Overrepresentation of human epidermal growth factor receptor 2 positive- and Luminal B breast cancer metastases in the eyes and orbit

Abstract

Background: Breast cancer is the most common cancer to spread to the choroid and orbit. Depending on a set of prognostic and predictive biomarkers, breast cancer can be divided into at least four distinct subtypes with separate treatment and clinical course.

Subjects: Thirty-two patients with metastases to the eye and periocular area diagnosed between 2005 and 2020, of which 11 also had primary tumour tissue available. Expression levels of oestrogen- (ER) and progesterone receptors (PR), Human epidermal growth factor receptor 2 (HER2) and the proliferation marker Ki67 were analysed.

Results: Twenty-five of 32 patients (78%) had a history of primary breast cancer, whereas the remaining 7 (22%) presented with metastatic disease. Of available metastases, 83% were positive for ER, 37% for PR, 54% for HER2, and 50% for Ki67. Metastases had significantly lower proportions of PR-positive cells than primary tumours, and the distribution of the Luminal A, Luminal B, HER2 enriched and triple-negative subtypes differed between primary tumours and metastases (P = 0.012): Six of 9 patients with a full set of biomarkers on both primary tumours and metastases switched subtype (67%), and 23 of 32 metastases (77%) were of the Luminal B subtype.

Conclusions: Nearly 4 in 5 breast cancer metastases in the eyes and orbit are of the Luminal B subtype, and a majority are HER2 positive. The breast cancer subtype frequently switches between primary tumours and metastases. Future studies should evaluate these results in larger cohorts.

Fig. 1. Transvitreal incisional biopsy from a choroidal metastasis of breast cancer.

A Irregular clusters of enlarged epithelioid cells grow in choroidal tissue with severe fibrotic changes, which may be a reaction to tumour infiltration and inflammation. B In larger magnification, the infiltrating tumour cells are seen with pleomorphism, hyperchromasia, and a tendency to form rounded gland-like structures. Most of the tumour cell nuclei were positive for ER (red, chromogen), but negative for PR (blue, haematoxylin). There was complete and intense membranous HER2 positivity in all tumour cells. The proliferation marker Ki67 was positive in a majority of tumour cell nuclei, in this area about 140 of 180 tumour cells (78%), which suggests a very high rate of proliferation. Any visible staining above background sufficed for positive classification of a tumour cell in stains with ER, PR and Ki67. ER oestrogen receptor. PR progesterone receptor. HER2 human epidermal growth factor receptor 2. Scale bars: A 200 µm. B 100 µm. ER, PR, HER2 and Ki67 40 µm.

Fig. 2. Biomarker expression in primary tumours and metastases.

A There was no significant difference in the proportion of ER-positive tumour cells between primary tumours and metastases (Mann-Whitney U P = 0.61). B Metastases had a significantly lower proportion of PR-positive cells (P = 0.036). C There was no significant difference in the proportion of Ki67 positive cells (P = 0.94). In contingency tables, there were no significant differences in the distribution of D HER2 positive tumours (Fisher’s exact P = 0.48), E ER-positive tumours (≥1% of tumour cells ER positive, P = 0.66), F PR positive tumours (≥20% of tumour cells PR positive, P = 0.48), or G Ki67 positive tumours (>25% of tumour cells Ki67 positive, P = 0.63). H The distribution of the Luminal A, Luminal B, HER2 enriched and triple-negative subtypes did however differ between primary tumours and metastases, with the Luminal B subtype being overrepresented in metastases (P = 0.012). ER oestrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2. Lines in A to C indicate paired cases, with primary tumour and metastasis from the same patient. *P < 0.05. ns non-significant.