Research from the Karolinska Institute in Sweden shows assessing whether breast cancer tumors are estrogen receptor (ER) positive or not is more accurately measured as a spectrum rather than just classifying them as positive or negative.

The researchers used a percentage method to classify whether tumors were ER positive or not and found that women who had ER positivity of 59% or lower had significantly worse outcomes when given standard therapy for ER positive breast cancer than those with 60% or higher positivity.

“For many years, breast cancer has been classified as either ER-positive or ER-negative, with ER positivity typically defined using a one percent or 10% cutoff. However, in routine clinical practice we often see tumors that fall between the two ends of the spectrum,” lead investigator Balazs Acs, MD, PhD, associate professor at the Karolinska, told Inside Precision Medicine. “ER expression appears to behave as a continuum rather than a simple positive-versus-negative biomarker.”

ER positive breast cancer, where the cancer feeds off estrogen, makes up as much as 80% of all breast cancer cases. Knowing ER status is important as it indicates whether a patient will respond to hormone blocking treatment, the standard therapy for this kind of cancer.

In this study, published in The Lancet Regional Health – Europe, 75,211 women with breast cancer diagnosed in Sweden between 2007 and 2023 were included. Acs and colleagues measured the percentage ER positivity of their tumors and classified the participants as ER-zero (0%), ER-low (1-9%), ER-mild (10-29%), ER-moderate (30-59%), and ER-high (60-100%).

“Our study is, to our knowledge, the first large nationwide population-based analysis to comprehensively evaluate patient characteristics, treatment patterns, survival, and molecular features across the entire ER spectrum,” says Acs.

“Patients with… ER-mild, had survival outcomes that were remarkably similar to those with ER-low and even ER-negative disease. We also found that patients with ER-mild and ER-moderate tumors had significantly worse survival than patients with strongly ER-positive tumors.”

Survival in the ER-mild and ER-mod groups was 59% and 31% worse than women in the ER-high group. Survival outcomes and molecular characteristics of those in the ER-mild group were very similar to those of patients in the ER-low and ER-zero groups.

Some patients classed as ER-mild or ER-mod were given chemotherapy in addition to endocrine therapy and this improved survival in these patients by 54% and 40%, respectively.

“Current classifications rely heavily on a single threshold, but our results suggest that tumor biology does not change abruptly at a specific percentage,” says Acs. “Better recognition of these subgroups may ultimately lead to more individualized treatment recommendations and more accurate discussions regarding prognosis.”

Acs and colleagues plan to continue their work in this area and explore factors that are currently unclear such as the role of additional biomarkers like progesterone receptor expression.

“We are also interested in exploring the biological mechanisms underlying the similarities between ER-low, ER-mild, and ER-negative tumors,” notes Acs. “Future studies will also need to validate these findings and investigate how ER expression should be incorporated into treatment decision-making and clinical trial design.”