Abstract P3-14-04: Tailored duration of adjuvant trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer
Authors: Yu Ke-Da , Zhou Zhi-Rui , Shao Zhi-Ming 
Published: March 2020

Abstract
Background: A number of clinical trials were conducted to assess the efficacy and toxicity of shorter durations of adjuvant trastuzumab compared with 12-month standard duration. However, the results were controversial and the reduced time varied among trials. To assess the effect of treatment time of adjuvant trastuzumab on the clinical outcomes at trial level, we performed a systematic literature search and a trial-level meta-regression analysis to figure out the appropriate time for trastuzumab treatment.
Methods: A comprehensive search of (neo)adjuvant trastuzumab in breast cancer in PUBMED and EMBASE databases from Jan 2000 to June 2019 was performed. We treated the “12-month trastuzumab” as the standard. The “shorter duration” is less than 12 months, including extreme value of 0-month for no trastuzumab. The primary clinical outcome is DFS. HR with 95% confidence intervals (CIs) should be reported. Shortened treatment time (months) and DFS outcome (expressed as HRs) were extracted from each trial. Meta-regression was performed using HR of DFS and shortened time of adjuvant trastuzumab in random-effects model. The coefficient of determination (R2) and the regression coefficient (β) were calculated. We also performed sensitivity analysis by omitting each study to find the potential outliers.
Results: A final set of 12 trials was included in the analysis. Five studies compared the 12-month trastuzumab with shorter duration in a non-inferiority setting and 7 studies compared with no trastuzumab in a superiority design (Table 1). The between-study variance τ2 is 0.0062 and the adjusted R2 is 63.14%, which means 63% of the variability among the effects on DFS can be explained by the shortened time of adjuvant trastuzumab, and the remaining between-study variance appears small at 0.0062. We estimated the effects of different shortened times of trastuzumab on DFS and the regression coefficients β of shortened treatment time is 0.04 (P=0.038, 95% CI, 0.0029-0.0788), indicating for each month reduced, the ln(HR) of DFS events increased 0.04. If transferred to HR, the values were 1.042 (e0.04), indicating the risk of DFS would increase 4.2% for each month trastuzumab shortened. Similarly, if 3-month reduced, the risk increased 12.7% (e0.12=1.127); 6-month reduction would increase risk of 27.1%, and 9-month, 43.3% (Table 2). Further subgroup analyses according to estrogen receptor status and lymph nodes status yielded qualitatively similar results.
Conclusion: We revealed a significant linear association between shortened time of trastuzumab and the risk of DFS events. These findings suggest that a shorter duration of trastuzumab might be appropriate for patients with lower-risk disease but unacceptable for those with high-risk disease. We believe that the duration of adjuvant trastuzumab should be tailored according to the risk, as well as toxicity and cost.
Table 1. Summary of included studies.IDITT numberTrial designHazard marginHR with 95% CIShortened time (month)EndpointMedian Follow-up (year)PHARE1691non-inferiority1.151.08 (0.93-1.25)6DFS7.5HORG481non-inferiority1.531.57 (0.86-2.10)6DFS3Short-HER1253non-inferiority1.291.15 (0.87-1.53)9.9DFS5.2SOLD2174non-inferiority1.31.39 (1.08-1.80)9.9DFS5.2PERSEPHONE4088non-inferiority1.291.07 (0.90-1.27)6DFS5.4E2198227superiorityNA1.18 (0.56-2.44)12DFS6.4NCCTG N98311944superiorityNA1.72 (1.52-1.92)12DFS8.4NSABP B-312102superiorityNA1.72 (1.52-1.92)12DFS8.4HERA3401superiorityNA1.45 (1.27-1.69)12DFS8BCRIG-0062147superiorityNA1.39 (1.18-1.64)12DFS10.3PACS04528superiorityNA1.16 (0.82-1.64)12DFS3.9NOAH235superiorityNA1.69 (1.11-2.63)12EFS3.2
Table 2. Shortened time of adjuvant trastuzumab and increased risk of DFSShortened Time (Month)Change in ln(HR)Increased relative risk of DFS eventsPredicted DFS in APT trial (%)Predicted DFS in N9831/B31 trials (%)10.044%937330.1213%927160.2427%916790.3643%9063120.4862%8958
Citation Format: Ke-Da Yu, Zhi-Rui Zhou, Zhi-Ming Shao. Tailored duration of adjuvant trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-04.