T-DM1 Confers Lower Cardiotoxicity Risk in HER2+ Advanced Breast Cancer

The use of ado-trastuzumab emtansine (T-DM1; Kadcyla) was associated with the lowest incidence of left ventricular ejection fraction (LVEF) decrease compared with 3 other trastuzumab-based regimens in the treatment of patients with HER2-positive breast cancer, according to findings from a meta-analysis published in JAMA Network Open.¹

Among 3531 patients who received T-DM1 in 5 studies, the rate of LVEF decrease was 1.09% (95% CI, 0.63%-1.88%; P = .05). Of 667 patients who received fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in 2 studies, 4.20% (95% CI, 2.91%-6.01%; P = .99) experienced LVEF decrease.

Additionally, the rate of LVEF decrease among 2929 patients who received trastuzumab (Herceptin) plus chemotherapy across 12 studies was 4.14% (95% CI, 2.26%-5.23%; P = .11). Of 2411 patients who received trastuzumab in combination with pertuzumab (Perjeta) and chemotherapy across 5 studies, 5.52% (95% CI, 3.41%-8.83%; P <.001) had LVEF decrease.

To adjust for a risk of publication bias associated with the T-DM1 studies, a trim-and-fill random effects model identified 1 additional study to yield a LVEF decrease rate of 0.94% (95% CI, 0.56%-1.57%). After visually inspecting the funnel plot for the T-DXd studies, investigators observed no obvious publication bias risk for this group.

A trim-and-fill approach was employed to adjust for potential publication bias related to the trastuzumab/chemotherapy studies; a random effects model added 5 other studies and showed an LVEF decrease rate of 4.85% (95% CI, 3.73%-6.28%). Investigators reported no obvious publication bias risk for the studies assessing trastuzumab/pertuzumab plus chemotherapy.

“This single-group systematic review and meta-analysis that indirectly compared the incidence of LVEF decrease across 4 chemotherapy regimens containing trastuzumab found that trastuzumab emtansine had the lowest incidence of LVEF decrease; trastuzumab deruxtecan, trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab plus chemotherapy had similar incidences of LVEF decrease,” lead study author Lakshya Seth, MD, from the Department of Internal Medicine at the University of Texas Southwestern Medical Center, wrote with coauthors in the publication.¹ “Trastuzumab emtansine and trastuzumab deruxtecan have shown promise in treating [HER2]-positive metastatic [breast cancer]; however, there is a paucity of data comparing the cardiotoxic effects among antibody drug conjugates [ADCs], of ADCs vs the standard-of-care trastuzumab-containing chemotherapy regimens, and the potential of ADCs as first-line therapy for both early-stage and metastatic [breast cancer].”

Investigators of this systemic review and meta-analysis evaluated the incidence of cardiotoxicity associated with ADCs vs standard chemotherapy combinations among 9538 patients with HER2-positive breast cancer who progressed on previous HER2-directed treatment. In December 2024, the study authors searched PubMed, ScienceDirect, Cochrane Library, and ClinicalTrials.gov for eligible studies conducted from 2000 to 2024.

As part of the review, investigators included phase 3 trials that assessed patients with locally advanced or metastatic HER2-positive breast cancer, studies that clearly defined LVEF decrease or heart failure, studies with clear definitions of LVEF monitoring frequency via echocardiography or multigated acquisition scan, and studies that clearly defined cardiovascular eligibility criteria.

The study’s primary end point was cardiotoxic effects based on the rate of LVEF decrease. Investigators completed the pooled analysis via logit-transformed proportions with the inverse variance method and a DerSimonian-Laird random-effects model to adjust for between-study variance.

According to the study authors, the meta-analysis did not permit direct comparison of the incidence of LVEF decrease between ADCs and standard regimens, noting that only 1 study included in the pooled analysis directly compared such outcomes.² It was also noted that secondary cardiovascular outcomes like atrial fibrillation, myocardial infarction, and coronary artery disease were not highlighted in the studies featured in the meta-analysis.

“The lower incidence of cardiotoxic effects observed in our meta-analysis with trastuzumab emtansine could be explained by the lack of the bystander effect with this ADC in contrast to trastuzumab deruxtecan, which does exhibit the bystander effect,” the study authors wrote.¹ “In contrast to trastuzumab emtansine, the bystander effect, along with the membrane permeability of trastuzumab deruxtecan, allows it to cross cell membranes and exhibit cytotoxic effects on surrounding tumor cells, irrespective of [HER2] levels, and has shown promise in treating [HER2] low or heterogenous and trastuzumab emtansine–refractory cancers.”

References

1. Seth L, Bhave A, Kollapaneni S, et al. Cardiotoxic effects of antibody drug conjugates vs standard chemotherapy in ERBB2-positive advanced breast cancer: a systematic review and meta-analysis. JAMA Netw Open. 2025;8(11):e2540336. doi:10.1001/jamanetworkopen.2025.40336.
2. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019;125(22):3974-3984. doi:10.1002/cncr.32392.