The International Journal of Biological Markers

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

The role of biomarkers is crucial in oncology for both early diagnosis and the personalization of cancer treatments. Tissue biomarkers have gained a central role as predictors of the response to an increasing number of anticancer agents; conversely, the clinical role of circulating biomarkers (c-TMs) is limited and has remained almost unchanged over the years. The position of guidelines is summarized and discussed with reference to the potential usefulness of c-TMs in those areas of application that cannot be covered by tissue biomarkers. The pipeline of translational research on biomarkers is briefly described; the differences among analytical validation, clinical validation, and clinical utility are discussed, emphasizing that the assessment of clinical utility is the ultimate step toward clinical use. The role of monitoring of appropriateness as a proxy indicator of how the research pipeline has actually worked is discussed, and data and c-TMs overordering rates are reported. The role and limits of guidelines to influence appropriate c-TMs ordering are discussed. The design of primary studies on c-TMs is examined, underlining that they mainly focus on clinical validation rather than on clinical utility. The role of regulatory boards is also briefly presented and discussed.

The discovery of molecular alterations that play key functions in pathways of tumor growth and survival have changed the treatment approach of several solid tumors. A number of biomarkers are now approved in clinical practice for the selection of patients to be treated with the specific targeted drug, and others are currently under study. None of these biomarkers are perfect and they have a number of biases. Novel treatment approaches, such as immunotherapy, require the development of more complex biomarker combinations as the mechanism of action of these drugs involves multiple parameters. In this short communication the principal approved biomarkers in solid tumors are discussed, with attention to the novel promising biomarkers that will be developed in the future.

Cancer is a complex disease characterized by a wide array of mutually interacting components constituting the tumor microenvironment (connective tissue, vascular system, immune cells), many of which are targeted therapeutically. In particular, immune checkpoint inhibitors have recently become an established part of the treatment of cancer. Despite great promise, only a portion of the patients display durable response. Current research efforts are concentrated on the determination of tumor-specific biomarkers predictive of response, such as tumor mutational burden, microsatellite instability, and neo-antigen presentation. However, it is clear that several additional characteristics pertaining to the tumor microenvironment play a critical role in the effectiveness of immunotherapy. Here we comment on the computational methods that are used for the analysis of the tumor microenvironment components from transcriptomic data, discuss the critical needs, and foresee potential evolutions in the field.

Liquid biopsy is routinely used to detect epidermal growth factor receptor mutations in advanced or metastatic lung cancer, due to some limitations of tissue genotyping, especially at relapse. However, the existence of a non-marginal proportion of oncogene-addicted lung cancers that can benefit from target therapy is rapidly expanding clinical relevance of plasma genotyping. Apart from static assessment of mutations in circulating free DNA, the fact that liquid biopsy is minimally invasive and can be repeated several times makes it a suitable assay for the dynamic monitoring of cancer response to treatment. It is likely that quantitative mutation assessment by liquid biopsy will be increasingly included in the design of innovative clinical trials for patient stratification purposes.

In the personalized medicine era, the field of immunohistopathology is evolving to provide even more precise diagnostic information to efficiently apply targeting therapies. In this regard, MultiSpectral fluorescence Imaging (MSI) is a powerful and reliable technique that provides a detailed and remarkable analysis of multiple biomarkers within their histological context. In particular, the analysis of the immune infiltrate in conjunction with the expression of immune checkpoint molecules could explain why the efficacy of the promising treatments based on immune modulator monoclonal antibodies is still limited. We analyzed the advantages and the pitfalls of applying MSI technology to investigate the immune infiltrate in correlation with programmed death-ligand 1 expression in paraffin embedded ovarian cancer samples.

Cancer causes inflammation as it progresses through healthy tissue. The differentiation of tumoral growth from the surrounding inflammatory change is paramount in planning surgeries seeking to preserve function. This retrospective study aims at illustrating how a careful use of imaging (computed tomography (CT)/magnetic resonance imaging (MRI)) can help to draw the line between infiltration and inflammation. Out of 72 cases of parosteal osteosarcoma in our institution we selected 22 which had pretreatment imaging, and out of those, 14 that had both MRI and CT. Using Fisher’s exact test, we evaluated the performance of each technique on accurately diagnosing medullary tumor infiltration, using histological analysis as a gold standard. All cases (14/14) demonstrated medullary abnormality on MRI, but only 6/14 (42.9%) demonstrated abnormality on CT. The 8/14 cases with MRI abnormality but no CT abnormality (57.1%) showed inflammation with no tumoral cells present on histological analysis. In the cases where the two examinations showed medullary abnormality (6/14) histology demonstrated tumoral infiltration. MRI demonstrated high sensitivity and negative predictive value, but low specificity and low positive predictive value and accuracy (P=1). CT demonstrated high sensitivity, specificity, high positive and negative predictive values and accuracy (P = 0.000333). MRI is highly sensitive for the detection of medullary abnormality but lacks specificity for tumor invasion. Correlation with CT is recommended in all cases of positive MR to add specificity for tumors. The adequate use of the two imaging methods allows to differentiate between inflammatory change and tumoral infiltration in POS, relevant for surgical planning.

The utility of positron emission tomography (PET) for the evaluation of response to immunotherapy has been considered a hot topic, particularly in the last 2 to 3 years. Different experiences have been collected in clinical practice, with 18F-Fluorodeoxyglucose (FDG) PET/computed tomography (CT), particularly in patients affected by lymphoma, malignant melanoma, and lung cancer. It has been tested in different settings of disease, from the prediction to the prognosis relative to the response to immunotherapy. In the present mini-review, some evidence is reported about the role of FDG PET/CT in patient candidates to or treated with immunotherapy.

The presence of hypoxia is a typical feature of solid tumors and has been identified in many neoplasms, favouring the survival of malignant cells in a hostile environment and the expression of an aggressive phenotype. Malignant brain tumors have large proportions of hypoxic tissue, thus contributing to resistance to radiation and chemotherapy. Positron emission tomography (PET) is an attractive technique to gain a non-invasive assessment of tumor hypoxia within the whole tumor, with 18F-fluoromisonidazole (18F-FMISO) and 18F-flouroazomycin arabinoside (18F-FAZA) being the most promising radiotracers. In this short review, we aim to discuss the available clinical studies focused on the use of 18F-FAZA PET/computed tomography in patients affected by high-grade glioma.

The goal of this review is to provide an overview of the studies aimed at integrating imaging parameters with molecular biomarkers for improving breast cancer patient’s diagnosis and prognosis. The use of diagnostic imaging to extract quantitative parameters related to the morphology, metabolism, and functionality of tumors, as well as their correlation with cancer tissue biomarkers is an emerging research topic. Thanks to the development of imaging biobanks and the technological tools required for extraction of imaging parameters including radiomic features, it is possible to integrate imaging markers with genetic data. This new field of study represents the evolution of radiology–pathology correlation from an anatomic–histologic level to a genetic level, which paves new interesting perspectives for breast cancer management.