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

person Qurat Ul Ain Riaz Sipra BUMC, Tucson, AZ info_outline Qurat Ul Ain Riaz Sipra, Irbaz Bin Riaz, Muhammad Husnain, Ammad Raina, Ahsan Khan, Maheen Akhtar, Zhen Wang, M. Hassan Murad, Roberto Antonio Leon-Ferre

Authors person Qurat Ul Ain Riaz Sipra BUMC, Tucson, AZ info_outline Qurat Ul Ain Riaz Sipra, Irbaz Bin Riaz, Muhammad Husnain, Ammad Raina, Ahsan Khan, Maheen Akhtar, Zhen Wang, M. Hassan Murad, Roberto Antonio Leon-Ferre Organizations BUMC, Tucson, AZ, Mayo Clinic, Rochester, MN, University of Miami/Sylvester Cancer Center, Miami, FL, Midwestern University, Sierra Vista, AZ, Multan Medical and Dental College, Multan, Pakistan, Dow University of Health Sciences, Karachi, Pakistan Abstract Disclosures Research Funding Other 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; I 2 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,I 2 0.00, p = 0.837) and DFS (HR, 1.14, 95% CI 1.02-1.26 , P = 0.016,I 2 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 ,I 2 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, I 2 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.