Abstract
Simple SummarySince the micro-environment of colonic tumors, including their immune structure would affect the response to treatments, we study the response of five groups of tumors clustered based on their immune patterns to a common colon cancer treatment. We develop a data driven mathematical model to investigate the behavior of key players in colonic tumors in each of these clusters in response to the FOLFIRI treatment. Although the model shows clear differences in the behavior of tumors in different clusters, it cannot suggest a unique optimal treatment strategy for each cluster. The results show that there is not much difference in the dynamics of tumors in response to 5-FU alone versus 5-FU plus Leucovorin. However, adding Irinotecan changes the dynamics of T-reg and dendritic cells leading to a remarkably slower tumor recurrence, especially for tumors in a cluster, which has the highest level of T-reg/T-helper ratio compared to the other clusters.Many colon cancer patients show resistance to their treatments. Therefore, it is important to consider unique characteristic of each tumor to find the best treatment options for each patient. In this study, we develop a data driven mathematical model for interaction between the tumor microenvironment and FOLFIRI drug agents in colon cancer. Patients are divided into five distinct clusters based on their estimated immune cell fractions obtained from their primary tumors’ gene expression data. We then analyze the effects of drugs on cancer cells and immune cells in each group, and we observe different responses to the FOLFIRI drugs between patients in different immune groups. For instance, patients in cluster 3 with the highest T-reg/T-helper ratio respond better to the FOLFIRI treatment, while patients in cluster 2 with the lowest T-reg/T-helper ratio resist the treatment. Moreover, we use ROC curve to validate the model using the tumor status of the patients at their follow up, and the model predicts well for the earlier follow up days.
Highlights
Colorectal cancer (CRC), the third most common cancer diagnosed in both men and women in the United States excluding skin cancers, is estimated to cause about52,980 deaths during 2021 [1]
We extend our previous model including the interaction between Fluorouracil, Leucovorin, Irinotecan, and various cell types in tumor to investigate the effect of these drugs on tumors in each cluster
The drug inputs are the median drug dosages from patients treated with FOLFIRI—770, 725 and 300 mg of 5-FU, Leucovorin and Irinotecan, respectively
Summary
Colorectal cancer (CRC), the third most common cancer diagnosed in both men and women in the United States excluding skin cancers, is estimated to cause about52,980 deaths during 2021 [1]. Radiation therapy and systemic therapies that use medications such as chemotherapy, targeted therapy, and immunotherapy are the treatment options depending on several factors such as the type and stage of the disease, the molecular analysis of the tumor, possible side effects and overall health of the patients [2,3]. Stage tumors can be curable with surgical resection while many patients with advance stage and metastatic CRC receive chemotherapy as a combination of treatment [4]. Survival rate remains poor for patients with metastatic CRC despite advances in the primary treatment of chemotherapy [6]. Predicting variability in response to treatments to increase survival rate and arrive at precision medicine, we need to understand disease progression and determine the major drivers for each patient
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