Should CDK4/6 inhibitor plus endocrine therapy be standard of care for ER-low (1–10%) HR+/HER2− metastatic breast cancer? A multicenter registry cohort.

1102 Background: ER-low (1–10%) HR+/HER2− metastatic breast cancer (MBC) is increasingly recognized as a distinct clinical subgroup with limited endocrine sensitivity, yet ER-low–specific evidence to guide optimal first-line treatment is sparse. We assessed real-world effectiveness of CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) in ER-low MBC and benchmarked outcomes against contemporaneous ER-high disease treated with the same approach. Methods: We performed a multicenter cohort study using a prospective institutional registry of women with HR+/HER2− MBC who initiated CDK4/6i (palbociclib/ribociclib/abemaciclib) plus an aromatase inhibitor or fulvestrant between January 2018 and October 2024, with follow-up through December 2024. ER expression by immunohistochemistry was categorized as low (1–10% or Allred 3–4), intermediate (10–66% or Allred 5–6), or high (>66% or Allred 7–8). Primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed by Kaplan–Meier/log-rank methods and multivariable Cox regression adjusting for age, ECOG performance status, progesterone receptor status, disease extent, CDK4/6i choice, and other clinicopathologic factors. Results: Among the 540 women with advanced HR+ HER2- breast cancer, 75% received CDK4/6i+ET in the first-line setting; ER-low tumors comprised 4.8% (n=26). ER-low disease had poor outcomes on CDK4/6i+ET with median PFS 2.9 months (95% CI 1.2–4.7) and median OS 12.6 months (95% CI 7.24–18.0), versus ER-high median PFS 23.3 months (95% CI 18.8–27.8) and median OS 49.7 months (95% CI 40.6–54.9) (log-rank p<0.001). ER-low status remained independently associated with inferior PFS (HR 10.6, 95% CI 5.02–22.4; p<0.001) and OS (HR 4.66, 95% CI 3.03–7.95; p<0.001) compared with ER-high after adjustment. Within the ER-low patients, the poor outcome was universally observed regardless of ET partner (AI vs fulvestrant), disease extent (visceral vs bone only), ECOG and HER2 status (low vs 0). Conclusions: ER-low HR+/HER2− MBC demonstrated very poor outcomes with CDK4/6i+ET, suggesting CDK4/6i plus AI/ET should not be assumed to be an effective default “standard HR+” approach for this subgroup. Given reported clinicopathologic and molecular similarities between ER-low/HER2− tumors and triple-negative breast cancer, ER-low–dedicated prospective trials and evaluation of TNBC-oriented strategies (including prioritization of chemotherapy-based regimens and TNBC clinical trial enrollment) are urgently needed.