Cardiac Toxicity of ErbB2-Targeted Therapies: What Do We Know?

doi:10.3816/CBC.2008.s.007

Clinical Breast Cancer

Volume 8, Supplement 3, March 2008, Pages S114-S120

https://doi.org/10.3816/CBC.2008.s.007 Get rights and content

Abstract

The potential for cardiac toxicity in association with targeted biologic agents was first observed with trastuzumab, a monoclonal antibody that targets the ErbB2/HER2 receptor. In the pivotal trial of trastuzumab in ErbB2-positive metastatic cancer, an increased incidence of serious cardiac events was observed, particularly when trastuzumab was administered in combination with anthracyclines. The ErbB2 receptor is expressed on cardiomyocytes, in addition to tumor tissue, where it exerts a protective effect on cardiac function; thus, interference with ErbB2-signaling may block this protective effect. However, in contrast to anthracycline-induced cardiac toxicity, trastuzumab-related cardiac dysfunction does not appear to increase with cumulative dose or to be associated with ultrastructural changes in the myocardium and is generally reversible. When used in adjuvant regimens for the treatment of ErbB2-positive early-stage breast cancer, trastuzumab has been shown to significantly improve disease-free and overall survival. The incidence of class III/IV congestive heart failure (CHF) ranged from 0.4%–3.8% in the major adjuvant trastuzumab trials. More recently, small-molecule tyrosine kinase inhibitors such as lapatinib have been investigated for the treatment of ErbB2-positive metastatic breast cancer. In a comprehensive analysis of cardiac safety data from all lapatinib trials completed to date, which included 3558 healthy volunteers and patients with a variety of solid cancers on 43 trials, the overall incidence of left ventricular ejection fraction declines was 1.6%, with 0.2% of patients experiencing symptomatic CHF. Risk factors that might predict for cardiac dysfunction with ErbB2-targeted therapy are actively under investigation and will aid in the identification of at-risk populations and in the development of strategies for risk minimization in the future. It is important to note that, while careful cardiac monitoring is required for all patients receiving ErbB2-targeted therapy in any disease setting, the overall impact of these agents on the outcomes of patients with ErbB2-positive breast cancer has been dramatic and positive.

References (38)

I Smith et al.
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
Lancet
(2007)
LE Ainger et al.
Daunomycin: a cardiotoxic agent
J Natl Med Assoc
(1971)
EA Lefrak et al.
A clinicopathologic analysis of adriamycin cardiotoxicity
Cancer
(1973)
DD Von Hoff et al.
Risk factors for doxorubicininduced congestive heart failure
Ann Intern Med
(1979)
J Alexander et al.
Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography
N Engl J Med
(1979)
M Billingham et al.
Anthracycline cardiomyopathy monitored by morphologic changes
Cancer Treat Rep
(1978)
B Mackay et al.
Assessment of anthracycline cardiomyopathy by endomyocardial biopsy
Ultrastruct Pathol
(1994)
MS Ewer et al.
Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity
J Clin Oncol
(2005)
MS Ewer et al.
A mathematical model for doxorubicin cardiotoxicity: added evidence for the concept of sequential stress
Proc Am Soc Clin Oncol
(2004)
MS Ewer et al.
Cardiac toxicity of trastuzumab-related regimens in HER2-overexpressing breast cancer
Clin Breast Cancer
(2007)

DJ Slamon et al.

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N Engl J Med

(2001)

DJ Slamon et al.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

(1987)

DJ Slamon et al.

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

(1989)

KR Chien

Herceptin and the heart—a molecular modifier of cardiac failure

N Engl J Med

(2006)

SA Crone et al.

ErbB2 is essential in the prevention of dilated cardiomyopathy

Nat Med

(2002)

MS Ewer et al.

Reversibility of trastuzumab- related cardiotoxicity: new insights based on clinical course and response to medical treatment

J Clin Oncol

(2005)

A Seidman et al.

Cardiac dysfunction in the trastuzumab clinical trials experience

J Clin Oncol

(2002)

K Lemmens et al.

Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase

Circulation

(2004)

DB Sawyer et al.

Modulation of anthracycline- induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1β and anti-erbB2: potential mechanism for trastuzumabinduced cardiotoxicity

Circulation

(2002)

Cited by (74)

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial
2020, JACC: CardioOncology
Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow–derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.
SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.
Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10⁸ allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers.
A total of 97% of subjects underwent successful study product injections; all allo-MSC–assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group.
In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC. (Stem Cell Injection in Cancer Survivors [SENECA]; NCT02509156)
Trastuzumab and Hypofractionated Whole Breast Radiotherapy: A Victorious Combination?
2018, Clinical Breast Cancer
The purpose of this study was to examine the impact of trastuzumab on acute skin and cardiac toxicity in patients with breast cancer treated with chemotherapy with or without trastuzumab and adjuvant whole breast hypofractionated radiotherapy (hypo-RT).
The study was conducted on 727 patients treated from April 2009 to October 2016. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases with grade (G) 3 primary tumor and close or positive margins. Acute and late toxicity was assessed prospectively during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. Multivariable logistic regression models were used to examine the onset of acute skin toxicity (≥ G2) in the whole study population, and the impact of trastuzumab on the onset of acute skin (≥ G2) or cardiac toxicity in the subgroup of 176 patients given chemotherapy.
A total of 176 patients received chemotherapy with anthracycline and taxane, and 51 (29%) of them were also treated with trastuzumab. Acute G1, G2, and G3 skin toxicity occurred, respectively, in 56.8%, 27.3%, and 1.1% of the patients given chemotherapy alone, and in 64.7%, 19.6%, and 0% of those given trastuzumab as well. Among the patients given chemotherapy, left ventricular ejection fraction (LVEF) toxicity developed with a severity of G1 (LVEF < 60%-50%) in 12 (6.8%) patients, G2 (LVEF < 50%-40%) in 2 (1.1%) patients, and G3 (LVEF < 40%) in 1 (0.6%) patient. Among the patients also given trastuzumab, 7 (13.7%) patients had G1 LVEF toxicity, and 1 (2%) patient had G2 LVEF toxicity. We found that patients given trastuzumab were at higher risk of cardiac toxicity ≥ G1 (odds ratio, 4.3; P = .01), and at lower risk of acute skin toxicity ≥ G2 (odds ratio, 0.4; P = .03) than patients given chemotherapy alone.
This analysis showed that trastuzumab with adjuvant hypo-RT for patients with breast cancer was generally well-tolerated in routine clinical practice. A longer follow-up will be necessary to assess late cardiac toxicity.
Association analysis of polymorphisms in EGFR, HER2, ESR1 and THRA genes with coronary artery diseases
2017, Egyptian Journal of Medical Human Genetics
Research in the genetic basis of coronary artery diseases (CAD) has identified some genes and pathways associated with diseases that would not be considered to underlie conventional risk factors. Among these genes there are the EGFR (epidermal growth factor receptor) receptor family genes and the regulation factor genes (such as thyroid hormone receptor α (THRA) and estrogen receptor α (ESR1)).
In this study we investigated the relation between 4 polymorphisms within EGFR, HER2 (human epidermal growth factor receptor 2), ESR1 and THRA genes and CAD.
The association analysis was performed with 151 healthy individuals and 151 CAD patients documented by angiography.
No significant difference was found in the allelic and genotypic frequency distribution of the four variants studied between the control and patient groups. We have also investigated the relationship of these polymorphic sites with clinical and biochemical parameters such as smoking habit, diabetes mellitus, hypertension, dyslipidemia, CAD severity, glucose, triglyceride, total cholesterol and urea levels. The EGFR and THRA variants were associated with glycemia and triglyceride levels, respectively. Also a significant correlation was found between the ESR1 polymorphism and the levels of urea and triglyceride.
Our results suggest the absence of any significant association between the four polymorphisms analyzed and CAD risk as well as disease severity.
Comparison of the 2007 and 2013 ASCO/CAP evaluation systems for HER2 amplification in breast cancer
2015, Pathology Research and Practice
Citation Excerpt :
In the last decade, targeted therapy in breast cancer has become part of routine clinical protocols all over the world. Trastuzumab, a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), is routinely used to treat patients with breast carcinoma who overexpress HER2 [2,3]; when combined with chemotherapy in the metastatic setting, trastuzumab improves progression-free survival and overall survival by years [4]. Other HER2-targeting drugs (e.g., the kinase inhibitor lapatinib [5], the antibody pertuzumab [6], the antibody–drug conjugate ado-trastuzumab emtansine [T-DM1] [7]) have been approved for use in the treatment of HER2-positive metastatic breast cancer.
It has been proven that chromosome 17 centromere (CEP17) amplification causes misleading human epidermal growth factor receptor 2 (HER2) gene fluorescence in situ hybridization (FISH) results, precluding anti-HER2-based therapy in some patients with breast carcinoma. We used the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) scoring criteria to evaluate HER2 amplification status in 175 cases of breast carcinoma with chromosome 17 polysomy. We used immunohistochemistry (IHC) to determine the HER2 amplification status, and 2-color FISH to detect CEP17, and reviewed the results of initial evaluation using the 2007 ASCO/CAP criteria. Of the 175 cases, 17, 95, and 63 were IHC 0/1+, 2+, and 3+, respectively. Evaluation of IHC HER2 status according to the 2013 ASCO/CAP criteria identified significantly more HER2-positive cases compared to cases evaluated using the 2007 criteria (p < 0.05). When the FISH results were evaluated in parallel with the 2013 criteria, we found that 22 cases were not HER2-negative despite the presence of polysomy 17, which, according to the 2013 criteria, indicates HER2-positive status. Our findings indicate that in breast carcinoma, HER2 status in the presence of polysomy 17 may vary with the scoring criteria used. In turn, performing FISH and evaluating samples using the 2013 ASCO/CAP criteria means that more patients with breast cancer may be appropriate for targeted treatment with trastuzumab, potentially improving their outcome.
Improving the efficacy and safety of engineered T cell therapy for cancer
2013, Cancer Letters
Citation Excerpt :
This expression may explain the observation that patients treated with CA IX CAR-T cells developed significant liver toxicity [41] (Table 1). Her2/neu is expressed in the lungs and bowels and may be inferred to exist at low levels in the heart by the cardiotoxicity observed in a minority of patients treated with trastuzumab [77]. One colon cancer patient treated with third generation Her2/neu (CD28-41BB-CD3z) CAR-T cells died 5 days after adoptive transfer; this patient died of what appears to be a cytokine storm and respiratory failure triggered by the recognition of low levels of antigen on lung epithelial cells [78].
Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential “on-target, off-organ” toxicity.
Effects of targeted lung cancer drugs on cardiomyocytes studied by atomic force microscopy
2023, Analytical Methods

View all citing articles on Scopus

This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of trastuzumab plus lapatinib with chemotherapy, lapatinib alone, or trastuzumab plus docetaxel and carboplatin for the adjuvant treatment of breast cancer; lapatinib plus trastuzumab for metastatic breast cancer; and lapatinib alone for breast cancer or other solid tumors.

Dr Perez has received research support from Genentech BioOncology, GlaxoSmithKline, Bristol-Myers Squibb, sanofi -aventis, Pfizer, and Novartis Oncology.

View full text

Cardiac Toxicity of ErbB2-Targeted Therapies: What Do We Know?

Abstract

Lancet

Daunomycin: a cardiotoxic agent

J Natl Med Assoc

A clinicopathologic analysis of adriamycin cardiotoxicity

Cancer

Risk factors for doxorubicininduced congestive heart failure

Ann Intern Med

Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography

N Engl J Med

Anthracycline cardiomyopathy monitored by morphologic changes

Cancer Treat Rep

Assessment of anthracycline cardiomyopathy by endomyocardial biopsy

Ultrastruct Pathol

Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity

J Clin Oncol

A mathematical model for doxorubicin cardiotoxicity: added evidence for the concept of sequential stress

Proc Am Soc Clin Oncol

Cardiac toxicity of trastuzumab-related regimens in HER2-overexpressing breast cancer

Clin Breast Cancer

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N Engl J Med

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

Herceptin and the heart—a molecular modifier of cardiac failure

N Engl J Med

ErbB2 is essential in the prevention of dilated cardiomyopathy

Nat Med

Reversibility of trastuzumab- related cardiotoxicity: new insights based on clinical course and response to medical treatment

J Clin Oncol

Cardiac dysfunction in the trastuzumab clinical trials experience

J Clin Oncol

Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase

Circulation

Modulation of anthracycline- induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1β and anti-erbB2: potential mechanism for trastuzumabinduced cardiotoxicity

Circulation