A systematic review and meta-analysis published in JAMA Network Open compared the cardiotoxicity of novel antibody-drug conjugates (ADCs) with that of standard trastuzumab-containing chemotherapy in patients with HER2-positive locally advanced or metastatic breast cancer, finding that treatment with ado-trastuzumab emtansine (T-DM1) resulted in the lowest incidence of left ventricular ejection fraction decrease. The other three regimens—fam-trastuzumab deruxtecan-nxki (T-DXd), trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab and chemotherapy—showed rates that were similar to each other, according to Seth et al. However, the investigators noted, “More research is needed into the cardiotoxic effects of these therapies.”
Study Details
The investigators conducted a meta-analysis to identify eligible studies in the PubMed, ScienceDirect, Cochrane Library, and ClinicalTrials.gov databases published between 2000 and 2024. Those selected—which included a total of 9,538 patients—met the following criteria:
- Phase III clinical trial that investigated locally advanced or metastatic HER2-positive breast cancer
- Clearly defined left ventricular ejection fraction decrease or heart failure definitions
- Clearly defined left ventricular ejection fraction monitoring frequency by echocardiography or multigated acquisition scan
- Consisted solely of either T-DM1, T-DXd, or one of the current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology–recommended first- to fourth-line chemotherapy regimens for unresectable stage IV HER2-positive breast cancer
- Clearly defined cardiovascular eligibility criteria.
Data extraction was performed by three reviewers. According to the investigators, a random-effects model was used for the pooled analysis. The primary outcome was cardiotoxic effects, which were defined as the incidence of decreased left ventricular ejection fraction.
Key Findings
Funnel plot asymmetry was observed for T-DM1 and trastuzumab plus chemotherapy, indicating a risk of publication bias; therefore, a trim-and-fill approach was applied for these analyses. For these two treatments, the trim-and-fill–adjusted pooled incidence rates of decreased left ventricular ejection fraction were 0.94% (95% confidence interval [CI] = 0.56%–1.57%) for T-DM1 and 4.85% (95% CI = 3.73%–6.28%) for trastuzumab plus chemotherapy.
For the remaining treatments, which did not show an obvious risk for publication bias, the pooled incidence rates of decreased left ventricular ejection fraction were 4.20% (95% CI = 2.91%–6.01%) for T-DXd and 5.52% (95% CI = 3.41%–8.83%) for trastuzumab plus pertuzumab and chemotherapy.
The investigators concluded, “This single-group systematic review and meta-analysis that indirectly compared the incidence of left ventricular ejection fraction decrease across four chemotherapy regimens containing trastuzumab found that [T-DM1] had the lowest incidence of left ventricular ejection fraction decrease; [T-DXd], trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab and chemotherapy had similar incidences of left ventricular ejection fraction decrease. [T-DM1] and [T-DXd] have shown promise in treating [HER2]-positive metastatic breast cancer; however, there is a paucity of data comparing the cardiotoxic effects among [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.”
Avirup Guha, MD, MPH, of the Medical College of Georgia at Augusta University, is the corresponding author of the article in JAMA Network Open.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
