Defining prognostic subgroups and treatment outcomes in estrogen receptor low-positive de novo metastatic breast cancer

BACKGROUND: Prognostic factors and treatment outcomes have been identified in estrogen receptor (ER) low-positive early-stage breast cancer. This study evaluates outcomes in ER low-positive de novo metastatic breast cancer (dnMBC) patients. METHODS: We conducted a retrospective cohort study of adults with human epidermal receptor-2 negative dnMBC diagnosed from 2018 to 2021 in the National Cancer Database. We classified ER status as negative (< 1%), low-positive (1-10%), or positive (11-100%). We compared overall survival by ER status using Cox regression, adjusting for age, metastatic sites, race/ethnicity, comorbidities, insurance, and treatment receipt. We then analyzed the cohort with ER low-positive patients stratified by progesterone receptor (PR) status, defined as negative (< 1%) or positive (1-100%). Among ER low-positive patients, we evaluated survival by first-course treatment. We distinguished cytotoxic chemotherapy from cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i) therapy based on the timing of endocrine therapy and chemotherapy. RESULTS: Among 27,672 patients, 3% had ER low-positive dnMBC. ER low-positive/PR-positive patients had longer median (95% CI) survival [19.8 (14.8-24.8) months] compared to both ER low-positive/PR-negative [11.8 (10.6-13.5) months] and ER-negative [12.9 (12.5-13.6) months] patients. ER low-positive/PR-positive patients had decreased risk of death compared to ER-negative patients (hazard ratio = 0.84, 95% CI 0.71-1.00), while ER low-positive/PR-negative patients did not. ER low-positive dnMBC patients who received chemotherapy followed by endocrine therapy (± CDK4/6i) or endocrine therapy + CDK4/6i had improved or similar survival compared to patients who received chemotherapy alone. CONCLUSIONS: PR-positivity identifies a subgroup of ER low-positive dnMBC patients with superior survival compared to ER-negative patients. First-line treatment incorporating endocrine therapy may be appropriate to consider for ER low-positive patients.