Case Report: Late choroidal metastasis from hormone receptor-positive, HER2-negative breast cancer responsive to first-line endocrine therapy.

1
Introduction
Metastatic lesions are the most common ocular malignant tumors. The prevalence of ocular metastases is estimated to be around 5-10% (1). Since the choroid is the only intraocular tissue that is located outside the blood-aqueous and blood-retinal barriers, choroidal metastases (CM) represent 90% of ocular metastases. Breast cancer is the primary source in 53% of cases (2). The median interval between breast cancer diagnosis and CM is 42.4 months, but cases occurring up to 34 years later have been reported (3, 4). CM are likely underdiagnosed since ocular examinations are not routinely performed in patients with metastatic cancer, even in those with mild ocular symptoms. Identification and treatment of CM is crucial since progression can lead to visual loss (5). We report a case of a 57-year-old female with metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer with choroidal, pulmonary, and osseous metastases who experienced an excellent response to first-line endocrine therapy in combination with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. We also conducted a literature review of similar cases. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

2
Case description
A 57-year-old female with a remote history of ER+, progesterone receptor-positive (PR+), HER2- invasive ductal carcinoma (IDC) of the left breast, originally diagnosed in April 1994, presented in 2023 with sudden central vision loss in her left eye. At the time of her initial diagnosis, she underwent a left mastectomy and axillary lymph node dissection (ALND), with pathology showing pT2 pN0 disease. She was treated with adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide but did not receive endocrine therapy for unknown reasons. An ophthalmologic examination in 2023 revealed an amelanotic choroidal lesion associated with macular edema. Subsequent computed tomography (CT) of the chest, abdomen, and pelvis demonstrated multiple pulmonary nodules, subpleural nodularity, mediastinal lymphadenopathy, and a small subcapsular hepatic lesion too small to characterize — findings concerning for metastatic recurrence of breast cancer.
Magnetic resonance imaging (MRI) of the orbits demonstrated subtle uveal thickening with possible retinal detachment/effusion in the left eye (Figure 1). MRI of the brain was unremarkable for intracranial metastasis. Given the visual symptoms and the known history of breast cancer, CM was suspected.
A CT-guided biopsy of a lung nodule confirmed metastatic breast carcinoma. Immunohistochemical (IHC) studies revealed that the carcinoma was ER+ (99%), PR+ (5%), and HER2 equivocal. Fluorescent in situ hybridization (FISH) was negative for amplification of the HER2 gene. A fluorodeoxyglucose positron emission tomography (FDG-PET) combined with CT scan demonstrated a pulmonary nodule with a maximum standardized uptake value (SUV) of 2.5, a subcarinal lymph node with a maximum SUV of 4.4, and a left pubic bone lesion with a maximum SUV of 7. An ophthalmologic examination, with color fundus photos (Figure 2), optical coherence tomography (OCT), and ophthalmic ultrasound (Figure 3), confirmed CM with serous retinal detachment in the left eye. The right eye was unaffected. A 36-gene panel genetic test was performed and was negative. A next-generation sequencing (NGS) DNA test showed no targetable mutations. A timeline of the patient’s treatment is shown in Figure 4.

3
Treatment
The patient was initiated on first-line therapy with an aromatase inhibitor (letrozole) and a CDK4/6 inhibitor (ribociclib) (6). Additionally, the patient received bone anti-resorptive therapy with denosumab to prevent skeletal-related events. Ribociclib was held after 1 cycle due to grade 3 hepatotoxicity. The patient was then switched to palbociclib, which was well tolerated with no further treatment delays.
Ophthalmologic follow-up 1 month after initiation of treatment showed an initial enlargement of the lesion with a small improvement in subretinal fluid, followed by dramatic regression of the CM and resolution of the subretinal fluid the following month. MRI of the orbits similarly confirmed resolution of the left globe lesion, and the patient continues to improve clinically.
The patient continues first-line endocrine therapy—palbociclib and letrozole—with good clinical, radiographic, and ophthalmic response. The patient’s most recent nuclear whole-body bone scan and CT scans of her chest, abdomen, and pelvis showed stable disease. Ophthalmologic evaluation confirmed excellent tumor regression on ophthalmic exam and imaging with no new lesions. The patient continues to follow up with oncology and ophthalmology.

4
Discussion
The main goal of CM treatment is vision preservation. Treatment options include systemic therapy as well as local interventions. While the gold standard for CM treatment is external beam radiotherapy, systemic medical therapy may be appropriate as a primary treatment, depending on factors such as cancer type, the likelihood of response to systemic treatment, and the extent of ocular disease and symptoms. Other local treatment modalities include photodynamic therapy and adjunctive intravitreal anti-vascular endothelial growth factor (VEGF), which are more commonly used in patients with poor performance status and limited life expectancy (7).
The choroid of the eye exhibits high vascular permeability. This property allows significant penetration of cancer-directed treatment. Since metastatic ER+/HER2- breast cancers respond very well to first-line endocrine therapy with a CDK4/6 inhibitor, it may be appropriate to defer the use of local therapies until CM progression. In our case, the patient had a very rapid response to first-line endocrine therapy with regression of her CM, which emphasizes the important role of a CDK4/6 inhibitor plus endocrine therapy as first-line treatment, even in cases of visceral involvement. CM in breast cancer indicates a poor prognosis and is associated with a high risk of central nervous system (CNS) involvement, significantly impacting the mortality and quality of life of affected patients. Based on the patient’s good response, we decided to save radiation therapy as a future treatment option if needed.
We conducted a literature search in PubMed to identify relevant case reports and case series published since 2006 (Table 1). We found a total of 27 cases: 25 female and 2 male patients diagnosed with late-onset CM originating from breast carcinoma. All patients had a history of HR+, HER2- breast cancer and developed ocular metastases several years after initial diagnosis. The latency period between primary breast cancer diagnosis and CM development varied significantly. In most cases, CM diagnosis was identified 2.5 years to over 25 years after the initial cancer diagnosis. In many cases, CM was the first clinical sign of systemic recurrence, underscoring the need for long-term vigilance in breast cancer survivors. Across all cases, systemic endocrine therapy was the main treatment, with consistently favorable outcomes. Among the reviewed cases, local therapy was infrequently employed. In addition to endocrine therapy, 1 patient received external beam radiation therapy, and another was treated with intravitreal bevacizumab. Both patients had favorable clinical responses. Systemic endocrine therapies such as aromatase inhibitors with or without gonadotropin-releasing hormone (GnRH) agonists (used to induce ovarian function suppression in premenopausal women) and CDK4/6 inhibitors or selective ER modulators were the predominant treatment modalities across cases. Local treatments such as radiotherapy were selectively applied at some point of their treatment trajectories, typically in cases with incomplete systemic control or to alleviate local ocular symptoms.
The largest case series included in this review (16) reported on 17 female patients with a mean interval of 7.6 years (range: 1 month-17 years) between initial breast cancer diagnosis and CM. In this cohort, 59% of patients with ER+ tumors demonstrated significant regression following treatment with aromatase inhibitors. Collectively, these findings support the efficacy of systemic endocrine therapy as a first-line treatment for CM in patients with HR+, HER2- breast cancer.
We believe it may be appropriate to treat choroidal metastases secondary to ER+, HER2- breast cancer with endocrine therapy in combination with CDK4/6 inhibitors and delay the use of local treatments until progression of CM.Large-scale clinical trials will likely not be feasible due to the low frequency of CM, which may require urgent or emergent therapy.
In the absence of large evidence-based studies, a multidisciplinary approach is always advised for the management of CM. This case contributes to the growing body of literature supporting the role of endocrine therapy and CDK4/6 inhibitors in the management of metastatic breast cancer, including CM.