HER2 Targeted Therapies cardiotoxicity
- Are also used in HER2-positive gastric and gastroesophageal cancers.
Trastuzumab, pertuzumab, ...
- Humanized monoclonal antibody
- Targets and inhibits HER2
- Markedly improved prognosis for women with HER2-positive breast cancers
- Prolonging survival in advanced, metastatic disease and by reducing the risk for cancer recurrence in the adjuvant setting
Conjugates such as ado-trastuzumab emtansine and trastuzumab-deruxtecan
- Are also used in specific settings for HER2-positive metastatic breast cancer
Increased risk for cardiac dysfunction and clinical heart failure
- Recognized in early trials
- Most frequently during concurrent anthracycline and trastuzumab treatment
- Cardiotoxicity caused by trastuzumab is not associated with cardiomyocyte necrosis histologically,
- Frequently occurs during ongoing therapy
- Commonly considered fully or partly reversible following therapy interruption
- Meta-analysis published in 2011
- Incidence was still reported to be relatively high
- Asymptomatic declines in systolic function reported to occur in 7.5%
- Symptomatic heart failure in 2% of patients
- More recent data from clinical trials suggest lower incidence rates
- SafeHer (A Safety and Tolerability Study of Assisted and Self-Administered Subcutaneous [SC] Herceptin [Trastuzumab] as Adjuvant Therapy in Early Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Breast Cancer) phase 3 study of subcutaneous trastuzumab for the treatment of HER2-positive early breast cancer
- Grade ?3 cardiac disorders were reported in 0.9%,
- Including heart failure in 0.3% of patients
- Low event rates both for patients treated with sequential or concurrent chemotherapy
- Population-based studies
- Report higher rates of LV dysfunction than in clinical trials
- Multicenter cohort study of 10,209 breast cancer survivors
- 5-year cumulative heart failure incidence
- 4.5% among patients treated with sequential anthracycline and trastuzumab therapy
- 0.8% in patients treated with anthracyclines only
- Since 2017 the Food and Drug Administration has approved pertuzumab in combination with trastuzumab in adjuvant treatment of HER2-positive breast cancer patients with high risk for recurrence.
- A higher rate of cardiac dysfunction was anticipated
- Rate of LV dysfunction is not substantially increased when both drugs are used concomitantly.
- Cardiotoxicity associated with newer antibody-drug conjugates such as ado-trastuzumab emtansine and trastuzumab-deruxtecan
- Is thought to be lower than for trastuzumab, but data are sparse
Cardioprotection against trastuzumab-associated cardiotoxicity
MANTICORE 101-Breast (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) trial
- 99 patients with HER2-positive early breast cancer, most of whom (77%) had not received prior anthracycline therapy, were randomized in a 1:1:1 double-blind fashion to the beta-blocker bisoprolol
- Perindopril, or placebo for the duration of trastuzumab therapy
- Stopped early after an interim analysis suggested futility
- Secondary analyses, both perindopril and bisoprolol attenuated the decline in LVEF associated with trastuzumab therapy CMR (-3% ± 4% with perindopril vs -1% ± 5% with bisoprolol vs -5% ± 5% with placebo; P = 0.001).
- Cardioprotective interventions were well tolerated and associated with fewer interruptions of trastuzumab therapy than placebo.
Dutch randomized, multicenter, placebo-controlled, double-blind clinical trial, Boekhout et al
- 210 patients with HER2-positive early breast cancer considered for adjuvant treatment with anthracycline-containing chemotherapy who were randomized to candesartan vs placebo.
- Candesartan did not affect changes in LVEF, cardiac troponin T, or N-terminal pro–B-type natriuretic peptide as continuous variables compared with placebo.
U.S. multicenter, randomized, placebo-controlled, double-blind trial, Guglin et a
- Included 468 patients with HER2-positive early breast cancer treated with trastuzumab
- Lisinopril, carvedilol, or placebo
- Started at the beginning of trastuzumab therapy, and follow-up was 12 months after completion of trastuzumab treatment
- No significant effect of lisinopril or carvedilol on the primary endpoint
- Incidence of cardiotoxicity in this trial was much higher than in most other recent trials
- 38% in the stratum with prior anthracycline exposure
- 25% in the stratum without
- Suggesting that potentially this was a higher risk cohort (alternatively, this may be related to study design and outcomes definitions)
- Stratified analyses lisinopril (HR: 0.53; 95% CI: 0.30-0.94) and carvedilol (HR: 0.49; 95% CI: 0.27-0.89) were associated with a significant reduction in the incidence of cardiotoxicity in the stratum with prior anthracycline exposure
- Results seem to favor the theory that the effect of preventive cardioprotective therapy may be greater in high-risk populations.
Trastuzumab treatment in patients with preexisting ventricular dysfunction
- Secondary cardioprotective therapy in patients with preexisting, asymptomatic LV dysfunction have been conducted
SAFE-HEaRt (Cardiac Safety Study in Patients With HER2 + Breast Cancer), 30 women with HER2-positive breast cancer and mildly reduced LVEFs (ie, between 40% and 50%) and no symptoms of heart failure
- Beta-blockers and ACE inhibitors was initiated
- Larger trials are clearly needed to confirm the safety of HER2-targeted therapy in patients with preexisting mild, asymptomatic ventricular dysfunction
Fluoropyrimidines are commonly used for (neo)adjuvant and palliative treatment of colorectal cancer. They can be administrated as bolus (2-15 min), continuous infusion (25-96 h), or orally. Fluoropyrimidines may cause coronary vasospasm resulting in myocardial ischemia with or without electrocardiographic changes.84 Symptoms may occur at any time during the treatment period.
Even though randomized placebo-controlled trials are lacking, a commonly accepted strategy to prevent cardiotoxicity from fluoropyrimidines is to optimize modifiable cardiac risk factors. Through case studies it has been shown that reintroduction can be attempted in patients with suspected vasospasm after initiation of long-acting nitrates and/or calcium-channel blockers.85,86 Additionally, bolus injection may be less cardiotoxic, as the vasospasm is thought to be related to accumulated metabolites rather than peak dose. The role of dihydropyrimidine dehydrogenase enzyme deficiency on cardiotoxicity is unclear.