Introduction
Cystoid macular edema (CME) is a macular condition in which there is the accumulation of fluid in the outer plexiform layers of the neurosensory retina leading to the formation of cystic spaces. Macular edema results either due to the breakdown of normal anatomical barriers: the inner and outer retinal barriers causing fluid leakage or due to dysfunction of retinal pigment epithelium (RPE). There are many conditions that can cause macular edema which is classified based on the pathologic mechanism of retinal dysfunction such as vascular (diabetic retinopathy, retinal vascular occlusions, and choroidal vascular diseases), ocular inflammatory disorders, sequelae of intraocular surgeries, retinal artery macro aneurysms, vitreomacular interface abnormalities (e.g., vitreomacular traction syndrome, epiretinal membrane, and macular hole), hereditary retinal dystrophies, drug-induced, anatomical abnormalities, and intraocular neoplasms.[1]
Letrozole is a nonsteroidal oral aromatase inhibitor used as an adjuvant and as a palliative therapy in the treatment of hormone receptor-positive breast cancers in postmenopausal women, after surgical removal of the tumor[2,3] and also could be used in premenopausal women with ovarian suppression. It acts by preventing the conversion of peripheral androgens to estrogens thereby reducing the estrogen production in the body. In recent years, aromatase inhibitors are used to reduce the incidence of tamoxifen-related ocular side effects. In the literature, there are case reports of CME induced by the use of aromatase inhibitors[4] as well as a case report of CME caused by letrozole.[5]
We report a case of bilateral CME in a postmenopausal woman on letrozole for breast cancer.
Case Report
A 62-year-old female was referred from oncology with complaints of gradually progressive painless reduction of vision in both eyes over the past 6 months (October 2020). She was diagnosed with right-sided Stage III infiltrative ductal carcinoma of the breast in December 2015. Subsequently, the patient received eight cycles of chemotherapy with four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel in 2016. The last chemotherapy cycle was received in May 2016. Then the patient underwent a modified radical mastectomy on the right side in 2016 and started on letrozole 2.5 mg daily followed by radiotherapy. She was continued on letrozole 2.5 mg from July 2016 to January 2021 and the disease was in remission. She was not on any other medications.
Past ocular history was unremarkable with both eyes having 1.0 vision documented in 2017.
The best-corrected visual acuity (BCVA) at presentation was 0.4 in the right eye and 0.5 in the left eye. Anterior segment examination was unremarkable except for early nuclear cataract in both eyes. Dilated fundoscopic examination revealed bilateral CME [Figure 1a and b]. Optical coherence tomography (OCT) of macula showed intraretinal and subretinal fluid with central macular thickness of 620 μm in the right eye [Figure 1c] and 434 μm in the left eye [Figure 1d]. Fundus fluorescein angiography showed bilateral macular leakage with petaloid pattern and enlarged foveal avascular zone which was more evident in the right eye than in the left eye [Figure 2a-d]. No other lesions were seen and both optic discs were normal. Multifocal electroretinogram (ERG) showed severe reduction in the amplitude of P1 wave centrally in both eyes suggestive of severe central macular dysfunction which was more apparent in the right eye than in the left eye [Figure 3a and b]. Based on the assumption of letrozole-related maculopathy and after consultation with the treating oncologist, the patient was instructed to stop using letrozole and an ophthalmic review was performed 3 months later. Following discontinuation of letrozole, macular edema was reduced but unfortunately patient developed a relapse of breast cancer with metastatic deposits in the sternum and lymph nodes prompting treatment with another agent fulvestrant and ribociclib along with 3 monthly denosumab. She was offered an intravitreal injection of anti-vascular endothelial growth factor; however, she opted not to proceed with the same due to deterioration of systemic status.
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Figure 1: (a and b) Fundus photographs revealing bilateral cystoid macular edema. (c and d) Optical coherence tomography showing bilateral cystoid macular edema. OD: Right eye, OS: Left eye
Figure 2: (a-d) Fundus fluorescein angiography (early and late phase) showing bilateral macular leakage. OD: Right eye, OS: Left eye
Figure 3: White arrow indicates disruption in the outer segment of photo receptors in the macular region of right eye (a and b) Multifocal electroretinogram showing a severe reduction in central amplitude of P1 wave in both eyes OD>OS. (c and d) resolution of macular edema 3 months after discontinuation of letrozole. OD: Right eye, OS: Left eye
Ocular examination 3 months after discontinuation of letrozole therapy revealed BCVA of 0.4 in the right eye and 0.63 in the left eye. OCT macula showed residual macular edema in both eyes with a central macular thickness of 452 μm in the right eye [Figure 3c] and 276 μm in the left eye [Figure 3d].
Discussion
Estrogens are observed to aid in the growth of certain types of breast cancers. Reducing the levels of estrogen or inhibiting the effects of estrogen leads to reduction in the tumor size or a delay in the progression of tumor growth.[6]
Letrozole is third-generation Type II aromatase inhibitor used to treat estrogen-dependent breast cancers. Aromatase inhibitors are a class of medications that are commonly used as adjuvant therapy in hormone receptor-positive breast cancers in postmenopausal women. Letrozole inhibits the aromatase enzyme by competitively binding with the heme of cytochrome P450 subunit of the enzyme resulting in the reduction of estrogen biosynthesis in all tissues. The aromatase enzyme reduces estrogen production by inhibiting the steroidal hydroxylation. In 1998, letrozole was approved by the United States Food and Drug Administration for the treatment of advanced breast cancer in postmenopausal women with hormone receptor-positive or unknown breast cancer as a second-line treatment on the basis of two randomized trials.
The effects of estrogen are mediated through alpha and beta estrogen receptors.[7,8] Both receptor subtypes are functionally active in the RPE, the neurosensory retina, and the choroid. They provide neuroprotection to the retinal cells.[9] Consequently, the loss of the neuroprotective effect of estrogen in the retina may be responsible for the breakdown of the blood-retinal barrier and vascular leakage.
Tamoxifen is a selective estrogen receptor modulator used as an adjuvant treatment in patients with hormone receptor-positive breast cancers. Tamoxifen usage increases the risk of cataract formation[10] and is known to cause retinopathy characterized by crystalline deposits in the macula and pseudo cystic foveal cavitation.[11] Tamoxifen may cause a toxic maculopathy which may progress despite discontinuation of medication.[12]
The ocular side effects of aromatase inhibitors appear to be less frequent and less severe when compared to tamoxifen. Visual disturbances are known side effects of aromatase inhibitors, but its incidence has been found to be variable. In our case, multifocal ERG showed reduced retinal responses in both eyes which indicate retinal toxicity possibly due to letrozole. Medical literature revealed evidence of retinopathy and maculopathy being secondary to aromatase inhibitors such as anastrozole and letrozole. Rare side effects include crystalline retinopathy, papilledema, macular edema, hemiretinal artery occlusions, retinal hemorrhages, reduction in thickness of Nerve fiber layer (NFL) as measured by OCT, dry eyes, and ocular surface abnormalities.[13,14]
In the first reported case of letrozole-associated macular edema, visual improvement and resolution of macular edema were noticed after discontinuation of medication and receiving intravitreal injection of ranibizumab. Reduction in macular edema is not necessarily correlated with visual improvement as in our case due to many reasons such as macular ischemia, disruption of the ellipsoid zone in OCT macula, old age, and chronicity of the condition.[15] Since these agents are being used to treat cancers that are life-threatening, management is to revise the course of therapy with the oncologist and their role in this regard is very crucial. Timely ophthalmic evaluation and a high index of suspicion are advised in the assessment of a patient on aromatase inhibitors who may present with visual disturbances.
In summary, we shared a rare case of bilateral letrozole-related CME in a postmenopausal woman who has breast cancer. To determine whether ophthalmic screening is necessary for patients on letrozole therapy, there must be strong evidence or larger cohort studies to base the future screening protocols. However, a comprehensive ophthalmic evaluation is recommended for patients on aromatase inhibitors such as anastrozole and letrozole therapy who may present with visual disturbances.
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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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