Biomarkers in Cancer Screening and Early Detection

Sudhir Srivastava, Sudhir Srivastava

• Publisher: Wiley-Blackwell
• Year: 2017
• ISBN:
  9781118468821
• Edition: 1
• Topic: Medicine
• Subtopic: Oncology

Prepared by world leaders on this topic, Biomarkers in Cancer Screening and Early Detection offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer biomarkers, from their discovery and development to their validation, clinical utility, and use in developing personalized cancer treatment.

• Offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer biomarkers
• Provides immediately actionable information – and hopefully also inspiration – to move discovery and clinical application forward
• Offers vital knowledge to help develop personalized cancer treatment for individual patients with specific cancers

Part I
Foundations of Biomarker Research

Chapter 1
Nuts and Bolts of Biomarker Research

Sharmistha Ghosh¹ and Sudhir Srivastava²

¹Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA

²Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

What is a biomarker?

A biomarker is a particular characteristic, or a molecular fingerprint, which indicates manifestation of a physiological state, and which can be objectively quantified to distinguish a normal state from a pathological condition (e.g., cancer) or a response to a therapeutic intervention. The National Cancer Institute (NCI) of the National Institutes of Health (NIH) defines biomarker as: “A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Biomarkers are also called molecular markers and signature molecules.” [1]

As a normal cell undergoes a complex process of transformation into a cancerous state, it is hoped that measurable characteristics can be analyzed to derive a meaningful clinical decision – either directly, from the early-stage tumor before it is palpable or detectable by sensitive screening technologies available at this time, or as a result of an immunological response to the tumor. The characteristics include a broad range of biochemical entities such as nucleic acids (e.g., DNA, mRNA, long and small [short] non-coding RNA), proteins, post-translationally modified proteins (e.g., phosphoproteins, glycoproteins, methylated proteins, glycolipids), sugars, lipids and small metabolites, as well as whole circulating cells or biophysical characteristics of tissues.

Failure to detect an identifiable molecular mar-ker may not be a negative predictor of malignancy, and a positive test for a molecular marker may not always be a positive predictor of malignancy. However, an ideal biomarker should indicate a reliable positive or negative correlation with the presence of the disease, which means that the clinical test for the biomarker should have high sensitivity (true positive rate – that is, the ability to correctly identify individuals with the disease) and specificity (true negative rate – that is, the ability to correctly identify individuals without the disease). The clinical value of a biomarker test is based on its positive predictive value (PPV), or how likely it is for test-positive individuals to actually have the disease, and its negative predictive value (NPV), or how likely it is for test-negative individuals to not have the disease. These again depend on the prevalence of the disease in the population of interest. Biomarkers also need to be easily accessible (e.g., by non-invasive methods for screening purposes), quantifiable, analyzable, and interpretable.

Why biomarker research is imperative

The development of cancer is preceded by numerous germline and somatic mutations, structural changes in chromosomes, and other genetic and epigenetic changes, which transform normal cells into benign tumors and, progressively, into malignant and metastatic forms. Cancer is a heterogeneous, multigenic group of diseases; the heterogeneity lies not only at the biochemical level (genes, proteins, metabolites), but also at the tissue and population level (e.g., [2–10]). The enormous complexity makes cancer detection, diagnosis, and treatment quite challenging. Although cancers diagnosed at earlier stages have a much better prognosis compared with cancers diagnosed at later stages, it is noteworthy that many cancer patients are diagnosed at a stage at which the cancer is too far advanced to be cured.

Currently, recommendations for early detection of cancer in average-risk individuals are available for colorectal, cervical, breast, endometrial (in menopausal women) and prostate cancers, and in high-risk individuals in the case of lung cancer. There has been a substantial increase in “cancer” incidence as a result of screening, but without a proportional decrease in mortality despite treatment. This implies that screening identifies a large reservoir of indolent cancers (overdiagnosis) [11], which would have never become symptomatic without screening, and did not require any treatment. However, because it is not known at this time which lesions are indolent, many individuals are put through intensive treatments unnecessarily, which often causes anxiety as well as substantial physical and financial harm. An extensive discussion on existing screening modalities, recommendations, and the consequences and complexities involved is beyond the scope of this chapter. A shared decision-making discussion between the patients and their physicians, based on existing data, and also taking into consideration an individual patient's values and philosophies on healthcare, is important [12].

The ability to identify tumors that are destined to progress, and which are associated with morbidity and mortality at an early stage, will allow effective treatment interventions and reduce deaths. Identification of tumor-specific molecular signatures is imperative for a new approach to early detection, diagnosis, prognosis, disease classification and risk prediction. It will also help to implement appropriate treatment decisions and therapeutic interventions, to monitor treatment response and efficacy (i.e., a measurable effect on a clinical end point), and to overcome drug resistance in a precise, patient-specific approach. Such practice of tailored “personalized medicine”, based on the molecular portraits of tumor cells, allows physicians to inform individual patients of the expected outcomes – for example, whether treatments or surveillance approaches will be beneficial, and when to stop treatment based on response to drug(s). An illustration of several windows of clinical relevance in the management of cancer during its course of development is shown where different biomarker profiles can be applied to each of these windows for optimal management of cancer (Figure 1.1).

Figure 1.1 Biomarker application in the clinic. A long window of opportunity for chemoprevention or any clinical intervention is divided into sub-windows, based on whether a risk assessment is made when the disease is non-measureable, or an early diagnosis is made based on screening for measurable characteristics of the tumor, or a clinical diagnosis is made when the disease is symptomatic or has recurred. Adapted from [13].

A few biomarkers discussed in this section underscore their utilization as clinical tools for facilitating diagnosis and treatment of tumors. Germline mutations in the high-penetrance genes breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), which are associated with hereditary susceptibility to breast and ovarian cancers, somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene in colorectal tumors which can act as predictive biomarker for adjuvant aspirin therapy, and metastatic melanoma patients who harbor v...