Heterogeneidad tumoral en imágenes PET-CT

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, Departamento de Estructura de la Materia, Física Térmica y Electrónica, leída el 28/01/2021Cancer is a leading cause of morbidity and mortality [1]. The most frequent cancers worldwide are non–small cell lung carcinoma (NSCLC) and breast cancer [2], being their management a challenging task [3]. Tumor diagnosis is usually made through biopsy [4]. However, medical imaging also plays an important role in diagnosis, staging, response to treatment, and recurrence assessment [5]. Tumor heterogeneity is recognized to be involved in cancer treatment failure, with worse clinical outcomes for highly heterogeneous tumors [6,7]. This leads to the existence of tumor sub-regions with different biological behavior (some more aggressive and treatment-resistant than others) [8-10]. Which are characterized by a different pattern of vascularization, vessel permeability, metabolism, cell proliferation, cell death, and other features, that can be measured by modern medical imaging techniques, including positron emission tomography/computed tomography (PET/CT) [10-12]. Thus, the assessment of tumor heterogeneity through medical images could allow the prediction of therapy response and long-term outcomes of patients with cancer [13]. PET/CT has become essential in oncology [14,15] and is usually evaluated through semiquantitative metabolic parameters, such as maximum/mean standard uptake value (SUVmax, SUVmean) or metabolic tumor volume (MTV), which are valuables as prognostic image-based biomarkers in several tumors [16-17], but these do not assess tumor heterogeneity. Likewise, fluorodeoxyglucose (18F-FDG) PET/CT is important to differentiate malignant from benign solitary pulmonary nodules (SPN), reducing so the number of patients who undergo unnecessary surgical biopsies. Several publications have shown that some quantitative image features, extracted from medical images, are suitable for diagnosis, tumor staging, the prognosis of treatment response, and long-term evolution of cancer patients [18-20]. The process of extracting and relating image features with clinical or biological variables is called “Radiomics” [9,20-24]. Radiomic parameters, such as textural features have been related directly to tumor heterogeneity [25]. This thesis investigated the relationships of the tumor heterogeneity, assessed by 18F-FDG-PET/CT texture analysis, with metabolic parameters and pathologic staging in patients with NSCLC, and explored the diagnostic performance of different metabolic, morphologic, and clinical criteria for classifying (malignant or not) of solitary pulmonary nodules (SPN). Furthermore, 18F-FDG-PET/CT radiomic features of patients with recurrent/metastatic breast cancer were used for constructing predictive models of response to the chemotherapy, based on an optimal combination of several feature selection and machine learning (ML) methods...El cáncer es una de las principales causas de morbilidad y mortalidad. Los más frecuentes son el carcinoma de pulmón de células no pequeñas (NSCLC) y el cáncer de mama, siendo su tratamiento un reto. El diagnóstico se suele realizar mediante biopsia. La heterogeneidad tumoral (HT) está implicada en el fracaso del tratamiento del cáncer, con peores resultados clínicos para tumores muy heterogéneos. Esta conduce a la existencia de subregiones tumorales con diferente comportamiento biológico (algunas más agresivas y resistentes al tratamiento); las cuales se caracterizan por diferentes patrones de vascularización, permeabilidad de los vasos sanguíneos, metabolismo, proliferación y muerte celular, que se pueden medir mediante imágenes médicas, incluida la tomografía por emisión de positrones/tomografía computarizada con fluorodesoxiglucosa (18F-FDG-PET/CT). La evaluación de la HT a través de imágenes médicas, podría mejorar la predicción de la respuesta al tratamiento y de los resultados a largo plazo, en pacientes con cáncer. La 18F-FDG-PET/CT es esencial en oncología, generalmente se evalúa con parámetros metabólicos semicuantitativos, como el valor de captación estándar máximo/medio (SUVmáx, SUVmedio) o el volumen tumoral metabólico (MTV), que tienen un gran valor pronóstico en varios tumores, pero no evalúan la HT. Asimismo, es importante para diferenciar los nódulos pulmonares solitarios (NPS) malignos de los benignos, reduciendo el número de pacientes que van a biopsias quirúrgicas innecesarias. Publicaciones recientes muestran que algunas características cuantitativas, extraídas de las imágenes médicas, son robustas para diagnóstico, estadificación, pronóstico de la respuesta al tratamiento y la evolución, de pacientes con cáncer. El proceso de extraer y relacionar estas características con variables clínicas o biológicas se denomina “Radiomica”. Algunos parámetros radiómicos, como la textura, se han relacionado directamente con la HT. Esta tesis investigó las relaciones entre HT, evaluada mediante análisis de textura (AT) de imágenes 18F-FDG-PET/CT, con parámetros metabólicos y estadificación patológica en pacientes con NSCLC, y exploró el rendimiento diagnóstico de diferentes criterios metabólicos, morfológicos y clínicos para la clasificación de NPS. Además, se usaron características radiómicas de imágenes 18F-FDG-PET/CT de pacientes con cáncer de mama recurrente/metastásico, para construir modelos predictivos de la respuesta a la quimioterapia, combinándose varios métodos de selección de características y aprendizaje automático (ML)...Fac. de Ciencias FísicasTRUEunpu

Analysis of Cross-Combinations of Feature Selection and Machine-Learning Classification Methods Based on [F-18]F-FDG PET/CT Radiomic Features for Metabolic Response Prediction of Metastatic Breast Cancer Lesions

Simple Summary Breast cancer is a leading cause of morbidity and mortality worldwide. The metastatic disease is largely responsible for cancer patient deaths, and its treatment implies usually different therapies. In this context, the prediction of response to treatment or depiction of treatment-resistant phenotypes is essential in clinical practice, especially in the new era of precision medicine. In this study, we used several combinations of feature selection methods and machine-learning classifiers to construct predictive models of the metabolic response to the treatment of metastatic breast cancer lesions. These models were based on clinical variables and radiomic features extracted from 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography/computed tomography ([F-18]F-FDG PET/CT) images, obtained prior to the treatment. Our main goal was to know if this prediction was feasible and to identify those combinations with better predictive performance. We found that several combinations were successful to predict the metabolic response to treatment, of which the least absolute shrinkage and selection operator (Lasso) + support vector machines (SVM) had the best mean performance in terms of area under the curve, in both training and validation cohorts. Model performances depended largely on the selected combinations. Background: This study aimed to identify optimal combinations between feature selection methods and machine-learning classifiers for predicting the metabolic response of individual metastatic breast cancer lesions, based on clinical variables and radiomic features extracted from pretreatment [F-18]F-FDG PET/CT images. Methods: A total of 48 patients with confirmed metastatic breast cancer, who received different treatments, were included. All patients had an [F-18]F-FDG PET/CT scan before and after the treatment. From 228 metastatic lesions identified, 127 were categorized as responders (complete or partial metabolic response) and 101 as non-responders (stable or progressive metabolic response), by using the percentage changes in SULpeak (peak standardized uptake values normalized for body lean body mass). The lesion pool was divided into training (n = 182) and testing cohorts (n = 46); for each lesion, 101 image features from both PET and CT were extracted (202 features per lesion). These features, along with clinical and pathological information, allowed the prediction model's construction by using seven popular feature selection methods in cross-combination with another seven machine-learning (ML) classifiers. The performance of the different models was investigated with the receiver-operating characteristic curve (ROC) analysis, using the area under the curve (AUC) and accuracy (ACC) metrics. Results: The combinations, least absolute shrinkage and selection operator (Lasso) + support vector machines (SVM), or random forest (RF) had the highest AUC in the cross-validation, with 0.93 +/- 0.06 and 0.92 +/- 0.03, respectively, whereas Lasso + neural network (NN) or SVM, and mutual information (MI) + RF, had the higher AUC and ACC in the validation cohort, with 0.90/0.72, 0.86/0.76, and 87/85, respectively. On average, the models with Lasso and models with SVM had the best mean performance for both AUC and ACC in both training and validation cohorts. Conclusions: Image features obtained from a pretreatment [F-18]F-FDG PET/CT along with clinical vaiables could predict the metabolic response of metastatic breast cancer lesions, by their incorporation into predictive models, whose performance depends on the selected combination between feature selection and ML classifier methods