| Summary: | Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043–1.1, <i>p</i> = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024–0.55, <i>p</i> = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013–0.42, <i>p</i> = 0.003). Overall, the survival time increased with reduced dose for both single drugs (<i>p</i> < 0.01) and combined drugs (<i>p</i> < 0.001), resulting in tumors with fewer proliferation cells (<i>p</i> = 0.0026) and more apoptotic cells (<i>p</i> = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.
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