Investigating the Long-term Cardiac Sequelae of Trastuzumab Therapy

NCT ID: NCT05019365

Last Updated: 2021-08-24

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-03-15
• Study Completion Date: 2022-11-25

Brief 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.

Detailed 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.

Conditions

Breast Cancer; HER2-positive Breast Cancer; Cardiotoxicity

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: RETROSPECTIVE

Study Groups

Participants with previous HER2 breast cancer

No interventions assigned to this group

Healthy Volunteers

No interventions assigned to this group

Eligibility Criteria

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.

• 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 (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.

• standard contraindication to CMR;
• suspected pregnancy

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

NHS Greater Glasgow and Clyde

OTHER

Sponsor Role: collaborator

Tenovus Scotland

OTHER

Sponsor Role: collaborator

University of Glasgow

OTHER

Sponsor Role: lead

Responsible Party

Kenneth Mangion

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Kenneth Mangion, MD PhD

Role: CONTACT

kenneth.mangion@ggc.scot.nhs.uk

0141 232 7600

Facility Contacts

Kenneth Mangion, MD PhD

Role: primary

kenneth.mangion@ggc.scot.nhs.uk

Other Identifiers

GN19ON381

Identifier Type: -

Identifier Source: org_study_id