Vasily Giannakeas1, Victoria Sopik1, Steven A Narod2. 1. Women's College Research Institute, Toronto, Ontario, Canada. 2. Women's College Research Institute, Toronto, Ontario, Canada. Electronic address: steven.narod@wchospital.ca.
Abstract
OBJECTIVE: Women with ovarian cancer are treated with debulking surgery and chemotherapy. The bulk of ovarian cancer cells are resistant to chemotherapy prior to the death of the patient. It is not clear if chemoresistance is an acquired property of cells under the selective pressure of chemotherapy or if it is an innate property of a small proportion of cancer cells from the outset. METHODS: We developed a mathematical model to describe ovarian cancer progression based on the assumption that a small proportion of ovarian cancer cells are chemoresistant from the beginning (0.1%) and that there is no acquired resistance. The doubling time was fixed at two months for sensitive cells and four months for resistant cells. RESULTS: The proportion of chemoresistant cells increased over time and at the time of death, 90% of cells were resistant. The typical patient responded to the first three rounds of chemotherapy but was non-responsive thereafter. When we assume that the doubling times of the cancer cells is not fixed, but varies according to a normal distribution, the mean doubling time of the cells diminishes with time from diagnosis and death ensues shortly after chemoresistance is observed. CONCLUSIONS: We show that a model of inherent resistance in ovarian cancer is able to recapitulate the clinical history of a typical patient with ovarian cancer and that it is not necessary to invoke acquired resistance. This observation has potential clinical implications about how to approach new therapies.
OBJECTIVE:Women with ovarian cancer are treated with debulking surgery and chemotherapy. The bulk of ovarian cancer cells are resistant to chemotherapy prior to the death of the patient. It is not clear if chemoresistance is an acquired property of cells under the selective pressure of chemotherapy or if it is an innate property of a small proportion of cancer cells from the outset. METHODS: We developed a mathematical model to describe ovarian cancer progression based on the assumption that a small proportion of ovarian cancer cells are chemoresistant from the beginning (0.1%) and that there is no acquired resistance. The doubling time was fixed at two months for sensitive cells and four months for resistant cells. RESULTS: The proportion of chemoresistant cells increased over time and at the time of death, 90% of cells were resistant. The typical patient responded to the first three rounds of chemotherapy but was non-responsive thereafter. When we assume that the doubling times of the cancer cells is not fixed, but varies according to a normal distribution, the mean doubling time of the cells diminishes with time from diagnosis and death ensues shortly after chemoresistance is observed. CONCLUSIONS: We show that a model of inherent resistance in ovarian cancer is able to recapitulate the clinical history of a typical patient with ovarian cancer and that it is not necessary to invoke acquired resistance. This observation has potential clinical implications about how to approach new therapies.