HER2 antibody-drug conjugates take the tear film and the corneal nerves with them

Design

Retrospective case series with in vivo confocal microscopy

Population

8 adults (15 eyes) on trastuzumab botidotin for HER2-mutated or HER2-positive solid tumours

Primary outcome

Clinical features of corneal adverse events

Effect

Corneal events in 8 of 8; onset 37.3 days (SD 5.9), peak 82.8 days (SD 14.3); OSDI 5.7 to 65.1; Schirmer 8.9 to 4.2 mm; tear break-up 9.6 to 3.4 seconds

Eight adults, 15 eyes, all on trastuzumab botidotin for HER2-mutated or HER2-positive solid tumours, all with corneal adverse events. Visual symptoms began a mean 37.3 days (SD 5.9) after the first dose and peaked at 82.8 days (SD 14.3). Ocular Surface Disease Index scores climbed from 5.7 (SD 2.7) to 65.1 (SD 13.3). Schirmer's test fell from 8.9 mm to 4.2 mm, tear break-up time from 9.6 seconds to 3.4 seconds, tear meniscus height from 0.23 mm to 0.14 mm.

The morphology is characteristic rather than generic dry eye. Slit-lamp and fluorescein examination showed pseudomicrocysts, punctate and diffuse punctate epitheliopathy and vortex keratopathy; in vivo confocal microscopy found cyst-like hyperreflective structures in the superficial epithelium and grape-like clusters through the wing and basal cells. It also showed thinning of the subbasal nerve plexus with reduced nerve density and focal discontinuities, which is the part that explains why symptoms outrun the visible staining and why recovery is slow.

This is a retrospective case series of eight patients with no comparator, so it describes a pattern rather than measuring an incidence. Its use is diagnostic: a patient six weeks into an antibody-drug conjugate who reports blurring and grit has drug-induced epitheliopathy until proven otherwise, and the referral should go back to the oncologist with a description specific enough to inform a dose decision, not a note saying dry eye.

• Take a cancer drug history covering the last three months in any new severe ocular surface disease.
• Examine for pseudomicrocysts and vortex keratopathy specifically; both point to the drug rather than to age-related dry eye.
• Document Ocular Surface Disease Index, Schirmer and tear break-up time at the first visit so a later change is interpretable.
• Write to the oncologist with the grade and the timeline, since dose interruption is their decision and needs your numbers.
• Warn patients starting a HER2 antibody-drug conjugate that symptoms typically begin in the second month, not the first week.

The statistics, in plain English

Every number here is a before-and-after mean in eight patients with no control group, so the spread is narrow mainly because the sample is tiny and homogeneous. The series cannot tell you how often this happens, only what it looks like when it does; treat the standard deviations as descriptive, not as precision.

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