Prevalence and Risk Factors of Tamoxifen Retinopathy

Abstract

Tamoxifen is a selective estrogen receptor modulator that is mainly used as an adjuvant treatment for patients with hormone receptor–positive breast cancer. Tamoxifen retinopathy is characterized by crystalline deposits1Vinding T. Nielsen N.V. Retinopathy caused by treatment with tamoxifen in low dosage.Acta Ophthalmol (Copenh). 1983; 61: 45-50Crossref PubMed Scopus (78) Google Scholar and pseudocystic foveal cavitations.2Doshi R.R. Fortun J.A. Kim B.T. et al.Pseudocystic foveal cavitation in tamoxifen retinopathy.Am J Ophthalmol. 2014; 157 (1291-1298.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The prevalence of tamoxifen retinopathy has been reported to be variable, ranging from 1.5%3Heier J.S. Dragoo R.A. Enzenauer R.W. et al.Screening for ocular toxicity in asymptomatic patients treated with tamoxifen.Am J Ophthalmol. 1994; 117: 772-775Abstract Full Text PDF PubMed Scopus (66) Google Scholar to 11.8%.1Vinding T. Nielsen N.V. Retinopathy caused by treatment with tamoxifen in low dosage.Acta Ophthalmol (Copenh). 1983; 61: 45-50Crossref PubMed Scopus (78) Google Scholar Because most previous studies were based only on the fundus examinations without OCT, it is assumed that the prevalence was underestimated.2Doshi R.R. Fortun J.A. Kim B.T. et al.Pseudocystic foveal cavitation in tamoxifen retinopathy.Am J Ophthalmol. 2014; 157 (1291-1298.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In this study, we aimed to estimate the prevalence of tamoxifen retinopathy using both fundus photography and OCT, as well as to uncover the associated risk factors. This study was approved by the Asan Medical Center Institutional Review Board (2017-1426) and conducted in adherence to the tenets of the Declaration of Helsinki. All participants provided informed consent. From a hospital database, we retrieved the list of female patients with breast cancer who had a history of tamoxifen prescription and had visited the ophthalmology clinic between January 2007 and November 2017. The diagnosis of tamoxifen retinopathy was based on characteristic findings, including pseudocystic foveal cavitation or photoreceptor layer disruption on OCT scans2Doshi R.R. Fortun J.A. Kim B.T. et al.Pseudocystic foveal cavitation in tamoxifen retinopathy.Am J Ophthalmol. 2014; 157 (1291-1298.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar or refractile crystalline depositions on both fundus photographs and OCT scans. Spectralis (Heidelberg Engineering, Heidelberg, Germany) spectral-domain OCT, OCT angiography (Optovue, Fremont, CA), and Cirrus OCT (Carl Zeiss Meditec, Dublin, CA) were used according to the availability. Exclusion criteria were (1) presence of structural deformation in the macula due to other pathologies; (2) history of vitreoretinal surgery; and (3) history of taking drugs that may cause toxic maculopathies. Information on tamoxifen use included age at initial tamoxifen use, duration of tamoxifen intake, and cumulative dose of tamoxifen intake. Clinical information included breast cancer stage, history of chemotherapy, menopausal status, and presence of systemic diseases, such as diabetes mellitus, hypertension, and hyperlipidemia. Body mass index (BMI) was calculated. Statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp, Armonk, New York, NY). A total of 1209 patients were identified initially, and among them 331 patients were found to have both fundus photography and spectral-domain OCT examinations after tamoxifen intake. A total of 25 patients were excluded on the basis of exclusion criteria. Because previous studies have shown that tamoxifen retinopathy occurs after 2 to 3 years of intake,2Doshi R.R. Fortun J.A. Kim B.T. et al.Pseudocystic foveal cavitation in tamoxifen retinopathy.Am J Ophthalmol. 2014; 157 (1291-1298.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,4Tang R. Shields J. Schiffman J. et al.Retinal changes associated with tamoxifen treatment for breast cancer.Eye (Lond). 1997; 11: 295-297Crossref PubMed Scopus (59) Google Scholar we excluded 55 patients who took tamoxifen for less than 2 years. A total of 251 patients were ultimately selected for analysis. According to the diagnostic criteria, 30 patients (12.0%) were diagnosed with tamoxifen retinopathy. Among them, 12 had only foveal cavitations, 4 had only refractile crystalline deposits, and 14 had both. A total of 19 patients had bilateral tamoxifen retinopathy, and 11 were unilateral. One of the patients with foveal cavitations developed bilateral macular holes. Only 8 of 30 patients had a symptom of decreased visual acuity or metamorphosia (Table S1, available at www.aaojournal.org). All patients were on the low-dose regimen for tamoxifen (20 mg/day). The mean age at initiation of tamoxifen use, the duration of tamoxifen intake, and the cumulative dose of tamoxifen exhibited no statistically significant differences between patients with tamoxifen retinopathy and those without (Table 1). Among clinical characteristics, BMI (24.4±3.3 kg/m2 vs. 23.0±3.2 kg/m2, P = 0.023) and the presence of hyperlipidemia (33.3% vs. 14.0%, P = 0.015) were significantly higher in patients with tamoxifen retinopathy. Multiple logistic regression analysis also showed a significant association between tamoxifen retinopathy and hyperlipidemia (odds ratio, 3.843; 95% confidence interval, 1.505–9.496, P = 0.004) and BMI (odds ratio, 1.142; 95% confidence interval, 1.012–1.284; P = 0.026), with hyperlipidemia showing a stronger association. However, the presence of diabetes mellitus, hypertension, and cardiovascular and cerebrovascular diseases were not different between the 2 groups. Breast cancer stage, the type of chemotherapeutic agents, history of hormone replacement therapy, and menopausal status were not associated with tamoxifen retinopathy (Table 1).Table 1Demographic and Clinical Characteristics of Study Patients According to the Presence of Tamoxifen RetinopathyTamoxifen Retinopathy (n = 30)No Tamoxifen Retinopathy (n = 221)P ValueAge at initial tamoxifen use (yrs)48.3±9.1 (32–67)47.5±8.8 (24–83)0.662Duration of tamoxifen intake (mos)53.5±10.9 (28–69)54.3±11.8 (25–99)0.825Tamoxifen cumulative dose (g)32.6±6.7 (17.0–41.9)33.0±7.3 (11.5–60.2)0.832BMI (kg/m2)24.4±3.3 (16.1–30.4)23.0±3.2 (17.1–35.3)0.023DM2 (6.7)26 (11.8)0.547HTN7 (23.3)36 (16.3)0.482Hyperlipidemia10 (33.3)31 (14.0)0.015Cardiovascular disease1 (3.3)6 (2.7)0.595Cerebrovascular disease1 (3.3)1 (0.5)0.225Breast cancer stage0.222 Stage 04 (13.3)41 (18.6) Stage 110 (33.3)80 (36.2) Stage 215 (50.0)67 (30.3) Stage 31 (3.3)30 (13.6) Stage 40 (0.0)3 (1.4)Chemotherapy17 (56.7)98 (44.3)0.282HRT history3 (10.0)20 (9.1)0.744Menopausal status0.377 Premenopause20 (66.7)168 (76.0) Postmenopause10 (33.3)53 (24.0)BMI = body mass index; DM = diabetes mellitus; HRT = hormone replacement therapy; HTN = hypertension.Data are presented as the mean ± standard error (range) for continuous variables and n (%) for categoric variables. Open table in a new tab BMI = body mass index; DM = diabetes mellitus; HRT = hormone replacement therapy; HTN = hypertension. Data are presented as the mean ± standard error (range) for continuous variables and n (%) for categoric variables. In some patients, refractile crystalline deposits seemed to fade out over time (Fig S1, available at www.aaojournal.org). Among the 10 patients who had OCT angiography, 9 had telangiectasia at the deep capillary plexus with and without right-angled vessels (Table S1).5Lee S. Kim H.A. Yoon Y.H. OCT angiography findings of tamoxifen retinopathy: similarity with macular telangiectasia type 2.Ophthalmol Retina. 2019; 3: 681-689Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Although this study was a retrospective review, we were able to examine the prevalence of tamoxifen retinopathy for the first time in a large population using OCT, which was found to be 12.0%. This is rather high in comparison with studies from the 1980 to 1990s, in which the prevalence was reported as 1.5%3Heier J.S. Dragoo R.A. Enzenauer R.W. et al.Screening for ocular toxicity in asymptomatic patients treated with tamoxifen.Am J Ophthalmol. 1994; 117: 772-775Abstract Full Text PDF PubMed Scopus (66) Google Scholar to 11.8%.1Vinding T. Nielsen N.V. Retinopathy caused by treatment with tamoxifen in low dosage.Acta Ophthalmol (Copenh). 1983; 61: 45-50Crossref PubMed Scopus (78) Google Scholar Because previous studies were based on fundus examinations only, cases of intraretinal cavitation without crystalline deposits might have been missed, resulting in an underestimation of tamoxifen retinopathy prevalence. Of note, in Korea, the incidence of breast cancer is highest in patients aged 40 to 49 years, unlike in the United States where the incidence increases with age until age 60 years.6Park E.H. Min S.Y. Kim Z. et al.Basic facts of breast cancer in Korea in 2014: the 10-year overall survival progress.J Breast Cancer. 2017; 20: 1-11Crossref PubMed Scopus (81) Google Scholar Approximately half of the patients are premenopausal,6Park E.H. Min S.Y. Kim Z. et al.Basic facts of breast cancer in Korea in 2014: the 10-year overall survival progress.J Breast Cancer. 2017; 20: 1-11Crossref PubMed Scopus (81) Google Scholar and 74.1% are hormone receptor-positive,6Park E.H. Min S.Y. Kim Z. et al.Basic facts of breast cancer in Korea in 2014: the 10-year overall survival progress.J Breast Cancer. 2017; 20: 1-11Crossref PubMed Scopus (81) Google Scholar exposing a large proportion of patients to tamoxifen. Aromatase inhibitor, which is known to have lower ocular toxicity, may be used only in postmenopausal women. Therefore, Korean patients seem to be at higher risk of tamoxifen retinopathy. It was noteworthy that a high BMI and the presence of hyperlipidemia were significantly associated with tamoxifen retinopathy. The mechanism of tamoxifen toxicity is still unknown. However, because tamoxifen is known to form drug-lipid complexes inhibiting normal catabolism of lipids in the lysosomes,7Nayfield S.G. Gorin M.B. Tamoxifen-associated eye disease. A review.J Clin Oncol. 1996; 14: 1018-1026Crossref PubMed Scopus (151) Google Scholar patients with hyperlipidemia and high BMI may have an increased risk of tamoxifen toxicity. Furthermore, the morphologic similarity with macular telangiectasia type 2 (MacTel2) suggests that Müller cell dysfunction also may be involved.2Doshi R.R. Fortun J.A. Kim B.T. et al.Pseudocystic foveal cavitation in tamoxifen retinopathy.Am J Ophthalmol. 2014; 157 (1291-1298.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Our study had several major limitations. First, we used convenience sampling, a retrospective review of patients who had visited our ophthalmology clinic, leading to a potential overestimation of prevalence. Also, we could not present the prevalence as a rate according to time because the hazard rate was not constant over time. Second, because the morphology of tamoxifen retinopathy is similar to that of MacTel2, some of the patients may have had concurrent MacTel2 disease. In conclusion, tamoxifen retinopathy was found to be more prevalent, when using OCT as a diagnostic tool, than previously estimated by fundus examination only. Moreover, patients with a high BMI and dyslipidemia were significantly more likely to have tamoxifen retinopathy. Download .pdf (50.5 MB) Help with pdf files Fig S1 Download .pdf (.28 MB) Help with pdf files Table S1