New findings from researchers at City St George’s, University of London indicate that providing patients with a second cancer treatment while a tumor is still shrinking under a first-line therapy could outperform current methods of retreating the cancer after relapse. The study, published in the journal Genetics, adapted mathematical models of evolutionary rescue theory of how plants and animals evolve in response to environmental pressures to discover how a second treatment before tumors have gained resistance mutations can improve cancer treatments.
Commenting on what the St. George’s team called a “kick it while it’s down” strategy, lead researcher Robert Noble, DPhil, a senior lecturer in applied mathematics said, “Although tumors may at first shrink under therapy, in many cases they eventually regrow. These relapses stem from a small number of cancer cells that have gained mutations making the cells resistant to the treatment.”
It has been well established that cancer cells evolve over time to survive by evading the tumor-killing properties of cancer therapies.
As the researchers wrote: “Just as species in an ecosystem interact, compete for resources, adapt to changing environmental conditions and undergo natural selection, so cancer clones rise and fall in a tumor ecosystem. Darwinian principles inevitably determine therapeutic responses including the emergence of resistance, which, despite pharmaceutical advances, remains the greatest challenge in oncology.”
Under treatment pressure, sensitive cancer cells are killed, but those resistant to the initial treatments survive and continue to grow. Evolutionary rescue theory describes how populations at risk of extinction can recover through adaptive mutations. Applied to cancer, it predicts that small, fragmented tumor populations are more vulnerable to stochastic extinction and less able to mount a successful adaptive response.
“First-line cancer treatment frequently fails due to initially rare therapeutic resistance,” the investigators wrote. “An important clinical question is then how to schedule subsequent treatments to maximize the probability of tumor eradication.” In this study, the team sought to determine when the optimal time is to apply a second “strike” of a new therapy.
“Whereas standard clinical practice is to wait for evidence of relapse, we confirm a recent hypothesis that the optimal time to switch to a second treatment is when the tumor is close to its minimum size before relapse, when it is likely undetectable,” they wrote.
To find the sweet spot for a second therapy the investigators adapted existing evolutionary rescue theory models for the first time to better understand at which point tumors are most vulnerable to treatment by preventing them from evolving treatment resistance. “Our approach yields clearer explanations and more general results than previous computational modeling, in that we perform a more systematic analysis of the parameter space and we obtain extensive analytical results.”
Their models examined how treatment efficacy, cost of resistance, intrinsic death rates, turnover, and carrying capacity influence extinction probability. The researchers determined that the optimal switching point is typically slightly before or slightly after the tumor nadir. Given clinical uncertainty in pinpointing that moment, they found that switching to a new therapy slightly later is generally preferable to switching too early, but waiting until the tumor becomes detectable again increases the probability that rescue mutants will emerge to drive cancer relapse.
The team also evaluated treatment combinations of unequal efficacy. In general, they found that higher efficacies in the therapies of both strikes increase tumor extinction probability at the optimal switching size, while again noting that the timing of the strikes could alter outcomes. The researchers also noted that under some conditions, a lower-efficacy first treatment followed by a higher-efficacy second treatment produced a broader window of high extinction probability.
While these findings could eventually pave the way for new treatment regimens across a range of tumor types, the researchers noted that this two-strike therapy is most likely to succeed in relatively small tumors. The team also noted the possibility that additional strikes following the same principle could increase extinction probabilities in larger tumors.
Three small clinical trials using this regimen are now underway in soft-tissue cancer, prostate cancer, and breast cancer, with further trials in development. The researchers write that their work “establishes a foundation for further experimental and clinical investigation of this evolutionarily-informed multi-strike treatment strategy.”
