Acute Subretinal Fluid Accumulation Induced by Futibatinib Therapy for Malignant Metastatic Breast Cancer
Abstract
Futibatinib is an irreversible inhibitor of fibroblast growth factor receptors and is currently the subject of phase II clinical trials for the treatment of metastatic carcinomas. We report a case of a 59-year-old woman with metastatic malignant breast cancer who developed acute symptomatic subretinal fluid (SRF) accumulation after two weeks of futibatinib therapy. The SRF resolved within two weeks after futibatinib cessation. The medication was subsequently restarted at a lower dose, and SRF recurred within two weeks. To our knowledge, this is the first case depicting rapidly reversible SRF accumulation with the use of futibatinib in a real-world clinical setting.
[Ophthalmic Surg Lasers Imaging Retina 2024;55:109–111.]
Introduction
Fibroblast growth factor receptors (FGFR) are a family of receptor tyrosine kinases involved in cell proliferation, cell migration, cell differentiation, and cell apoptosis. Overexpression of FGFR can cause abnormal cancer cell proliferation in cancers such as breast, glioblastoma, and hepatocellular cell carcinoma, and is thus the target of many chemotherapy agents.1–3 This class of drugs shows promise in targeted anti-cancer therapy.
In the eye, FGFR signaling plays a vital role in the development and repair of retinal pigmented epithelium (RPE) cells.4 Retinal toxicities resulting from targeted cancer therapy have been reported previously, including serous retinal detachments, cystoid macular edema, and central serous chorioretinopathy.2,5,6 In this article, we present a patient who was treated with an FGFR inhibitor for metastatic malignant breast cancer and developed subretinal fluid (SRF) accumulation.
Case Report
A 59-year-old woman with a history of metastatic breast cancer was evaluated for double vision and vitreous floaters in the left eye (OS) of four days duration. Previous optical coherence tomography (OCT) from a visit one month prior revealed only a mild epiretinal membrane OS and no SRF (Figure 1A).
Optical coherence tomography of the patient's left eye at baseline and after initiating futibatinib. (A) Baseline examination from one month prior to presentation revealed mild epiretinal membrane. (B) Pocket of subretinal fluid (SRF) after 17 days of futibatinib therapy. (C) Spontaneous decrease in SRF two days after cessation of treatment. (D) Complete resolution of SRF two weeks after cessation of treatment. (E) Recurrence of SRF while on a reduced dose of futibatinib.
At the visit, her visual acuity with glasses and pinhole correction was 20/20 in the right eye (OD) and 20/30 OS. There was no afferent pupillary defect. Intraocular pressure was measured to be 12 mmHg in both eyes. Anterior segment examination was unremarkable without signs of inflammation and demonstrated mild cataracts in both eyes. Dilated posterior segment examination was unremarkable OD and showed a mild epiretinal membrane with SRF in OS, which was confirmed with OCT (Figure 1B).
Review of her medications revealed that she was started on daily 20 mg futibatinib, a FGFR inhibitor, for her metastatic breast cancer two weeks prior to presentation. The SRF accumulation was hypothesized to be related to her futibatinib therapy; thus, after discussion with her medical oncologist, the futibatinib therapy was stopped by her medical oncologist to monitor the symptoms and efficacy of the drug. Follow-up evaluations demonstrated spontaneous reduction in SRF two days after cessation of futibatinib therapy (Figure 1C) and complete resolution after two weeks (Figure 1D). Her symptoms also improved, with reduction in double vision and visual acuity improvement at two days, with a final vision of 20/25 two weeks after stopping futibatinib.
After discussions with her medical oncologist, futibatinib was restarted at a lower dose of 16 mg daily. However, after two weeks at the lower dose, she reported seeing floaters, and her visual acuity was 20/25. OCT at this time showed recurrence of SRF (Figure 1E).
Discussion
FGFR inhibitors are a targeted therapy that have demonstrated antitumor activity through downstream suppression of the JAK/STAT, PI3K/AKT, and MAPK/MEK/RAS/RAF pathways.7 The FGFR system has been one of the more promising therapeutic targets investigated for breast cancer due to the heterogeneous nature of the disease.7 Futibatinib is a third-generation, highly selective inhibitor of FGFR1-4 that forms a covalent adduct within the FGFR kinase domain P-loop, and its irreversible binding makes it less susceptible to mutations.8
In this article, we report a case of reversible unilateral acute SRF accumulation with oral futibatinib use. Accumulation of SRF occurred over two weeks following initiation of treatment and began to improve as quickly as two days following discontinuation of the treatment, with complete resolution observed at two weeks. In a phase I study, 10 of 83 (12%) patients with advanced solid tumors taking futibatinib developed serous retinal detachments.9 In our case, the patient's presentation of SRF resembles symptoms of ocular toxicities resulting from previously described FGFR inhibitor use.4,10,11 The retina expresses targets involved in the mitogen-activated protein kinase pathway and is affected by FGFR inhibition. Accumulation of SRF in the absence of retinal vein occlusions has been seen in patients treated with MEK inhibitors.12 The MAPK pathway plays a role in the regulation of tight junctions and water permeability in RPE cells with emphasis on the fluid transport channel aqua-porin-1.11,13 When aquaporin homeostasis is interrupted, fluid accumulates, causing symptoms associated with retinopathy.14 In most cases, resolution of SRF following discontinuation of FGFR inhibitors is seen between 1–2 months.4,6,14 Our patient demonstrated rapid resolution of SRF and associated symptoms, with fluid reducing within two days and completely resolving 2 weeks after cessation of therapy. The rapid resolution of SRF is similar to reversible retinopathy from pemigatinib, a selective inhibitor of FGFR1-3, with resolution within a week of pemigatinib cessation.15,16 Further research to outline the specific modifications on the molecular pathway caused by different FGFR inhibitors may help explain the differences in resolution time.
Reports of retinal toxicity associated with futibatinib therapy are limited. To our knowledge, this is the first case reported outside of phase I clinical trial of rapidly reversible retinopathy associated with futibatinib. MEK-associated retinopathy, usually occurring as serous detachments, affects up to 90% of patients, but many of these patients do not exhibit any noticeable symptoms.10 The subtlety of presenting symptoms may contribute to the scarcity of reported instances of retinopathy associated with futibatinib. Furthermore, this emphasizes the need for ophthalmologic monitoring of patients undergoing targeted therapy.
As use of futibatinib therapy increases and next-generation inhibitors develop, oncologists should carefully coordinate with ophthalmologists regarding managing ocular toxicities and the safe optimization of dosage to balance the risks and benefits of fubibatinib's application. Timely detection and management of ocular adverse effects can prevent permanent damage to the retina and avoid potential visual complications. More extensive ophthalmologic evaluation of patients will be needed to better understand the pathogenesis of ocular adverse effects associated with this class of medication. A comprehensive understanding of the underlying mechanisms will facilitate development of strategies for preventing and managing these ocular side effects.
- 1.. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019; 381(4):338–348.
10.1056/NEJMoa1817323 PMID:31340094 > Crossref MedlineGoogle Scholar - 2.. Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors. BMC Ophthalmol. 2020; 20(1):19.
10.1186/s12886-019-1285-9 PMID:31918686 > Crossref MedlineGoogle Scholar - 3.. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res. 2012; 18(7):1855–1862.
10.1158/1078-0432.CCR-11-0699 PMID:22388515 > Crossref MedlineGoogle Scholar - 4.. Reversible retinopathy associated with fibroblast growth factor receptor inhibitor. Case Rep Ophthalmol. 2022; 13(1):57–63.
10.1159/000519275 PMID:35350233 > Crossref MedlineGoogle Scholar - 5.. Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials. Invest New Drugs. 2023; 41(1):173–181.
10.1007/s10637-022-01321-8 PMID:36471215 > Crossref MedlineGoogle Scholar - 6.. Reversible macular lesions in the setting of oral panfibroblast growth factor inhibitor for the treatment of bladder cancer. J Vitreoretin Dis. 2018; 2(2):111–114.
10.1177/2474126417751724 > CrossrefGoogle Scholar - 7.. The FGF/FGFR system in breast cancer: oncogenic features and therapeutic perspectives. Cancers (Basel). 2020; 12(10):3029.
10.3390/cancers12103029 PMID:33081025 > Crossref MedlineGoogle Scholar - 8.. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023; 388(3):228–239.
10.1056/NEJMoa2206834 PMID:36652354 > Crossref MedlineGoogle Scholar - 9.. Phase I study of the irreversible fibroblast growth factor receptor 1–4 inhibitor futibatinib in Japanese patients with advanced solid tumors. Cancer Sci. 2023; 114(2):574–585.
10.1111/cas.15486 PMID:35838190 > Crossref MedlineGoogle Scholar - 10.. Fibroblast growth factor receptor inhibitor-associated retinopathy. JAMA Ophthalmol. 2020; 138(10):1101–1103.
10.1001/jamaophthalmol.2020.2778 PMID:32789485 > Crossref MedlineGoogle Scholar - 11.. Choroidal and choriocapillaris morphology in pan-FGFR inhibitor-associated retinopathy: a case report. Diagnostics (Basel). 2022; 12(2):249.
10.3390/diagnostics12020249 PMID:35204340 > Crossref MedlineGoogle Scholar - 12.. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. Eye (Lond). 2015; 29(8):1003–1012.
10.1038/eye.2015.82 PMID:26043707 > Crossref MedlineGoogle Scholar - 13.. Aquaporin-1 channels in human retinal pigment epithelium: role in transepithelial water movement. Invest Ophthalmol Vis Sci. 2003; 44(6):2803–2808.
10.1167/iovs.03-0001 PMID:12766090 > Crossref MedlineGoogle Scholar - 14.. Clinical and morphologic characteristics of fibroblast growth factor receptor inhibitor-associated retinopathy. JAMA Ophthalmol. 2021; 139(10):1126–1130.
10.1001/jamaophthalmol.2021.3331 PMID:34473206 > Crossref MedlineGoogle Scholar - 15.. Multifocal serous retinopathy with pemigatinib therapy for metastatic colon adenocarcinoma. Int J Retina Vitreous. 2021; 7(1):34.
10.1186/s40942-021-00305-9 PMID:33892812 > Crossref MedlineGoogle Scholar - 16.. Favorable management of repeated serous retinal detachment with continued tumor response in a patient with intrahepatic cholangiocarcinoma during treatment with pemigatinib. Intern Med. 2023; 62(8):1151–1155.
10.2169/internalmedicine.0150-22 PMID:35945011 > Crossref MedlineGoogle Scholar
