A pooled analysis on therapy response and prognosis of patients with low HR-positive, HER2-negative early breast cancer has been published in European Journal of Cancer
Hormone receptor (HR) expression is one of the most important breast cancer biomarkers for therapeutic strategies. Because of the challenges surrounding a low-HR positivity in breast cancer, the updated ASCO/CAP guidelines 2020 introduced a new category of estrogen receptor (ER)-low positive cases and recommended establishing specific standard operating procedures to validate and interpret such a result, but continue to recommend 1% nuclear ER staining as the threshold to predict potential clinical benefit from endocrine therapy treatment (Allison et al. Arch Pathol Lab Med 2020). However, in acknowledgement of possible overlapping with triple-negative breast cancer (TNBC), the guidelines encourage clinicians to discuss with patients the limited data on this subgroup of ER-low positive cases.
To address the lack of information about clinical outcomes of this low HR-positive subgroup in the neoadjuvant setting, this study compared negative [ER and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expressions in 2765 patients with HER2-negative breast cancer from neoadjuvant clinical trials GeparQuinto and GeparSepto. Endpoints were pathological complete response (pCR), disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). In addition, RNA sequencing (N=38) was performed to identify gene expression patterns and molecular subtypes of low-HR tumours.
A total of 94 (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. No significant differences in pCR rates were detected between low HR-positive tumours (27.7%) and TNBC (35.5%). DFS and DDFS were also not different (DFS: hazard ratio 1.26 [95%CI 0.87-1.83], log-rank p=0.951 and DDFS: hazard ratio 1.17 [95%CI 0.78-1.76], log-rank p=0.774). Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38 [95%CI 0.23-0.63], but better DFS (hazard ratio 0.48 [95%CI 0.33-0.70]) and DDFS (hazard ratio 0.49 [95%CI 0.33-0.74]) compared to patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%).
In summary, HER2-negative breast cancer classified as having low HR-positivity shows a similar clinical behaviour to TNBC, with increased pCR rates, poor survival and a basal-like gene expression signature when compared to strong HR-positive tumours in the neoadjuvant setting. Hence, patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
Villegas SL, Nekljudova V, Pfarr N, et al. Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors - An analysis of 2765 patients from neoadjuvant clinical trials. Eur J Cancer. 2021