Estrogen receptor‐low breast cancer: Biology chaos and treatment paradox

Abstract

Hormone receptor testing mainly serves the purpose of guiding treatment choices for breast cancer patients. Patients with estrogen receptor (ER)-positive breast cancers show significant response to endocrine therapy. However, the methods to define ER status and eligibility for treatment remain controversial. Despite recent guidelines considering staining ≥1% of tumor nuclei by immunohistology as ER-positive, it has raised concerns on the benefit of endocrine therapy for tumors with ER 1%-10% expression, termed "ER-low positive". This subgroup accounts for 3% to 9% of all patients and is likely to have unique molecular features, and therefore distinct therapeutic response to endocrine therapy compared with ER-high positive tumors. The latest guidelines did not provide detailed descriptions for those patients, resulting in inconsistent treatment strategies. Consequently, we aimed to resolve this dilemma comprehensively. This review discusses molecular traits and recent ER-low positive breast cancer innovations, highlighting molecular-targeted treatment rather than traditional unified endocrine therapy for future basic and clinical research.

De‐escalation of five‐year adjuvant endocrine therapy in patients with estrogen receptor‐low positive (immunohistochemistry staining 1%‐10%) breast cancer: Propensity‐matched analysis from a prospectively maintained cohort

“…It seems that the dichotomous ER status (as negative or positive) limited predictive and prognostic values, and ER-low positive status might provide additional information among ER-positive patients. 6 Cancer May 1, 2022…”

“…Currently, different multigene tools (such as 21‐gene and 70‐gene panels) have been developed to stratify patients with early, ER‐positive, human epidermal receptor 2 (HER2)‐negative breast cancer into different risk groups to guide the use of chemotherapy. It seems that the dichotomous ER status (as negative or positive) limited predictive and prognostic values, and ER‐low positive status might provide additional information among ER‐positive patients 6 …”

Chemotherapy Shows a Better Efficacy Than Endocrine Therapy in Metastatic Breast Cancer Patients with a Heterogeneous Estrogen Receptor Expression Assessed by 18F-FES PET

“…Endocrine therapy remains to be the first choice for the first line treatment of luminal type MBC patients, both in guidelines and clinical practice [ 22 , 23 ]. However, among patients with a low ER expression, endocrine therapy seems to be less effective [ 15 ]. Traditionally, we tend not to use combined treatment of ET and CT because of the antagonism of chemotherapy-induced cytotoxicity by antiestrogens [ 24 ].…”

“…Our results showed the opposite results, which further demonstrated that patients with ER heterogeneity had a completely different biological behavior and treatment response from ER positive patients. On the other hand, besides the fact that ET is not suitable for ER/PR negative patients, researchers also found that patients with a ER low expression had worse treatment outcomes for ET and overall survival compared with a ER high expression [ 15 ]. This phenomenon, to some extent, suggests that patients with ER heterogeneity might be similar to those with a low ER expression or negative ER expression.…”

“…Previous studies indicate that patients with low positive ER (ER expression 1–10%) have unique molecular features and thus are more sensitive to chemotherapy (CT) rather than endocrine therapy (ET) [ 15 ]. We considered whether a similar situation happens in patients with ER heterogeneity.…”