Abstract Body (Do not enter title and authors here):
Background
Novel antibody-drug conjugates (ADCs) such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd) have shown efficacy in treating HER2-positive breast cancer (BC) that has progressed on prior HER2-targeted therapy. We aimed to compare the incidence of cardiotoxicity of these novel ADCs to standard-of-care chemotherapy regimens containing trastuzumab for HER2-positive locally advanced/metastatic BC.

Methods
We searched PubMed, ScienceDirect, Cochrane Library, and clinicaltrials.gov to identify phase III clinical trials that investigated patients with locally advanced/metastatic HER2-positive BC treated with either T-DM1, T-DXd, trastuzumab + chemotherapy (TC), or trastuzumab + pertuzumab + chemotherapy (TPC). We performed a single-arm meta-analysis that compared the pooled incidence of LVEF decrease across the four chemotherapy regimens.

Results
All analyses accounted for publication bias if present. In the 5 studies that included 3531 patients who received T-DM1, a pooled analysis demonstrated a 0.94% [95% CI: 0.56 – 1.57] incidence of LVEF decrease. In the 2 studies that included 667 patients who received T-DXd, a pooled analysis demonstrated a 4.20% [95% CI: 2.91 – 6.01] incidence of LVEF decrease. In the 12 studies that included 2929 patients who received TC, a pooled analysis demonstrated a 4.85% [95% CI: 3.73 – 6.28] incidence of LVEF decrease. In the 5 studies including 2411 patients who received TPC, a pooled analysis demonstrated a 5.52% [95% CI: 3.41 – 8.83] incidence of LVEF decrease.

Conclusion
In our single-arm meta-analysis indirectly comparing the incidence of LVEF decrease across four chemotherapy regimens containing trastuzumab, we found that T-DM1 had the lowest incidence of LVEF decrease, and T-DXd, TC, and TPC had similar incidences of LVEF decrease. While T-DM1 and T-DXd have shown promise in treating HER2-positive metastatic BC that has progressed, there is a paucity of data comparing the cardiotoxicity between ADCs, of ADCs vs. the standard of care trastuzumab-containing chemotherapy regimens, and of the potential of ADCs as first-line therapy for metastatic BC.