Estrogen Receptor-Low Breast Cancer: A Gray Zone
- ER-low (1-10%) breast cancer remains a biologic gray zone. Retrospective data support use of endocrine therapy, but these tumors often behave more like triple-negative disease, particularly when high-grade.
- The benefit of targeted therapies in metastatic ER-low disease is unclear. Agents such as PI3K pathway inhibitors are often used by extrapolation rather than strong prospective evidence.
- Neoadjuvant chemo-immunotherapy may redefine management. The KEYNOTE-756 trial evaluating chemotherapy ± pembrolizumab has shown improved pCR, with EFS data pending and potential implications for high-risk ER-low patients.
Estrogen receptor-low (ER-low) breast cancer occupies one of the most challenging gray zones in breast oncology. These tumors don’t behave like classic hormone receptor-positive disease, yet they are not fully triple-negative either, leaving clinicians to navigate decision-making around endocrine sensitivity, appropriate use of chemotherapy, and the role of targeted and immune-based therapies.
“These ER-low patients — it is an entity. It is a phenomenon. We as a field have known about this for a long time,” says Dr. Neil Vasan, a breast cancer oncologist who runs the Vasan Lab at NYU Langone.
How these ER-low tumors should be managed isn’t clear cut. Retrospective data suggest that even minimal ER expression may confer some endocrine responsiveness.
“Many, many decades ago, ER positivity was actually defined as 10% or greater. Then that number became lower, and there’s actually even high-quality retrospective data showing that even [with] low levels of ER, those patients still benefit from endocrine therapy,” Dr. Vasan explains. “So we do give endocrine therapy.”
However, endocrine therapy alone is rarely considered adequate for many of these patients.
“Do we also need to give chemotherapy? Do we also need to give different cytotoxic agents?” Dr. Vasan asks. Clinically, many ER-low tumors present as high-grade and highly proliferative, supporting the view that they share biologic features with triple-negative breast cancer and may require more aggressive systemic therapy.
Another unresolved issue is the value of targeted therapies commonly used in hormone receptor-positive disease. “It’s not so clear that the women with low ER in the metastatic setting benefit from the targeted therapies that we give,” Vasan says. This uncertainty extends to PI3 kinase pathway inhibitors. “I think that’s still an open question. We offer it because we don’t really have other things to offer.”
As a result, treatment decisions in ER-low disease are frequently extrapolated from both hormone receptor-positive and triple-negative paradigms, rather than guided by dedicated prospective data.
The Future Of Treating ER-Low Breast Cancer
“Where the ER-low status has clearly become a biomarker — or at least an entity that we’re thinking about expanding our therapies — is in the neoadjuvant setting,” Dr. Vasan says.
This approach is informed by advances in triple-negative breast cancer, where multi-agent chemotherapy plus immunotherapy has become standard for high-risk, locally-advanced disease. Investigators are now evaluating whether similar chemo-immunotherapy strategies should be applied to high-grade ER-positive tumors, including ER-low cancers.
The KEYNOTE-756 study is evaluating chemotherapy with or without pembrolizumab in patients with high-risk ER-positive breast cancer. The trial has already demonstrated an improvement in pathologic complete response, with anticipated further data to come. “That will be a very exciting trial,” Dr. Vasan says. “And if that does lead to approval, that would help I think a very good number of patients.”
Clinical Takeaway
In current practice, most clinicians continue to classify ER-low tumors as hormone receptor-positive and recommend endocrine therapy, frequently layering in chemotherapy — particularly for high-grade or high-risk disease. Most also maintain a lower threshold to treat these patients in a TNBC-like manner.
Until prospective data mature, ER-low breast cancer will remain a biologically and clinically heterogeneous population requiring individualized, risk-adapted treatment strategies.
