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
Abstract
Summary 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 10.13039/100004325AstraZeneca/Daiichi Sankyo.