Imaging Versus Cardiac Biomarker Monitored HER2 Directed Therapy in Patients With Breast Cancer

Study Overview
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Brief Summary
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Due to a risk of heart failure during HER2 directed therapy in breast cancer, treatment is monitored with imaging of myocardial function, which is resource demanding for both patients and the health care system. The purpose of this study is to evaluate, if biomarkers can replace imaging based examinations of myocardial function during HER2 directed therapy.

Detailed Description
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About 15% of breast cancer tumors express the Human Epidermal Growth Factor Receptor 2 (HER2), which is associated with a poor prognosis. Antibodies (trastuzumab and pertuzumab) directed against HER2 have in addition to traditional chemotherapy significantly improved survival in HER2 positive breast cancer, but induce a risk of left ventricular dysfunction and heart failure. Regular imaging based evaluation of myocardial function is therefore recommended during HER2 directed therapy by either an echocardiography or a MUGA scan, which is associated with radiation exposure. Both types of scans are resources demanding for both patients and the healthcare system, and since biomarkers have been proposed as another modality in assessment of myocardial injury, the purpose of this study is to evaluate, if biomarkers can replace imaging based examinations of myocardial function during HER2 directed therapy. The study is designed as a national multicenter, randomized study, which will include Odense University Hospital, Herlev and Gentofte University Hospital and Aarhus University Hospital. It will be possible to include more sites. Patients with localized HER2-positive breast cancer scheduled for HER2 proper therapy will be randomized 1: 1 to: Standard imaging monitored treatment as recommended by DBCG guidelines with measurement of LVEF by MUGA scan or echocardiography in weeks 0, 9, 18, 30 and 48 of the treatment period. At each control visit, biomarkers are also taken, which are blinded until the end of the study. Biomarker monitored treatment with measurement of NT-proBNP and cTNT / TNI in weeks 0, 9, 18, 30 and 48 of the treatment period. At each of these follow-up visits, MUGA scans or echocardiography are also performed, but the results are blinded to the staff responsible for treatment decisions. In the group followed by standard imaging monitoring, cardiotoxicity will be managed according to standard clinical guidelines. Cardiotoxicity in the biomarker group will be suspected in case of a doubling of NT-proBNP from baseline (but minimum 125 pg / ml) and / or an increase in troponins to above 99th percentile. If these criteria are met, imaging is triggered, which in practice is a blinding of the result of the examination already performed. The primary endpoint of the study is LVEF measured by cardiac MRI scan three months after completion of HER2-directed therapy.

Official Title
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A National Randomized Non-inferiority Trial: Imaging Versus Cardiac Biomarker Monitored HER2 Directed Therapy in Patients With Breast Cancer

Conditions
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Cardiotoxicity, HER2-positive Breast Cancer

Intervention / Treatment
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* Diagnostic Test: Biomarkers: Troponins and natriuretic peptides


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with non-metastatic HER2 positive breast cancer Scheduled for standard chemotherapy and HER2 directed therapy with trastuzumab +/- pertuzumab Age > 18 years Sinus rhythm on ECG NT-proBNP below125 pg/ml Troponin below threshold limit value LVEF > 55% by MUGA scan or an echocardiogram Exclusion Criteria: Contra indications for cardiac magnetic resonance imaging (CMRI) Chronic obstructive pulmonary disease with FEV1 <80 % of predicted

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard imaging monitored treatment<br>Standard care + biomarkers, which are blinded until end of study. | |
| Experimental: Intervention biomarker monitored treatment<br>biomarker monitored treatment + imaging, which is blinded until end of study | Diagnostic Test: Biomarkers: Troponins and natriuretic peptides<br>* Biomarker monitored treatment with measurement of NT-proBNP and cTNT / TNI in weeks 0, 9, 18, 30 and 48 of the treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) | LVEF on cardiac MR. | Three months after treatment has ended. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of treatment interruptions due to suspected cardiotoxicity | Number of times treatment was paused due to suspected cardiotoxicity either based on imaging or biomarkes as defined in the protocol. | Through study completion, an average of 1 year. | 
| The number of MUGA scans/echocardiograms | The number of MUGA scans/echocardiograms preformed during the study periode. | Through study completion, an average of 1 year. | 
| The cumulative doses of trastuzumab and pertuzumab | The cumulative doses of trastuzumab and pertuzumab in mg. | After end of treatment, an average of 1 year after inclusion. | 
| The proportion of patients treated for cardiotoxicity. | Number of patients referred to tratment for heart failure in the department of cardiology. | Through study completion, an average of 1 year | 
| Change in self-reported health status measured with EQ-5D-5L questionnaire | An Index score and a Visual Analogue Scale (VAS). | At baseline, at treatment week 9, 18, 30 and 48 and three months after end of treatment. | 
| Correlation between radiotherapy and cardiac function. | Correlation between location and dose of the radiotherapy with changes in biomarkers, LVEF and ECG. | Through study completion, an average of 1 year |