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Determining duration of HER2-targeted therapy using stem cell extinction models
Lindsay Riley1, Hua Zhou, Kenneth Lange
1Department of Biomathematics, School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Introduction:
Trastuzumab dramatically improves survival in breast cancer patients whose tumor overexpresses HER2. A subpopulation of cells in human breast tumors has been identified with characteristics of cancer stem cells. These breast cancer stem-like cells (BCSCs) rely on HER2 signaling for self-renewal, suggesting that HER2-targeted therapy targets BCSCs even when the bulk of the tumor does not overexpress HER2. In order to guide clinical trials examining HER2-targeted therapy in the adjuvant setting, we propose a mathematical model to examine BCSC population dynamics and predict optimal duration of therapy.
Methods:
Varying the susceptibility of BCSCs to HER2-targeted therapy, we quantify the average time to extinction of BCSCs. We expand our model using stochastic simulation to include the partially differentiated tumor cells (TCs) that represent bulk tumor population and examine effects of plasticity on required duration of therapy.
Results:
Lower susceptibility of BCSCs and increased rates of dedifferentiation entail longer extinction times, indicating a need for prolonged administration of HER2-targeted therapy. We predict that even when therapy does not appreciably reduce tumor size in the advanced cancer setting, it will eventually eradicate the tumor in the adjuvant setting as long as there is at least a modest effect on BCSCs.
Conclusions:
We anticipate that our results will inform clinical trials of targeted therapies in planning the duration of therapy needed to eradicate BCSCs. Our predictions also address safety, as longer duration of therapy entails a greater potential impact on normal stem cells that may also be susceptible to stem cell-targeted therapies.
Insights
HER2-targeted therapy can eradicate breast cancer stem-like cells (BCSCs), even in early-stage treatment. Prolonged therapy duration is crucial for BCSC extinction, guiding clinical trials for optimal treatment strategies.
Area of Science:
- Oncology
- Mathematical Biology
- Cancer Stem Cell Research
Background:
- Trastuzumab enhances survival in HER2-overexpressing breast cancer.
- Cancer stem-like cells (BCSCs) in tumors rely on HER2 signaling for self-renewal.
- HER2-targeted therapy may impact BCSCs even if the bulk tumor doesn't overexpress HER2.
Purpose of the Study:
- To develop a mathematical model for BCSC population dynamics.
- To predict the optimal duration of HER2-targeted therapy in the adjuvant setting.
- To guide clinical trials for HER2-targeted therapies.
Main Methods:
- Quantified BCSC extinction time by varying therapy susceptibility.
- Expanded the model using stochastic simulation to include tumor cells (TCs).
- Examined the impact of cell plasticity on therapy duration.
Main Results:
- Lower BCSC susceptibility and higher dedifferentiation rates necessitate longer therapy.
- HER2-targeted therapy can eventually eradicate tumors in the adjuvant setting.
- Therapy is effective if it has a modest impact on BCSCs, even if tumor size reduction is not significant.
Conclusions:
- Results inform clinical trials on the necessary duration of targeted therapy to eradicate BCSCs.
- Predictions address safety concerns regarding potential impacts on normal stem cells with prolonged therapy.
