Breast (Edinburgh, Scotland) · 2026
Interplay between HER2-Low status, hormone receptor expression, and therapeutic response to cyclin-dependent kinase 4/6 inhibitors as first-line treatment in luminal-like metastatic breast cancer: The CYCLHER study.
СтатьяМногоцентровое исследованиеНаблюдательное исследованиеНазвание и аннотация: Перевод в очереди
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Pontolillo Letizia, Munzone Elisabetta, Vigneri Paolo, Pistelli Mirco, Palazzo Antonella, La Verde Nicla, Mazzotta Marco, Paris Ida, Alesini Daniele, Santini Daniele, Cannita Katia, Orlandi Armando, Magnolfi Emanuela, Giacinti Laura, Raffaele Mimma, Carbognin Luisa, Santoro Angela, Rossi Alessandro, Arcuri Giorgia, Sangalli Claudia, Garrone Ornella, Mulè Antonio, Valenza Carmine, Berardi Rossana, Tortora Giampaolo, Bria Emilio, Curigliano Giuseppe, Giannarelli Diana, Fabi Alessandra
Аннотация
BACKGROUND: In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), the prognostic significance of estrogen receptor (ER), progesterone receptor (PgR), and HER2 immunohistochemical expression levels in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains unclear. The CYCLHER study was designed to evaluate treatment outcomes and identify biologically driven prognostic factors.
METHODS: CYCLHER (NCT06243432) is a retrospective, multicenter study conducted across 16 Italian oncology centers. Patients with HR+/HER2- mBC who received first-line endocrine therapy (ET) plus CDK4/6i between November 2016 and May 2023 were included. ER, PgR and HER2 status were assessed on metastatic or primary tumor samples. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and attrition rate. Optimal cut-off values for ER and PgR expression were determined using Cut-off Finder v1.0.
RESULTS: Among 597 eligible patients, median rwPFS was 28.1 months at a median follow-up of 41 months. HER2-low status emerged as a negative prognostic factor, being independently associated with shorter rwPFS compared to HER2-0 (p = 0.02). ER ≥ 87% and PgR ≥60% were associated with improved rwPFS, DCR, and 5-year OS rates. A prognostic score derived from the three biomarkers identified four groups with significantly different rwPFS outcomes (global log-rank p < 0.0001). The first-to-second line attrition rate was 16.2% (95% CI 12.4-20.0). The identified biomarkers did not significantly impact treatment outcomes in the second-line setting.
CONCLUSIONS: CYCLHER confirms the prognostic relevance of ER, PgR, and HER2 expression in patients with HR+/HER2-mBC treated with CDK4/6i. HER2-low status was associated with poorer outcomes, supporting its potential role as a negative prognostic marker. The proposed score may facilitate personalized treatment strategies and enhance risk stratification in clinical practice.
METHODS: CYCLHER (NCT06243432) is a retrospective, multicenter study conducted across 16 Italian oncology centers. Patients with HR+/HER2- mBC who received first-line endocrine therapy (ET) plus CDK4/6i between November 2016 and May 2023 were included. ER, PgR and HER2 status were assessed on metastatic or primary tumor samples. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and attrition rate. Optimal cut-off values for ER and PgR expression were determined using Cut-off Finder v1.0.
RESULTS: Among 597 eligible patients, median rwPFS was 28.1 months at a median follow-up of 41 months. HER2-low status emerged as a negative prognostic factor, being independently associated with shorter rwPFS compared to HER2-0 (p = 0.02). ER ≥ 87% and PgR ≥60% were associated with improved rwPFS, DCR, and 5-year OS rates. A prognostic score derived from the three biomarkers identified four groups with significantly different rwPFS outcomes (global log-rank p < 0.0001). The first-to-second line attrition rate was 16.2% (95% CI 12.4-20.0). The identified biomarkers did not significantly impact treatment outcomes in the second-line setting.
CONCLUSIONS: CYCLHER confirms the prognostic relevance of ER, PgR, and HER2 expression in patients with HR+/HER2-mBC treated with CDK4/6i. HER2-low status was associated with poorer outcomes, supporting its potential role as a negative prognostic marker. The proposed score may facilitate personalized treatment strategies and enhance risk stratification in clinical practice.
Предметные рубрики MeSH
AdultAgedFemaleHumansMiddle AgedBiomarkers, TumorBreast NeoplasmsCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Erb-b2 Receptor Tyrosine KinasesItalyPrognosisProgression-Free SurvivalProtein Kinase InhibitorsReceptors, EstrogenReceptors, ProgesteroneRetrospective StudiesTreatment OutcomeAminopyridinesPurines