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Microstructural and neural impairment of the ocular surface induced by HER2-targeted ADCs: a prospective longitudinal
Liu Yang1, Mengchen Cui1, Shulan Huang1
1Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
Aims:
To characterise the clinical and morphological features of ocular surface toxicity induced by human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates (ADCs) in patients with HER2-positive breast cancer, guiding clinical intervention.
Methods:
21 HER2-positive breast cancer patients receiving HER2-ADC therapy were enrolled. Assessments included best corrected visual acuity, the Ocular Surface Disease Index, conjunctival lissamine green staining, tear break-up time, tear meniscus height, Meibomian Gland Score, Strip Meniscometry Tube (SMTube strips), corneal sensitivity (Cochet-Bonnet esthesiometry), anterior segment optical coherence tomography and in vivo confocal microscopy (IVCM) to evaluate morphology, corneal nerve fibre density and length, and endothelial cell density. Transmission electron microscopy (TEM) was performed in selected cases. All parameters were compared from baseline to follow-up.
Results:
Ocular surface toxicity occurred in 85.7% (18/21) of patients after HER2-ADC therapy, with a mean onset at 28.0±8.4 days. Vortex-like keratopathy progressed from inferior subepithelial microcysts to linear deposits and a vortex pattern. IVCM revealed severe subepithelial nerve fibre fragmentation and loss. TEM revealed epithelial extracellular matrix fibrosis, mitochondrial damage (swelling, disordered cristae, vacuolisation), nuclear alterations (chromatin dispersion, electron-dense deposits) and suspected endocytic vesicles. Lesions appeared dose- and time-dependent and showed partial reversibility. After 12 cycles, corneal structure and transparency showed restoration trends.
Conclusion:
HER2-ADC-induced ocular surface toxicity presents as vision loss, dry eye and selective damage to corneal epithelium (vortex-like keratopathy) and nerves (nerve fibre loss and reduced sensitivity), which is dose- and time-dependent and partially reversible.
Insights
Human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates (ADCs) can cause ocular surface toxicity, including vision loss and dry eye, in breast cancer patients. This toxicity affects the corneal epithelium and nerves but is dose-dependent and partially reversible.
Area of Science:
- Ophthalmology
- Oncology
- Drug Development
Background:
- HER2-targeted antibody-drug conjugates (ADCs) are crucial in treating HER2-positive breast cancer.
- Ocular surface toxicity is a potential side effect of these therapies.
- Understanding these toxicities is vital for patient management and treatment optimization.
Purpose of the Study:
- To characterize the clinical and morphological features of ocular surface toxicity induced by HER2-ADCs.
- To identify specific ocular structures affected by HER2-ADC therapy.
- To provide guidance for clinical interventions in patients with HER2-positive breast cancer.
Main Methods:
- Enrolled 21 patients with HER2-positive breast cancer undergoing HER2-ADC therapy.
- Conducted comprehensive ocular assessments including visual acuity, dry eye questionnaires, and advanced imaging (OCT, IVCM, TEM).
- Evaluated corneal morphology, nerve fiber density, and endothelial cell density, comparing baseline to follow-up.
Main Results:
- Ocular surface toxicity occurred in 85.7% of patients, with a mean onset of 28 days.
- Vortex-like keratopathy, nerve fiber fragmentation, and loss of corneal sensitivity were observed.
- TEM revealed epithelial fibrosis and mitochondrial damage, with lesions showing dose- and time-dependency and partial reversibility.
Conclusions:
- HER2-ADC therapy can induce significant ocular surface toxicity, manifesting as vision loss and dry eye.
- Corneal epithelium and nerves are selectively damaged, presenting as vortex-like keratopathy and reduced sensitivity.
- The toxicity is dose- and time-dependent and shows potential for partial recovery after treatment cessation or reduction.
