Abstract B16: Mathematical modeling identifies optimum palbociclib dosing schedules for the treatment of estrogen receptor-positive (ER+) breast cancer patients
Authors: Stein Shayna , Nardone Agostina , Liu Weihan , Cohen Gabriella , Guarducci Cristina , Brown Myles , Jeselsohn Rinath , Michor Franziska 
Published: June 2020

Abstract
Fulvestrant and other endocrine therapies are widely used to treat estrogen receptor-positive (ER+) breast cancer, although most patients eventually develop treatment resistance. Endocrine therapy-resistant tumors have been shown to be sensitive to cyclin-dependent kinases 4/6 (CDK4/6) inhibitors, including palbociclib, abemaciclib, and ribociclib, which have recently been approved to be used in combination with endocrine therapies to treat ER+ breast cancers. Given the large number of possible pairwise drug combinations, systematically comparing different combinations and administration schedules experimentally is difficult, though it has been shown that altering therapy administration schedules can substantially improve treatment outcomes. Here, we develop a novel mathematical model to characterize the pharmacodynamic response to fulvestrant-palbociclib combination therapy in fulvestrant-sensitive and -resistant MCF7 cells. We use a cell cycle explicit model to describe changes in the G1/S transition rates in response to the combination therapy, and a Bayesian statistical inference approach to estimate model parameters from the in vitro data. We then combine the results from our pharmacodynamic model with published pharmacokinetic data to systematically compare dose administration schedules computationally. We use in silico clinical trials to identify treatment schedules within the clinical toxicity limits that are predicted to be more effective than the current standard of care. Our results suggest that continuous dosing of 75mg of palbociclib with no treatment holiday is more effective for slowing down tumor growth and lowering overall tumor burden than the current palbociclib treatment standard (125mg of palbociclib per day, three weeks on, followed by a one-week holiday). We predict that both palbociclib treatment strategies are most effective when combined with the current standard fulvestrant administration schedule, even when considering various levels of fulvestrant resistance. Thus, we plan to compare the two palbocilib schedules described above in combination with the current standard fulvestrant therapy in an investigator-led clinical trial at Dana-Farber Cancer Institute. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment strategies in search of optimal combination dosing strategies for ER+ breast cancer.
Citation Format: Shayna Stein, Agostina Nardone, Weihan Liu, Gabriella Cohen, Cristina Guarducci, Myles Brown, Rinath Jeselsohn, Franziska Michor. Mathematical modeling identifies optimum palbociclib dosing schedules for the treatment of estrogen receptor-positive (ER+) breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B16.