Receptor discordance between primary tumors and nodal metastases and correlation with the 21-gene recurrence score in early-stage, estrogen receptor-positive, node-positive breast cancer.

Abstract

Background: In estrogen receptor (ER)-positive, HER2-negative breast cancer, systemic therapy decisions are often made on the biomarker status of the primary tumor, along with the Oncotype DX Recurrence Score^® (RS). Biomarker testing of nodal metastases is not routine, despite reported receptor discordance. We quantified ER/PR/HER2 discordance between primary tumors and axillary lymph node metastases and evaluated associations with RS and clinicopathologic features.

Methods: We conducted a retrospective study of women with stage II-III, ER-positive, HER2-negative, node-positive invasive breast cancer who underwent upfront surgery and Oncotype DX testing of the primary tumor between 2016 and 2020. ER, PR, and HER2 immunohistochemistry (IHC) was performed on archived nodal metastases. Discordance in ER/PR percent positivity and HER2 IHC score between primary and lymph node metastases was scored ordinally from 0 to 2 for no, mild, or marked difference, respectively. Associations with RS, tumor and nodal burden, and treatment were analyzed using standard parametric and nonparametric tests with statistical significance set at p < 0.05.

Results: Of 555 patients with RS testing, 91 patients met inclusion criteria and 73 had available nodal tissue. Discordance in at least one receptor was high overall, occurring in 56/73 (77%) cases. The discordance rate for ER was 15%, PR was 32%, and HER2 was 66% (58% mild, 8% marked). One case demonstrated loss of ER positivity in the node, and 14 demonstrated loss of PR positivity in the node; no primary HER2-negative tumor converted to HER2-positive (IHC 3+) disease in the node. Greater amount of HER2 discordance was associated with larger primary tumors and larger size of nodal metastatic deposits. Higher RS correlated with lower primary ER and PR expression and higher volume of nodal burden (p < 0.05 for each) but was not significantly associated with receptor discordance.

Conclusions: Receptor discordance between primary tumors and nodal metastases is common, with most shifts occurring within the HER2-spectrum. There was a trend toward higher RS and ER or HER2-receptor discordance. HER2 discordance was also associated with larger tumor size and larger size of nodal metastasis. As strategies emerge to target HER2-low cohorts and to include ER-low/HER2-negative disease within treatment regimens for TNBC, it may become important to consider receptor testing of nodal disease in the future.