Abstract
BackgroundTrastuzumab-induced cardiotoxicity (TIC) can lead to early discontinuation of adjuvant therapy, however there is limited evidence on long-term survival outcomes in patients with operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) experiencing treatment interruption or discontinuation.MethodsThe primary objective of the study was to evaluate disease-free survival (DFS) in non-metastatic, HER2-positive, female BC patients who experienced treatment interruption or early discontinuation of trastuzumab therapy. Clinical and histopathological data were collected on 400 patients at The Ohio State University, an NCI-designated comprehensive cancer center between January 2005 and December 2015. Treatment interruption was defined as any delay of ≥2 weeks during trastuzumab therapy, including permanent cessation prior to completing planned therapy. TIC was defined as LVEF < 50% or > 15 points decline from baseline as evaluated by 2D echocardiogram after initiation of (neo) adjuvant therapy. DFS was defined as the time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as the time from diagnosis to death or last known follow up. OS/DFS estimates were generated using Kaplan-Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHR) for OS/DFS.ResultsA total of 369 patients received trastuzumab therapy; 106 (29%) patients experienced treatment interruption at least once and 42 (11%) permanently discontinued trastuzumab prior to completing planned therapy. TIC was the most common reason for interruption (66 patients, 62%). The median duration of trastuzumab in patients with treatment interruption was 11.3 months (range: 0.5–16.9) with 24 (23%) patients receiving ≤6 months of therapy. This duration includes the time delay related to treatment interruption. Patients with any treatment interruption had worse DFS (aHR: 4.4, p = 0.001) and OS (aHR: 4.8, p < 0.001) after adjusting for age, stage, grade, ER, node status and TIC.ConclusionsTreatment interruption or early discontinuation of trastuzumab therapy in early HER2-positive BC, most often from TIC, is an independent prognostic marker for worse DFS and OS in operable HER2-positive BC. Future prospective studies should consider targeting at-risk populations and optimizing cardiac function to avoid interruption in trastuzumab therapy.
Highlights
Breast cancer (BC) is a heterogeneous disease broadly categorized into three distinct phenotypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) overexpression [1]
HER2-Neu gene amplification and/or overexpression accounts for 15–20% of all newly diagnosed cases in the United States, which results in an aggressive biology associated with a higher risk of recurrence compared to HRpositive disease [2]
HER2 expression was confirmed per ASCO-CAP guidelines at the time of diagnosis defined by immunohistochemistry of 3+, a fluorescent in situ hybridization (FISH) result of ≥6 HER2 gene copies per nucleus, or a FISH ratio (HER2 gene signals to chromosome 17 centromeric signals) of ≥2.2
Summary
Breast cancer (BC) is a heterogeneous disease broadly categorized into three distinct phenotypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) overexpression [1]. A recent open-label, phase III randomized trial compared 6 months vs 12 months of adjuvant trastuzumab therapy and showed that shorter duration was non-inferior to standard 1 year of therapy and resulted in less cardiac toxicity. They demonstrated that a four-year disease-free survival (DFS) was 89% (95% CI 88–91) in both arms. Trastuzumab-induced cardiotoxicity (TIC) can lead to early discontinuation of adjuvant therapy, there is limited evidence on long-term survival outcomes in patients with operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) experiencing treatment interruption or discontinuation
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