Abstract
Background: Angiotensin Converting Enzyme inhibitors (ACEis) and beta-blockers (BB) are suggested to prevent and treat trastuzumab-related cardiac toxicity. We performed a prospective clinical trial in women experiencing mild cardiac toxicity (MCT) while on adjuvant treatment with trastuzumab. Methods: MCT was defined as an asymptomatic absolute decrease in LVEF of ≥ 10 percentage units to >50%. Treatment consisted of enalapril 2.5 mg bid and carvedilol 3.75 mg bid, which were up-titrated to 10 mg bid for the enalapril and 6.25 mg bid of carvedilol. In patients receiving study drug, the primary study end-point was LVEF recovery, which was defined as a post-trastuzumab LVEF returning to no less than −5 percentage points of the baseline value. Results: 103 patients were enrolled, 100 started trastuzumab, and 98 completed the planned treatment. Sixteen patients (16%) had MCT and received study drugs until trastuzumab completion. None of these patients achieved a post-trastuzumab LVEF recovery. Nevertheless, treated patients had significantly higher median LVEF recovery from nadir to post-trastuzumab LVEF in (8% points vs. 4% points, respectively, p = 0.004), resulting in no difference in post-treatment LVEF values compared to patients without MCT. Conclusion: Treatment of MCT with ACEis and BB allows faster LVEF recovery from nadir values and should be further studied in this setting.
Highlights
We found a 1% incidence of symptomatic cardiac toxicity leading to treatment discontinuation and a 98% trastuzumab completion rate with no treatment delays due to cardiac events
These results provide a rationale for de-escalating strategies and a randomized study of early targeted pharmacological intervention in women receiving trastuzumab-based adjuvant therapy for breast cancer
Considering results, strengths and limitations, our data hint at a potential utility of targeted intervention with cardiac drugs in cases of asymptomatic, mild left ventricular ejection fraction (LVEF) reductions
Summary
Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) oncogene characterizes approximately 15–20% of patients with breast cancers (BC) and is associated with early disease progression and poor prognosis [1,2].Trastuzumab, a recombinant humanized monoclonal antibody that binds the extracellular domain of HER2, improves overall survival (OS) and disease-free survival (DFS) in patients with early, HER2 positive operable breast cancer [3]. trastuzumab is generally well tolerated, cardiac dysfunction is a significant adverse effect, especially in patients with prior or concomitant exposure to anthracycline-based chemotherapy [4].In a recent pooled analysis of three pivotal randomized clinical trials, 11.3% of the women in the trastuzumab arms experienced a cardiac event, which was mildly symptomatic or asymptomatic for the majority of them (8.7%) [5]. Trastuzumab-related cardiac toxicity may lead to definitive interruption of trastuzumab and long-term cardiac sequelae For this reason, especially in the early breast cancer setting, guidelines on how to treat cardiac dysfunction during treatment have been widely adopted [4]. Sixteen patients (16%) had MCT and received study drugs until trastuzumab completion. None of these patients achieved a post-trastuzumab LVEF recovery. Treated patients had significantly higher median LVEF recovery from nadir to post-trastuzumab LVEF in (8% points vs 4% points, respectively, p = 0.004), resulting in no difference in post-treatment LVEF values compared to patients without MCT. Conclusion: Treatment of MCT with ACEis and BB allows faster LVEF recovery from nadir values and should be further studied in this setting
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