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Ann Oncol. 2012 March; 23(3): 791–800.
Published online 2011 June 10. doi:  10.1093/annonc/mdr294
PMCID: PMC3331733

Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab

Abstract

Background:

Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab.

Patients and methods:

A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF).

Results:

Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD.

Conclusions:

Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agents.

Keywords: cardiac, combination, HER, pertuzumab, safety

introduction

Pertuzumab, the first in a new class of targeted anticancer agents known as human epidermal growth factor receptor (HER) 2 dimerization inhibitors, inhibits the ability of HER2 to pair with other HER family members [1]. Dimerization is essential for HER signaling and is required for cell growth and survival in many tumor types (Figure 1A). In addition to blocking cell signaling, pertuzumab is capable of inducing antibody-dependent cell-mediated cytotoxicity [10].

Figure 1.
Human epidermal growth factor receptor (HER) 2 signaling pathways involved in tumorigenesis and cardiac survival. (A) In breast cancer cells, HER dimer formation results in cross-phosphorylation of the dimer tyrosine kinase domain and leads to the initiation ...

Besides their essential role in cell growth and survival, HER2 and HER4 receptors are also important for homeostatic mechanisms in the cardiac myocyte [11]. HER2 and HER4 are crucial for mouse embryonic heart development [12, 13], and it has been demonstrated in rodents that HER2 expression is required for the development of ventricular muscles and valves, while activation of HER2 promotes cardiomyocyte survival [5, 14]. Moreover, in adult rat myocardium, neuregulin signaling through HER2:HER4 heterodimers mediates synthesis and stabilization of myocardial structural proteins and attenuates myocyte death [5]. Although mice with a cardiac-restricted deletion of HER2 survive into adulthood and initially show no phenotypic abnormalities, they develop progressive cardiomyopathy with left ventricular dysfunction and dilation and are more susceptible to cardiac stress [15]. HER signaling is also thought to play an important role in the sympathovagal control systems of the heart [16, 17]. Therefore, despite the anticancer benefits offered by HER2-targeted agents, there is justified concern regarding the potential for undesirable effects on the heart.

An asymptomatic decline in left ventricular ejection fraction (LVEF), known as left ventricular systolic dysfunction (LVSD), is recognized as a potential side-effect of therapy with the HER2-targeted monoclonal antibody trastuzumab [8, 18], although symptomatic heart failure (HF) is relatively uncommon [17]. In a meta-analysis of randomized trials employing adjuvant trastuzumab in patients with HER2-positive early breast cancer, the likelihood of cardiac toxicity was 2.45-fold higher in patients receiving trastuzumab compared with those not receiving trastuzumab [19]. Most cases of LVSD are asymptomatic and normalize on withdrawal of therapy [20]. Myocardial dysfunction with anti-HER2 therapy is thought to result primarily from a loss of tertiary organization of the contractile proteins [6], which explains the high rate of reversibility [21]. Discontinuation of trastuzumab and treatment of cardiac dysfunction with standard HF therapy may allow subsequent rechallenge with trastuzumab in selected patients [22], although not all patients recover completely, even with appropriate HF management [23, 24]. Conversely, exposure to anthracycline is associated with ultrastructural changes and LVSD that may be more permanent if not detected early and managed appropriately [25, 26]. It is likely that the underlying mechanism of anthracycline-induced cardiotoxicity is different from that resulting from anti-HER2 treatments [6]; however, the two types of cardiotoxicity are not completely independent, and anti-HER2 treatment has the potential to worsen anthracycline toxicity [6, 27]. This may be due to the inhibition by trastuzumab of the HER2:HER4 dimer-activated pathways that play a crucial role in cardiomyocyte growth and repair mechanisms during times of stress (Figure 1B and C) [8, 9, 18]. Moreover, the incidence of cardiac dysfunction is higher in patients who have had prior anthracycline treatment, a known cause of myocyte death, compared with those who have been previously treated with a taxane, suggesting that inhibition of cardiac repair mechanisms is a clinically relevant determinant of LVSD [28]. Nonetheless, in most cases, LVSD attributable to trastuzumab is recoverable with early identification and careful reassessment [22, 29, 30]. The cardiac safety of the oral small molecule HER1/HER2 inhibitor lapatinib has also been evaluated. In a pooled analysis of clinical trial data for 3689 healthy volunteers and patients with various cancers [31], the rate of adverse cardiac events was low and, events were generally reversible. A more recent study in patients with trastuzumab-refractory metastatic breast cancer (MBC) demonstrated a low level of symptomatic and asymptomatic cardiac events when lapatinib was given in combination with trastuzumab [32].

Pertuzumab has demonstrated promising efficacy in combination with trastuzumab in patients with MBC [33, 34]. In this report, we provide an exploratory but comprehensive analysis of the pertuzumab cardiac safety data currently available from the phase II clinical trials that were designed to explore the efficacy of pertuzumab as monotherapy and in combination with trastuzumab and other anticancer agents. Cardiac end points were included in these studies, facilitating an exploratory analysis of the cardiac safety of pertuzumab. The current analysis was undertaken to provide insight for clinicians and guidance for future studies.

materials and methods

The incidence of cardiac dysfunction is described from all completed and ongoing Roche and Genentech phase II studies in which full-dose pertuzumab was given as a single agent (Table 1). Data are also included from any study in which pertuzumab was combined with cytotoxic anti-epidermal growth factor receptor (EGFR) (erlotinib) or anti-HER2 (trastuzumab) therapies (Table 1), excluding ongoing studies where data analyses are yet to take place. The phase II studies were primarily designed to explore the efficacy of pertuzumab, but cardiac end points were included to assess for cardiac safety.

Table 1.
Overview of studies included in the analysis

Cardiac exclusion criteria were similar across all studies with respect to baseline LVEF (<50%–55%) and maximum prior cumulative dose of anthracyclines (doxorubicin >360 mg/m2, epirubicin >720 mg/m2, mitoxantrone >120 mg/m2, and idarubicin >90 mg/m2) (Table 1). All patients underwent routine cardiac monitoring by echocardiography or multiple-gated acquisition scans in general every two to four cycles (Table 1).

As different definitions of LVSD and symptomatic HF were used across the studies included in the current analysis, data were reassessed to identify all patients in any study who met standardized criteria for LVSD, regardless of their cardiac status according to the original trial criteria. Asymptomatic LVSD was defined as a decrease from baseline in LVEF of ≥10 absolute percentage points to a value of <50% at any post-baseline LVEF assessment. LVEF readings were conducted and assessed by the participating study centers (local assessment) for all except one study (BO17929). For this study, central evaluations of LVEF were also conducted. HF was defined as symptomatic LVSD and was based on a decrease from baseline in LVEF of ≥10 absolute percentage points to a value of <50% at any post-baseline LVEF assessment accompanied by a physician diagnosis of a cardiac event, including any symptom plausibly associated with HF (including dyspnea, edema, and fatigue) and/or any recording of HF by an investigator.

pertuzumab as a single agent

Pertuzumab was given as a single agent in phase II studies in ovarian cancer, non-small-cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and MBC in which HER2 was not overexpressed [3539]. Single-agent pertuzumab was also given to the third cohort of patients with HER2-positive MBC enrolling in the phase II BO17929 study, primarily investigating the efficacy and safety of pertuzumab plus trastuzumab [40] (Table 1). Patients included in these studies had experienced progression or recurrent disease despite previous treatment. Patients in studies TOC2689g, TOC2572g, TOC2682g, BO17004, and BO16934 had not received any prior HER2-targeted therapy [3539], whereas those in BO17929 had progressed following trastuzumab-based chemotherapy [40, 45].

pertuzumab in combination with cytotoxic agents

Patients received pertuzumab in combination with non-anthracycline-containing cytotoxic therapy in phase I/Ib studies for various solid tumors and in phase II studies for ovarian cancer [4144] (Table 1). Patients with advanced solid tumors were treated with pertuzumab in combination with cytotoxic agents following progression during or after standard therapy [41, 42], whereas patients with platinum-sensitive [44] or platinum-resistant [43] ovarian cancer were treated with pertuzumab plus cytotoxic agents after first-line therapy.

pertuzumab in combination with the anti-HER2 trastuzumab

Two studies have been reported in which patients with MBC who experienced disease progression during trastuzumab treatment received pertuzumab and trastuzumab together [33, 45]. In these studies, the majority of patients had also received prior anthracycline treatment. In one of these studies (BO17929), patients were stratified into one of the three treatment cohorts. Cohorts 1 and 2 received pertuzumab in combination with trastuzumab following disease progression on trastuzumab plus chemotherapy. A third patient cohort was included following a protocol amendment [40]. These patients received pertuzumab as monotherapy following disease progression on trastuzumab plus chemotherapy; if they experienced disease progression during pertuzumab monotherapy, they were switched to pertuzumab plus trastuzumab.

pertuzumab in combination with the anti-EGFR agent erlotinib

The combination of pertuzumab and erlotinib—an inhibitor of EGFR tyrosine kinase signaling—is being investigated in an ongoing study in patients with locally advanced or metastatic NSCLC that has progressed following chemotherapy [46] (Table 1).

results

Information for 598 unique patients treated with pertuzumab alone or in combination was available for the current analysis (Table 2). Of these, 331 received pertuzumab as a single agent, 175 were treated with pertuzumab in combination with non-anthracycline-containing cytotoxic agents, 93 were treated with pertuzumab in combination with the anti-HER2 monoclonal antibody trastuzumab, and 15 were treated with pertuzumab in combination with the anti-EGFR agent erlotinib. Of the 93 patients receiving pertuzumab in combination with trastuzumab, 16 had already received pertuzumab as a single agent. The majority of patients in each of the MBC trials (>70%) had received prior anthracycline therapy (Table 2).

Table 2.
Incidence of asymptomatic left ventricular systolic dysfunction and symptomatic heart failure, by study

Exposure to pertuzumab in these clinical studies varied considerably depending upon the indication. The shortest exposures were in patients with prostate cancer (study BO17004), in whom the median treatment duration was 3 cycles, with a range of 2–11 cycles. The longest pertuzumab exposures were in patients with HER2-positive breast cancer (study BO17929). In this study, median pertuzumab exposure was 9 cycles, with a range of 1–26 cycles.

pertuzumab as a single agent

Data from 331 (231 non-breast cancer and 100 MBC) patients with available cardiac data who received pertuzumab as a single agent were included in the analysis. Studies in patients with ovarian cancer [35], NSCLC, and CRPC [3638] demonstrated that pertuzumab was associated with a 5.6% (13/231) incidence of asymptomatic LVSD, with no documented cases of symptomatic HF. Similarly, among 100 patients with MBC and available post-baseline data who received pertuzumab [39, 40], asymptomatic LVSD occurred in 10.0% of patients (10/100) (Table 2). A single case of symptomatic HF was documented among patients treated with single-agent pertuzumab; this patient with MBC was a former smoker with hypertension and prior anthracycline therapy [39] (Table 3). Evidence of reduced LVEF was initially recorded on study day 290 after 14 cycles of pertuzumab (last dose given on day 275). The next cycle of pertuzumab was delayed by 4 weeks and was given on study day 323. An event of congestive HF was recorded on day 344 and, the patient was withdrawn from the study.

Table 3.
Characterization of pertuzumab-treated patients experiencing symptomatic heart failure (all studies)

pertuzumab in combination with cytotoxic agents

Of the 175 patients treated with pertuzumab in combination with non-anthracycline-containing cytotoxic agents who had available cardiac data, a total of six patients (3.4%) developed asymptomatic LVSD. Two of these patients were being treated with pertuzumab plus docetaxel (Taxotere, sanofi-aventis, Bridgewater, NJ) for advanced solid tumors [42] and four with pertuzumab plus gemcitabine- or carboplatin-based chemotherapy for ovarian cancer [43, 44] (Table 2). In addition, two patients, both with ovarian cancer, developed symptomatic HF [43, 44]. One of these patients had no documented cardiac risk factors, whereas the other was a smoker with hypertension and hyperlipidemia (Table 3). The first of these two patients, a 41-year-old woman, was treated with pertuzumab in combination with paclitaxel (Taxol, Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin. HF was recorded at cycle 2 and treatment was discontinued. The second patient, a 59-year-old female smoker with chronic obstructive pulmonary disease, hypertension, and hyperlipidemia received pertuzumab in combination with gemcitabine. A gradual decline in LVEF was noted between cycles 6 and 14 and therapy was withdrawn at cycle 15 due to HF.

pertuzumab in combination with the anti-HER2 agent trastuzumab

In total, 93 patients who received pertuzumab in combination with trastuzumab were analyzed for cardiac events. Asymptomatic LVSD was observed in six patients (6.5%), all of whom had MBC that had progressed following trastuzumab therapy [33, 45] (Table 2). In addition, one patient with MBC that had progressed after trastuzumab experienced symptomatic HF at cycle 2. This patient had extensive left chest wall disease and had been treated with left chest wall irradiation and prior anthracyclines (Table 3) [33].

Patients with refractory HER2-positive MBC that had relapsed on prior trastuzumab-containing therapy were examined in study BO17929 [45]. In this study, patients were selected for adequate cardiac function at baseline and treatment was associated with a low incidence of clinical cardiac events. Three of 66 patients (4.5%) in cohorts 1 and 2 experienced asymptomatic LVSD. No patient experienced systolic HF (Table 2), and in two patients, the asymptomatic LVSD resolved while continuing trastuzumab plus pertuzumab therapy [45]. One of 16 patients (6.3%) in cohort 3 who received pertuzumab and trastuzumab following progressive disease on pertuzumab monotherapy experienced asymptomatic LVSD (Table 2). Data from a smaller National Cancer Institute-sponsored study (TOC3487s) [33] demonstrated a higher incidence of left ventricular dysfunction, with 2 of 11 patients (18.2%) experiencing asymptomatic LVSD and 1 patient (9.1%) developing symptomatic HF (Table 2). However, in this trial, patients were not excluded if they had experienced previous trastuzumab-associated cardiac dysfunction, and cardiac monitoring was carried out more frequently than in study BO17929 (every 3 weeks versus every 6 weeks) (Table 1).

pertuzumab in combination with the anti-EGFR agent erlotinib

None of the 15 patients treated with a combination of pertuzumab and erlotinib who were assessable for cardiac toxicity demonstrated LVSD or HF (Table 2) [46].

timing of LVSD and HF events in relation to pertuzumab dosing

The median timing of LVSD and HF events was around cycle 4 (range 1–15 cycles) with 34/39 events (87%) occurring between cycles 1 and 7.

discussion

The results of this analysis demonstrate that pertuzumab (exposure ranging from a median of 3 cycles [range 2–11] to a median of 26 cycles [range 1–26]) was generally well tolerated. The incidence of LVSD was low, with most events being asymptomatic and detected at scheduled evaluations. The median timing of LVSD and HF was around cycle 4 (range 1–15) with 34/39 (87%) events occurring between cycles 1 and 7. Additionally, when pertuzumab was given in combination with trastuzumab or non-anthracycline-containing cytotoxic chemotherapy, there was no marked increase in observed cardiac dysfunction. In this analysis of 598 unique patients exposed to pertuzumab, 35 (5.9%) cases of asymptomatic LVSD and 4 (0.7%) cases of symptomatic HF were reported. There have been several recent publications examining HF rates among breast cancer patients receiving trastuzumab as adjuvant therapy as well as in patients with more advanced MBC [24, 30, 47]. In two studies, patients received trastuzumab in the adjuvant setting [30, 47]. In the first of these, Perez et al. [30] recorded an HF rate of 2.8% for patients with primary, operable HER2-positive breast cancer treated with paclitaxel followed by trastuzumab, and 3.3% for those treated with paclitaxel plus trastuzumab followed by trastuzumab alone. More recently, Russell et al. [47] reported a symptomatic HF rate of 2.0% for 133 patients receiving adjuvant trastuzumab therapy. In a study designed to evaluate the role of troponin I in predicting cardiac damage, Cardinale et al. [24] reported that among 251 women receiving treatment for early and advanced breast cancer with trastuzumab, 42 (16.7%) experienced trastuzumab-induced cardiotoxicity. In all three studies, whether patients were receiving adjuvant treatment or therapy for metastatic cancer, patients were selected on the basis of good performance status, adequate cardiac function (as indicated by baseline LVEF), and other indicators of physiological status, including adequate liver and bone marrow function and absence of significant medical history. Patients on these studies were, therefore, of broadly similar physiological status. Probably the major difference between these populations of patients receiving trastuzumab and, indeed, between these trastuzumab patients and those described in the current analysis who were treated with pertuzumab, however, is the difference in timing between the anthracycline and anti-HER2 therapies they received. Those patients receiving adjuvant therapy were more likely to have had recent exposure to anthracycline, whereas in those being treated for MBC, substantial periods of time (up to several years) may have elapsed since anthracycline exposure, and this should be considered when making comparisons between studies.

In one small study investigating pertuzumab plus trastuzumab in MBC progressing after trastuzumab-containing therapy [33], a higher rate of cardiac events was recorded than in any of the other studies. The reasons for this are unclear but may be a result of the lack of screening for adequate cardiac function during prior treatment with trastuzumab, closer monitoring, using a variety of monitoring methods, and a more stringent definition of LVSD (a decrease in LVEF of ≤55% from baseline).

It is likely that the careful selection of patients lacking cardiac comorbidities may contribute to the low rate of cardiac events observed in studies where pertuzumab and trastuzumab are combined. In study BO17929, patients were excluded if they had experienced LVEF declines during previous trastuzumab therapy [45], and in ongoing phase II and III breast cancer studies [NEOSPHERE (NCT00545688) and CLEOPATRA (NCT00567190), respectively], patients are excluded if they have any relevant cardiac history (including HF), uncontrolled hypertension, or poorly controlled diabetes mellitus. Furthermore, in these studies, patients must have a limited lifetime exposure to anthracyclines below 360 mg/m2 for doxorubicin or liposomal doxorubicin or equivalent dosing for epirubicin, mitoxantrone, and idarubicin. It is anticipated that data from the CLEOPATRA study, which has a planned enrollment of 800 patients, will provide further insights into the safety profile of pertuzumab in combination with trastuzumab. It should also be noted that the presence of HER2-positive breast cancer tends to be skewed toward younger patients, who are less likely to have cardiovascular problems [48].

It is possible that pertuzumab may appear to have a relatively low cardiotoxic potential due to the timing of anthracycline and pertuzumab treatment. In the adjuvant trastuzumab trials, a shorter time between anthracycline and trastuzumab treatment appeared to bear a higher risk of trastuzumab-associated cardiotoxicity [8]. Due to the design of the studies in this analysis, the time between anthracycline and pertuzumab treatment was generally long—in most cases, several months or years. In the adjuvant trastuzumab trials, most patients received the first dose of trastuzumab between 3 and 12 weeks after the end of anthracycline-based therapy [33, 40, 45].

implications for use of anti-HER2 therapies

The results of this analysis indicate that pertuzumab has the potential to induce cardiac dysfunction and HF, although it is currently difficult to assess whether the rate is similar to that of trastuzumab. The results also highlight that it is vital for physicians to examine the full medical history of patients before they receive anti-HER2 therapies, to identify potential risk factors for cardiac dysfunction, and an LVEF assessment before chemotherapy to identify patients at higher risk of anti-HER2 cardiotoxicity [49, 50]. Cardiac status should be optimized before treatment with anti-HER2 therapies, and the potential benefits of treatment should be balanced against any potential cardiac risk [51]. Recent preliminary evidence suggests that the preventative use of angiotensin-converting enzyme inhibitors in high-risk patients receiving high-dose chemotherapy (identified by elevations in troponin I cardiac markers) may prevent cardiac dysfunction with anti-HER2 therapy [51].

In the current analysis, most patients with breast cancer had received prior anthracycline therapy, but the majority of this exposure occurred early in the course of the disease (as either neoadjuvant or adjuvant therapy), and no patient had been exposed to anthracyclines beyond the established limits of lifetime exposure. A study [TRYPHAENA (NCT00976989)] is ongoing to evaluate the safety and efficacy of combined treatment of HER2-positive breast cancer with trastuzumab, pertuzumab, and epirubicin in the neoadjuvant setting.

In summary, as a single agent or in combination with cytotoxic agents, including trastuzumab, pertuzumab has been generally well tolerated by patients enrolled in the ongoing clinical trial program, with a low incidence of cardiac dysfunction, apparently similar to that associated with trastuzumab. Nonetheless, it is important that cardiac risk factors are taken into account when making a decision regarding treatment with pertuzumab.

funding

This analysis was sponsored by F. Hoffmann-La Roche Ltd and Genentech, Inc.

disclosures

MB is an employee of Genentech and has a stock interest in Roche; C. Neate is an employee of Roche Products Ltd, UK; GR is an employee of Roche Products; DL has acted as a consultant to AstraZeneca; TS has received a commercial research grant from Roche, speaker bureau honoraria from sanofi-aventis and Chugai, and has acted as a consultant to GSK.

Acknowledgments

Support for third-party writing assistance for this manuscript, furnished by Adelphi Communications Ltd, was provided by F. Hoffmann-La Roche Ltd.

References

1. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127–137. [PubMed]
2. Baselga J, Swain SM. Novel anticancer targets: revisiting HER2 and discovering HER3. Nat Rev Cancer. 2009;9:463–475. [PubMed]
3. Tzahar E, Waterman H, Chen X, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16:5276–5287. [PMC free article] [PubMed]
4. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421:756–760. [PubMed]
5. Zhao YY, Sawyer DR, Baliga RR, et al. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem. 1998;273:10261–10269. [PubMed]
6. Sawyer DB, Zuppinger C, Miller TA, et al. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1β and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105:1551–1554. [PubMed]
7. Baliga RR, Pimental DR, Zhao YY, et al. NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK. Am J Physiol. 1999;277:H2026–H2037. [PubMed]
8. De Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies—what have we learned so far? Target Oncol. 2009;4:77–88. [PubMed]
9. Chien KR. Herceptin and the heart—a molecular modifier of cardiac failure. N Engl J Med. 2006;354:789–790. [PubMed]
10. Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330–9336. [PubMed]
11. De Keulenaer GW, Doggen K, Lemmens K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res. 2010;106:35–46. [PubMed]
12. Lee KF, Simon H, Chen H, et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995;378:394–398. [PubMed]
13. Gassmann M, Casagranda F, Orioli D, et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature. 1995;378:390–394. [PubMed]
14. Camenisch TD, Schroeder JA, Bradley J, et al. Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors. Nat Med. 2002;8:850–855. [PubMed]
15. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–465. [PubMed]
16. Lemmens K, Fransen P, Sys SU, et al. Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation. 2004;109:324–326. [PubMed]
17. Okoshi K, Nakayama M, Yan X, et al. Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation. 2004;110:713–717. [PubMed]
18. Perez EA. Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin Breast Cancer. 2008;8(Suppl 3):S114–S120. [PubMed]
19. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of HER-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153. [PMC free article] [PubMed]
20. 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. [PubMed]
21. Procter M, Suter TM, De Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the herceptin adjuvant (HERA) trial. J Clin Oncol. 2010;28:3422–3428. [PubMed]
22. 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. [PubMed]
23. Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol. 2007;25:3525–3533. [PubMed]
24. Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–3916. [PubMed]
25. Gianni L, Herman EH, Lipshultz SE, et al. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol. 2008;26:3777–3784. [PMC free article] [PubMed]
26. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213–220. [PubMed]
27. Pentassuglia L, Graf M, Lane H, et al. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res. 2009;315:1302–1312. [PubMed]
28. 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. [PubMed]
29. Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin Adjuvant Trial. J Clin Oncol. 2007;25:3859–3865. [PubMed]
30. Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol. 2008;26:1231–1238. [PubMed]
31. Perez EA, Koehler M, Byrne J, et al. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83:679–686. [PubMed]
32. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–1130. [PubMed]
33. Portera CC, Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res. 2008;14:2710–2716. [PubMed]
34. Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. J Clin Oncol. 2007;25(Suppl 18) (Abstr 1004)
35. Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol. 2006;24:4324–4332. . Erratum in: J Clin Oncol 2008; 26: 2793. [PubMed]
36. Herbst RS, Davies AM, Natale RB, et al. Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res. 2007;13:6175–6181. [PubMed]
37. Agus DB, Sweeney CJ, Morris MJ, et al. Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J Clin Oncol. 2007;25:675–681. [PubMed]
38. De Bono JS, Bellmunt J, Attard G, et al. Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol. 2007;25:257–262. [PubMed]
39. Gianni L, lladó A, Bianchi G, et al. Open-label, Phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a HER2 dimerization inhibitor, in patients with HER2-negative metastatic breast cancer. J Clin Oncol. 2010;28:1131–1137. [PubMed]
40. Baselga J, Cortes J, Fumoleau P, et al. Pertuzumab and trastuzumab: responses to 2 biological agents in patients with HER2-positive breast cancer which had previously progressed during therapy with each agent given separately: a new biological and clinical observation (Abstr 5114) San Antonio Breast: Cancer Symposium, San Antonio, TX,; December 9–13, 2009.
41. Albanell J, Montagut C, Jones ET, et al. A phase I study of the safety and pharmacokinetics of the combination of pertuzumab (rhuMab 2C4) and capecitabine in patients with advanced solid tumors. Clin Cancer Res. 2008;14:2726–2731. [PubMed]
42. Attard G, Kitzen J, Blagden SP, et al. A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours. Br J Cancer. 2007;97:1338–1343. [PMC free article] [PubMed]
43. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol. 2009;28:1215–1223. [PubMed]
44. Kaye SB, Poole CJ, Bidzinski M, et al. A randomised phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab (P) versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer. J Clin Oncol. 2008;26(Suppl 18S) (Abstr 5520) [PubMed]
45. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that had progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–1144. [PubMed]
46. Felip E, Ranson M, Cedrés S, et al. A Phase I, dose-escalation study to determine the maximum tolerated dose of erlotinib when combined with pertuzumab in previously treated non-small-cell lung cancer patients. (Abstr 506). 3rd Congress of the European Society for Medical Oncology, Stockhom, Sweden, September 12–16, 2008.
47. Russell SD, Blackwell KL, Lawrence J, et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. 2010;28:3416–3412. [PubMed]
48. Fehrenbacher B, Habel LA, Capra AM, et al. Incidence, demographic and tumor characteristics of HER2-positive invasive breast cancer in a large, unselected population, 2000−2006. (Abstr 3058). San Antonio Breast Cancer Symposium: San Antonio, TX, December 9–13, 2009.
49. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009;100:684–692. [PMC free article] [PubMed]
50. Mackey JR, Clemons M, Cote MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008;15:24–35. [PMC free article] [PubMed]
51. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114:2474–2481. [PubMed]

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