Abstract
Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.
Author summary The individual cells within a cancer cell population are not all equal. The heterogeneity among them can strongly affect disease progression and treatment success. Recent diagnostic advances allow measuring how the characteristics of this heterogeneity change over time. To match these advances, we developed deterministic and stochastic trait-based models that capture important characteristics of the intratumour heterogeneity and allow to evaluate different treatment types that either do or do not interact with this heterogeneity. We focus on growth rate as the decisive characteristic of the intratumour heterogeneity. We find that by shifting the trait distribution of the cancer cell population, the growth rate-dependent treatment delays an eventual relapse compared to the growth rate-independent treatment. As a downside, however, we observe a refuge effect where slower-growing subpopulations are less affected by the growth rate-dependent treatment, which may decrease the likelihood of successful therapy. We find that navigating along this trade-off may be achieved by sequentially combining both treatment types, which agrees qualitatively with current clinical practice. Interestingly, even rather large intervals between treatment changes allow for close-to-optimal treatment results, which again hints towards a practical applicability.
Competing Interest Statement
MB performed contract research for Affimed, Amgen and Regeneron, served on the advisory board of Amgen and Incyte, and in the speaker bureau of Amgen, Janssen, Pfizer and Roche.
