Ado-trastuzumab emtansine (T-DM1; Kadcyla) is associated with a lower risk of heart damage compared with other trastuzumab-based regimens in patients with HER2-positive breast cancer, according to a meta-analysis published in JAMA Network Open.
The analysis included 9,538 patients across 5 phase 3 trials of antibody-drug conjugates (ADCs) and standard chemotherapy regimens. Among 3,531 patients receiving T-DM1, just 1.09% experienced a decrease in left ventricular ejection fraction (LVEF), a key measure of heart function. By contrast, LVEF decreases occurred in 4.20% of 667 patients treated with trastuzumab deruxtecan (T-DXd; Enhertu), 4.14% of 2,929 patients treated with trastuzumab plus chemotherapy, and 5.52% of 2,411 patients treated with trastuzumab plus pertuzumab and chemotherapy.
To account for potential publication bias, researchers used a trim-and-fill random effects model, which adjusted the LVEF decrease rate for T-DM1 to 0.94% and for trastuzumab plus chemotherapy to 4.85%. No significant publication bias was found for T-DXd or trastuzumab/pertuzumab studies.
“This meta-analysis found that T-DM1 had the lowest incidence of LVEF decrease compared with other trastuzumab-based regimens,” said lead author Dr. Lakshya Seth from the University of Texas Southwestern Medical Center. He noted that while both T-DM1 and T-DXd show promise in treating HER2-positive metastatic breast cancer, data comparing their heart-related side effects and potential as first-line therapy remain limited.
The study analyzed trials from 2000 to 2024 that included patients with locally advanced or metastatic HER2-positive breast cancer and clearly defined heart function monitoring and cardiovascular eligibility criteria. The primary endpoint was cardiotoxicity, measured by LVEF decrease, analyzed using a random-effects model to account for study variability.
Investigators highlighted that only one trial directly compared ADCs with standard trastuzumab-based chemotherapy, and secondary cardiovascular outcomes such as atrial fibrillation or myocardial infarction were not systematically reported.
The lower heart risk observed with T-DM1 may relate to its lack of a bystander effect, unlike T-DXd, which can cross cell membranes to affect neighboring tumor cells and shows activity in HER2-low or T-DM1–resistant cancers.
Related topic：
