New features in MEK retinopathy
The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors.
A 71-year-old man presented with ‘circular, green patches’ in his central vision for 2 weeks. He had multiple relapsed stage IV BRAF gene mutant malignant melanoma. He was on treatment with Dabrafenib (Tafinlar) for 7 months and Trametinib (Mekinist) for 4 months respectively. The fundus looked normal. The OCT scan showed bilateral symmetrical cystoid macular edema, intraretinal and subretinal fluid, thickening of elliposoid zone and subretinal granular deposits. The symptoms resolved with temporary cessation of chemotherapy but OCT signs persisted.
This case report identifies two new remarkable features of MEK retinopathy as thickening of ellipsoid zone and ‘starry sky’ pattern of distribution of subretinal granular deposits. These changes signify photoreceptors/ RPE toxicity and dysfunction. The subretinal granular deposits showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. The molecularly targeted therapy has revolutionized the cancer treatment and increased the survival rate. These agents are relatively new and recently approved for clinical use and most of them are associated with ocular toxicities. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.
KeywordsMEK retinopathy Molecular chemotherapy MEK inhibitors BRAF inhibitors Ocular toxicity
- MAPK/ERK, MEK
National Institute of Clinical Excellance: NICE mitogen-activated protein kinase/ extracellular regulated kinase
twice a day
once a day
optical coherence tomography
retinal pigment epithelium
fibroblast growth factor receptor
Common Terminology Criteria for Adverse Events
Anticancer therapy as chemotherapeutic agents, hormonal and molecular targeted treatments can produce ocular toxicity. The ocular adverse events (AE) can occur due to effect on cellular proliferation, disruption of ocular immune privilege or direct toxicity to ocular structures. Whereas conventional chemotherapy targets both normal and rapidly dividing cells, newer agents tend to exploit tumour-specific genetic alterations in signal transduction pathways.
Almost 50% of malignant melanomas have somatic mutation of BRAF gene . BRAF inhibitors act on enzyme B-Raf, which plays a role in the regulation of cell growth. Dabrafenib is a BRAF inhibitor that was approved by National Institute of Clinical Excellance (NICE) in United Kingdom (UK) for treating unresectable or metastatic BRAF V600 mutation-positive melanoma in 2014. Another molecular pathway commonly affected in malignant melanomas is mitogen-activated protein kinase/ extracellular regulated kinase (MAPK/ERK) also known as MEK pathway. Trametinib is a MEK inhibitor that inhibits MEK1 and MEK2 genes. Clinical trial data demonstrated that resistance to Dabrafinib and other BRAF inhibitors occurs within 6 to 7 months . This resistance can be overcome by the combination of BRAF inhibitor Dabrafenib with the MEK inhibitor Trametinib [2, 3, 4]. Trametinib in combination with Dabrafenib for treating unresectable or metastatic melanoma was approved by NICE in UK in 2016.
Whereas Dabrafenib disturbs ocular immune privilege and is commonly associated with uveitis, Trametinib and other MEK inhibitors usually develop retinal toxicity considered as ‘class effect’ [5, 6]. ‘MEK retinopathy’ is an umbrella term used to describe the dose- and time- dependent retinal side-effects observed with MEK inhibitor therapy [5, 6]. MEK inhibitor clinical trials have reported ocular toxicities in 5–38% of treated patients. . The wide range of incidence may be due to the lack of uniformity in the description, diagnosis and reporting of the same condition, differences in potency of MEK inhibition, schedule of administration and the frequency of ophthalmologic assessment across trials .
Discussion and conclusion
MEK retinopathy usually presents acutely within the first week of the first dose. The retinal features described in MEK retinopathy include central serous retinopathy, serous retinal detachment, cystoid macular edema, intra-retinal fluid and cysts and thin choroid. Most of these features are identified on optical coherence tomography scans [6, 7, 8, 9, 10]. The retinopathy is typically bilateral and symmetrical [5, 6, 7, 8, 9]. In cases where only one eye is affected, other diagnoses should be considered . Symptoms of MEK retinopathy can vary from being asymptomatic to blurred vision, altered color perception, shadows, light sensitivity, metamorphopsia and glare. Cases are often mild, short-lived, self-limiting, and do not interfere with activities of daily living [8, 11, 12, 13]. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment . The retinopathy partially recovers, but can still be detected many months later . Retinal thinning and retinal atrophy have been observed after long-term treatment  Cessation of life-extending treatment with MEK inhibitors is not indicated when SRF is present .
MEK pathway and its activation by the fibroblast growth factor receptor (FGFR) plays prominent role in the maintenance, survival and repair of RPE. Inhibition of this pathway leads to degeneration of RPE cells. The pathophysiology of MEK retinopathy is due to acute RPE toxicity which results in RPE hyperpermeability and breakdown of the retinal–blood barrier [15, 16, 17].
The treatment of MEK retinopathy is based on Common Terminology Criteria for Adverse Events (CTCAE) criteria, widely used for AE reporting in oncology studies, include a 4-category grading scheme for retinopathy according to symptom severity . Asymptomatic patients and mild retinopathy with vision better than 6/12 do not require interruption of dosing as mild symptoms and OCT abnormalities frequently resolve within days after continued dosing. This suggests that many patients with MEK retinopathy develop tachyphylaxis to continued MEK inhibitor therapy. For significant visual symptoms or vision below 6/12, patients should be instructed to interrupt dosing with MEK inhibitor therapy. When symptoms resolve, patients may be rechallenged at the same dose of MEK inhibitor therapy with close monitoring following re-initiation of treatment. For toxicities with severe visual impairment or interruption of daily activities, MEK inhibitor treatment should be discontinued and when symptoms and OCT findings resolve, patients may be rechallenged at a lower dose [5, 18].
Our case showed bilateral, symmetrical changes within the retina in the form of cystoid edema, intra-retinal fluid and sub-retinal fluid signifying abnormal RPE permeability. Two new features were identified as thickening of ellipsoid zone and characteristically distributed subretinal granular deposits. The thickening of the ellipsoid zone could be due to swelling of the photoreceptors secondary to RPE toxicity and dysfunction affecting the photoreceptor nutrition. The subretinal granular deposits overlying a normal appearing RPE showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. Although the intra-retinal and sub-retinal fluid reduced, the ellipsoid layer changes and the granular changes persisted signifying ongoing RPE dysfunction despite reduced dosage even though the patient became asymptomatic. We were unable to perform fundus fluorescein angiography and electrodiagnostic tests which could have potentially shed more light on the structural and functional changes in retina.
In this case report we identified two new features of MEK retinopathy not previously described in literature. Introduction of molecularly targeted therapy have revolutionized the cancer treatment and increased the survival rate. Most of these agents are associated with ocular toxicities. These agents are relatively new and recently approved by NICE for clinical use in cancer treatment. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.
We would like to acknowledge medical photographers, Mr. Victor Beattie, Mr. Tony Johnston and Mr. Martin Mcleod for taking clinical images, OCT and AF scans.
This supplement and the meeting on which it was based were sponsored by Novartis (tracking number OPT17-C041). Novartis did not contribute to the content and all authors retained final control of the content and editorial decisions. Novartis have checked that the content was compliant with the Association of the British Pharmaceutical Industry Code of Practice.
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About this supplement
This article has been published as part of BMC Ophthalmology Volume 18 Supplement 1, 2018: The Novartis Ophthalmology Case Awards 2017. The full contents of the supplement are available online at https://bmcophthalmol.biomedcentral.com/articles/supplements/volume-18-supplement-1.
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