Group C: Tumor Detection, Diagnosis, and PrognosisThere are four questions in this group.
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What properties of pre-cancerous lesions or their microenvironment predict the likelihood of progression to malignant disease?
Background: Not all tumors detected early should be treated. Uncertainty about the clinical behavior of a non-malignant lesion, such as the so-called “in situ carcinomas” of the prostate gland, esophagus, or breast, often lead to more aggressive treatment than may be warranted and can result in net harm to the patient. In addition, the inherent uncertainty in predicting the outcome of a given cancer, whether treated or not, can result in poor communication to the patient of the actual risk, leading to treatment decisions that may not be appropriate for the given benefit/risk profile. This Provocative Question seeks the identification of the characteristics of pre-cancerous lesions or their microenvironment that will allow the accurate prediction of progression to dangerous stages of tumor development.
Feasibility: Major advances in genomic and proteomic technologies that can genotype and phenotype small collections of cells and the microenvironment in which these cells proliferate, are resulting in a better understanding of how molecular profiles relate to cell phenotype and behavior. New knowledge will help determine whether malignant properties are conferred stochastically, or whether early lesions differ in their likelihood of malignant progression in definable and reproducible ways, thus allowing for more accurate prognostic determinants. Prospective studies could lead to substantial improvements in the accuracy with which the clinical behavior of a given lesion can be predicted.
Implications of success: Improved prediction of clinical risk could help clinicians better communicate risk/benefit profiles to patients and help patients, together with their doctors, make better-informed treatment decisions. Understanding which tumors are most likely to progress could also identify where therapeutic advances are most urgently needed. Insight into the biological basis for this stratification would be an important advance in the field, with broad relevance across organ sites. These changes could improve the overall benefit of early detection by reducing the risk of harm from overtreatment.
What molecular or cellular events establish tumor dormancy after treatment and what leads to recurrence?
Background: Even apparently successful cancer therapy may leave or induce dormant tumors or other types of minimal residual disease. These dormant tumors may remain stable for decades and, in the best cases, will not present further danger to the patient. However, frequently these tumors may undergo changes that are poorly understood and become aggressive, dangerous lesions. This Provocative Question seeks a molecular understanding of how these dormant tumors are generated and, in addition, what might lead to their re-emergence as malignant tumors.
Feasibility: Perhaps the most difficult aspect of this question will be to identify a system where these dormant tumors can be studied in a reproducible manner. The use of mouse models may be possible or there may be types of human tumors that, when treated under specific regimens, frequently result in the appearance of dormant tumors. In these cases, it presumably will be the recurrent tumors arising from dormancy that will be available for careful study. These tumors could be profiled using modern biological methodologies to study potential similarities or differences.
Implications of success: This is a stage of tumor development that has been difficult to study to date, and, for that reason, we know very little about how these dormant tumors develop or why malignant variants eventually arise and cause tumor recurrence. Advances in methods to study these stages of tumor development and the characterization of the primary tumors for comparison will allow determination of how dormant tumors arise, how to detect these types of tumors after treatment, and which ones will be most important to follow.
How do variations in tumor-associated immune responses among patients from distinct well-defined populations, such as various racial/ethnic or age groups, contribute to differences in cancer outcomes?
Background: There are clear disparities in cancer incidence and mortality rates found among diverse population groups, defined by race/ethnicity, age, or socio-economic status, that can be partially explained by differences in lifestyle and diet, age distribution, environmental and occupational exposure to carcinogens, or inadequate access to and affordability of health care. Some populations experience less favorable cancer outcomes compared to others. For example, African-American patients have a significantly greater risk of mortality due to prostate and breast cancer than their non-Hispanic white counterparts. Biological differences in genomics, gene expression and cellular immune response elements between diverse age, racial and ethnic populations have been previously reported. Variations among tumors and tumor-associated immunological differences between African-Americans and non-Hispanic whites and between older and younger patient populations have been implicated in cancer health disparities. Research is needed to validate these disparities in immune response and explore specific mechanisms and pathways that may explain these differences. Indeed, numerous differentially expressed genes have been reported to cluster around immune response and cytokine signaling pathways among patients from distinct well-defined populations such as various racial/ethnic, age groups, or groups afflicted with various co-morbid conditions. In turn these groups also experience unfavorable cancer outcomes. This Provocative Question seeks investigations that can functionally link immunological-related differences found among various well-defined populations to reduction of cancer health disparities.
Feasibility: Responsive applications to this PQ will include comparative studies to examine differences in immune response profiles between diverse populations. Demonstrated differences in immune signatures including immune cell infiltration, chemotaxis, and cytokine profiles, studies directed at characterization of immune response markers related to the tumor or with tumor-adjacent stroma as well as consequent cascade of events involving signal transduction and pathways differentially activated among diverse well-defined populations such as those defined by race/ethnicity or age could provide starting points for these studies. The goal of this work should be explain how these immune variations contribute to the aggressiveness or poor outcome of cancer in these populations.
Implications of success: It is expected that successful applications will lead to studies that will increase our understanding of the biological mechanisms that contribute to disparate cancer outcomes among diverse populations. Results from funded projects are expected to serve as a solid foundation for development of tangible strategies directed at eliminating these biologically-based sources of cancer outcome inequalities.
What in vivo imaging methods can be developed to portray the "cytotype" of a tumor — defined as the identity, quantity, and location of each of the different cell types that make up a tumor and its microenvironment?
Background: Tumors are now understood to be complex multicellular units composed of a vast array of different tumor and host cells. The tumor and its microenvironment interact to influence how a tumor will evolve over time, how it will respond to therapeutic attack, and how dangerous it will be to the patient. This Provocative Question requires the development of sophisticated imaging methods to characterize this multicellular structure in order to predict how the microenvironment influences tumor behavior. There are many potential approaches to examining the tumor microenvironment, but one of the most valuable would be non-invasive imaging. An important step in developing such a characterization would be to determine the tumor “cytotype”. Here, we define the cytotype as the identity, quantity, and location of the different cells that make up a tumor and its microenvironment.
Feasibility: Building methods to record a tumor cytotype will come in stages. One avenue of development will need to focus on the careful identification of cell types within a tumor and its microenvironment. Specific probes that define subtypes of tumor cells or cells of its microenvironment will need to be established and verified. It seems reasonable that some investigators will concentrate on classes of cells in the tumor microenvironment. For example, a careful examination of tumor-infiltrating immune cells may be a reasonable approach. Another major avenue of work will tackle the quantitation and display of cells in 3-dimensional space, particularly with regard to their physical proximity to tumor cells, and the cellular architecture which might change over time. Some scientists may imagine methods to study differences in the tumor cells themselves. Carefully consideration of what types of tumors will be best suited for such studies and what tumor samples will be available for study is crucial. In some cases, mouse models may be better suited for reducibility and ease of sampling, but attention to how such methods will be adapted for human application is important. Since the imaging field is making rapid progress toward real time, in vivo monitoring of tumor phenotypes, the following question should be addressed: How will the characterization of tumor cytotypes be incorporated into this increasingly sophisticated view of the tumor in situ?
Implications of success: The ultimate goal this work will be to determine how different tumor cytotypes influence tumor behavior. Imaging methods that will identify different types of tumor architectures promise to improve all types of cancer diagnoses.