Factors That Predict Biological Aggressiveness in Estrogen Receptor–Positive / Human Epidermal Growth Factor Receptor 2–Negative / Lymph Node–Negative Breast Cancer

Background: Traditionally, breast cancer is staged using TNM criteria: tumor size (T), nodal status (N), and metastasis (M). The Oncotype DX assay provides a recurrence score (RS) based on genomics that predicts the likelihood of distant recurrence in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–)/lymph node–negative (LN–) tumors. Methods: We retrospectively reviewed the medical records of patients with ER+/HER2–/LN– breast cancer tumors who were evaluated between 2007 and 2017 with Oncotype DX RS. We compared the RS to tumor size, patient age, progesterone receptor (PR) status, and LN immunohistochemistry to assess for factors that may independently predict recurrence risk. We also compared tumor size to tumor grade. Results: The data set included 296 tumors: 248 ER+/PR-positive (PR+)/HER2– and 48 ER+/PR-negative (PR–)/HER2–. RS ranged from 0 to 66, patient age ranged from 33 to 77 years, and tumor size ranged from 1 to 65 mm. No significant correlation was found between age and RS (r=–0.073, P=0.208). PR– tumors had a significantly higher RS regardless of size (PR– mean RS 30.8 ± 12.7; PR+ mean RS 16.3 ± 7.3; t(53)=7.6, P<0.0001). No significant correlation was seen between tumor size and RS for all tumors (r=–0.028, P=0.635), and this finding remained true for the PR+ tumor subgroup (r=0.114, P=0.072). However, a significant negative correlation was seen between tumor size and RS in the PR– subgroup (r=–0.343, P=0.017). Further analysis to ensure that differences in tumor grade did not account for this correlation showed equal distribution of well differentiated, moderately differentiated, and poorly differentiated tumors with no significant correlation between tumor size and grade. Conclusion: Increasing tumor size may not be associated with increasing biological aggressiveness. Traditionally, smaller tumors are thought to be lower risk and larger tumors higher risk, with a tendency to use chemotherapy with large tumors. However, our data showed a negative correlation between tumor size and RS in the PR– subgroup. A tumor with PR negativity that reaches a large size without metastasizing may suggest a favorable tumor biology. These tumors may not receive as much benefit from chemotherapy as previously thought. Also, the higher RS seen in smaller PR– tumors may demonstrate PR– status as a predictor for higher risk of distant recurrence. We propose that all tumors meeting the ER+/PR–/LN– criteria, regardless of size, should be considered for genotyping, with the RS used to guide chemotherapy benefit.