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.
In patients with hormone receptor-positive/HER2-negative metastatic breast cancer, HER2-low status is linked to shorter progression-free survival when treated with CDK4/6 inhibitors.
Where it sits
this study against the rest of the leuprorelin corpusSummary and findings
The CYCLHER study evaluated treatment outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer receiving first-line endocrine therapy plus CDK4/6 inhibitors. Among 597 eligible patients, the median real-world progression-free survival (rwPFS) was 28.1 months at a median follow-up of 41 months. HER2-low status was associated with shorter rwPFS compared to HER2-0 (p = 0.02).
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
Background
The study investigates the prognostic significance of estrogen receptor (ER), progesterone receptor (PgR), and HER2 expression in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer treated with cyclin-dependent kinase 4/6 inhibitors. Previous research has indicated variable outcomes based on these biomarkers, but their specific roles in treatment response remain unclear. This study aims to clarify these relationships and their implications for treatment strategies.
Methods
CYCLHER is a retrospective, multicenter study involving 597 patients from 16 Italian oncology centers who received first-line endocrine therapy plus CDK4/6 inhibitors between November 2016 and May 2023. The primary endpoint was real-world progression-free survival (rwPFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and attrition rate. Biomarker status was assessed on tumor samples.
Results
The primary endpoint, median rwPFS, was 28.1 months at a median follow-up of 41 months. HER2-low status was associated with shorter rwPFS compared to HER2-0 (p = 0.02). Higher levels of ER (≥ 87%) and PgR (≥ 60%) correlated with improved rwPFS, DCR, and 5-year OS rates. A prognostic score derived from the biomarkers indicated significant differences in rwPFS outcomes across four groups (global log-rank p < 0.0001).
Interpretation
The findings align with prior literature suggesting that ER and PgR levels can influence treatment outcomes in metastatic breast cancer. However, while the statistical significance of these findings is clear, the clinical significance of the differences in rwPFS may be limited, particularly for small effect sizes. The retrospective nature of the study and lack of impact in the second-line setting are notable confounds that may affect the applicability of these results in practice.
Key findings
- Median rwPFS was 28.1 months at a median follow-up of 41 months.
- HER2-low status was 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.
- First-to-second line attrition rate was 16.2% (95% CI 12.4-20.0).
- Global log-rank p < 0.0001 for rwPFS outcomes across four prognostic groups.
Limitations
- Retrospective study design.
- Multicenter variability may introduce confounding.
- Impact of biomarkers not significant in second-line treatment.
- Short follow-up duration may limit long-term outcome assessment.