Short versus long duration of adjuvant trastuzumab (T) in HER2+ breast cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

Abstract

e12057 Background: Several RCTs have evaluated a shorter duration of T ( < 12 months) with hopes of similar efficacy, reduced cardiotoxicity, cost and burden of treatment. Of the 5 major studies, PERSPHONE showed that 6 months was non-inferior compared to 12 months. However, four additional studies of shorter duration failed to demonstrate non-inferiority. Therefore, we performed an updated systematic review and a meta-analysis to assess the optimal duration of adjuvant T. Methods: MEDLINE, EMBASE, Cochrane, Scopus and conference proceedings were searched to identify RCTs comparing one year of adjuvant T with a shorter duration in early-stage HER2+ breast cancer. The DerSimonian-Laird random-effects Meta-Analysis was performed using CMAv3 software to derive pooled Hazard Ratio (HR) estimates for overall survival (OS, Disease-Free Survival (DFS) and Odds Ratio(OR) estimates of cardiac toxicity. Q-test was used to assess between-study heterogeneity; I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. The risk for bias was assessed using the Cochrane Collaboration’s tool. Results: We screened 1772 citations and identified 5 studies(n = 11,377) for analysis. 5691 patients were randomized to 12 months of adjuvant T while 5686 were randomized to a shorter duration (3 studies evaluated 6 vs 12 months, 2 studies evaluated 9 weeks vs 12 months). OS (HR, 1.16, 95% CI 1.03-1.31, P= 0.015,I2 0.00, p= 0.837) and DFS (HR, 1.14, 95% CI 1.02-1.26 , P = 0.016,I2 14.90, p= 0.319) were significantly worse in patients receiving shorter duration T as compared to 12 months. Cardiotoxicity was significantly higher in the 12 month group vs shorter duration (OR, 2.10, 95% CI 1.58-2.80, p = 0.000 ,I2 51.182, p= 0.085). Grade 3/4 cardiac events and cardiac events leading to discontinuation of therapy were significantly higher in patients receiving 12 months (HR 2.06, 95% CI 1.60-2.63, P = 0.000, I2 3.967, p= 0.384). There was no significant heterogeneity among studies. Risk of bias was low. Conclusions: Twelve months of adjuvant T is associated with significantly better DFS and OS compared to a shorter duration. As such, 12 months should remain the standard of care for most patients. There is an unmet need to identify lower risk groups which might do well with from shorter duration of HER2-directed therapy.

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.…”

“…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.…”

“…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. However, our meta-analysis has some irreplaceable advantages compared with previous similar meta-analyses: (1) The detailed full text was provided in our meta-analysis, and ours could supplement some important information compared with the two previous metaanalyses (36,37).…”

“…Fourthly, previous meta-analyses (36)(37)(38)(39) lacked relevant registration information in PROSPERO, which was indispensable for performing meta-analyses. However, our meta-analysis has some irreplaceable advantages compared with previous similar meta-analyses: (1) The detailed full text was provided in our meta-analysis, and ours could supplement some important information compared with the two previous metaanalyses (36,37). (2) We only concentrated on 6 months of trastuzumab rather than several different short durations, so our meta-analysis had greater accuracy and possibly less bias than most similar meta-analyses (26,27,(36)(37)(38)(39).…”

“…However, our meta-analysis has some irreplaceable advantages compared with previous similar meta-analyses: (1) The detailed full text was provided in our meta-analysis, and ours could supplement some important information compared with the two previous metaanalyses (36,37). (2) We only concentrated on 6 months of trastuzumab rather than several different short durations, so our meta-analysis had greater accuracy and possibly less bias than most similar meta-analyses (26,27,(36)(37)(38)(39). (3) Unlike most similar meta-analyses (26,27,(36)(37)(38)(39), we included the full texts of all relevant RCTs, and we made full use of the full texts and Supplementary Materials of these RCTs.…”