Preface

Chapter 7 **Ovarian Reserve Markers: An Update 113**

Castro and Clara Esteban-Pérez

Samuel N. Uwaezuoke

**VI** Contents

Sanja Josef Golubic

**Application 195**

Anabela Cordeiro-da-Silva

Chapter 12 **Biomarkers and Heart Failure 225**

Hakan Altay

Chapter 8 **Biomarkers of Common Childhood Renal Diseases 125**

Chapter 9 **Molecular Diagnostics of Pulmonary Diseases Based on Analysis of Exhaled Breath Condensate 141**

Chapter 11 **Biomarkers in Leishmaniasis: From Basic Research to Clinical**

Chapter 10 **Topological Biomarker of Alzheimer's Disease 169**

Tereza Kačerová, Petr Novotný, Ján Boroň and Petr Kačer

Sofia Esteves, Inês Costa, Célia Amorim, Nuno Santarem and

Harold Moreno-Ortiz, Iván Darío Acosta, Elkin Lucena-Quevedo, Luis Alejandro Arias-Sosa, Alix Eugenia Dallos-Báez, Maribel Forero-

> A biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. This book discusses biomarkers for various conditions.

> In Part I, chapters focus on breast cancer—the most common cancer in women accounting for about one third of cancer cases in this population and more than 10% of all cancers worldwide—and pancreatic cancer. Another chapter covers methodological challenges in microRNA profiling and data analysis.

> In Part II, chapters focus on different biomarkers of non-cancer diagnoses/diseases, includ‐ ing sepsis, childhood renal diseases, pulmonary diseases, Alzheimer's, leishmaniasis, and heart failure.

> The chapter on sepsis addresses the use of blood and serum biomarkers and clinical scores for the diagnosis and prognosis of septic patients. In trauma, fibrin degradation product and D-dimer have been used to predict the likelihood of haemorrhage, whereas in cardiac pul‐ monary arrest, they are used to predict the return of spontaneous circulation. The chapter on clinical application of coagulation biomarkers explains this phenomenon. The chapter on ox‐ idative status pathways discusses the unique property of the human oxidative status. The chapter on ovarian reserve markers talks about anti-Mullerian and follicle-stimulating hor‐ mones. The chapter on childhood renal diseases covers biomarkers of acute and chronic kid‐ ney diseases in children, such as urinary tract infection and diabetic nephropathy.

> Measurement of biomarkers in exhaled breath condensate offers a novel way of monitoring lung inflammation and damage by oxidation stress, and provides insight into the physiolo‐ gy of the disease as mentioned in the chapter on molecular diagnostics of pulmonary diseas‐ es. A chapter on Alzheimer's talks about topological biomarkers hidden in auditory sensory gating network, and a chapter on the neglected tropical disease leishmaniasis, which causes high mortality worldwide, explores the possibility of using biomarkers to develop a rapid diagnosis kit for universal use. The final chapter is on heart failure and biomarkers.

> I hope that this book will be of particular interest to researchers, scientists, clinicians, and students from medicine, cancer biology, cell and molecular biology, and other related areas.

> > **Dr. Ghousia Begum** Indian Institute of Chemical Technology, India

**Section 1**

**Biomarkers of Cancer**

**Section 1**

**Biomarkers of Cancer**

**Chapter 1**

Provisional chapter

**Biomarkers in Breast Cancer**

Biomarkers in Breast Cancer

Serena Bertozzi, Ambrogio P Londero, Luca Seriau, Roberta Di Vora, Carla Cedolini and Laura Mariuzzi

> Breast cancer is the most common cancer in women and its incidence experienced an important increase, thanks to the introduction of a systematic screening. The increased incidence of early breast cancer has led to debates on its over-treatment, which may cause unnecessary harm to patients with favorable prognosis. Therefore, modern research is in the quest of finding the perfect prognostic marker to avoid overtreatment in patients with a favorable prognosis. In this perspective, many molecular markers have been studied in the last decades in order to provide both a useful prognostic tool, able to determine whether the cancer is likely to be indolent or aggressive, and a possible therapeutic target. In this chapter, we review the current knowledge about the principal biomarkers, which are usually immunohistochemically tested on breast surgical specimens, including ER and PR, Mib1/Ki-67 and HER2/neu expression. Furthermore, we will analyze other possible prognostic markers which may have in the future a key role in breast cancer management, such as several multigene panels (OncotypeDX, Mammaprint, NanoString Prosigma). Finally, we will discuss the role of genetic tests for some know genetic mutations associ-

DOI: 10.5772/intechopen.77320

ated with higher breast cancer susceptibility (BRCA1 and 2 genes).

Keywords: breast cancer, biomolecular markers, biohumoral markers, therapy target,

Breast cancer is the most common cancer in women, accounting for about one-third of cancer cases in women and more than 10% of all cancers worldwide [1], and its incidence experienced an important increase, thanks to the introduction at the beginning of this century of a systematic mammographic screening in the most developed countries, and the subsequent successful detection of an always greater number of early breast cancers [2–4]. The incidence of breast

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Serena Bertozzi, Ambrogio P Londero, Luca Seriau, Roberta Di Vora, Carla Cedolini and Laura Mariuzzi

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77320

Abstract

prognostic factors

1. Introduction

#### **Biomarkers in Breast Cancer** Biomarkers in Breast Cancer

Serena Bertozzi, Ambrogio P Londero, Luca Seriau, Roberta Di Vora, Carla Cedolini and Laura Mariuzzi Serena Bertozzi, Ambrogio P Londero, Luca Seriau, Roberta Di Vora, Carla Cedolini and Laura Mariuzzi

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77320

#### Abstract

Breast cancer is the most common cancer in women and its incidence experienced an important increase, thanks to the introduction of a systematic screening. The increased incidence of early breast cancer has led to debates on its over-treatment, which may cause unnecessary harm to patients with favorable prognosis. Therefore, modern research is in the quest of finding the perfect prognostic marker to avoid overtreatment in patients with a favorable prognosis. In this perspective, many molecular markers have been studied in the last decades in order to provide both a useful prognostic tool, able to determine whether the cancer is likely to be indolent or aggressive, and a possible therapeutic target. In this chapter, we review the current knowledge about the principal biomarkers, which are usually immunohistochemically tested on breast surgical specimens, including ER and PR, Mib1/Ki-67 and HER2/neu expression. Furthermore, we will analyze other possible prognostic markers which may have in the future a key role in breast cancer management, such as several multigene panels (OncotypeDX, Mammaprint, NanoString Prosigma). Finally, we will discuss the role of genetic tests for some know genetic mutations associated with higher breast cancer susceptibility (BRCA1 and 2 genes).

DOI: 10.5772/intechopen.77320

Keywords: breast cancer, biomolecular markers, biohumoral markers, therapy target, prognostic factors

## 1. Introduction

Breast cancer is the most common cancer in women, accounting for about one-third of cancer cases in women and more than 10% of all cancers worldwide [1], and its incidence experienced an important increase, thanks to the introduction at the beginning of this century of a systematic mammographic screening in the most developed countries, and the subsequent successful detection of an always greater number of early breast cancers [2–4]. The incidence of breast

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cancer is also rapidly rising in developing countries, so that it will become in the next decades a major health burden in both developed and developing countries.

In fact, about 60% of ER-positive tumors, but only about 8% of ER-negative ones showed an objective response to endocrine therapy. The small proportion of patients who respond to hormone therapy with ER-negative disease may be mostly due to false-negative receptor assay

Biomarkers in Breast Cancer

5

http://dx.doi.org/10.5772/intechopen.77320

The identification of the estrogen receptor has not only proved to be a successful therapeutic target for the treatment and prevention of breast cancer, but has also represented a selective molecular model for all subsequent efforts to design oncological targeted therapies. Estrogen and progesterone receptor (PR), together with the HER2 status represent the most important molecular markers in the standard care of all primary, recurrent, and metastatic breast cancer patients, and the standardized assessment of the ER/PR/HER2 status is crucial in the evalua-

Hormonal receptor-positive disease represents usually an indolent and slowly growing tumor with longer time to recurrence. The responsiveness of a tumor to hormone therapy is an important parameter in breast cancer management in both adjuvant and metastatic settings.

The ER is a ligand-regulated, cytoplasmic receptor that belongs to the steroid nuclear receptor family, which in the ER-positive breast disease, promotes cell proliferation, survival, and invasion. The key components of ER are the DNA-binding domain, which binds with high affinity and specificity to estrogen response elements (ERE sequence) of DNA to regulate the transcription rates of target genes, and the ligand-binding domain, which binds estrogens [16]. The binding of estrogen to its receptor is essential for its translocation into the nucleus, where it functions as a transcription factor and transduces hormonal signals into a large variety of

Two forms of ER, ERα and ERβ, are encoded by two separate genes that are differentially expressed in tissues. In the normal mammary gland, both ERα and ERβ bind estradiol to control cell proliferation and differentiation [17, 18]. ERα is also responsible for estrogeninduced mitogenic signaling in epithelial cells in breast, uterine, and ovarian tissues [19] and is prevalently expressed by breast cancer cells [20], whereas ERβ is usually associated with less aggressive tumors, as it inhibits both ERα-mediated transcription and estradiol-induced proliferation in various types of cancer cells [21]. The ERα/ERβ ratio may play a critical role in the

Estradiol binding to ER activates the receptor through phosphorylation, which undergoes conformational changes and dissociates proteins which usually tightly wrap the DNA [23]. Thereafter, ER binds to the ERE sequence within the gene promoter, and dynamically and sequentially recruits various regulatory protein complexes that contribute to chromatin

ER-mediated transcription involves also other multiple coregulatory proteins, which coordinately act to influence gene transcription, cell cycle regulation, cell differentiation and apoptosis.

The clinical aspects of anti-hormonal treatments are exposed in the following sections.

results.

tion of every newly diagnosed breast cancer.

physiological responses in various target organs.

regulation of estradiol activity in breast cancer cells [22].

remodeling and enhance transcriptional activity [24].

2.1. Biology of hormone receptors

Improvement in the adjuvant chemotherapy and endocrine therapy decreased breast cancer mortality by approximately 50%. However, the increased incidence of early breast cancer has led to debates on its overtreatment, which not only increases social and family burden, but may also cause unnecessary harm to patients with a favorable prognosis [5, 6]. Therefore, the research is focusing on the development of new adjuvant therapies with a more precise target and fewer side effects. In this perspective, many molecular markers have been studied in the last decades in order to provide both a useful prognostic tool, able to determine whether the cancer is likely to be indolent or aggressive [7, 8], and a possible therapeutic target.

Breast cancer includes a heterogeneous group of tumors with a wide spectrum of morphologically and molecularly different subtypes, resulting in different biological behaviors, presentation, and prognosis. Along with the disease stage and the patient performance, the molecular pattern of the tumor is fundamental to identify patients who will particularly benefit from a given treatment. Among the molecular markers associated with breast cancer, the estrogen receptor (ER), the progesterone receptor (PR), the human epidermal growth factor receptor (HER2) and the Mib1/Ki-67 proliferation index are the most important ones and are firmly established in the standard care of all primary, recurrent, and metastatic breast cancer patients.

In this chapter, we review the clinical relevance of the principal biomarkers, which are usually immunohistochemically tested on breast surgical specimens. We discuss about their implication in the prognosis and treatment of breast cancer patients, and thus how this information is translated to treatment decision-making, the valid assays for these markers, and the guidelines for testing them. Furthermore, we analyze other possible prognostic markers which may have in the future a key role in breast cancer management, such as several multigene panels, which have been developed to predict the possibility of distant metastasis in the hormonal receptorpositive disease [9–11]. Finally, we discuss the role of genetic tests for some know genetic mutations associated with higher breast cancer susceptibility in the screening and follow-up of women at high risk.
