Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials

Abstract

Background: One year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab. Methods: A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled. Results: Six studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03-1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01-1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09-1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43-0.62; p < 0.00001). Conclusions: Though correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.

Dual HER2 Blockade versus a Single Agent in Trastuzumab-Containing Regimens for HER2-Positive Early Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…e LN status, another important factor affecting the clinical treatment decisions, has been shown in clinical studies that LN + patients are more likely to benefit from dual-targeting therapy [24,42], but our results suggested that, despite the more pronounced EFS/iDFS benefit in LN + patients, there was no significant interaction between survival and LN status (p � 0.18). Similarly, a recent metaanalysis assessing the optimal duration of trastuzumab treatment also showed no significant interaction between survival and HR status or LN status (p for interaction test, 0.26 and 0.60) [47]. e guidelines recommend using an interaction test for subgroup analyses, as evidenced that inappropriate subgroup-specific analysis was of low reliability and the problem may be underestimated [48].…”

Six Months vs. 12 Months of Adjuvant Trastuzumab Among Women With HER2-Positive Early-Stage Breast Cancer: A Meta-Analysis of Randomized Controlled Trials

“…Admittedly, our meta-analysis is not the first to compare short durations vs. 12 months of trastuzumab, and there are at least six similar meta-analyses or systematic reviews so far (26,27,(36)(37)(38)(39). However, these similar studies were found to have some serious limitations.…”

“…A multicenter phase III RCT also showed that the 1-year duration of treatment was associated with an improved DFS (HR = 1.53, 95% CI: 1.16-2.01, P = 0.001) and better OS (HR = 1.61, 95% CI: 1.13-2.29, P = 0.008) among early breast cancer participants treated with trastuzumab concurrently (16). Furthermore, a recent metaanalysis with six RCTs compared the therapeutic effect and toxicity between short durations (9 weeks and 6 months) and 1 year of trastuzumab, and the sub-analyses also showed that patients treated with trastuzumab concurrently in the 1-year group had an improved DFS (HR = 1.22, 95% CI: 1.09-1.38, P = 0.0008) (27). In conclusion, improved survival was more evident among patients treated with concurrent trastuzumab and with ER-negative breast cancer.…”

“…Firstly, the two studies presented at ASCO 2019 provided only brief abstracts rather than detailed full-text articles, and they may lack some important information (36,37). Secondly, most similar studies compared short durations vs. 12 months of trastuzumab, but we concentrated on 6 months of trastuzumab rather than several different short durations (26,27,(36)(37)(38)(39). There may be substantial bias if 6 months and other different short durations are combined arbitrarily.…”

“…There may be substantial bias if 6 months and other different short durations are combined arbitrarily. Thirdly, brief abstracts of some relevant RCTs were included in similar meta-analyses published before June 2019 (26,27,(36)(37)(38)(39), because the latest results of two key RCTs (15,16) were published in the Lancet journal in June 2019; this may have substantially decreased the reliability of their final outcomes. Fourthly, previous meta-analyses (36)(37)(38)(39) lacked relevant registration information in PROSPERO, which was indispensable for performing meta-analyses.…”