Authors’ Response: The disastrous triple hit–taxane-induced retinal toxicity in a patient with breast cancer and a pathogenic USH2A variant

Paclitaxel (Taxol) is an anti-tumor drug with high efficacy and otherwise low toxicity and is the first natural phytochemical drug approved and used effectively to treat breast cancer, ovarian cancer, lung cancer, sarcoma, lymphoma, and other diseases.[1] Nonetheless, with increasing use of these agents, there have been increasing reports of adverse reactions encountered,[2] including ocular side effects like vision loss, dry eye, lacrimal duct obstruction, conjunctivitis, glaucoma, optic neuropathy, epiphora, macular edema, and blindness caused especially on combinations of these agents with cisplatin.[3] The mechanism of ocular side effects induced by taxanes is mediated by their effects of taxanes on cell proliferation and apoptosis, microtubules, oxidative and mitochondrial stress, cell degeneration, stem cell regeneration, ischemia, cellular junctions, and tissue fibrosis.[2] The ocular side effects of taxanes and their mechanisms are as below:[2] Diseases in ocular surface: Taxane promotes interstitial fibrosis of lacrimal duct mucosa and leads to lacrimal duct obstruction. It further inhibits cell proliferation in the cornea and eye surface, causing the dysfunction of stem cells, predisposing to dry eye, conjunctivitis, and keratopathy. Diseases in the lid margins: Taxane induces inflammation and blockage of the meibomian duct. Diseases in retina: Taxane results in the dysfunction of Müller cells and the accumulation of intracellular fluid as well as damage of RPE barrier function leading to macular edema. Diseases in lenticular tissue: Taxane induces the apoptosis of lens epithelial cells and the formation of lens fibers, predisposing to cataract. Diseases of the optic nerve: Taxane may result in transient vascular spasm, resulting in neurological defects. The reassuring part of these adverse effects, especially those on the ocular surface, is that these are reversible after withdrawal of the agent and require only symptomatic treatment with good recovery within a few days and up to 5 months after cessation of the agent.[4] Looking at USH2A mutations; they are the leading cause of autosomal recessive non-syndromic retinitis pigmentosa (nsRP), accounting for 12–25% of the reported cases.[5] The mutation spectrum is extremely heterogenous and includes more than 1500 mutations of which 690 variants could be pathogenic, which span the whole USH2A gene, consisting of nonsense, missense, deletions, duplications, splicing variants, and pseudo-exon inclusion variants. Most mutations are private, but several are more prevalent such as the recurrent c.2299delG, pGlu767Serfs*21 (rs80338903) variant. This is the most frequent pathogenic mutation; being responsible for approximatively 24.5% pathogenic variants of USH2A. The c.2299delG mutation especially has been reported in patients from Northern and Southern Europe, North America, South America, North and South Africa, and China.[2,6] In the case report by Mohan et. al.,[7] the authors describe a 76-year-old lady with a pathogenic heterozygous mutation in USH2A c.2299delG, p.(Glu767Serfs*21), who developed bilateral cystoid macular edema (CME), retinal pigmentary changes, and worsening visual acuity secondary to nab-paclitaxel chemotherapy. The authors speculate that her proven carrier state of a pathogenic USH2A gene mutation may have predisposed the phenotype of taxane-induced retinal toxicity, which included a pigmentary retinopathy and CME resembling retinitis pigmentosa. As expected in such disorders and also as described previously, her symptoms were reversible, and she reported improvement in her quality of life with improved vision on discontinuation of the offending anti-cancer agent, but on doing so, she unfortunately succumbed to her breast cancer. Although significant progress has been made in the understanding of USH2A-related disorders, we still do not have any approved treatments for the retinal symptoms of USH2A-related disease. Current treatment modalities for USH2A-related disorders include as follows:[8] USH2A-targeted therapy, which manipulate levels of USH2A USH2A-independent therapy, which aims to prevent retinal degeneration through targeting common disease pathways such as cell death or oxidative stress. Thus, coming back to taxane chemotherapy, till effective treatments of adverse effects are not available, the role of baseline eye examinations and regular follow-up examinations for patients on treatment with taxane chemotherapy cannot be overemphasized.[2] To conclude, this case report is unique as it describes in a single patient, a heterozygous mutation in USH2A, and an unfortunate retinal adverse effect with nab-paclitaxel (taxane) chemotherapy used to alleviate a breast cancer; the authors correctly hypothesize possible taxane-induced retinal toxicity in the pathogenic USH2A variant carrier