The effect of tumor composition on the success of adaptive therapy: the case of metastatic castrate-resistant prostate cancer

Abstract

Prostate-specific antigen (PSA) is the most commonly used serum marker for prostate cancer. It plays a role in cancer detection, treatment monitoring, and more recently, in guiding adaptive therapy protocols, where treatment is alternated based on PSA levels. However, the relationship between PSA levels and tumor volume remains poorly understood. Empirical evidence suggests that different cancer cell types produce varying amounts of PSA. Despite this, current mathematical cancer models often assume either that all cell types contribute equally to PSA levels or that only certain subpopulations produce PSA at fixed rates. In this study, we compare Zhang et al.'s classical adaptive therapy protocol with the standard of care, which involves continuous maximum tolerable dose treatment, under different assumptions regarding PSA production. Specifically, we explore the possibility that testosterone-dependent, testosterone-producing, and testosterone-independent cells contribute to PSA production to varying degrees. We use the time to competitive release as a proxy for the time to disease progression. Our findings indicate that adaptive therapy consistently results in a longer time to competitive release compared to the standard of care, regardless of the assumptions about PSA production. However, when testosterone-independent cells are the sole PSA producers, Zhang et al.'s adaptive therapy protocol becomes inapplicable, as PSA levels never fall to half of their initial value, preventing therapy discontinuation. Additionally, we observe that the number and duration of treatment cycles in adaptive therapy are highly sensitive to assumptions about how much each cell type contributes to PSA production. Overall, our results emphasize the need for a deeper understanding of patient-specific PSA dynamics, which could enhance the effectiveness of adaptive therapy in prostate cancer treatment.