Abnormal Corneal Lesions Induced by Trastuzumab Emtansine: an Antibody–Drug Conjugate for Breast Cancer

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CASE REPORT

Abnormal Corneal Lesions Induced by Trastuzumab Emtansine: An Antibody–Drug Conjugate for Breast Cancer

Mayuko Tsuda, MD,* Yoji Takano, MD,*† Chika Shigeyasu, MD,* Shigeru Imoto, MD, PhD,‡ and Masakazu Yamada, MD, PhD*

been introduced.1 Trastuzumab emtansine (Kadcyla; Chugai Purpose: To report a case of atypical corneal lesions presumably Pharmaceutical Co., Ltd, Tokyo, Japan) is a new ADC induced by trastuzumab emtansine, an antibody–drug conjugate that is developed for the treatment of human epidermal growth designed to selectively deliver cytotoxic agents to human epidermal factor receptor 2 (HER2)–positive breast cancer.2 Trastuzu- growth factor receptor 2 (HER2)–positive breast cancer cells. mab emtansine received approval in 2013 in the United Case: A 64-year-old Japanese woman developed bilateral corneal States and the European Union and in 2014 in Japan. Breast epithelial abnormalities that originated from the limbus. The corneal cancers with overexpression of HER2 are associated with lesions covered the superior area in the right eye and both superior and a higher risk of recurrence with a shorter time to relapse, lower survival rates, and greater therapeutic resistance inferior areas including the visual axis in the left eye. The patient had 3,4 advanced ductal carcinoma of the left breast and had been receiving compared with HER2-normal disease. Trastuzumab, anticancer treatment with trastuzumab emtansine for 15 months. After a HER2-binding monoclonal antibody, alone stops growth switching the chemotherapy from trastuzumab emtansine monother- of cancer cells by binding to the HER2, whereas emtansine, a derivative of maytansine, enters the cells and destroys apy to the combination of docetaxel, trastuzumab, and pertuzumab, the 2 abnormal corneal lesions showed gradual improvement. them by inhibiting microtubule polymerization. Trastuzu- mab emtansine was developed to overcome systemic Conclusions: As corneal epithelial cells express human epidermal toxicity associated with maytansine and to enhance tumor- growth factor receptor 2 under normal conditions, such cells may also be specificdelivery.4 targeted by trastuzumab emtansine and lead to corneal epithelial lesions. Although ADC is designed to enhance tissue specific- Key Words: ity, the presence of similar targets in healthy tissues may adverse effect, breast cancer, cornea, epidermal growth result in a variety of drug-related toxicities, including ocular factor, human epidermal growth factor receptor 2 toxicities.1 HER2 is a member of the human epidermal (Cornea 2016;35:1378–1380) growth factor receptor (EGFR) family and has been detected in corneal and conjunctival epithelium.5 Reported ocular adverse effects of trastuzumab emtansine were dry eye, ecently, a new therapeutic class of anticancer drugs called increased lacrimation, blurring of vision, and conjunctivitis.4 Rantibody–drug conjugates (ADCs), comprising a tumor However, they were recognized to be grade 1 and 2, and no antigen-specific antibody linked to a cytotoxic drug, has severe corneal complications with visual impairment have been reported. We here report a case of atypical corneal lesions presumably induced by trastuzumab emtansine. Received for publication February 29, 2016; revision received March 11, 2016; accepted March 11, 2016. Published online ahead of print May 5, 2016. CASE PRESENTATION From the *Department of Ophthalmology, Kyorin University School of Medicine, Mitaka, Japan; †Department of Ophthalmology, Kawasaki A 64-year-old Japanese woman was referred to our Municipal Ida Hospital, Kawasaki, Japan; and ‡Department of Breast ophthalmological department for persistent corneal abnormal- Surgery, Kyorin University School of Medicine, Mitaka, Japan. ities in both eyes for 4 months in May 2015. At the initial visit, The authors have no funding or conflicts of interest to disclose. M. Tsuda wrote and edited the manuscript as a major contributor. M. Yamada her best-corrected visual acuity was 20/20 in the right eye and conceptualized the case report and was involved in caring for the patient. 20/50 in the left eye. Slit-lamp examination with fluorescein C. Shigeyasu, Y. Takano, and S. Imoto were involved in the treatment of vital staining revealed the invasion of irregular slightly hazy the patient and revision of the paper for intellectual content. All authors corneal epithelium from the limbus (Fig. 1). The corneal lesions fi read and approved the nal manuscript. covered the superior area in the right eye, and both superior and All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national inferior areas including the visual axis in the left eye. The research committee. lesions were slightly thickened and exhibited conjunctiva-like Written informed consent was obtained from the patient for publication of this fluorescein permeability. No conjunctival congestion or staining case report and all accompanying images. of conjunctival epithelium was observed. A Schirmer test was Reprints: Masakazu Yamada, MD, PhD, Department of Ophthalmology, fi Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 12 and 16 mm, and tear lm break-up time was 4 and 5 seconds 181-8611, Japan (e-mail: [email protected]). in the right and left eyes, respectively. Other ophthalmic Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. examinations were unremarkable.

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Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 35, Number 10, October 2016 Antibody–Drug Conjugate for Breast Cancer

The patient had not suffered from any ocular DISCUSSION injury or inflammatory eye disease. She had not used Since Savage and Cohen first demonstrated the contact lens or any ophthalmic solutions before she stimulatory effect of epidermal growth factor (EGF) on consulted the local ophthalmologist. She was prescribed corneal epithelial proliferation,6 theroleofEGFandits 0.3% hyaluronic acid solution and 0.1% fluorometholone receptors on corneal epithelial integrity have been exten- suspension to be administered 4 times daily. The patient sively investigated. Four EGF receptors, namely EGFR/ had been diagnosed with advanced ductal carcinoma of erbB1/HER1, erbB2/HER2/neu, erbB3/HER3, and erbB4/ the left breast (T4N4M1) 4 years previously and had HER4, have been identified.Ofthese,EGFRismainly received anticancer treatment consisting of docetaxel expressed by the basal cells of corneal epithelium that have (Taxotere; Sanofi K.K., Tokyo, Japan) and trastuzumab the greatest proliferative potential. In contrast, ErbB2 is (Herceptin; Chugai Pharmaceutical Co., Ltd). This was preferentially expressed by the superficial ocular surface then followed by additional treatments with trastuzumab epithelia.5 Peterson et al7 reported that under normal emtansine every 3 weeks as monotherapy for 15 months. conditions, EGF was the only endogenous growth factor Otherwise, her history and systemic condition present at concentrations near the ligand’s Kd for the were unremarkable. receptor, indicating that EGF is the primary mediator of Judging from her history and objective findings, we corneal epithelial homeostasis. suspected that trastuzumab emtansine might be the cause Considering the role of EGF and its ligands on the of the corneal lesions. After discussions with the oncol- ocular surface, it is understandable that cancer treatments ogist (S.I.) concerning this possibility, the chemotherapy targeting EGFR such as cetuximab (an EGFR monoclonal was switched from trastuzumab emtansine monotherapy antibody) and gefitinib (an EGFR kinase inhibitor) may result to the combination of docetaxel, trastuzumab, and in corneal complications including diffuse punctate keratitis pertuzumab (Perjeta; Chugai Pharmaceutical Co., Ltd) and corneal erosion.8,9 Concerning HER2, a case of bilateral in June 2015. Topical medication consisting of corneal ulceration induced by trastuzumab (a HER2 mono- 0.3% hyaluronic acid and 0.1% fluorometholone was clonal antibody) was recently reported.10 In this report, we continued unchanged. describe a case of atypical corneal lesions associated with Six weeks after the discontinuation of trastuzumab trastuzumab emtansine. Although trastuzumab emtansine was emtansine, regression of corneal epithelial abnormalities designed to selectively deliver cytotoxic agents to HER2- was observed. Her best-corrected visual acuity in the positive tumor cells, corneal epithelial cells, which express lefteyeimprovedto20/20,asthelesionregressed HER2 under normal conditions, can also be a target for beyond the visual axis. Although the abnormal corneal the drug. lesions continued to show gradual improvement, In our case, invasions of abnormal epithelium from the complete resolution has not been attained to date limbus were seen in both eyes. Differential diagnosis of this (February 2016). condition includes keratitis medicamentosa, partial limbal

FIGURE 1. Photographs of slit-lamp biomicroscope with ﬂuorescein staining and blue ﬁlter. At the initial presentation, abnormal corneal lesions covered the superior area in the right eye (A); both superior and inferior areas involving the visual axis in the light eye (B). Regression of corneal epithelial abnormalities was observed both in the right eye (C) and in the left eye (D), 3 months after the discontinuation of trastuzumab emtansine.

Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Tsuda et al Cornea Volume 35, Number 10, October 2016 stem cell deficiency, and ocular cicatricial pemphigoid. REFERENCES However, because of the lack of any history of ocular injury, 1. Eaton JS, Miller PE, Mannis MJ, et al. Ocular adverse events associated chronic inflammatory eye disease, or prolonged usage of with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31:589–604. ophthalmic solution, we speculate that trastuzumab emtansine 2. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique might be the cause of the corneal lesions. Improvement of antibody-drug conjugate in development for human epidermal growth corneal changes was observed after discontinuation of factor receptor 2-positive cancer. Clin Cancer Res. 2011;17:6437–6447. trastuzumab emtansine, although complete remission was 3. Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with not attained. The switch to combined chemotherapy including trastuzumab in HER2-positive breast cancer: results from the Gepar- Quattro study. J Clin Oncol. 2010;28:2024–2031. trastuzumab may be responsible for the partial resolution of 4. Burris HA III, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody corneal lesions. drug conjugate trastuzumab-DM1 for the treatment of human epidermal It should be noted that trastuzumab emtansine is growth factor receptor 2 (HER2)-positive breast cancer after prior HER2- more likely to exhibit ocular adverse effects compared directed therapy. J Clin Oncol. 2011;29:398–405. than trastuzumab alone. Conjunctivitis was reported as an 5. Liu Z, Carvajal M, Carraway CA, et al. Expression of the receptor tyrosine kinases, epidermal growth factor receptor, ErbB2, and ErbB3, in adverse effect in 2.5% of patients in a clinical trial for human ocular surface epithelia. Cornea. 2001;20:81–85. 3 trastuzumab, whereas ocular adverse effects, including 6. Savage CR Jr, Cohen S. Proliferation of corneal epithelium induced by dry eye, increased lacrimation, blurring of vision, and epidermal growth factor. Exp Eye Res. 1973;15:361–366. conjunctivitis, were reported in 31.3% of patients in 7. Peterson JL, Phelps ED, Doll MA, et al. The role of endogenous a study for trastuzumab emtansine.6 Trastuzumab emtan- epidermal growth factor receptor ligands in mediating corneal epithelial homeostasis. Invest Ophthalmol Vis Sci. 2014;55:2870–2880. sine is designed to exhibit its anticancer effects not only 8. Foerster CG, Cursiefen C, Kruse FE. Persisting corneal erosion under by blocking the HER2-signaling pathway, but by selec- cetuximab (Erbitux) treatment (epidermal growth factor receptor anti- tively delivering cytotoxic agents. The mechanism of body). Cornea. 2008;27:612–614. action may lead to severe adverseeffectsontheocular 9. Shah NT, Kris MG, Pao W, et al. Practical management of patients with non- small-cell lung cancer treated with gefitinib. J Clin Oncol. 2005;23:165–174. surface. Both ophthalmologists and oncologists should be 10. Orlandi A, Fasciani R, Cassano A, et al. Trastuzumab-induced corneal aware of corneal complications possibly induced by ulceration: successful no-drug treatment of a “blind” side effect in a case trastuzumab emtansine. report. BMC Cancer. 2015;15:973.