Taxane-induced retinal toxicity in a pathogenic USH2A variant carrier

Dear Editor, We would like to report the case of a 76-year-old female with a 10-year history of infiltrating lobular breast cancer with peritoneal metastases who developed bilateral cystoid macular edema (CME), pigmentary retinopathy, and worsening visual acuity secondary to nab-paclitaxel chemotherapy. She was treated with various chemotherapeutics, including tamoxifen and palliative nab-paclitaxel infusions, for the previous 2 years and presented to the retina clinic after a year of blurry vision in both eyes. We speculate that a pathogenic USH2A gene mutation may have predisposed her to taxane-induced retinal toxicity. On presentation, best-corrected visual acuity (BCVA) was 20/100 in both eyes. Slit-lamp exam revealed 2+ nuclear sclerosis in both eyes. Dilated fundus exam revealed mild retinal vascular attenuation and CME in both eyes, with pigmentary changes and a mild spiculated appearance in both nasal peripheries [Fig. 1a and b]. Optical coherence tomography confirmed CME with significant intra- and subretinal fluid in both eyes [Fig. 2a].Figure 1: (a) Fundus photographs and (b) autofluorescence of the right eye (left panel) and left eye (right panel) (Optos®, Optos UK) showing pigmentary changes in the nasal periphery of both eyes with a mild spiculated appearance, suggesting pigmentary retinopathy. (c) Fluorescein angiographs of both eyes show peripheral staining most prominent in the nasal quadrants, and the left eye (right panel) demonstrates non-leaking cystoid macular edema with late staining in zone 1Figure 2: (a) Optical coherence tomography (OCT) of the right eye (left image) and right eye (left image) (Heidelberg Spectralis, Heidelberg Engineering, Germany) showing cystoid macular edema (CME) with significant intra-and subretinal fluid at presentation. (b) OCT on 6-week follow-up (3 weeks after last paclitaxel infusion) showing improvement in CME. (c) OCT on 12-week follow-up (9 weeks after last paclitaxel infusion) showing resolution of CMEAfter a 4-week trial of topical prednisolone acetate 1% and ketorolac eye drops four times daily failed to improve CME and BCVA remained stable, these medications were tapered, and topical dorzolamide 2% eye drops were prescribed three times daily for both eyes. Fluorescein angiography demonstrated non-leaking CME with late staining in both eyes [Fig. 1c]. Following extensive discussion and counseling with her oncologist, she elected to discontinue nab-paclitaxel and was switched to trastuzumab deruxtecan, receiving one infusion along with denosumab 12 weeks after her last nab-paclitaxel infusion. CME resolved 9 weeks after her last nab-paclitaxel infusion, and BCVA improved to 20/80 in both eyes [Fig. 2b and c]. Genetic testing revealed a pathogenic heterozygous mutation in USH2A c.2299delG, p.(Glu767Serfs*21), associated with Usher syndrome, an autosomal recessive condition causing combined sensorineural deafness and RP.[1] Taxane-induced retinopathy can lead to visual deterioration with CME, but in rare cases, pigmentary changes suggestive of RP have been observed, as described by Tang et al.[2] and Enzsoly et al.,[3] with the use of docetaxel. The phenotypic overlap of rare RP-like retinopathy with recent chemotherapy merits investigation into a possible genetic predisposition for taxane-induced retinopathy. To our knowledge, no studies have reported an association between a USH2A mutation and a predisposition to taxane-induced retinal toxicity. However, heterogeneity in phenotypic manifestations for carriers of syndromic diseases coupled with the onset of this rare chemotherapeutic side effect make it difficult to rule out a gene-related predisposition. Discontinuing the offending chemotherapy can be considered to treat taxane-induced retinopathy if alternatives fail. Much like a case described by Yokoe et al.,[4] taxane cessation resolved CME and improved BCVA in both eyes in our patient, and improved energy levels. Unfortunately, the patient’s overall prognosis was poor, and she died in hospice care 12 weeks after her last visit. The decision to alter life-prolonging treatment should be carefully discussed with patients. Our case highlights a possible association between the USH2A carrier state and taxane-induced retinal toxicity. Further research is needed to determine whether patients with pre-existing mutations are truly at an increased risk for chemotherapy-induced retinal toxicity. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. No identifiable information was used. Ethics A retrospective chart review of a clinical case was conducted, in compliance with the tenets of the Declaration of Helsinki. Financial support and sponsorship: This research was supported by NIH Center Core Grant P30 EY030413 and a Challenge Grant from Research to Prevent Blindness to the University of Texas Southwestern Medical Center. Conflicts of interest: There are no conflicts of interest.