T-DM1 showed the lowest LVEF decline vs other HER2-targeted regimens, underscoring key differences in cardiac safety.
Data from a single-group systematic review and meta-analysis demonstrated a differentiated cardiotoxicity profile across trastuzumab-containing regimens used in HER2-positive breast cancer, with ado-trastuzumab emtansine (T-DM1; Kadcyla) showing the lowest incidence of left-ventricular ejection fraction (LVEF) decline.1 Findings from the analysis also showed that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), trastuzumab (Herceptin) plus chemotherapy, and trastuzumab plus pertuzumab (Perjeta) and chemotherapy exhibited comparable rates of LVEF decrease.
Results from the pooled analyses demonstrated distinct patterns of LVEF decline among the evaluated therapies. T-DM1 was assessed across 5 studies and was associated with a decrease in LVEF incidence of approximately 1.09% (95% CI, 0.63%-1.88%). Given an observed risk of publication bias, a trim-and-fill adjustment was applied, yielding a slightly lower estimated incidence of 0.94% (95% CI, 0.56%-1.57%).
For T-DXd, pooled results from 2 studies showed a 4.20% (95% CI, 2.91%-6.01%) incidence of LVEF decline, with no discernible evidence of publication bias on visual inspection of the funnel plot. Standard trastuzumab plus chemotherapy regimens demonstrated a pooled LVEF decrease incidence of 4.14% (95% CI, 2.26%-5.23%) across 12 studies. After applying a trim-and-fill correction to account for potential publication bias, the adjusted incidence increased modestly to 4.85%(95% CI, 3.73%-6.28%). Tastuzumab combined with pertuzumab and chemotherapy, which was evaluated in 5 studies, was associated with a 5.52% (95% CI, 3.41%-8.83%) incidence of LVEF decline. No indications of publication bias were identified for this regimen.
Investigators noted that this difference may be explained by biologic distinctions between the agents. T-DM1 lacks a bystander effect, limiting its cytotoxic activity to HER2-expressing cells. In contrast, T-DXd’s membrane-permeable payload exerts cytotoxic effects beyond target cells, enabling activity in HER2-low, heterogeneous, or T-DM1–refractory disease, but potentially increasing off-target toxicity. This mechanism aligns with the higher rate of adverse effects leading to treatment interruption, dose reduction, or discontinuation observed with T-DXd in the pivotal phase 3 DESTINY-Breast03 trial (NCT03529110).2
“This single-group systematic review and meta-analysis that indirectly compared the incidence of LVEF decrease across 4 chemotherapy regimens containing trastuzumab found that T-DM1 had the lowest incidence of LVEF decrease; T-DXd, trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab plus chemotherapy had similar incidences of LVEF decrease,” Lakshya Seth, MD, an internal medicine resident physician at the University of Texas Southwestern Medical Center in Dallas, and his coauthors wrote in their conclusion 1
This systematic review and meta-analysis were conducted in accordance with PRISMA reporting guidelines and evaluated cardiotoxicity outcomes associated with trastuzumab-containing regimens for HER2-positive breast cancer. Study authors performed a literature search in December 2024 and included studies published between 2000 and 2024 across 4 databases: PubMed, ScienceDirect, Cochrane Library, and ClinicalTrials.gov. The search strategy used combinations of keywords, MeSH terms, and Boolean operators. The review was not registered, and no protocol was prepared.
The analysis included phase 3 clinical trials, which enrolled patients with locally advanced or metastatic HER2-positive breast cancer. Trials were required to define LVEF monitoring procedures, specify criteria for LVEF decline or heart failure, and include regimens limited to T-DM1, T-DXd, or first- through fourth-line National Comprehensive Cancer Network–recommended chemotherapy options for patients with unresectable stage IV HER2-positive disease. Cardiovascular eligibility criteria also needed to be explicitly stated.
A total of 6899 records were identified for the control group during the initial literature search. After removal of 4590 duplicate entries, 2309 studies proceeded to abstract screening, of which 2223 were excluded based on predefined criteria. Eighty-six full-text articles were then assessed for eligibility, and 15 studies ultimately met the inclusion criteria for the final meta-analysis.
Of these, 10 studies evaluated trastuzumab plus chemotherapy, 3 studies assessed trastuzumab plus pertuzumab and chemotherapy, and 2 studies included both regimens. Collectively, the trastuzumab plus chemotherapy studies enrolled 2929 patients, while the trastuzumab plus pertuzumab plus chemotherapy studies included an additional 2411 patients. These datasets formed the comparative foundation for evaluating cardiotoxicity across standard trastuzumab-based regimens in HER2-positive breast cancer.
Study screening was completed by 3 blinded reviewers, with discrepancies resolved collaboratively. Extracted data elements included study identifiers, treatment regimen, trial characteristics, patient demographics, HER2 and hormone receptor status, dosing schedules, and definitions and incidence of LVEF decline or heart failure. Study quality was assessed using the Jadad scale. None of the included trials reported heart failure as an outcome.
The primary objective of the meta-analysis was to estimate the pooled incidence of cardiotoxicity associated with trastuzumab-based regimens. Analyses were conducted using logit-transformed proportions, an inverse variance–weighted approach, and a DerSimonian–Laird random-effects model. Heterogeneity was assessed with Cochran Q and quantified by I². Publication bias and small-study effects were evaluated using funnel plots and the Egger test, with trim-and-fill adjustments applied when appropriate. The threshold for statistical significance was set at P < .05. All analyses were performed using R version 4.4.2, and results were visualized using forest plots.
