Mathematical modeling identifies optimum palbociclib-fulvestrant dose administration schedules for the treatment of estrogen receptor-positive breast cancer patients.

Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors such as palbociclib are approved for the treatment of metastatic estrogen receptor-positive (ER+) breast cancer in combination with endocrine therapies, and significantly improve outcomes in patients with this disease. However, given the large number of possible pairwise drug combinations and administration schedules, it remains unclear which clinical strategy would lead to best survival. Here, we developed a computational, cell cycle-explicit model to characterize the pharmacodynamic (PD) response to palbociclib-fulvestrant combination therapy. This PD model was parameterized, in a Bayesian statistical inference approach, using in vitro data from cells with wild-type estrogen receptor (WT-ER) and cells expressing the activating missense ER mutation, Y537S, which confers resistance to fulvestrant. We then incorporated pharmacokinetic (PK) models derived from clinical data into our computational modeling platform. To systematically compare dose administration schedules, we performed in silico clinical trials based on integrating our PD and PK models as well as considering clinical toxicity constraints. We found that continuous dosing of palbociclib is more effective for lowering overall tumor burden than the standard, pulsed-dose palbociclib treatment. Importantly, our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment strategies in search of optimal combination dosing strategies of other cell-cycle inhibitors in ER+ breast cancer.