Remarkable progress has recently been made in the treatment of locally advanced, hormone receptor-positive, HER2-negative breast cancer with a high risk of recurrence, thanks to the addition of abemaciclib to endocrine therapy. This combination has led to a significant improvement in invasive disease-free survival. However, despite the combination's acceptable safety profile, 38% of patients experience grade 3 or higher diarrhea, and 23% experience grade 3 or higher neutropenia. This toxicity can lead to the premature discontinuation of treatment, limiting the benefits of this molecule. As with all oral therapies, the pharmacokinetics of abemaciclib lie at the intersection of efficacy and toxicity and can be modified by several external factors.
The hypothesis of the study is that abemaciclib's toxicity is correlated with its plasma levels and that its concentration is modified by certain patient characteristics. To this end, a pharmacokinetic model of abemaciclib could be developed using a prospective, multicenter, real-world blood dosage study. This study will describe the relationship between abemaciclib concentration and diarrhea and severe neutropenia, as classified by CTCAE, as well as potential clinical and drug interactions.
It is hoped that this model demonstrates the importance of monitoring abemaciclib concentrations. This could lead to a therapeutic trial in which the abemaciclib dose is adjusted according to concentration to limit toxicity while maintaining efficacy.
Women ≥ 18 years old
Having breast cancer of all histologies combined
Type Luminal A or B with positive hormone receptors (>10% expression for estrogen receptor and/or progesterone receptor) and HER2 negative or low epidermal growth receptor (according to GEFPICS1 definition)
Stage 2 or stage 3 according to the international classification, translated into the SENORIF recommendation
Hypersensitivity to any of the excipients listed in section 6.1 of the abemaciclib (Verzenios) SPC
History of treatment with an anti-CDK4/6 (palbociclib, ribociclib, abemaciclib) for any indication
History of invasive cancer of any histology within the last 2 years, except for superficial skin tumors, not considered to be in complete remission
Presence of functional or inflammatory colorectal disease (Crohn's disease, ulcerative colitis) causing chronic diarrhea (as defined by the WHO as at least 3 bowel movements per day and/or liquid stools for at least 1 month)
Single group
Blood samples for PK
Biological/VaccineThree additional blood tubes will be collected during routine biological tests.
Questionnaire
Other interventionEQ-5D-5L
Determine the relationship between the probability of occurrence of a severe diarrheal adverse event and plasma exposure to abemaciclib and its metabolites in patients with RH+HER2- breast cancer at high risk of recurrence receiving adjuvant abemaciclib
The probability of severe diarrhea (grades 2, 3, and 4 according to CTCAE v5.0) occurring based on exposure to abemaciclib and its metabolites (M2 and M20) will be characterized by a joint mixed-effects model combining longitudinal, pharmacokinetic (continuous type), and toxicity data (survival type).
Determine the relationship between the occurrence of severe neutropenic adverse events and plasma exposure to abemaciclib and its metabolites in patients with HR+, HER2- breast cancer at high risk of recurrence who are receiving adjuvant abemaciclib
The probability of severe neutropenia (grades 3 and 4 according to the current CTCAE) occurring based on exposure to abemaciclib and its metabolites (M2 and M20) will be characterized by a joint mixed-effects model combining longitudinal pharmacokinetic (continuous) and pharmacodynamic (neutrophil concentration, continuous) data. pharmacokinetic (continuous type) and pharmacodynamic (concentration of neutrophils, continuous type) data.
Develop a joint pharmacokinetic/pharmacodynamic (PK/PD) mixed-effects model that includes data on abemaciclib and metabolite concentrations, neutrophil counts, and severe diarrhea
The mixed-effects PK/PD model was validated using standard diagnostic tools, such as data fit diagnostic plots, visual predictive checks, estimation accuracy, and shrinkage.
Evaluate the free fraction (fu) of abemaciclib concentrations at different protocol treatment times in the target population (only at Poitiers University Hospital)
Free concentrations of abemaciclib will only be measured for patients enrolled at Poitiers University Hospital. The "fu" of abemaciclib concentrations will be modeled within the mixed-effects PK/PD model and any correlation with clinical-biological covariates will be evaluated. This exploratory analysis will only be performed on patients enrolled at Poitiers University Hospital for pre-analytical technical reasons. The technique has only been validated on the mass spectrometer in the pharmacology department at Poitiers University Hospital.
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