Abstract P1-13-01: Duration of adjuvant trastuzumab in HER-2 positive breast cancer: Pooled results of overall, and disease-free survivals from meta-analyses of randomized controlled trials
Authors: Niraula S , Gyawali B 
Published: February 2018

Background: The duration of one year of trastuzumab for treatment of HER-2 positive breast cancer was chosen arbitrarily. Randomized controlled trials (RCTs) have since explored efficacy of shorter durations of trastuzumab compared to 1 year, but the results from such RCTs are inconsistent, and are subject to different interpretations due mainly to varying definitions of non-inferiority.

Methods: Systematic search of pubmed, embase, and major conference proceedings was performed to identify RCTs comparing outcomes of one year versus shorter trastuzumab in the adjuvant treatment of breast cancer. Efficacy outcomes [Hazard Ratios (HR) for Overall Survival (OS) and Disease Free Survival (DFS) with respective 95% Confidence Intervals (CI)] and toxicity outcome [Odds Ratios (OR) and 95% CI for cardiac events] from each study were weighted using generic inverse variance approach and pooled in a meta-analysis using RevMan 5.3 software. Heterogeneity among studies was assessed using tau2 and i2 statistics. Interactions on overall results by hormone receptor status, and nodal status were assessed using chi2 statistics.

Results: Three RCTs involving 5,114 patients reported outcomes on both OS and DFS. Two studies evaluated 6 months and 1 study evaluated 9 weeks of adjuvant trastuzumab, compared to 1 year. Individual RCTs had failed to demonstrate non-inferiority of shorter duration compared to 1 year based on various pre-specified upper limits of CI (of &lt;1.15, &lt;1.29 and &lt;1.59, respectively). Pooled analyses demonstrated statistically significant improvements in both OS (HR 0.78, 95% CI: 0.62-0.98), and DFS (HR 0.80, 95% CI 0.73-0.93) with the use of 1 year of trastuzumab compared to shorter durations suggesting superiority favoring 1 year of treatment, despite non-inferiority designs of individual trials. Sensitivity analyses based on duration of the experimental arm (9 weeks or 6 months) did not influence the direction, or size of overall effects. Pooled sub-group analyses demonstrated no interaction by hormone receptor status, or nodal status on overall results (p for sub-group difference = 0.73, and 0.52, respectively). Odds of cardiac events increased significantly with 1 year of treatment. (table 1)

Conclusion: Pooled analyses of RCTs demonstrated a significant improvement in overall, and disease-free survivals with 1 year of adjuvant trastuzumab compared to shorter durations for adjuvant treatment of HER-2 positive breast cancer. One year of trastuzumab should remain as the standard of care. Cardiotoxicity increased significantly with the longer treatment.

Hazard Ratios of Overall and Disease Free Survivals of 1 Year of Adjuvant Trastuzumab Compared to Shorter Durations in Treatment of HER2 positive Breast CancerOUTCOMESHAZARD RATIO95% CONFIDENCE INTERVALp (DIFFERENCE)INTERACTION TESTOVERALL SURVIVAL0.780.62 - 0.980.04DISEASE FREE SURVIVAL (DFS)0.800.70 - 0.930.004DFS - ESTROGEN RECEPTOR POSITIVE0.820.66 - 1.030.09CHI SQ. 0.12; p(SUBGROUP-DIFFERENCE)0.73DFS - ESTROGEN RECEPTOR NEGATIVE0.780.63 - 0.970.005DFS - NODE POSITIVE0.760.63 - 0.920.004CHI SQ. 0.42; p(SUBGROUP-DIFFERENCE)0.52DFS - NODE NEGATIVE0.870.60 - 1.260.46CARDIAC EVENTS2.65 (ODDS RATIO)2.00 - 3.50&lt;0.001

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Citation Format: Niraula S, Gyawali B. Duration of adjuvant trastuzumab in HER-2 positive breast cancer: Pooled results of overall, and disease-free survivals from meta-analyses of randomized controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-01.