Microstructural and neural impairment of the ocular surface induced by HER2-targeted ADCs: a prospective longitudinal study with ultrastructural insights.

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.