The Effect of Early Neutropenia on PFS with Ribociclib Treatment in Advanced Breast Cancer

Technical Summary: The Effect of Early Neutropenia on PFS with Ribociclib Treatment in Advanced Breast Cancer

Problem Statement
In the treatment of hormone receptor-positive (HR+) metastatic breast cancer, resistance to endocrine therapy remains a primary limitation. While the addition of Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, such as ribociclib, to endocrine therapy has significantly improved progression-free survival (PFS), the management of adverse events is critical for maintaining treatment adherence. Neutropenia is the most common side effect of this drug class. While certain adverse events (e.g., acneiform rash with EGFR inhibitors) have been correlated with improved treatment response, the prognostic significance of neutropenia induced by CDK4/6 inhibitors remains unclear. This study investigates whether the timing and severity of neutropenia during ribociclib treatment serve as prognostic indicators for PFS in patients with advanced breast cancer.

Methodology
This was a single-center, retrospective study conducted at Ondokuz Mayıs University Faculty of Medicine involving 67 female patients diagnosed with metastatic breast cancer between January 2020 and December 2023.

• Inclusion Criteria: Patients receiving ribociclib (600 mg/day, 3-weeks-on/1-week-off) combined with endocrine therapy (letrozole or fulvestrant) in the first or second line of treatment.
• Exclusion Criteria: Male patients, those requiring dose reductions below 600 mg, and patients with elevated creatinine or liver enzymes (ALT/AST) necessitating dose adjustments.
• Data Collection: The study analyzed demographic data, immunohistochemical markers (ER, PR, Ki67, CerbB2/HER2), metastatic site distribution, and neutropenia parameters (severity and time of onset).
• Statistical Analysis: Survival analysis was performed using the Kaplan-Meier method with log-rank tests. Univariate and multivariate Cox proportional hazards regression models were utilized to evaluate prognostic factors for PFS. Statistical significance was set at p < 0.05.

Key Contributions and Results
The study evaluated 67 patients with a mean age of 53.22 years. Key findings include:

1. Neutropenia and PFS:

   • Timing: Patients who developed neutropenia within the first 3 months of treatment exhibited significantly shorter PFS compared to those developing it later or not at all (χ²=13.769; p=0.001).
   • Severity: Patients with neutrophil counts dropping below 1,000/µL had significantly shorter PFS compared to those with counts above 1,000/µL (χ²=12.932; p=0.002).
   • Cox Regression: In univariate analysis, neutrophil counts below 1,000 were significantly associated with an increased hazard of progression (HR=1.562; p=0.049). However, in multivariate analysis, neutropenia severity and timing lost their status as independent predictors of progression risk.

2. Immunohistochemical Markers:

   • CerbB2 (HER2): A statistically significant difference in PFS was observed based on CerbB2 scores. Specifically, patients with a score of 1+ demonstrated significantly longer PFS compared to those with a score of 2+ (p=0.005). In multivariate analysis, a CerbB2 score of 1+ was an independent predictor of lower progression risk (HR=0.070; p=0.021).
   • Other Markers: No statistically significant associations were found between PFS and ER levels, PR levels, Ki67 levels, or the baseline Neutrophil-to-Lymphocyte Ratio (NLR) (p > 0.05).

3. Metastatic Burden:

   • Patients with single-site metastases had longer PFS (20.37 months) compared to those with two or more metastatic sites (13.59 months).

Significance and Claims
The paper concludes that while neutropenia is the most prevalent adverse event associated with ribociclib, its occurrence—specifically early onset and severity (neutrophils <1,000)—is associated with shorter progression-free survival in univariate analyses. However, the authors modestly claim that these neutropenia-related parameters do not function as independent prognostic factors when analyzed alongside other clinical variables in multivariate models.

Conversely, the study identifies CerbB2 status, particularly the distinction between score 1+ and 2+, as a significant and independent prognostic factor for PFS in this cohort. The authors suggest that while neutropenia may correlate with clinical outcomes, it likely reflects a shared biological domain with other factors rather than acting as a standalone mechanism. The study highlights the need for larger, multicenter investigations to further elucidate the relationship between treatment-induced neutropenia and therapeutic efficacy, noting that current findings are limited by the retrospective nature and small sample size of the single-center study.