Prognostic value of hormone receptor expression in patients with HR+/HER2− advanced BC treated with first-line ET+CDK4/6i: results from the multicentre observational, real-world PALMARES-2 study

Background: Endocrine therapy (ET) plus Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) is the recommended first-line treatment for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2− aBC). The prognostic value of the spectrum of Oestrogen Receptor (ERα) and Progesterone receptor (PgR) expression remains poorly investigated in this setting. Methods: We used updated data from the largest annotated dataset from the multicentre, real-world, Italian study PALMARES-2 (NCT06805812) to evaluate the association between ERα expression and real-world Progression-Free Survival (rwPFS), or time-to-chemotherapy (rwTTC), in patients with HR+/HER2− aBC treated with first-line ET plus CDK4/6/i. ERα expression was classified as low-intermediate (LI: 1–49%), high (H: 50–89%) or very-high (VH: 90–100%). We also assessed the prognostic value of combining PgR (<20% vs. ≥20%) and ERα expression. Multivariable Cox regression models were used to adjust associations for clinically relevant covariates. Findings: Among 4115 patients with available ERα assessment, 157 (3.8%) had ER-LI, 967 (23.5%) had ER-H and 2991 (72.7%) had ER-VH tumours. Median rwPFS and rwTTC increased progressively with increasing ERα expression (ER-LI: 10.6 and 14.3 months; ER-H: 20.5 and 29.9 months; ER-VH: 28.5 and 40.7 months, respectively; p < 0.001). PgR expression provided additional prognostic stratification, with patients with ER-VH/PgR-high tumours showing the longest median rwPFS (32.4 months, 95% CI 30.2–34.9), while those with ER-LI/PgR-low tumours had the shortest (8.3 months; 95% CI 6.9–12). Interpretation: Effectiveness of first-line ET plus CDK4/6i in patients with HR+/HER2− aBC worsens progressively with decreasing ERα expression, and PgR expression adds further prognostic discrimination, with low ERα and PgR expression identifying a subgroup of patients with particularly poor outcomes. Our findings, if confirmed by future studies, can help clinicians in personalising treatment choices and follow-up strategies in this clinical context. Funding: PALMARES-2 is an academic investigator-initiated study partially supported by AstraZeneca/Daiichi Sankyo.