risk of cardiotoxicity in the adjuvant setting continue to evolve.

Cardiac safety data from the individual trials of adjuvant sequential anthracycline trastuzumab have been reported.

Risk of substantial cardiotoxicity is low but is highest with doxorubicin plus cyclophosphamide → taxane/trastuzumab regimens and is negligible with docetaxel, carboplatin and Herceptin® (TCH).

Baseline risk factors for congestive heart failure should be considered prior to making a decision to use an anthracycline- and trastuzumab-containing regimen.

Most important risk factors for development of congestive heart failure have been identified and include: age over 55 years, baseline left ventricular ejection fraction of 50–54% and pre-existing hypertension.

Future perspective

Current data support the use of adjuvant regimens that combine trastuzumab with chemotherapy; however, many questions regarding the optimal use of trastuzumab remain unanswered.

Based on the BCIRG 006 data, which demonstrated that TCH had similar efficacy but negligible cardiotoxicity compared with the anthracycline-containing arm, TCH should be offered to all women with HER2-positive breast cancer to allow them to make an informed risk–benefit decision regarding adjuvant systemic therapy.

Additional follow-up data of N9831 will address the question of whether sequential therapy of trastuzumab following paclitaxel differs from the combined use of trastuzumab with paclitaxel.

The comparison of 1 year of trastuzumab with the unreported arm of HERA (2 years of trastuzumab) will address the question of duration of therapy (i.e., if longer therapy is better).

Trials are also ongoing to address the question of whether a shorter duration of therapy will be as effective as the current standard 52-week regimen. If confirmed, this would reduce the cost of trastuzumab treatment and may potentially lead to less cardiotoxicity.

Two second-generation randomized trials, Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-positive Breast Cancer (BETH) and Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), are testing the addition of bevacizumab and the role of lapatinib, respectively, in adjuvant therapy of HER2-positive breast cancer.

Several other agents such as pan-HER inhibitors, heat shock proteins, insulin-like growth factor inhibitors, and other HER2-targeted monoclonal antibodies, such as pertuzumab, are being developed and tested and may be available for clinical use in the future.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Role of Trastuzumab in the Adjuvant Treatment of HER2-Positive Early Breast Cancer

Abstract

Keywords

HER-receptor family

Trastuzumab in metastatic breast cancer

Trastuzumab & cardiac dysfunction in metastatic breast cancer trials

Randomized trials of adjuvant trastuzumab

Design of adjuvant trials of trastuzumab

NSABP B-31, NCCTG N9831, BCIRG 006 & the HERA trial

Cardiac eligibility criteria & cardiac monitoring

Efficacy results of adjuvant trastuzumab trials

NSABP B-31/NCCTG N9831

BCIRG-006

HERA trial

Cardiac toxicity data from adjuvant trials

NSABP B-31

NCCTG N9831

BCIRG 006

HERA

Future perspective

Footnotes

References