Trastuzumab emtansine (T-DM1/Kadcyla, Genentech Inc) is an antibody-drug conjugates (ADCs) used to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer [1]. Here, we report corneal changes observed after T-DM1 treatment, accompanied by associated refractive and corneal topographic alterations. Written informed consent for publication of the research details and clinical images was obtained from the patient.

A 46-year-old female patient presented with bilateral blurred vision, mainly near vision deterioration, 2 weeks after starting the second round of chemotherapy and hormone therapy with letrozole, goserelin, and T-DM1. Her uncorrected distant visual acuity was 0.7 in both eyes and best-corrected distant visual acuity was 1.0 in both eyes; however, her uncorrected near visual acuity was 0.63 in both eyes. Hyperopic astigmatism was observed in both eyes (Supplementary Fig. 1A). Slit-lamp examination revealed numerous subepithelial microcyst-like epithelial changes (MECs), forming paracentral rings in both corneas (Fig. 1A, 1B). Topography revealed central flattening in both eyes (Fig. 1C, 1D).

Six months later, MECs had partially resolved; however, epithelial abnormalities were noted on the nasal sides of both eyes (Fig. 1E, 1F). Topography showed mild improvement in the previously flattened central zone (Fig. 1G, 1H) and hyperopia was decreased (Supplementary Fig. 1B). She was prescribed artificial tears four times daily.

Three weeks later, she complained of foreign body sensation in both eyes. Pseudodendrite-like epithelial abnormalities were observed on the nasal sides of each cornea (Supplementary Fig. 2A, 2B). To exclude herpesviral keratitis associated with chemotherapy-induced immunosuppression, tear polymerase chain reaction testing for herpesviridae (types 1-6) was performed, and 0.15% ganciclovir gel (Virgan, Samil Pharm) was applied five times daily. Following a negative result, ganciclovir was tapered to twice a week for 1 week and then discontinued.

Three months after completing 14 cycles of T-DM1, most symptoms had resolved. The uncorrected distant visual acuity was 0.8 in the right eye and 0.9 in the left eye. Corneal abnormalities had resolved, topography had normalized (Fig. 1I-1L), and refraction had remained stable (Supplementary Fig. 1C). The uncorrected near visual acuity was 1.0 in the right eye and 0.8 in the left eye.

Two types of corneal side effects have been identified in T-DM1 treated patients: MECs and corneal epithelial abnormalities. Deklerck et al. [2] reported MECs in 10 of 12 patients treated with T-DM1, with no significant complications after autologous serum treatment. In contrast, Tsuda et al. described persistent bilateral corneal epithelial abnormalities in a patient after 15 months of T-DM1 therapy [3]. T-DM1 contains DM1 (emtansine), a cytotoxic microtubule inhibitor, which disrupts cell division and migration [1]. Although T-DM1 targets specific antigens, corneal toxicity may occur through three mechanisms: (1) macropinocytosis, in which nonspecific uptake cleaves the linker and prematurely releases cytotoxins; (2) a bystander effect, where cytotoxins from dying cells affect adjacent cells; and (3) extracellular linker cleavage by matrix proteases, allowing passive cytotoxin diffusion [1,4]. MECs and epithelial abnormalities, including the pseudodendrite-like finding observed in this case, may represent corneal changes associated with T-DM1. To our knowledge, this is the first case demonstrating both MECs and epithelial abnormalities following T-DM1 therapy.

Currently, 11 ADCs have received US Food and Drug Administration approval for cancer treatment [4]. Among them, three (belantamab mafodotin, mirvetuximab soravtansine, and tisotumab vedotin) are associated with MECs. Of these, belantamab mafodotin is the most extensively studied, with MECs reported in 72% of treated patients. These events led to treatment delays in 47% and dose reductions in 25% [4]. Unlike the peripheral-to-central progression of MECs seen with belantamab mafodotin [5], which often results in visual impairment, the MECs in our case were paracentrally located, remained stationary, and resolved spontaneously without significant visual loss.

Although previous studies did not indicate a dose-related toxicity of T-DM1 [1,2], T-DM1 may still pose a risk for ocular toxicity, as suggested by case involving belantamab mafodotin and the report by Tsuda et al. [3]. This contrasts with Deklerck et al. [2]’s suggestion that therapy may continue despite MECs and symptoms may be managed with autologous serum and lubricants. Therefore, regular monitoring of VA, refraction, and corneal topography, in addition to multidisciplinary collaboration with the oncology team would be necessary, although permanent vision loss is rare with T-DM1.