Tumor heterogeneity: a central foe in the war on cancer

A new paradigm

Treatment of a tumor is one of the major selective pressures that shapes its evolution and recent evidence has emerged that these selective pressures can be highly dynamic. Study findings have shown that there is a cost associated with evolution of resistant subclones and, if the selective pressure of therapy is removed, that cost may become too high, such that resistant subclones are then outcompeted by drug-sensitive ones. There have been reports of reversal of drug resistance when drug treatment is interrupted.

The current treatment paradigm is to try to eliminate tumors by hitting them hard and fast with the maximum tolerated dose (MTD) of a drug. However, there is increasing appreciation that this may be inadvertently fostering more rapid disease progression because it selects for the emergence of resistant cells and eliminates all their competitors (Figure 2).

This is driving a potential paradigm shift, in which researchers are applying concepts from evolutionary biology and the control of invasive species to the treatment of cancer. Instead of completely eliminating a cancer, a strategy of adaptive therapy could be used to set up competition between different subclones and keep tumor growth in check by exploiting the high cost of resistance.²²

Adaptive therapy involves the use of treatment holidays, intermittent dosing schedules or reduced drug doses, rather than using the MTD. Adaptive therapy was tested recently in mice with triple-negative and estrogen receptor-positive breast cancer. The standard maximum dose of chemotherapy was compared with adaptive therapy with either reduced doses or skipped doses as the tumor responded. Tumor growth initially decreased with all 3 treatment scenarios, but then regrew when chemotherapy was stopped or doses were skipped. However, adaptive therapy with lower doses resulted in long-term stabilization of the tumor where treatment was eventually able to be withdrawn.²³ Clinical trials of several different types of adaptive therapy strategies are ongoing (Table 3).