Initial tumor composition shapes resistance evolution and treatment outcomes in non-small cell lung cancer

The way resistance to treatment evolves and impacts treatment outcomes in non-small cell lung cancer (NSCLC) is influenced significantly by the initial composition of the tumor, according to a study. Researchers used a mathematical model based on game theory, and tested it against data from alectinib-sensitive and alectinib-resistant H3122 NSCLC cells cultivated under various treatment and environmental conditions.

They discovered that the impact of resistance evolution on a cell's fitness was heavily dependent on how prevalent resistant cells were at the start.

When resistant cells were initially scarce, resistance developed more quickly, and a higher level of resistance led to a growth advantage for the tumor. Conversely, if resistant cells were already plentiful, increasing resistance resulted in a fitness cost for the tumor. Regardless of the initial resistance level, the presence of more resistant cells generally led to decreased treatment efficacy.

In scenarios where resistance was beneficial, once the tumor reached a stable state, keeping resistant cells out was crucial. Furthermore, the optimal dosage for treatment, measured by the maximum tolerated dose, did not always lead to the longest progression-free time. Instead, intermediate doses often proved more effective when they maintained the tumor's initial growth rate at a minimal level.

These findings imply that any treatment strategy for NSCLC should not just consider the current number of resistant cells, but also how resistance is evolving and what benefits or drawbacks it currently confers to individual patients.