PhD defence C.L. (Louwrens) Braal

Dissertation in short:

Breast cancer is the most frequently diagnosed type of cancer among women in the Western world.1–3 Pharmacotherapy plays an essential role in the treatment of breast cancer. In this thesis, several examples are presented to provide guidance on individualising pharmacotherapy from both a pharmacokinetic and pharmacodynamic perspective. In the mentioned chapters below, results of clinical studies are described to optimise treatment with tamoxifen (Section I) or a CDK4/6 inhibitor (Section II) in patients with hormone sensitive breast cancer.

Tamoxifen is considered one of the first targeted therapies in oncology.4–8 Tamoxifen is mainly used in the adjuvant setting of hormone sensitive breast cancer and reduces the risk of disease recurrence.9,10 CDK4/6 inhibitors  – palbociclib, ribociclib and abemaciclib – are used in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.11,12 Both tamoxifen and the various CDK4/6 inhibitors are administered orally. Despite considerable differences between patients, tamoxifen and CDK4/6 inhibitors are prescribed at a fixed dose.

The difference in absorption, distribution, metabolism or elimination (ADME) of an orally administered drug results in a high interindividual variability of drug concentrations.13 Patients with low exposure to a drug have an increased risk of reduced efficacy, while patients with a high exposure are more susceptible to suffer from treatment-related adverse events. With orally administered anticancer drugs (targeted therapies), it is estimated that ± 30% of patients are underdosed and ± 15% are overdosed, despite dose adjustments for renal or hepatic impairment.