Cardiac magnetic resonance imaging-based myocardial strain study for evaluation of cardiotoxicity in breast cancer patients treated with trastuzumab: A pilot study to evaluate the feasibility of the method

Nakano, Shintaro; Takahashi, Masahiro; Kimura, Fumiko; Senoo, Taiki; Sendo, Toshiaki; Ueda, Shigeto; Tanno, Jun; Senbonmatsu, Takaaki; Kasai, Takatoshi; Nishimura, Shigeyuki

doi:10.5603/cj.a2016.0023

Cited by 53 publications

(34 citation statements)

References 31 publications

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“…In addition, the cardiotoxic effects of trastuzumab such as decreased left ventricular ejection fraction, congestive heart failure and even death are commonly encountered in routine clinical practice[37,38]. As reported by C. Kent Osborne in the American Society of Clinical Oncology (ASCO) Annual Meeting on June 4 2016, studies on crosstalk between estrogen and growth factor receptor pathways may reveal new strategies to overcome endocrine therapy resistance.…”

Section: Introductionmentioning

confidence: 99%

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

Chen

Weng

et al. 2017

PLoS ONE

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PurposeTo investigate the effects of trastuzumab (herceptin) and fulvestrant (falsodex) either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue.MethodsCells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined.ResultsCell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI<1 and DRI>1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P<0.05). Interestingly, fulvestrant, in combination with trastuzumab, did not significantly alter the rate of apoptosis (in comparison with fulvestrant alone), in the BT-474 cell line (P>0.05). Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P<0.05), and the combination of trastuzumab and fulvestrant reversed the effects of fulvestrant alone on p-Akt and p-Erk protein expression levels. Using ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic mouse models, we showed that a combination of both drugs resulted in a stronger inhibition of tumor growth (P<0.05) and a greater decrease in the levels of activated MED1 (p-MED1) expressed in tumor issues compared with the use of either drug as a single agent.ConclusionsWe demonstrate that the administration of trastuzumab and fulvestrant in combination results in positive synergistic effects on both, ZR-75-1 and BT-474 cell lines. This combinatorial approach is likely to reduce physiological side effects of both drugs, thus providing a theoretical basis for the use of such combination treatment in order to resolve HR+/HER2+ triple positive breast cancer that has previously been shown to be resistant to endocrine treatment alone.

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Section: Introductionmentioning

confidence: 99%

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

Chen

Weng

et al. 2017

PLoS ONE

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“…To the best of our knowledge, there have been only two published studies utilizing CMR to evaluate the effects of trastuzumab therapy on the RV [17, 18]. However, it is difficult to draw conclusions from these previous studies as trastuzumab was only utilized in a third (15/46) of patients in one study [18], while only 9 of 16 patients in the other study were evaluated by CMR [17].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is difficult to draw conclusions from these previous studies as trastuzumab was only utilized in a third (15/46) of patients in one study [18], while only 9 of 16 patients in the other study were evaluated by CMR [17]. Furthermore, neither study had follow-up beyond 1 year.…”

Section: Discussionmentioning

confidence: 99%

“…RV dysfunction is known to be a poor prognosticator in a variety of other cardiovascular diseases [9–16]. However, there are limited data regarding trastuzumab induced toxicity affecting the right ventricle (RV) [17, 18]. The initial studies on cardiotoxic effects in breast cancer patients utilized radionuclide ventriculography [19, 20] and echocardiography [21–24], which have limited accuracy in evaluating RV owing to its shape and position, in addition to inherent drawbacks of each modality [25].…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study

Barthur

Brezden-Masley

Connelly

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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BackgroundThere are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab.MethodsProspective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters.ResultsOf the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1–59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5–55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8–56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1–58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17).ConclusionIn patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity.Trial registrationClinicalTrials.gov Identifier: NCT01022086. Date of registration: November 27, 2009.

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“…A pilot study looking at the feasibility of cardiac MRI monitoring noted reduced longitudinal and circumferential strains at 6 months that reflected subclinical LV dysfunction and might assist with borderline detection of cardiotoxicity at an earlier stage. However, the predictive value of reduced strain for subsequent clinically significant heart failure was not determined and the results were not directly compared to echocardiography (57). …”

Section: Monitoring Trastuzumab-induced Cardiotoxicitymentioning

confidence: 99%

Incidence, Diagnosis, and Treatment of Cardiac Toxicity From Trastuzumab in Patients With Breast Cancer

Nowsheen

Viscuse

O’Sullivan

et al. 2017

Curr Breast Cancer Rep

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Purpose of review Treatment with trastuzumab is a cornerstone of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer treatment, but carries an unfortunate risk of toxicity to the cardiovascular system. Here we review recent findings on trastuzumab-associated cardiotoxicity, focusing on its incidence, diagnosis, and treatment. Recent findings Screening with multigated acquisition scan (MUGA) or echocardiogram (ECHO) is recommended to assess cardiac function prior to and during trastuzumab therapy. Because trastuzumab-induced cardiotoxicity is typically reversible, cessation of trastuzumab and/or administration of first line heart failure agents effectively restores cardiac function in most cases. Severe trastuzumab-induced cardiotoxicity is rare enough that the risk-benefit ratio still weighs in favor of its use in the vast majority of patients with HER2+ breast cancer. Summary An improved understanding of the pathophysiology underlying trastuzumab-induced cardiotoxicity and the identification of patients at highest risk will allow us to continue to safely administer trastuzumab in patients with breast cancer.

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Cardiac magnetic resonance imaging-based myocardial strain study for evaluation of cardiotoxicity in breast cancer patients treated with trastuzumab: A pilot study to evaluate the feasibility of the method

Abstract: (Cardiol J 2016; 23, 3: 270-280)

Cited by 53 publications

References 31 publications

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study

Incidence, Diagnosis, and Treatment of Cardiac Toxicity From Trastuzumab in Patients With Breast Cancer

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