Trastuzumab-Induced Early Corneal Melt in HER2-Positive Breast Cancer: A Case Report and Review

Introduction

Trastuzumab (Herceptin) is a chemotherapeutic monoclonal antibody used in the treatment of metastatic HER2+ breast cancer. Human epidermal growth factor receptor 2 (HER2) is a membrane tyrosine kinase and an oncogene overexpressed in around 20% of breast cancers. Upon ligand binding, HER2 receptors undergo dimerization resulting in a downstream signaling cascade causing proliferation of cells, as well as influx of anti-apoptosis signals [1]. HER2 has thus become a target for several treatments for HER2+ breast cancers. Trastuzumab inhibits the downstream signaling cascade by binding to the HER2 receptors, preventing dimerization and subsequently impairing the proliferation and anti-apoptosis mechanisms. Common side effects of trastuzumab include flu-like symptoms, such as fever, chills, myalgias, headaches and diarrhea. More serious, but rarer systemic side effects include congestive heart failure and renal failure [2,3]. In addition to the systemic side effects mentioned above, ocular complications may also occur. It has been mostly associated with conjunctivitis, keratitis and dry eye syndrome as it affects the conjunctival and corneal epithelial cells turnover with development of subsequent inflammation [4–6]. Epidermal growth factor receptors are found in various tissues beyond the tumor cells, such as corneal and limbal tissues [7]. Known ocular complications include the development of corneal marginal infiltrates as well as subtle midperipheral microspherules, documented in 2 case reports from 2015 and 2018, respectively [8,9]. The typical dosing regimen for trastuzumab monotherapy, or in combination with paclitaxel, for HER2+ metastatic breast cancer is an initial one-time loading dose of 4 mg/kg during the first week of treatment, followed by a dose of 2 mg/kg weekly until disease progression [10]. However, alternative dosing regimens have also been used for treatment. Herein, we describe a unique case of rapidly progressive bilateral corneal ulceration in a patient receiving treatment with trastuzumab for metastatic HER2+ breast cancer after 2 doses of chemotherapy.

Case Report

A 59-year-old woman presented for ophthalmic evaluation following approximately 2 weeks of crusting and gritty sensation in both eyes (OU), along with a more recent decline in vision, worse in the left eye (OS). The patient’s medical history was significant for infiltrating ductal carcinoma of the breast (ER 80%, PR 50%, and HER2+) with metastasis to the axillary lymph nodes, lungs, spine, left adrenal gland, calvarium, orbit, and skull base with epidural and dural extension. The patient required spinal fusion surgery and repair of multiple pathological vertebral fractures, after which the patient was started on Letrozole (Femara, Novartis) and intravenous (IV) trastuzumab (Herceptin; Genentech) for her breast cancer. The patient received a loading dose of 416 mg (weight-adjusted dosing at 8 mg/kg) with a plan set in place to continue IV trastuzumab every 3 weeks.

Due to her crusting and injection OS, she had been started on TobraDex ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.1%; Alcon Laboratories Inc, Fort Worth, TX) due to concern for bacterial conjunctivitis by the primary medical team. On MRI, the patient was found to have a right-sided orbital metastasis involving the right sphenoid bone, infiltration of the anterior and posterior clinoid processes, and compression of the right optic nerve at the orbital apex (Figure 1). Due to a significant decrease in vision OS and the cornea becoming “hazy”, she was transferred for formal ophthalmic evaluation. The patient admitted to a history of oral HSV lesions, but no ocular history.

On examination, the patient’s visual acuity (VA) was 20/400 in the right eye (OD) and hand motion (HM) OS. She had a relative afferent pupillary defect (RAPD) OD, with decreased color vision on Ishihara color plates OD (OS was unable to be assessed due to her poor VA). On portable slit lamp exam, the left cornea revealed a flat anterior chamber and a 5-mm corneal ulcer, perforated centrally with iris tissue plugging the perforation (Figure 2). OD demonstrated several epithelial defects without perforation (Figure 3A, 3B).

Corneal cultures were obtained, and she was started on a regimen of fortified vancomycin and tobramycin in the left eye, as well as oral vitamin C and doxycycline. The patient denied any rheumatological symptoms, and autoimmune and inflammatory panels were all negative. Corneal cultures ultimately grew no organisms. Due to the perforation, she underwent an emergency penetrating keratoplasty (PK) with temporary tarsorrhaphy in the left eye (Figure 4).

During her follow-up visits, the patient had neurotrophic keratopathy in both eyes, with decreased sensation. She continued using antibiotic eyedrops, lubricating ointments, and autologous serum eye drops in both eyes, while following steroid regimen in the left eye following the PK. Oncology was consulted given her recent chemotherapy and plan for upcoming treatment. Given the negative rheumatologic workup and negative corneal cultures, there was high suspicion that trastuzumab may have been the inciting agent, and the medication was halted in conjunction with the hematology/oncology team.

On subsequent visits it was found that the ocular surface in the graft failed to re-epithelize, and the patient eventually needed repeat PK after 3 months, which cleared and epithelialized in a year (Figure 5). Trastuzumab was not reinitiated, and no further melts were noted.

Discussion

Our understanding of corneal ulceration in those receiving trastuzumab therapy involves its interaction with epidermal growth factor receptors in other tissues. It is known that epidermal growth factor receptors are expressed in corneal, limbal and conjunctival epithelium [5–7]. Consequently, the expression of these receptors in the cornea inadvertently creates a target on which trastuzumab can act upon and may cause epithelial defects and possible corneal ulceration [8,9,11,12]. This is thought to occur due to the inhibition of epidermal growth factor receptor in the cornea, which is responsible for stimulating the proliferation of epithelial cells and stratification during corneal wound healing. Agresta et al suggested that because some patients receiving trastuzumab may not be following with an ophthalmologist prior to initiation of treatment, visual symptoms may be underestimated and attributed to other causes and such findings can be missed [13]. Therefore, their recommendation suggests all patients receiving treatment with trastuzumab who have eye complaints should undergo full ophthalmological evaluation. Obtaining a baseline slit lamp examination to evaluate ocular and corneal health prior to treatment with trastuzumab may also be of benefit for these patients to address any changes in vision that may occur during treatment. Corneal melts develop rarely, but may present with symptoms such as dry eye, vision changes, or foreign body sensation. However, according to FDA data only 11% of patients receiving trastuzumab reported dry eye syndrome only for which no changes in treatments were introduced [12].

There have been several cases reported of corneal epithelial damage during trastuzumab use. Peeters et al describe a case in which a patient developed symptoms of foreign body sensation and visual acuity deficits, later found to be due to corneal melting, after only 3 cycles of trastuzumab treatment [11]. Treatment was discontinued and shortly after the patient was treated with topical antibiotics, antivirals, lubricants and steroids, the follow-up bio-microscopy showed improvement in the corneal changes. Trastuzumab was resumed in this patient, after which a new region of corneal melting was noted with corneal epitheliopathy and thinning. Thus, trastuzumab was discontinued again, resulting in improvement of visual deficits. The same observation was noted a third time with resumption and subsequent discontinuing of trastuzumab. This report also notes the interesting correlation between trastuzumab use and development of corneal pathology. Interestingly, our patient only received an initial loading dose of 416 mg (weight-adjusted dosing of 8mg/kg) prior to developing ocular symptoms. It is unclear why the patient’s symptoms began early in her treatment course, after just a single dose, but it is possible that a high loading dose of 8 mg/kg, which is the maximum, may have been excessively toxic to the corneal tissue. Moreover, her imaging results show multiple metastatic lesions all over the body, including at the orbit apex. Thus, it is possible that these lesions affected the function of the branches of the trigeminal nerve, leading to an already compromised ocular surface even prior to trastuzumab therapy. Development of such aggressive corneal complications after minimal dosing of trastuzumab therapy along with these orbital imaging results has not been reported before. With more cases emerging, it is crucial to encourage patients, both in the in-patient and outpatient settings, to inform their physicians of any new ocular symptoms.

In certain severe cases of corneal ulceration, as discussed in our report, more specific treatments such as corneal bandaging and surgical intervention are required. However, this also provides an interesting opportunity to investigate other treatment modalities depending on the severity. Orlandi et al described a case in which a patient suffering from trastuzumab-induced corneal ulceration received autologous serum, blood-derived products obtained from the patient’s own blood, in the form of eye drops to treat these ulcerations [8]. Autologous serum was applied in the conjunctival sac, which led to rapid healing of the ulcerative keratitis in a few days and eventually complete resolution of the corneal ulcerations after a week of treatment. Though the exact mechanism is not completely clear, it is believed that ligands that can act on the HER2 receptor, can be derived from these samples of autologous serum. These ligands can then induce a local response, acting specifically on the epidermal growth factor receptors on the cornea and limbal tissue and promote normal signaling. This would result in proliferation of epithelial cells and stratification of corneal and limbal tissue. Though this does not necessarily suggest a new option for treatment, it may deserve more investigation as a possible adjuvant treatment in conjunction with traditional forms of treatment. Trastuzumab remains a cornerstone drug in the treatment of HER2+ cancers. As clinicians, it is crucial to both be aware of the side effects of this drug and notice when patients develop such side effects.

Conclusions

Development of ocular surface complications can occur at any cycle of trastuzumab treatment. Therefore, it is imperative to educate caregivers and develop preventive measures such as regular ophthalmic evaluations. In conclusion, we recommend close follow-up for patients who develop even mild ocular symptoms while on trastuzumab therapy.