A Model of Gastric Mucosal pH Regulation: Extending Sensitivity Analysis Using Sobol' Indices to Understand Higher Moments.

Several recent theoretical studies have indicated that a relatively simple secretion control mechanism in the epithelial cells lining the stomach may be responsible for maintaining a neutral (healthy) pH adjacent to the stomach wall, even in the face of enormous electrodiffusive acid transport from the interior of the stomach. Subsequent work used Sobol' Indices (SIs) to quantify the degree to which this secretion mechanism is "self-regulating" i.e. the degree to which the wall pH is held neutral as mathematical parameters vary. However, questions remain regarding the nature of the control that specific parameters exert over the maintenance of a healthy stomach wall pH. Studying the sensitivity of higher moments of the statistical distribution of a model output can provide useful information, for example, how one parameter may skew the distribution towards or away from a physiologically advantageous regime. In this work, we prove a relationship between SIs and the higher moments and show how it can potentially reduce the cost of computing sensitivity of said moments. We define γ -indices to quantify sensitivity of variance, skewness, and kurtosis to the choice of value of a parameter, and we propose an efficient strategy that uses both SIs and γ -indices for a more comprehensive sensitivity analysis. Our analysis uncovers a control parameter which governs the "tightness of control" that the secretion mechanism exerts on wall pH. Finally, we discuss how uncertainty in this parameter can be reduced using expert information about higher moments, and speculate about the physiological advantage conferred by this control mechanism.

Investigating tumor-host response dynamics in preclinical immunotherapy experiments using a stepwise mathematical modeling strategy.

Immunotherapies such as checkpoint blockade to PD1 and CTLA4 can have varied effects on individual tumors. To quantify the successes and failures of these therapeutics, we developed a stepwise mathematical modeling strategy and applied it to mouse models of colorectal and breast cancer that displayed a range of therapeutic responses. Using longitudinal tumor volume data, an exponential growth model was utilized to designate response groups for each tumor type. The exponential growth model was then extended to describe the dynamics of the quality of vasculature in the tumors via [18F] fluoromisonidazole (FMISO)-positron emission tomography (PET) data estimating tumor hypoxia over time. By calibrating the mathematical system to the PET data, several biological drivers of the observed deterioration of the vasculature were quantified. The mathematical model was then further expanded to explicitly include both the immune response and drug dosing, so that model simulations are able to systematically investigate biological hypotheses about immunotherapy failure and to generate experimentally testable predictions of immune response. The modeling results suggest elevated immune response fractions (> 30 %) in tumors unresponsive to immunotherapy is due to a functional immune response that wanes over time. This experimental-mathematical approach provides a means to evaluate dynamics of the system that could not have been explored using the data alone, including tumor aggressiveness, immune exhaustion, and immune cell functionality.

Comparing mechanism-based and machine learning models for predicting the effects of glucose accessibility on tumor cell proliferation.

Glucose plays a central role in tumor metabolism and development and is a target for novel therapeutics. To characterize the response of cancer cells to blockade of glucose uptake, we collected time-resolved microscopy data to track the growth of MDA-MB-231 breast cancer cells. We then developed a mechanism-based, mathematical model to predict how a glucose transporter (GLUT1) inhibitor (Cytochalasin B) influences the growth of the MDA-MB-231 cells by limiting access to glucose. The model includes a parameter describing dose dependent inhibition to quantify both the total glucose level in the system and the glucose level accessible to the tumor cells. Four common machine learning models were also used to predict tumor cell growth. Both the mechanism-based and machine learning models were trained and validated, and the prediction error was evaluated by the coefficient of determination (R2). The random forest model provided the highest accuracy predicting cell dynamics (R2 = 0.92), followed by the decision tree (R2 = 0.89), k-nearest-neighbor regression (R2 = 0.84), mechanism-based (R2 = 0.77), and linear regression model (R2 = 0.69). Thus, the mechanism-based model has a predictive capability comparable to machine learning models with the added benefit of elucidating biological mechanisms.

Towards integration of time-resolved confocal microscopy of a 3D in vitro microfluidic platform with a hybrid multiscale model of tumor angiogenesis.

The goal of this study is to calibrate a multiscale model of tumor angiogenesis with time-resolved data to allow for systematic testing of mathematical predictions of vascular sprouting. The multi-scale model consists of an agent-based description of tumor and endothelial cell dynamics coupled to a continuum model of vascular endothelial growth factor concentration. First, we calibrate ordinary differential equation models to time-resolved protein concentration data to estimate the rates of secretion and consumption of vascular endothelial growth factor by endothelial and tumor cells, respectively. These parameters are then input into the multiscale tumor angiogenesis model, and the remaining model parameters are then calibrated to time resolved confocal microscopy images obtained within a 3D vascularized microfluidic platform. The microfluidic platform mimics a functional blood vessel with a surrounding collagen matrix seeded with inflammatory breast cancer cells, which induce tumor angiogenesis. Once the multi-scale model is fully parameterized, we forecast the spatiotemporal distribution of vascular sprouts at future time points and directly compare the predictions to experimentally measured data. We assess the ability of our model to globally recapitulate angiogenic vasculature density, resulting in an average relative calibration error of 17.7% ± 6.3% and an average prediction error of 20.2% ± 4% and 21.7% ± 3.6% using one and four calibrated parameters, respectively. We then assess the model's ability to predict local vessel morphology (individualized vessel structure as opposed to global vascular density), initialized with the first time point and calibrated with two intermediate time points. In this study, we have rigorously calibrated a mechanism-based, multiscale, mathematical model of angiogenic sprouting to multimodal experimental data to make specific, testable predictions.

Analysis of simplicial complexes to determine when to sample for quantitative DCE MRI of the breast.

PURPOSE: A method is presented to select the optimal time points at which to measure DCE-MRI signal intensities, leaving time in the MR exam for high-spatial resolution image acquisition. THEORY: Simplicial complexes are generated from the Kety-Tofts model pharmacokinetic parameters Ktrans and ve . A geometric search selects optimal time points for accurate estimation of perfusion parameters. METHODS: The DCE-MRI data acquired in women with invasive breast cancer (N = 27) were used to retrospectively compare parameter maps fit to full and subsampled time courses. Simplicial complexes were generated for a fixed range of Kety-Tofts model parameters and for the parameter ranges weighted by estimates from the fully sampled data. The largest-area manifolds determined the optimal three time points for each case. Simulations were performed along with retrospectively subsampled data fits. The agreement was computed between the model parameters fit to three points and those fit to all points. RESULTS: The optimal three-point sample times were from the data-informed simplicial complex analysis and determined to be 65, 204, and 393 s after arrival of the contrast agent to breast tissue. In the patient data, tumor-median parameter values fit using all points and the three selected time points agreed with concordance correlation coefficients of 0.97 for Ktrans and 0.67 for ve . CONCLUSION: It is possible to accurately estimate pharmacokinetic parameters from three properly selected time points inserted into a clinical DCE-MRI breast exam. This technique can provide guidance on when to capture images for quantitative data between high-spatial-resolution DCE-MRI images.

MRI-Based Digital Models Forecast Patient-Specific Treatment Responses to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to characterize tumor cell movement, proliferation, and treatment-induced cell death. Two evaluation frameworks were investigated using: (i) images acquired before and after two cycles of A/C for calibration and predicting tumor status after A/C, and (ii) images acquired before, after two cycles, and after four cycles of A/C for calibration and predicting response following NAST. For Framework 1, the concordance correlation coefficients between the predicted and measured patient-specific, post-A/C changes in tumor cellularity and volume were 0.95 and 0.94, respectively. For Framework 2, the biologically based model achieved an area under the receiver operator characteristic curve of 0.89 (sensitivity/specificity = 0.72/0.95) for differentiating pathological complete response (pCR) from non-pCR, which is statistically superior (P < 0.05) to the value of 0.78 (sensitivity/specificity = 0.72/0.79) achieved by tumor volume measured after four cycles of A/C. Overall, this model successfully captured patient-specific, spatiotemporal dynamics of TNBC response to NAST, providing highly accurate predictions of NAST response. SIGNIFICANCE: Integrating MRI data with biologically based mathematical modeling successfully predicts breast cancer response to chemotherapy, suggesting digital twins could facilitate a paradigm shift from simply assessing response to predicting and optimizing therapeutic efficacy.

Towards Patient-Specific Optimization of Neoadjuvant Treatment Protocols for Breast Cancer Based on Image-Guided Fluid Dynamics.

OBJECTIVE: This study establishes a fluid dynamics model personalized with patient-specific imaging data to optimize neoadjuvant therapy (i.e., doxorubicin) protocols for breast cancers. METHODS: Ten patients recruited at the University of Chicago were included in this study. Quantitative dynamic contrast-enhanced and diffusion weighted magnetic resonance imaging data are leveraged to estimate patient-specific hemodynamic properties, which are then used to constrain the mechanism-based drug delivery model. Then, computer simulations of this model yield the subsequent drug distribution throughout the breast. By systematically varying the dosing schedule, we identify an optimized regimen for each patient using the maximum safe therapeutic duration (MSTD), which is a metric balancing treatment efficacy and toxicity. RESULTS: With an individually optimized dose (range = 12.11-15.11 mg/m2 per injection), a 3-week regimen consisting of a uniform daily injection significantly outperforms all other scheduling strategies (P < 0.001). In particular, the optimal protocol is predicted to significantly outperform the standard protocol (P < 0.001), improving the MSTD by an average factor of 9.93 (range = 6.63 to 14.17). CONCLUSION: A clinical-mathematical framework was developed by integrating quantitative MRI data, advanced image processing, and computational fluid dynamics to predict the efficacy and toxicity of neoadjuvant therapy protocols, thus enabling the rational identification of an optimal therapeutic regimen on a patient-specific basis. SIGNIFICANCE: Our clinical-computational approach has the potential to enable optimization of therapeutic regimens on a patient-specific basis and provide guidance for prospective clinical trials aimed at refining neoadjuvant therapy protocols for breast cancers.

Quantitative multiparametric MRI predicts response to neoadjuvant therapy in the community setting.

BACKGROUND: The purpose of this study was to determine whether advanced quantitative magnetic resonance imaging (MRI) can be deployed outside of large, research-oriented academic hospitals and into community care settings to predict eventual pathological complete response (pCR) to neoadjuvant therapy (NAT) in patients with locally advanced breast cancer. METHODS: Patients with stage II/III breast cancer (N = 28) were enrolled in a multicenter study performed in community radiology settings. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI data were acquired at four time points during the course of NAT. Estimates of the vascular perfusion and permeability, as assessed by the volume transfer rate (Ktrans) using the Patlak model, were generated from the DCE-MRI data while estimates of cell density, as assessed by the apparent diffusion coefficient (ADC), were calculated from DW-MRI data. Tumor volume was calculated using semi-automatic segmentation and combined with Ktrans and ADC to yield bulk tumor blood flow and cellularity, respectively. The percent change in quantitative parameters at each MRI scan was calculated and compared to pathological response at the time of surgery. The predictive accuracy of each MRI parameter at different time points was quantified using receiver operating characteristic curves. RESULTS: Tumor size and quantitative MRI parameters were similar at baseline between groups that achieved pCR (n = 8) and those that did not (n = 20). Patients achieving a pCR had a larger decline in volume and cellularity than those who did not achieve pCR after one cycle of NAT (p < 0.05). At the third and fourth MRI, changes in tumor volume, Ktrans, ADC, cellularity, and bulk tumor flow from baseline (pre-treatment) were all significantly greater (p < 0.05) in the cohort who achieved pCR compared to those patients with non-pCR. CONCLUSIONS: Quantitative analysis of DCE-MRI and DW-MRI can be implemented in the community care setting to accurately predict the response of breast cancer to NAT. Dissemination of quantitative MRI into the community setting allows for the incorporation of these parameters into the standard of care and increases the number of clinical community sites able to participate in novel drug trials that require quantitative MRI.

Quantitative magnetic resonance imaging and tumor forecasting of breast cancer patients in the community setting.

This protocol describes a complete data acquisition, analysis and computational forecasting pipeline for employing quantitative MRI data to predict the response of locally advanced breast cancer to neoadjuvant therapy in a community-based care setting. The methodology has previously been successfully applied to a heterogeneous patient population. The protocol details how to acquire the necessary images followed by registration, segmentation, quantitative perfusion and diffusion analysis, model calibration, and prediction. The data collection portion of the protocol requires ~25 min of scanning, postprocessing requires 2-3 h, and the model calibration and prediction components require ~10 h per patient depending on tumor size. The response of individual breast cancer patients to neoadjuvant therapy is forecast by application of a biophysical, reaction-diffusion mathematical model to these data. Successful application of the protocol results in coregistered MRI data from at least two scan visits that quantifies an individual tumor's size, cellularity and vascular properties. This enables a spatially resolved prediction of how a particular patient's tumor will respond to therapy. Expertise in image acquisition and analysis, as well as the numerical solution of partial differential equations, is required to carry out this protocol.

Biologically-Based Mathematical Modeling of Tumor Vasculature and Angiogenesis via Time-Resolved Imaging Data.

Tumor-associated vasculature is responsible for the delivery of nutrients, removal of waste, and allowing growth beyond 2-3 mm3. Additionally, the vascular network, which is changing in both space and time, fundamentally influences tumor response to both systemic and radiation therapy. Thus, a robust understanding of vascular dynamics is necessary to accurately predict tumor growth, as well as establish optimal treatment protocols to achieve optimal tumor control. Such a goal requires the intimate integration of both theory and experiment. Quantitative and time-resolved imaging methods have emerged as technologies able to visualize and characterize tumor vascular properties before and during therapy at the tissue and cell scale. Parallel to, but separate from those developments, mathematical modeling techniques have been developed to enable in silico investigations into theoretical tumor and vascular dynamics. In particular, recent efforts have sought to integrate both theory and experiment to enable data-driven mathematical modeling. Such mathematical models are calibrated by data obtained from individual tumor-vascular systems to predict future vascular growth, delivery of systemic agents, and response to radiotherapy. In this review, we discuss experimental techniques for visualizing and quantifying vascular dynamics including magnetic resonance imaging, microfluidic devices, and confocal microscopy. We then focus on the integration of these experimental measures with biologically based mathematical models to generate testable predictions.

A time-resolved experimental-mathematical model for predicting the response of glioma cells to single-dose radiation therapy.

PURPOSE: To develop and validate a mechanism-based, mathematical model that characterizes 9L and C6 glioma cells' temporal response to single-dose radiation therapy in vitro by explicitly incorporating time-dependent biological interactions with radiation. METHODS: We employed time-resolved microscopy to track the confluence of 9L and C6 glioma cells receiving radiation doses of 0, 2, 4, 6, 8, 10, 12, 14 or 16 Gy. DNA repair kinetics are measured by γH2AX expression via flow cytometry. The microscopy data (814 replicates for 9L, 540 replicates for C6 at various seeding densities receiving doses above) were divided into training (75%) and validation (25%) sets. A mechanistic model was developed, and model parameters were calibrated to the training data. The model was then used to predict the temporal dynamics of the validation set given the known initial confluences and doses. The predictions were compared to the corresponding dynamic microscopy data. RESULTS: For 9L, we obtained an average (± standard deviation, SD) Pearson correlation coefficient between the predicted and measured confluence of 0.87 ± 0.16, and an average (±SD) concordance correlation coefficient of 0.72 ± 0.28. For C6, we obtained an average (±SD) Pearson correlation coefficient of 0.90 ± 0.17, and an average (±SD) concordance correlation coefficient of 0.71 ± 0.24. CONCLUSION: The proposed model can effectively predict the temporal development of 9L and C6 glioma cells in response to a range of single-fraction radiation doses. By developing a mechanism-based, mathematical model that can be populated with time-resolved data, we provide an experimental-mathematical framework that allows for quantitative investigation of cells' temporal response to radiation. Our approach provides two key advances: (i) a time-resolved, dynamic death rate with a clear biological interpretation, and (ii) accurate predictions over a wide range of cell seeding densities and radiation doses.

Towards an Image-Informed Mathematical Model of In Vivo Response to Fractionated Radiation Therapy.

Fractionated radiation therapy is central to the treatment of numerous malignancies, including high-grade gliomas where complete surgical resection is often impractical due to its highly invasive nature. Development of approaches to forecast response to fractionated radiation therapy may provide the ability to optimize or adapt treatment plans for radiotherapy. Towards this end, we have developed a family of 18 biologically-based mathematical models describing the response of both tumor and vasculature to fractionated radiation therapy. Importantly, these models can be personalized for individual tumors via quantitative imaging measurements. To evaluate this family of models, rats (n = 7) with U-87 glioblastomas were imaged with magnetic resonance imaging (MRI) before, during, and after treatment with fractionated radiotherapy (with doses of either 2 Gy/day or 4 Gy/day for up to 10 days). Estimates of tumor and blood volume fractions, provided by diffusion-weighted MRI and dynamic contrast-enhanced MRI, respectively, were used to calibrate tumor-specific model parameters. The Akaike Information Criterion was employed to select the most parsimonious model and determine an ensemble averaged model, and the resulting forecasts were evaluated at the global and local level. At the global level, the selected model's forecast resulted in less than 16.2% error in tumor volume estimates. At the local (voxel) level, the median Pearson correlation coefficient across all prediction time points ranged from 0.57 to 0.87 for all animals. While the ensemble average forecast resulted in increased error (ranging from 4.0% to 1063%) in tumor volume predictions over the selected model, it increased the voxel wise correlation (by greater than 12.3%) for three of the animals. This study demonstrates the feasibility of calibrating a model of response by serial quantitative MRI data collected during fractionated radiotherapy to predict response at the conclusion of treatment.

Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology.

We provide an overview on the use of biological assays to calibrate and initialize mechanism-based models of cancer phenomena. Although artificial intelligence methods currently dominate the landscape in computational oncology, mathematical models that seek to explicitly incorporate biological mechanisms into their formalism are of increasing interest. These models can guide experimental design and provide insights into the underlying mechanisms of cancer progression. Historically, these models have included a myriad of parameters that have been difficult to quantify in biologically relevant systems, limiting their practical insights. Recently, however, there has been much interest calibrating biologically based models with the quantitative measurements available from (for example) RNA sequencing, time-resolved microscopy, and in vivo imaging. In this contribution, we summarize how a variety of experimental methods quantify tumor characteristics from the molecular to tissue scales and describe how such data can be directly integrated with mechanism-based models to improve predictions of tumor growth and treatment response.

Evaluating patient-specific neoadjuvant regimens for breast cancer via a mathematical model constrained by quantitative magnetic resonance imaging data.

The ability to accurately predict response and then rigorously optimize a therapeutic regimen on a patient-specific basis, would transform oncology. Toward this end, we have developed an experimental-mathematical framework that integrates quantitative magnetic resonance imaging (MRI) data into a biophysical model to predict patient-specific treatment response of locally advanced breast cancer to neoadjuvant therapy. Diffusion-weighted and dynamic contrast-enhanced MRI data is collected prior to therapy, after 1 cycle of therapy, and at the completion of the first therapeutic regimen. The model is initialized and calibrated with the first 2 patient-specific MRI data sets to predict response at the third, which is then compared to patient outcomes (N = 18). The model's predictions for total cellularity, total volume, and the longest axis at the completion of the regimen are significant within expected measurement precision (P< 0.05) and strongly correlated with measured response (P < 0.01). Further, we use the model to investigate, in silico, a range of (practical) alternative treatment plans to achieve the greatest possible tumor control for each individual in a subgroup of patients (N = 13). The model identifies alternative dosing strategies predicted to achieve greater tumor control compared to the standard of care for 12 of 13 patients (P < 0.01). In summary, a predictive, mechanism-based mathematical model has demonstrated the ability to identify alternative treatment regimens that are forecasted to outperform the therapeutic regimens the patients clinically. This has important implications for clinical trial design with the opportunity to alter oncology care in the future.

Towards integration of 64Cu-DOTA-trastuzumab PET-CT and MRI with mathematical modeling to predict response to neoadjuvant therapy in HER2 + breast cancer.

While targeted therapies exist for human epidermal growth factor receptor 2 positive (HER2 +) breast cancer, HER2 + patients do not always respond to therapy. We present the results of utilizing a biophysical mathematical model to predict tumor response for two HER2 + breast cancer patients treated with the same therapeutic regimen but who achieved different treatment outcomes. Quantitative data from magnetic resonance imaging (MRI) and 64Cu-DOTA-trastuzumab positron emission tomography (PET) are used to estimate tumor density, perfusion, and distribution of HER2-targeted antibodies for each individual patient. MRI and PET data are collected prior to therapy, and follow-up MRI scans are acquired at a midpoint in therapy. Given these data types, we align the data sets to a common image space to enable model calibration. Once the model is parameterized with these data, we forecast treatment response with and without HER2-targeted therapy. By incorporating targeted therapy into the model, the resulting predictions are able to distinguish between the two different patient responses, increasing the difference in tumor volume change between the two patients by > 40%. This work provides a proof-of-concept strategy for processing and integrating PET and MRI modalities into a predictive, clinical-mathematical framework to provide patient-specific predictions of HER2 + treatment response.

Integrating transcriptomics and bulk time course data into a mathematical framework to describe and predict therapeutic resistance in cancer.

A significant challenge in the field of biomedicine is the development of methods to integrate the multitude of dispersed data sets into comprehensive frameworks to be used to generate optimal clinical decisions. Recent technological advances in single cell analysis allow for high-dimensional molecular characterization of cells and populations, but to date, few mathematical models have attempted to integrate measurements from the single cell scale with other types of longitudinal data. Here, we present a framework that actionizes static outputs from a machine learning model and leverages these as measurements of state variables in a dynamic model of treatment response. We apply this framework to breast cancer cells to integrate single cell transcriptomic data with longitudinal bulk cell population (bulk time course) data. We demonstrate that the explicit inclusion of the phenotypic composition estimate, derived from single cell RNA-sequencing data (scRNA-seq), improves accuracy in the prediction of new treatments with a concordance correlation coefficient (CCC) of 0.92 compared to a prediction accuracy of CCC = 0.64 when fitting on longitudinal bulk cell population data alone. To our knowledge, this is the first work that explicitly integrates single cell clonally-resolved transcriptome datasets with bulk time-course data to jointly calibrate a mathematical model of drug resistance dynamics. We anticipate this approach to be a first step that demonstrates the feasibility of incorporating multiple data types into mathematical models to develop optimized treatment regimens from data.

Optimal Control Theory for Personalized Therapeutic Regimens in Oncology: Background, History, Challenges, and Opportunities.

Optimal control theory is branch of mathematics that aims to optimize a solution to a dynamical system. While the concept of using optimal control theory to improve treatment regimens in oncology is not novel, many of the early applications of this mathematical technique were not designed to work with routinely available data or produce results that can eventually be translated to the clinical setting. The purpose of this review is to discuss clinically relevant considerations for formulating and solving optimal control problems for treating cancer patients. Our review focuses on two of the most widely used cancer treatments, radiation therapy and systemic therapy, as they naturally lend themselves to optimal control theory as a means to personalize therapeutic plans in a rigorous fashion. To provide context for optimal control theory to address either of these two modalities, we first discuss the major limitations and difficulties oncologists face when considering alternate regimens for their patients. We then provide a brief introduction to optimal control theory before formulating the optimal control problem in the context of radiation and systemic therapy. We also summarize examples from the literature that illustrate these concepts. Finally, we present both challenges and opportunities for dramatically improving patient outcomes via the integration of clinically relevant, patient-specific, mathematical models and optimal control theory.

Anti-HER2 induced myeloid cell alterations correspond with increasing vascular maturation in a murine model of HER2+ breast cancer.

BACKGROUND: Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment. METHODS: HER2+ tumor-bearing mice (N = 46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and α-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N = 10) were used to quantify differences in tumor cytokines between control and treated groups. RESULTS: Immunophenotyping showed an increase in macrophage infiltration 24 h after trastuzumab treatment (P ≤ 0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P = 0.02). Increases in vessel maturation index (i.e., the ratio of α-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R = 0.33, P = 0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-α, IL-1ß, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P ≤ 0.05). CONCLUSIONS: Preliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.

Forecasting tumor and vasculature response dynamics to radiation therapy via image based mathematical modeling.

BACKGROUND: Intra-and inter-tumoral heterogeneity in growth dynamics and vascularity influence tumor response to radiation therapy. Quantitative imaging techniques capture these dynamics non-invasively, and these data can initialize and constrain predictive models of response on an individual basis. METHODS: We have developed a family of 10 biologically-based mathematical models describing the spatiotemporal dynamics of tumor volume fraction, blood volume fraction, and response to radiation therapy. To evaluate this family of models, rats (n = 13) with C6 gliomas were imaged with magnetic resonance imaging (MRI) three times before, and four times following a single fraction of 20 Gy or 40 Gy whole brain irradiation. The first five 3D time series data of tumor volume fraction, estimated from diffusion-weighted (DW-) MRI, and blood volume fraction, estimated from dynamic contrast-enhanced (DCE-) MRI, were used to calibrate tumor-specific model parameters. The most parsimonious and well calibrated of the 10 models, selected using the Akaike information criterion, was then utilized to predict future growth and response at the final two imaging time points. Model predictions were compared at the global level (percent error in tumor volume, and Dice coefficient) as well as at the local or voxel level (concordance correlation coefficient). RESULT: The selected model resulted in < 12% error in tumor volume predictions, strong spatial agreement between predicted and observed tumor volumes (Dice coefficient > 0.74), and high level of agreement at the voxel level between the predicted and observed tumor volume fraction and blood volume fraction (concordance correlation coefficient > 0.77 and > 0.65, respectively). CONCLUSIONS: This study demonstrates that serial quantitative MRI data collected before and following radiation therapy can be used to accurately predict tumor and vasculature response with a biologically-based mathematical model that is calibrated on an individual basis. To the best of our knowledge, this is the first effort to characterize the tumor and vasculature response to radiation therapy temporally and spatially using imaging-driven mathematical models.