Investigating the Long-term Cardiac Sequelae of Trastuzumab Therapy

Breast Cancer Clinical Trial

Official title:

Investigating the Long-term Cardiac Sequelae of Trastuzumab Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05019365
• Other study ID #: GN19ON381
• Status: Recruiting
• Start date: March 15, 2021
• Est. completion date: November 25, 2022

Study information

• Verified date: August 2021
• Source: University of Glasgow
• Contact: Kenneth Mangion, MD PhD
• Phone: 0141 232 7600
• Email: kenneth.mangion[@]ggc.scot.nhs.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The introduction of trastuzumab for the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer has had a major impact upon cancer outcomes. However, cardiac toxicity remains a substantial concern. Conventionally, this toxicity has been considered as a transient and reversible phenomenon occurring in the immediate peri-treatment period in around 20% of patients. Current guidelines recommend monitoring heart function during treatment and at completion. Recent registry data suggest that trastuzumab-related cardiotoxicity may also manifest in the longer-term. The nature and longer-term prevalence of left ventricular dysfunction with HER2 positive breast cancer treated with trastuzumab is unclear. The aim of this project is to define the prevalence of left ventricular dysfunction late after completion of trastuzumab therapy.

Description:

In 2014, there were 45,535 cases of breast cancer diagnosed in England and Wales(1). Predicted 10-year survival in 2015, from data by the National Statistics office was estimated at 81%(2). Breast cancer is the most common malignancy in Scotland and the second most common cause of death(3). Around 1 in 4 of these cancers overexpress human epidermal growth factor receptor 2 (HER2). For these patients, trastuzumab is a recommended and highly effective component of a chemotherapy regime that usually includes an anthracycline(4).

Up to a quarter of patients treated with trastuzumab will develop cardiac dysfunction(5-7), conventionally defined as an asymptomatic >10% fall in left ventricular ejection fraction (LVEF) to an absolute LVEF <50%, or symptomatic heart failure(8). The risk is greater in patients who have received prior anthracyclines(9). Trastuzumab-related cardiotoxicity has, typically been considered to be a reversible phenomenon which recovers with interruption or cessation of treatment(10-14). The long-term benefit of cardioprotective treatment with angiotensin converting enzyme inhibitors or beta blockers when cardiotoxicity is detected is unclear(8) and these agents are often either not continued or not be prescribed at all.

The incidence of cardiac dysfunction or heart failure in the longer-term is not well-defined (12,14-20) . Clinical trials, which have excluded patients with baseline cardiovascular comorbidity, report no excess of cardiovascular events after the first two years(21-23) but observational studies report a much higher incidence of up to 23.8%(9,24). A landmark analysis of patients with a history of breast cancer (median follow-up 9 years) reported that patients treated with anthracycline chemotherapy and trastuzumab were three-fold more likely to develop heart failure than those treated with anthracycline alone. Importantly, these data were derived from a population censored at one year and reflect 'late' manifestations of cardiotoxicity rather than ongoing symptoms from an early diagnosis(25). This important study reported the incidence of symptomatic heart failure and not LV dysfunction which would be expected to be substantially more prevalent(26). Furthermore, the long-term implications of an apparently transient drop in LVEF during treatment are unclear.

Cardiovascular magnetic resonance (CMR) is the gold standard for the assessment of LV function(27). Previous work has demonstrated that CMR may be better able to identify small changes in LVEF related to chemotherapeutic agents(18,28,29). CMR has superior accuracy and precision when compared with echocardiography and allows myocardial tissue characterisation(30,31). My proposed CMR protocol will generate important insights into the long-term cardiac effects of trastuzumab and further novelty will be provided by the incorporation of tissue mapping methods(32) and LV strain assessment(33,34). Via collaboration with mathematicians I will also derive computational models.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: November 25, 2022
• Est. primary completion date: May 25, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• patients with HER2 positive breast cancer who received anthracycline-containing chemotherapy followed by trastuzumab at least 5 years prior to enrolment;

• age >18 years.

Exclusion Criteria:

• standard contraindication to CMR (ex: pacemaker, metallic implant);

• pregnancy;

• eGFR <30 ml/min/1.73 m2) past medical history of heart failure or left ventricular systolic dysfunction.

Healthy Volunteers:

Twenty age and sex matched healthy volunteers will undergo a similar CMR protocol.

Inclusion Criteria:

• least 18 years (they will be matched to the study participants)

• no prior medical history (including cardiovascular health problems, medication or systemic illness)

Exclusion Criteria:

• standard contraindication to CMR;

• suspected pregnancy

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Cardiotoxicity
• HER2-positive Breast Cancer

Locations

Country	Name	City	State
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow

Sponsors (3)

Lead Sponsor	Collaborator
University of Glasgow	NHS Greater Glasgow and Clyde, Tenovus Scotland

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	T1 relaxation times (global and segmental)	Left ventricular (LV) Parametric maps (T1, T2, Extracellular volume) will be assessed using a 16 segment model with bespoke MRI analysis software.	Through study completion, on average <2years.
Other	T2 decay time (global and segmental)	Left ventricular (LV) Parametric maps (T1, T2, Extracellular volume) will be assessed using a 16 segment model with bespoke MRI analysis software.	Through study completion, on average <2years.
Other	Extracellular volume fraction (ECV) (global and segmental)	Left ventricular (LV) Parametric maps (T1, T2, Extracellular volume) will be assessed using a 16 segment model with bespoke MRI analysis software.	Through study completion, on average <2years.
Other	Presence of scar by late gadolinium enhancement (LGE)	Late gadolinium enhancement will be assessed using a 16 segment model with bespoke MRI analysis software.	Through study completion, on average <2years.
Other	Aortic Stiffness	Aortic stiffness will be assessed using MRI sequences.	Through study completion, on average <2years.
Other	ECG abnormalities	Rhythm and heart rate will be recorded. Evidence of LVH, ST segment deviations and T wave flattening/inversion, and conduction abnormalities including QRS and QT interval will be recorded.	Through study completion, on average <2years.
Other	Computational Modelling	To identify novel biomarkers of heart pump function through the generation of computational models in patients who received trastuzumab and age matched healthy volunteers.	Through study completion, on average <2years.
Primary	Left Ventricular Systolic Dysfunction	To define the prevalence of left ventricular dysfunction in patients who received trastuzumab chemotherapy at least 5 years previously	Through study completion, on average <2years.
Primary	Reduced Global Longitudinal Strain (global and segmental)	GLS less than 2 standard deviations from normal reference range, using Displacement Encoding with Stimulated Echoes (DENSE) MRI.	Through study completion, on average <2years.
Primary	Reduced Circumferential Strain (global and segmental)	GCS less than 2 standard deviations from normal reference range, using Displacement Encoding with Stimulated Echoes (DENSE) MRI.	Through study completion, on average <2years.