Patient treatment and outcome after breast cancer orbital and periorbital metastases: a comprehensive case series including analysis of lobular versus ductal tumor histology

Due to the rarity of OM, we took a unique approach in identifying affected patients. The Text Information Extraction System (TIES) developed by investigators within the Department of Biomedical Informatics at the University of Pittsburgh provided us with the ability to search for specific terms or phrases in pathological and radiological reports of all patients treated at UPMC hospitals. All reports in TIES are de-identified. As a natural language processing platform, TIES translates simple search terms into ontologies which are used to search through patient reports. These ontologies consist of the NCI Metathesaurus’ synonyms and abbreviations, thus making the search for a specific term not limited by word arrangement or spelling. Temporal combination of two queries consisting of many different ontologies gave us the ability to search for patients that were diagnosed with breast cancer in one report and with OM in another.

This retrospective case series does not represent a comprehensive review of all patients seen at our institution, as the initial search through TIES was limited to cases with available pathology and radiology reports. Eligibility criteria were (A) breast cancer confirmed in a pathology report and (B) metastatic involvement of structures in and around the eye suspected clinically and confirmed in either a radiology or pathology report. A filter was set to only include female patients to reduce false positive results. The search criteria in TIES were purposefully broad as to not exclude any OM caused by breast cancer. The search results in TIES were then manually validated to ensure that criteria A and B were met.

After obtaining institutional review board approval from the University of Pittsburgh (IRB Number PRO15050502), we requested identified data for patients in whom the TIES search indicated primary breast cancer and OM. Clinical notes, pathology reports, radiology reports, therapeutic regimens, and outcome for these patients were manually reviewed by members of the investigative clinical team. We will hereafter refer to the resultant group of patients identified by the TIES search and validated by manual chart review as the “OM cohort.”

Patient and tumor characteristics for the OM cohort, including histological subtype, estrogen receptor (ER), progesterone receptor (PR), HER2/neu receptor status, involvement of axillary lymph nodes, and initial stage at diagnosis were obtained from available clinical and/or pathology reports. Outcome information including identification of metastatic sites was obtained via review of the treating oncologist’s notes, radiology reports, and/or pathology reports. Sites of metastases were grouped into eye, lung, bone, liver, central nervous system (CNS), distant lymph nodes, ovary, peritoneum, gastrointestinal tract, skin, local recurrence, and “other” metastatic sites.

Tumor tissue from three patients identified through TIES was available for histological analysis. Formalin Fixed, Paraffin Embedded (FFPE) paired primary tumor and OM tissue was available from one patient; only OM tissue was available for the other two patients. Tissue sections were cut (4 μm) and stained, one with hematoxylin and eosin (H&E), one with an E-cadherin antibody, and one with an estrogen receptor (ER) antibody. For antibody staining, the slides were deparaffinized, rehydrated, and stained using a standard histology protocol. Antigen retrieval was performed using a citrate buffer (Dako, Carpinteria, CA) in a decloaking chamber at 123 °C before being stained using an Autostainer Plus (Dako) platform with TBST rinse buffer (Dako). The E-cadherin antibody (Mouse monoclonal – 4A2C7, Invitrogen, Carlsbad, CA) was applied using a 1:500 dilution at room temperature followed by a secondary antibody of Mach 2 Mouse HRP (Biocare Medical, Pacheco, CA). The ER antibody (Mouse monoclonal – 1D5, Dako) was applied using a 1:100 dilution at room temperature followed by a secondary antibody anti-mouse HiDef HRP Polymer System (Cell Marque, Rocklin, CA). Pictures were taken using a × 200 magnification with the software SPOT imaging.

Time to first OM was calculated as the time between initial diagnosis of breast cancer and the first diagnosis of metastatic involvement of the orbital or periorbital structures. Disease-free survival (DFS) was calculated as the time from initial breast cancer diagnosis until the first recurrence, while distant metastasis-free survival (DMFS) was defined as the time between the initial breast cancer diagnosis and first diagnosis of a distant metastasis. Survival after OM was calculated as the time between first diagnosis of an OM and death or last follow-up for censored patients. Overall survival (OS) was calculated as the time between diagnosis of the primary breast cancer and death or last follow-up for censored patients.

The TIES search yielded 41,590 female breast cancer patients diagnosed between 1981 and 2018. Search criteria of breast cancer and OM yielded 221 cases, but the initial search resulted in a large amount of false positive results. A manual review of the TIES data for these cases eliminated 189 cases in which either primary breast cancer or OM could not be confirmed. Identified data from the remaining 32 patients was then analyzed via a more comprehensive review of the patient medical records. OM originating from a breast primary could not be confirmed in four cases, and those cases were thus excluded. The final resultant OM patient cohort with confirmed breast cancer metastatic to the orbit or periorbit included 28 cases diagnosed between 1995 and 2016 (Fig. 1).

Patient characteristics of the OM cohort are shown in Table 1. The median age at initial diagnosis of breast cancer was 55 (range 28–77 years). ER and PR status were positive in 75.0% and 60.7% of the primary tumors, respectively, and HER2/neu status was positive in 10.7% of cases. The histological subtype of the primary tumor was IDC in 14/28 of the patients (50%), ILC in 9/28 of the patients (32.1%), and mixed ILC/IDC subtype in 2/28 tumors (7.1%). The histological subtype of 3/28 tumors (10.7%) could not be identified.

Comparison of the patient and primary tumor characteristics from the OM cohort to those patients with any metastases from breast cancer in the UPMC Network Cancer Registry can be found in Table 1. The relative proportion of patients with ILC and/or mixed histology was significantly higher in the OM cohort compared to all patients with MBC in the UPMC Network Cancer Registry (p = 0.0007). No statistically significant differences in ER, PR, and HER2/neu receptor status between these two groups were found. Patients with OM were more likely to have higher stages at diagnosis (p = 0.0011) and higher frequency of axillary lymph node involvement (p = 0.0492) compared to other patients with MBC in the UPMC Network Cancer Registry.

In the OM cohort, 10/28 patients (35.7%) had metastases limited to the left eye, and 9/28 patients (32.1%) had a metastasis limited to the right eye. Interestingly, 9/28 patients (32.1%) had metastatic involvement of both eyes. Of these patients, 4/9 had ILC, 1/9 had IDC, 2/9 had mixed ILC/IDC tumor subtype, and 2/9 had unknown tumor subtype. Most (78.6%) of patients in the OM cohort had OM not effecting the globe, 14.3% had metastases that were exclusively intraocular, and 7.1% had tumors with metastatic involvement of ophthalmic tissue inside and outside of the globe. Of the metastases outside of the globe, the majority (11/22, 50%) were in the rectus muscles. Four of these metastases to the extraocular muscles originated from a primary that was solely comprised of IDC. Of the 6 patients with intraocular metastases, 3 had metastases to the optic nerve and 3 had metastases to the choroid. Metastases to the eyelid were reported in 5/28 patients (17.9%). A detailed representation of the location of all OM is displayed in Fig. 2a.

We performed a histological analysis of three cases from the OM cohort (OM 1, 24, and 26) who had available tumor tissue. For case 24, two samples of the primary breast tumor and one biopsy of the OM was available for review (Fig. 2b). The two breast primary tumor specimens were primarily composed of ILC but also contained IDC cells. We thus confirmed the initial diagnosis of a mixed ILC/IDC subtype. However, interestingly, only ILC cells were present in the paired OM for this patient, as was evident by their negative staining for E-cadherin and their single file growth pattern (Fig. 2b). Biopsies of the OM for cases 1 and 26 were also available for analysis (Fig. 2c). Case 1’s primary tumor was of IDC origin according to pathology reports, and the OM also displayed IDC histology. The histological subtype of the primary tumor of case 26 is not known; the OM stained strongly for E-cadherin, suggesting IDC histology.

At a median follow-up of 78.4 months after diagnosis of primary breast cancer, 2/28 patients from the OM cohort were still alive (7.1%), 24/28 were confirmed to be deceased (85.7%), and 2/28 patients were lost to follow-up (7.1%). Median overall survival was 82.1 months, with a median DFS of 26.4 months and a median DMFS of 34.2 months. There is no significant difference in OS, DFS, and DMFS in the OM cohort compared to other patients with MBC in the UPMC Network Cancer Registry (Table 1). Median time to first OM was 46.7 months, which was not statistically different between patients with ILC vs. IDC (Fig. 3). Time to first OM in the OM cohort was not significantly different than time to other sites of metastasis in the Metastatic Breast Cancer Database (Additional file 1). DMFS was longer (35.05 months) for patients with ILC compared to patients with IDC (23.34 months) in the OM cohort, supporting a tendency for late relapse for ILC. However, after a diagnosis of a first distant metastasis of any kind, the remaining median survival of patients with ILC (21.4 months) was significantly shorter than that of patients with IDC in the OM cohort (55.3 months, p = 0.03) (Fig. 4).

In the OM cohort, 12/28 patients (42.9%) developed OM as their first distant metastasis (Fig. 5). Out of the seven patients with de novo stage IV disease, three had OM at the initial presentation. OM were the second most frequent site of first distant metastasis after bone, which was the first site of distant metastasis in 15/28 patients (53.6%). Involvement of distant lymph nodes was the first site of distant metastasis in 5/28 patients (17.9%). While only 2/28 (7.1%) patients had CNS involvement when they were diagnosed with distant metastatic disease, 13 additional patients later developed CNS metastases as a second or subsequent metastatic event. This proportion of patients 15/28 (53.6%) in the OM cohort that developed CNS metastases throughout the course of their disease is significantly higher than the 420/1495 (28.1%) of patients in the Metastatic Breast Cancer Database that developed CNS metastases (p = 0.0053). CNS metastases preceded the diagnosis of OM in 2/15 patients (13.3%), they were diagnosed after the OM in 6/15 patients (40.0%), and finally they were diagnosed concurrently with OM in 7/15 patients (46.7%). Of note, only 4 of the 15 CNS metastases (26.7%) originated from an ILC primary. The most frequent sites of distant metastases throughout the course of the disease other than the ophthalmic region were bone (16/28; 92.9%), CNS (15/28; 53.6%), liver (12/28; 42.9%), distant lymph nodes (12/28; 42.9%), and lung (9/28; 32.1%). A detailed representation of the chronological sequence of metastatic progression for all 28 patients is displayed in Fig. 5 (detailed data in Additional file 2). The earliest metastases after diagnosis of the primary breast cancer in the OM cohort were bony metastases (median 43.6 months), followed by OM (median 46.7 months), and then metastases to distant lymph nodes (median 55.0 months). These were then succeeded by CNS metastases (median 63.0 months), liver metastases (median 69.4 months), and lung metastases (median 70.4 months).

Of the 28 patients with OM, 14 received adjuvant hormonal therapy. The number of lines of systemic therapy for metastatic disease for all patients in the OM cohort can be seen in Table 2. Anastrozole was the most frequently administered first-line therapy for advanced disease (to 7 patients), followed by Fulvestrant (to 4 patients) and then Tamoxifen, Capecitabine, Letrozole, Docetaxel, and Paclitaxel (the latter 5 were all administered to 3 patients as first-line therapy). Second-line therapies were most frequently Fulvestrant, Capecitabine, and Anastrozole (to 5, 4, and 3 patients respectively) while as third-line therapies, Fulvestrant was administered most frequently (to 6 patients), followed by Tamoxifen, Docetaxel, and Mitoxantrone (all administered to 3 patients). ER-positive and ER-negative patients were included in this analysis.

We identified 20/28 patients in the OM cohort (71.4%) with available radiation records. Four of these patients received radiation therapy more than once, sometimes to different sites (see Table 2), resulting in 25 separate treatments. The most common locations treated were the entire orbit (13/25, 52%), followed by the eyelid (5/25, 20%), retrobulbar area (4/25, 16%), and intraocular area (3/25, 12%). The median dose prescribed was 30 Gray (Gy) (range 10–60 Gy) in 12 (range 2–30 fractions) fractions. The most common radiation technique utilized was 3D-conformal for 16/25 treatments (64%), electron for 5/25 treatments (20%), intensity-modulated radiation therapy (IMRT) for 3/25 treatments (12%), and 1 patient received stereotactic body radiation therapy (SBRT) (4%).