The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach - Katarzyna Rygiel - E-Book

The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach E-Book

Katarzyna Rygiel

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Beschreibung

This comprehensive reference is a timely exploration of two vital aspects of triple-negative breast cancer. The volume offers a holistic perspective and empowering patients to navigate the challenges of triple-negative breast cancer (TNBC) with knowledge and confidence.

Understanding Ethnic Disparities and Targeted Therapies: This section provides a critical overview of the ethnic disparities and the latest targeted therapies available for patients facing advanced or metastatic triple-negative breast cancer (TNBC).
Empowering Patients and Enhancing Communication: This section dives into the essential role of patient education, empowerment, effective communication with medical teams, and psychological or supportive approaches, providing invaluable insights into managing advanced or metastatic breast cancer (BC).

Key Features:
Introduces a groundbreaking perspective on the TNBC journey, encouraging patients to view their battle with the disease as an opportunity to leverage modern pharmacological advancements and psychological support for improved outcomes.
Bridges the gap between clinical or research-related aspects of BC management and the personal needs and expectations of patients, promoting a more holistic approach.
Invites perspectives from a wide range of medical professionals, from oncologists and cardiologists to psychologists and nurses, to engage in open dialogues with patients, offering practical education and crucial support.
Provides a wealth of helpful resources (including an appendix) for both patients and their medical caregivers, fostering a comprehensive and supportive approach to managing TNBC.
This book is an informative resource for medical professionals, researchers, and patients, who want to understand the complexities of triple-negative breast cancer and apply current knowledge in their clinical and caregiving practice.

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Table of Contents
BENTHAM SCIENCE PUBLISHERS LTD.
End User License Agreement (for non-institutional, personal use)
Usage Rules:
Disclaimer:
Limitation of Liability:
General:
FOREWORD
PREFACE
Part 1
Unraveling Ethnic Disparities in Triple-Negative Breast Cancer (TNBC): Exploring The Impact of Metabolic, Reproductive, Environmental, and Social Factors on the Disease Course in African-American (AA) Women Population
Abstract
INTRODUCTION
How Can we Approach Ethnic Disparities in TNBC Survival? – A Roadmap of Possible Underlying Biologic and Non-biologic Risk Factors or Causes of TNBC in AA vs. EA (or NHW) Women
A SPOTLIGHT ON THE FAMILY HISTORY AND GENETIC MUTATIONS: THE IMPACT OF ETHNICITY ON MOLECULAR MAKE-UP IN TNBC
SOCIOECONOMIC DISPARITIES IN BC – A LINK BETWEEN THE ECONOMIC DEPRIVATION AND DYSFUNCTIONAL HEALTHCARE PATH
BEHAVIORAL AND CULTURAL FACTORS ACCOUNTING FOR BC DISPARITIES IN AA WOMEN
THE UNDERESTIMATED ROLE OF INSUFFICIENT PHYSICAL ACTIVITY AS A RISK FACTOR IN BC DISPARITIES – REFLECTIONS FROM THE SELECTED CLINICAL STUDIES
Impact of Inadequate Nutrition on BC Disparities –Insights from Major Clinical Studies
CONCLUSION
References
A Closer Look at the Androgen Receptor (AR)-positive and AR-negative Metastatic Triple-Negative Breast Cancer: Can We Apply Novel Targeted Therapeutics?
Abstract
INTRODUCTION
Various Molecular Subtypes of TNBC
THE UNDETERMINED PROGNOSTIC VALUE OF ANDROGEN RECEPTOR (AR) IN WOMEN WITH TNBC
THE INFLUENCE OF ANDROGEN RECEPTOR (AR) ON POTENTIAL THERAPEUTIC CHOICES IN PATIENTS WITH TNBC
DIFFICULTIES WITH STANDARDIZATION OF ANDROGEN RECEPTOR (AR) TESTING
TARGETED APPROACHES TO TNBC RESISTANT TO THERAPY: FOCUSING ON “WEAK POINTS” OF AGGRESSIVE CANCERS
Immune Checkpoint Inhibitors (ICI) (Atezolizumab and Pembrolizumab)
POLY-ADP-RIBOSE POLYMERASE (PARP) INHIBITORS (OLAPARIB AND TALAZOPARIB)
Anti-Trop-2 Antibody-drug Conjugate (ADC) (Sacituzumab Govitecan-hziy)
SELECTED ACTIONABLE PHARMACOLOGIC TARGETS AND EMERGING THERAPIES ON THE HORIZON
CONCLUSION
REFERENCES
Liquid Biopsy: Insights Into Monitoring Tumor Dynamics and Response to Therapy in Patients with Breast Cancer
Abstract
INTRODUCTION
HOW LIQUID BIOPSY CAN BE USED IN MONITORING METASTATIC BC PROGRESSION AND TREATMENT?
Translating a Learning Experience from the SOLAR-1 Trial into Clinical Practice: The Approval of Alpelisib and Therascreen
An Importance of ctDNA Mutational Analysis in the Management of Patients with Metastatic BC
CIRCULATING TUMOR DNA ANALYSIS TO HELP DIRECT THERAPY IN ADVANCED BC (PLASMAMATCH): THE UNIQUE TOOL TO IDENTIFY SENSITIVITY
AN IMPACT OF THE LIQUID BIOPSY ON THE PERSONALIZED TREATMENT OF WOMEN WITH METASTATIC BC
Useful Ways of Predicting the Patients’ Survival and BC Recurrence
Can the Circulating Tumor Cell (CTC) Count be Used for a Selection of the First-line Therapy (CHT or ET) in Women with HR–positive, HER2-negative Metastatic BC?
Can ctDNA Monitoring During the Neoadjuvant Chemotherapy (CHT) Course Reveal a Patient's Risk for Distant BC Metastases?
Can Lack of ctDNA Clearance in Early Period of Neoadjuvant Chemotherapy (NAC) be a Predictor of Poor Response to Treatment?
How to Predict the BC Metastatic Relapse Before the Clinical Recurrence?
CONCLUSION
REFERENCES
Importance of Biomarker Conversions as “Road Signs” to Manage Women with Metastatic Breast Cancer: How To Use Them for Personalized Care of These Patients?
Abstract
INTRODUCTION
Common Conversions of Biomarker’s Status in Metastatic Breast Cancer
Alterations of the Biomarker’s Status in Metastatic Breast Cancer and Their Potential Role in the Prognosis and Therapy
Common Biomarkers or Their Combinations Matched With Targeted Treatments For Breast Cancer
Biomarkers’ Shifts in Metastatic Breast Cancer and Their Reassessment: A Potential Role in the Prognosis and Treatment
CONSIDERATIONS OF INTERTUMOR AND INTRATUMOR HETEROGENEITY: CHALLENGES AND OPPORTUNITIES
Tumor Evolution and Its Connections with Changing of the Biomarker’s Status in Metastatic Breast Cancer
CONCLUSION
REFERENCES
Putting It All Together: Clinical Pearls of Recently Approved Therapies for Triple-Negative Breast Cancer
Abstract
INTRODUCTION
A Special Task of PARP Inhibitors: Targeting Enzymes That Repair DNA Damage
Who Can Benefit the Most from PARP Inhibitors? - Good News from the OlympiAD and the EMBRACA Trials for Women with Metastatic BRCA-positive TNBC
Shifting Gears to Immunotherapy: Who Can Be A Winner?
The Role of Ventana and Dako Assay in PD-L1 Testing
Sacituzumab Govitecan - An Antibody Drug Conjugate (ADC) Starting the “Optimistic Wave” of Therapy for Patients with Metastatic TNBC
A Spotlight on HER2-low BC: Diagnostic Challenges to HER2 Status Interpretation
The Remarkable Place of ADCs for Patients with Metastatic TNBC and HER2-low BC
How to Put Immune Checkpoint Inhibitors and PARP Inhibitors Into Perspective? Considerations of Targeted Therapeutic Options and Their Sequence in Patients with TNBC Associated With the BRCA Mutation and PD-L1 Positivity
CONCLUSION
REFERENCES
The Way Out From the Labyrinth of Anticancer Therapies for Patients with Breast Cancer: How Can We Improve Their Cardiac Safety and Quality of Life?
Abstract
INTRODUCTION
Frequent Side Effects of Anticancer Treatments and Their Perception in Patients with Breast Cancer
A Spotlight On Two “Faces” of Pain Secondary to Anticancer Therapies in Patients with Breast Cancer: Peripheral Neuropathy and Lymphedema
HOW CAN WE APPROACH DEPRESSION AND COGNITIVE IMPAIRMENT IN PATIENTS WITH BREAST CANCER FROM DIFFERENT PERSPECTIVES?
How Can We Address the Management of Menopausal Symptoms in Younger Women Undergoing Chemotherapy for Breast Cancer?
How to Assess Cardiotoxicity Related to Treatments for Breast Cancer?
May Standard Pharmacotherapy for Heart Failure Provide Cardioprotective Effects for Women with Breast Cancer?
How to Reduce Cardiotoxicity Related to Treatments for Breast Cancer? Focus on Cardio-Oncology, Rehabilitation, and Integrative Interventions
Further Directions: Efforts to Develop the “Knowledge Network” for Personalized Medicine Goals
CONCLUSION
REFERENCES
Can We Find A Noninvasive Tool of Precision Medicine That Can Always Be Used For the Individualized Treatment of Women With Breast Cancer?
Abstract
INTRODUCTION
The Goals and Tools of Precision Medicine
AN EMERGING P4 MODEL: TRANSFORMATION FOR A NEW HEALTHCARE SYSTEM
A Role of Personomics as A Tool to Fulfill the Unmet Healthcare Needs
The Aliki Initiative: Teaching Personomics In The Academic Setting
Unique Values of the Patient-centered, “Humanistic” Approach to Medical Management
Current Possibilities of Personalized Medical Care for Women with Breast Cancer
COMMON LIMITATIONS OF PERSONALIZED MEDICAL CARE FOR WOMEN WITH BREAST CANCER
Selected Therapeutic Targets in Advanced or Metastatic TNBC
CONCLUSION
REFERENCES
Part 2
Distress – Our “Internal Enemy”: How to “Disarm” or Lessen its Negative Impact on the Psychophysical Condition of Women with Triple-Negative Breast Cancer?
Abstract
INTRODUCTION
What Can Patients with Cancer, Cancer Care Teams, and Caregivers Do When the Distress Becomes Very Serious?
Simple Tools to Help Measure Distress
How to Take an Active Role in Personal Management of the Cancer-related Distress and Cooperate with the Cancer Care Team? – The Art of “Do's” and “Don'ts”
Helpful Options to Manage Cancer-related Distress and its Complications
CONCLUSION
REFERENCES
Teaching the Brain How to Counteract Distress: Practical Lessons About the Stress and Relaxation Responses for Women with Triple-Negative Breast Cancer
Abstract
INTRODUCTION
Opposite Physiologic Actions of Two Parts of The Autonomic Nervous System (ANS) – the Sympathetic Nervous System (SNS) and The Parasympathetic Nervous System (PNS)
How the Parasympathetic Nervous System (PNS) Activation can be Applied to Benefit Women with TNBC?
Combining the Awareness about Autonomic Nervous System (ANS) Signals with Informal Applications of Cognitive and Behavioral Interventions: How to Make a Positive Transformation?
Eliciting Relaxation Response to Restore a Calming Balance of the Mind and a Healing Potential of the Body
How to Teach the Brain to Reengage in the Repair of Some Stress-Related Damages? – A Therapeutic “Menu” to Choose from, for Women with TNBC
CONCLUSION
REFERENCES
An Intersectional Neuroscience Approach for Disadvantageous Populations: Meditation Practice as a Possible Support Option for Women with Breast Cancer?
Abstract
INTRODUCTION
Intersectional Neuroscience (IN) - A Novel Research Model That Can Help Determine Mental States during Meditation in Diverse Populations of Participants
Evaluating Multivariate Maps of BODY Awareness (EMBODY) - The Innovative Task to “Decipher” Mental States During the Breath-focused Meditation
A Possible Application of the Community-Based Participatory Research (CBPR) to Introduce Intersectional Methodology to Bridge the Gap between Research and Practice
How the Different Attentional States During the Breath-focused Meditation Can be Measured?
Employing an Intersectional Neuroscience Approach to Develop Metrics of Meditation Practice in Disadvantageous Groups of Participants: A Possible Future Strategy for Women with Breast Cancer
CONCLUSION
REFERENCES
May We Adjust the “Third Wave” of Cognitive and Behavioral Therapies (CBT) and Psychological Processes of Change for Women with Breast Cancer?
Abstract
INTRODUCTION
An Advent of the “Third-Wave” Cognitive and Behavioral Therapies and Process-Based Approaches to Patients with Breast Cancer
A Focus on Context and Function: A Combined Approach from the Cognitive and Behavioral Directions
How Can We Accommodate the Key Psychological Processes of Change to Help Achieve the Patient’s Personalized Goals More Effectively?
Psychological processes of change in six basic domains: A focus on flexible therapeutic options vs. traditional signs or symptoms analysis in the scope of their applications
Cognition
Affect
Attention
Self
Motivation
Behavior
Psychological Flexibility – the Courage of Overcoming Barriers by Using Cross-Dimensional Concepts
Functional Analytic Psychotherapy (FAP) – Potential Values to the Patients and Their Clinical/Cancer Care Teams
CONCLUSION
REFERENCES
Exceptional Responders: Exploring the Molecular “Make-up” of Patients with Cancer Who Experienced Recovery
Abstract
INTRODUCTION
The Exceptional Responders Initiative (ERI) – New Hopes and Challenges Uncovered by a Pilot Study
An Impact of Precision Oncology on the Exceptional Responders Initiative (ERI)
Selected Tools of Precision Oncology Applied in the Exceptional Responders Initiative (ERI)
The NCI-MATCH Trial - A Molecular Analysis Facilitating the Choice of Optimal Oncologic Therapy
Challenges in Investigating the Exceptional Responders and Exceptional Responses
Future Steps to Unlock the Door to Novel Anticancer Treatments
The Power of Integrated Studies –The Interface Between the Patients, Tumors, and Socio-epidemiological Risk Factors for Malignancies
A Spotlight on The Network of Enigmatic Exceptional Responders (NEER)
CONCLUSION
REFERENCES
Radical Remissions: Unique Lessons from Patients with Cancer Who Were Able to Defy the Odds and Recover
Abstract
INTRODUCTION
“The Radical Remission Project”-Directions for Future Research and Navigation Through the Labyrinth of False Hope
Individual Patterns Used by Some Patients who Experienced Unusual Recovery from Cancer and Typical Reasons for Refusing Conventional Oncology Treatments
Basic Expectations of “Exceptional” Patients with Cancer and “Reversible” Obstacles from their Healthcare Professionals
The Pillars of Effective Communication between Oncology Patients and Their Physicians
Complementary and Integrative Medicine (CIM) and Integrative Oncology: Beneficial “Links” in the Care of Patients with Cancer
The Integrative Oncology Scholars (IOS) program – Bridging the Gap in the Comprehensive Cancer Care
CONCLUSION
REFERENCES
How Can We Redefine Hope and Gratitude to Help Patients with Breast Cancer Build Their “New Life”?
Abstract
INTRODUCTION
Precious “Secrets” of Long-term Survivors of Breast Cancer
A “Fresh Look” at Hope, Gratitude, and Spirituality Concepts in the Context of Patients with Breast Cancer
Gratitude in the Brain: Cerebral Representation of the Gratitude Model
How to Discover a New Meaning in Life? – Simple “Takeaways” for Patients with Breast Cancer
Psychosomatic and Social Experiences of Younger and Older Women with Breast Cancer: A Unique Learning Opportunity
Common Differences in the Psychosocial Perceptions of Breast Cancer Diagnosis and Therapy between Younger and Older Women
Impact of the Diagnosis and Treatment of Breast Cancer on Personal Relationships with the Spouse, Children, and Older Parents
Invisible “Enemy” - Fear of Cancer Recurrence (FCR) and Feasible Interventions to Control FCR in the Care for Survivors of Breast Cancer
CONCLUSION
REFERENCES
The Self-kindness Component of Mindfulness Meditation: A Helpful Strategy to Enhance Emotion Regulation and Reduce the Depression and Distress Symptoms in Women with Breast Cancer
Abstract
INTRODUCTION
The Self-kindness – A Basic Component of Mindfulness Meditation That Can Improve Emotion Regulation, Decrease Distress Perception and Increase Resilience
Two Opposite Directions of the Emotion Regulation - Self-kindness Strategy and Rumination Process
The Combination of Attention, Sense of Self, Behavior, and Motivation – A Busy “Intersection” Where the “Traffic” Can be Controlled by the Self-kindness Approach
CONCLUSION
REFERENCES
Compassion-Focused Therapy (CFT): Introducing a Process-based System of Psychotherapy to Help Patients with Breast Cancer
Abstract
INTRODUCTION
A Concept of Compassion as an Innovative Therapeutic Modality Using Behavioral Approaches - Possible Benefits of CFT for the Patients with Breast Cancer
Accessible Techniques for Enhancing the Bidirectional Mind and Body Connections
A Different Perspective on Possible “Reprogramming” Negative Emotions: A Psychoeducation and Behavioral Practices for Improvement of the Patients’ Functioning
Challenges in Introducing Novel Integrated Care Models - Considering the Use of Horizon Scanning Methodologies
Enabling and Constraining Factors to the Horizon Scanning for Novel Integrated Healthcare Models
CONCLUSION
REFERENCES
How Can Medical Professionals Maintain Compassion for Their Patients with Breast Cancer?
Abstract
INTRODUCTION
Why Compassion and Empathy Are So Crucial To Delivering The High-Quality Healthcare?
How The Healthcare Professionals Could Maintain Their Compassion or Empathy in a Daily Practice?
Lessons Learned From Studies of Medical Professionals about Their Strategies for Maintaining Compassion and Empathy for Patients
The Transactional Model of Compassion (TMC): An Important Process to Enhance Compassion Skills
Sustainable Compassion Training (SCT): A Potential Strategy to be Used by Medical Practitioners
Navigating Through the Main Strategies for Compassion in the Patient Care – Helpful Directions to Consider for Medical Professionals
The Importance of Applying Process-Based Interventions to the Clinical/Cancer Care Teams First, and then, to Their Patients
CONCLUSION
REFERENCES
APPENDIX
Metastatic Breast Cancer
Highlights for patients with breast cancer to remember & practical questions to ask
Where does Breast Cancer (BC) Start?
How does BC Spread in the Body?
How do you choose an optimal treatment plan for a woman with triple-negative breast cancer (TNBC)?
What is the Role of Monitoring in Patients with TNBC?
What are some Recommended or Preferred Options in the Systemic Therapy for HER2-negative BC?
How BC Progression can be Manifested?
What are the main topics that a patient with BC and her physician need to discuss before considering an application of the new line of systemic therapy?
What are the most Important Steps in Shared Decision-making?
Which factors usually play a role in the personal or shared decision-making of patients with BC?
In which way a second opinion can be helpful for a woman diagnosed with BC?
What are the main benefits of attending support groups?
Possible questions to ask doctors about BC diagnosis, prognosis, and treatment options
References & Resources
Helpful Medical Terminology
The Management of Metastatic Triple-Negative Breast Cancer:
An Integrated and Expeditionary Approach
Authored by
Katarzyna Rygiel
Department of Family Practice
Medical University of Silesia (SUM)
3 Maja St., 41-800, Zabrze
Poland

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FOREWORD

Nowadays, several women with breast cancer (BC) experience positive therapeutic effects and longer survival. However, certain BC subtypes, like triple-negative breast cancer (TNBC) (in the advanced or metastatic stages) remain the major challenge, because of their aggressive behavior, heterogeneity, high recurrence rates, and resistance to traditional therapies. One important reason why TNBC is so difficult to treat is the lack of targetable receptors (such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER 2)) on the malignant cell’s surface. This feature, together with a propensity for visceral metastases, presents an unmet medical need.

Although the latest research advances in the BC area have resulted in some innovative therapeutic strategies, many of these novel agents have certain toxic effects, and therefore, careful patient selection, monitoring, and prompt treatment of side effects are required. To yield the benefits of new targeted therapies and to counteract their possible toxicities, both sides that are involved in TNBC care, the healthcare professionals and the patients must be well-prepared for long-term cooperation. Such collaborative efforts demand clinician’s updated knowledge about novel therapeutic strategies and clinical trials in the TNBC area. Also, building professional relationships and communication networks with the patients and their caregivers is very important.

At the same time, the patients themselves need to be adequately informed about some basic principles of TNBC, and they should be personally engaged in the therapeutic course of their disease. For instance, the patients need to learn some skills, such as self-observation and self-care, as well as precise communication with the treatment team members. It appears that pharmaceutical care would be a perfect avenue to accomplish the objectives of safe and effective BC care. However, in the reality of typical, busy oncology centers, these necessities are often difficult to fulfill, due to various reasons (e.g., lack of time, incentives, and organizational support). In the face of these demands, the book titled: ”The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach” offers a possible solution.

One of the remarkable features of this book is a reader-friendly presentation of topics in form of the well-structured graphs and tables, which contain helpful, multidisciplinary information. A brought thematic spectrum of this book, contained in separate chapters (organized in the form of two, conveniently overlapping parts), provides a clear, comprehensive, and updated knowledge base for medical care teams in Breast Care Units and other oncology settings. It should be noted that this is another book of this author, in which she responds to the challenge of combining the efforts of members of medical care teams, with various areas of expertise (e.g., physicians, pharmacists, diagnosticians, physical therapists, psychologists, and nurses) to work together, to achieve improvement in health condition and the quality of life of the patients with TNBC, and other subtypes of BC.

The author very insightfully analyses many therapeutic aspects of BC and emphasizes the crucial role of education and overcoming barriers of fear or uncertainty. Moreover, she highlights the necessity of embarking on a difficult path that leads to accomplishing beneficial effects (not only in terms of clinical parameters but also in the psychological domains of a patient’s life). This is particularly important since in patients with TNBC, receiving multiple medications is often related to an adverse phenomenon of polypharmacy, often observed in multi-morbidity, associated with poly-therapy. Therefore, limiting the adverse effects of recommended therapies to a necessary minimum would be extremely beneficial (e.g., with regard to many new targeted therapies). This demanding task is primarily addressed to both physicians and pharmacists, who should create two integrated “pillars” of patient management. In addition, this book promotes the concept of patient-centered, personalized care. It encourages clinicians to be open-minded, adequately trained, and ready to constantly exchange their expertise to serve the afflicted patients with BC to improve their outcomes.

Finally, this book provides many useful, easily accessible tools to attain these goals. It would be very important for medical and pharmacy students or residents to be introduced to these integrative concepts of care from the early stages of their professional education. As an academic teacher with many years of experience, I would definitely recommend this book as a practical reference in many educational environments, for teaching multidisciplinary teams of medical professionals and students, as well as patient advocates, caregivers, and women suffering from BC.

Lucyna Bułaś Department of Pharmaceutical Technology Faculty of Pharmaceutical Sciences in Sosnowiec Kasztanowa 3, 41-200 Sosnowiec Poland

PREFACE

Despite recent therapeutic advances in metastatic triple-negative breast cancer (TNBC), it still remains an incurable disease. The latest progress in the TNBC research has resulted in some innovative therapeutic options, such as immunotherapy, antibody-drug conjugates (ADC), and inhibitors of poly (ADP-ribose) polymerase (PARP), which can be applied in combination (or in sequence) with standard chemotherapy (CHT) regimens. Such targeted therapies bring some hope with regard to the prognosis for many women suffering from metastatic TNBC. However many of these novel agents have some serious adverse effects, and thus, the right patient selection, careful monitoring, and rapid delivery of medical therapies to relieve side effects are imperative.

To address these issues, a book titled: “The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach” integrates multidisciplinary knowledge and experience from the perspective of medical professionals and researchers in the TNBC area, and combines it with the patient’s point of view. This book is composed of two parts.

PART 1

An Overview of the Ethnic Disparities and Current or Emerging Targeted Therapies for Patients with Advanced or Metastatic Triple-Negative Breast Cancer (TNBC).

PART 2

The Role of Patient Education, Empowerment, and Communication with Medical Teams, and Psychological or Supportive Approaches in Advanced or Metastatic Breast Cancer (BC).

The first chapter of Part 1 introduces some important aspects of ethnicity, obesity associated with metabolic syndrome and chronic inflammation, as well as reproductive, social, and environmental factors, which can greatly influence TNBC outcomes. This is critically important for an understanding of the risk, development, and progression of TNBC in various ethnic groups, such as African American (AA) and European American (EA) women. Moreover, considerations of predisposing and aggravating environmental, socioeconomic, and behavioral factors, which may have a major impact on BC prevention, course, and survival are briefly presented.

Consecutive chapters of Part 1 discuss current and emerging targeted therapies for patients with advanced or metastatic TNBC, based on recent, major clinical trial results. Recommendations for clinicians and patients are briefly summarized at the end of each chapter. The last chapter of Part 1 describes a noninvasive “tool” of Precision Medicine that may be considered for the individualized treatment of women with BC. This tool attempts to link the main clinical objectives with the personal goals of the patients suffering from advanced or metastatic TNBC or other difficult-to-treat BC subtypes.

The initial chapters of Part 2 provide focused psychoeducational information for patients with advanced or metastatic stages of BC (e.g., TNBC subtype). This information is designed to facilitate clear communication between the patients and the treatment team members. Subsequent chapters of Part 2 contain different cognitive and behavioral concepts and examples of the relevant therapeutic strategies. They include easily available techniques for coping with stress, which accompanies women with BC, during multiple diagnostic and therapeutic stages, and often aggravates their health conditions.

Traditionally, in the majority of publications concerning BC, the medical and psychological topics are usually presented as two separate groups of problems, while in reality, such a division is rather artificial, since these issues are always interrelated. To properly address this need, the book highlights an integrative approach to these deeply interconnected areas. Also, the added value of this book consists of blending the latest evidence from research trials in the TNBC area with clinical practice and feasible psycho-educational approaches, which can be suitable for individual patients and their caregivers. Combining targeted treatments for TNBC with effective coping with distress (commonly associated with uncertain or poor prognosis and overwhelming adverse effects of different targeted therapies) as well as simple lifestyle modifications represent the key elements, that can substantially ameliorate outcomes, even in the most vulnerable patients with metastatic TNBC.

Importantly, this book bridges the gap between the strictly clinical or research-related aspects of BC management and the personal needs and expectations of patients with BC. It also invites medical professionals who are physicians, psychologists, pharmacists, and researchers in the field of BC to conduct open dialogues with patients, aimed at their practical education and support. It also includes helpful resources for the support of both the patients and their medical caregivers, as “partners” and “co-passengers” of their joint “expedition” to conquer BC and reclaim the necessary balance or comfort in life.

In addition, this book presents a novel concept of a challenging journey for patients with TNBC (or other aggressive subtypes of BC, especially in advanced or metastatic stages), which can be perceived or interpreted as a series of stimulating “adventures” and meaningful educational events. This, in turn, can shed some bright light on a serious, chronic disease, like BC, and its interconnected risk factors. Such an approach may positively influence the attitude of many women suffering from BC. Hopefully, instead of approaching a diagnosis and therapy of TN BC as a terrifying “war”, composed of devastating ”battles”, the patients may change their perspective on this life-threatening disease, and view it as a real opportunity to use the modern armamentarium of current pharmacologic therapies and noninvasive, cost-effective, feasible psychological, and supportive modalities to improve their outcomes.

Finally, the purposely changed narration, used in many chapters, is intended to re-direct many suboptimal cognitive and emotional stereotypes, which are often perpetuated by numerous patients with BC. To accomplish these long-term goals, it is necessary to teach the medical team members to positively “re-orient” women with BC, so that they can stay motivated, and engaged in active participation in their oncology care. It requires a lot of time, effort, initiative, expertise, and cooperation within multidisciplinary teams of medical providers. However, in the long run, this may beneficially transform the approach to BC, its management, and prevention. Simultaneously, well-educated and empowe- red patients may be able to communicate and integrate their efforts with the professional actions of the medical teams, in charge of their care.

Katarzyna Rygiel Department of Family Practice Medical University of Silesia (SUM) 3 Maja St., 41-800, Zabrze Poland

Part 1

An Overview of the Ethnic Disparities and Current or Emerging Targeted Therapies for Patients with Advanced or Metastatic Triple-Negative Breast Cancer (TNBC).

“What lies behind us and what lies before us are tiny matters compared to what lies within us.”

Oliver Wendell Holmes

Unraveling Ethnic Disparities in Triple-Negative Breast Cancer (TNBC): Exploring The Impact of Metabolic, Reproductive, Environmental, and Social Factors on the Disease Course in African-American (AA) Women Population

Katarzyna Rygiel

Abstract

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) in which the expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) is absent or very low. TNBC consists of approximately 15-30% of the invasive BC cases in the United States (US) Women with TNBC represent a heterogeneous population with regard to their ethnicity and biology including the genetic make-up metabolic or hormonal profile as well as the socioeconomic status (SES) cultural behavioral educational levels. Notably African-American (AA) women usually have a higher prevalence of TNBC and a worse prognosis compared to European-American (EA) or Non-Hispanic White (NHW) women. The goal of this chapter is to elucidate the possible interplay of inherited and acquired, often lifestyle-related risk factors which can stimulate the initiation and development of the most aggressive subtypes of TNBC in AA women compared to their EA (or NHW) counterparts. In particular this chapter explores some ethnic disparities in TNBC mainly in the example of the US where such disparities have been studied in clinical research. This chapter also focuses on differences in TNBC risk factors healthcare patterns clinical outcomes between AA and EA (or NHW) women. It briefly discusses the multi-factorial etiology of these disparities e.g genetic, hormonal, metabolic, behavioral, cultural, socio-economical and environmental. Presented short analysis of a dynamic blend of inherited and acquired variables also provides some directions for the reduction of these disparities, to improve TNBC outcomes, among women from ethnic groups, such as AA.

Keywords: Acquired, Ethnic groups, Healthcare disparities, Inherited, Risk factors, Triple-negative breast cancer (TNBC).

INTRODUCTION

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC), in which the expression of the estrogen receptor (ER),

progesterone receptor (PR), and human epidermal growth factor receptor (HER2) is absent or very low [1]. TNBC consists of approximately 15-30% of the invasive BC cases in the United States (US) [1]. In general, African-American (AA) women have a higher incidence of TNBC, worse outcomes, and higher mortality rates compared to European-American (EA) (or non-Hispanic White (NHW)) women [2]. In addition, TNBC is more prevalent in western sub-Saharan African patients compared to their EA (or NHW) counterparts [2]. TNBC risk factors and possible causes can be divided into inherited (or biologic) and acquired (or non-biologic) categories [3]. An inherited or genetically determined ancestry and acquired or socio-environmental factors can considerably influence the outcomes of patients with TNBC [3]. This is a complicated network that is very difficult to untangle and classify into separate domains. However, there are some distinctive patterns that can be recognized. For instance, the genes that women inherit, affect the way how they metabolize certain medications, what adverse effects they may experience from specific pharmaceutic agents, and what kind of therapies could be the most suitable or contraindicated for them.

A recent study has indicated certain similarities in TNBC, especially with regard to genetics, tumor biology, and environmental risk factors, which were noted in African and AA patients with BC [4]. Also, various observations suggest that the West African origin of women afflicted with BC could have been related to their inherited susceptibility to TNBC [5, 6]. Moreover, some changes in the expression of many genes, connected with the cell’s growth, differentiation, invasion, and metastasis, have been revealed in BC tumors of AA females, to a higher degree than in the EA (or NHW) women [7]. In addition to genetic or molecular differences, an advanced BC presentation at diagnosis, and a higher burden of metabolic comorbidities, certain unequal socioeconomic standards (e.g., residential, occupational, or educational) can contribute to poor survival rates, especially among AA women [8]. Similarly, various socio-environmental determinants widely influence how the surrounding world interacts with women with BC, from different ethnic populations [9]. In this dynamic exchange process, both conscious and unconscious biases may, to some degree, have an important impact on shaping bilateral relationships between women with BC (or at high risk for BC) and the medical systems or local community services, where they live, work or go to school.

The aim of this chapter is to elucidate the potential interplay of biological and non-biological risk factors, which can stimulate the initiation and development of the most aggressive subtypes of TNBC. In particular, this chapter explores ethnic disparities in TNBC between AA women and their EA counterparts (mainly in the example of the US, where such disparities have been studied in clinical research). It focuses on some differences in TNBC risk factors, healthcare patterns, and clinical outcomes, between AA and EA (or NHW) women. It briefly discusses the multi-factorial etiology of these disparities (e.g., genetic, hormonal, reproductive, metabolic, behavioral, cultural, socioeconomic, and environmental). This chapter also indicates some clear directions, on how to reduce the above-mentioned disparities, in order to improve TNBC outcomes, especially among AA women.

How Can we Approach Ethnic Disparities in TNBC Survival? – A Roadmap of Possible Underlying Biologic and Non-biologic Risk Factors or Causes of TNBC in AA vs. EA (or NHW) Women

It should be highlighted that certain differences in the genetic makeup and the tumor biology of BC exist between AA women and their EA (or NHW) counterparts.

Although it has been reported that BC incidence rates are similar for AA and EA (or NHW) women, the TNBC incidence rates in the younger group (e.g., before 45 years of age) are higher among AA, compared to EA (or NHW) females [9]. In contrast, in the older group (e.g., between 60 and 84 years of age), the BC incidence rates are higher in EA (or NHW) women than in their AA counterparts. Nevertheless, AA women have a higher probability of dying from BC at any age [9, 10]. In light of such ethnic disparities in BC survival, some specific BC risk factors and possible causes have been proposed (e.g., relevant to the hormonal, metabolic, and reproductive processes) [11].

In general, BC subtypes include the ER-positive and HER2-positive, the ER-positive and HER2-negative, and the basal-like (BL) BC, which is considered to be synonymous with the triple-negative (TNBC) (characterized by an absent or very low expression of the ER, PR, and HER2). In fact, TNBC usually represents the most aggressive BC subtype [1, 9, 11]. Notably, the incidence of TNBC in AA, predominantly in younger females, is two times higher than the one in EA (or NHW) women [9, 10]. Also, it has been noted that pregnancy and multi-parity augment the risk of TNBC (while these reproductive factors decrease the risk of HR-positive BC) [12]. Since AA usually have more children at a younger age, and they engage in short breastfeeding periods, their risk of TNBC increases, compared to EA (or NHW) women [12]. Moreover, according to a recent study, it has been shown that TNBC in women of African ancestry was characterized by a more common loss of androgen receptor (AR) expression, and worse overall survival (OS) compared to those of European ancestry [13]. Notably, AA women with an AR-negative TNBC have expressed a specific molecular signature, and predominance of BL1, BL2, and immunomodulatory (IM) subtypes of TNBC (Fig. 1) [13].

Fig. (1)) TNBC in women of African ancestry - a frequent loss of AR expression, common BL1, BL2 or IM subtypes, and poor outcomes. TNBC, triple-negative breast cancer; AR, androgen receptor; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor2; BL, basal-like; IM, immunomodulatory.

Also, AA patients with AR-negative TNBC usually have a more aggressive disease course and worse prognosis, compared to those with AR-positive TNBC [13, 14]. In addition, some other differences between AA and EA (or NHW) women include the blood levels of sex hormones, growth factors, and the expression of steroid hormones or growth factor receptors, tumor suppressor genes, or chromosomal abnormalities [15-18]. Such biological discrepancies among AA and EA (or NHW) women may have an impact on therapeutic recommendations and clinical outcomes in patients with from these ethnic groups (Fig. 2).

Fig. (2)) TNBC heterogeneity and new or emerging therapeutic targets. TNBC, triple-negative breast cancer; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor2; AR, androgen receptor; BL, basal-like; IM, immunomodulatory; M, mesenchymal; MSL, mesenchymal stem-like; LAR, luminal androgen receptor; BRCA, breast cancer gene; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; Trop-2, trophoblast cell surface antigen 2; PIK3CA, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mechanistic (mammalian) target of rapamycin; PTEN, phosphatase and tensin; EGFR, epidermal growth factor receptor; PARP, poly (ADP-ribose) polymerase; ADC, antibody-drug conjugate; AA, African-American.

Furthermore, many non-biological issues, such as socioeconomic disadvantages (e.g., related to low income and lack of medical insurance), limited access to healthcare facilities (e.g., causing significant delays in BC screening, diagnostic tests, or modern therapies), unsafe neighborhood, deprivation of nutritious food, lack of comfortable zones for physical exercises or recreation, as well as uncontrolled daily stress (e.g., due to violence, injustice, poverty, uncertainty, or insecurity) are often superimposed on genetic, hormonal, and metabolic components, especially in AA women [9, 19, 20]. Such a combination of biological and non-biologic variables, associated with TNBC can deteriorate outcomes in AA women (Fig. 3) [9, 19, 20].

Fig. (3)) Multifactorial risk factors and possible causes that influence adverse prognosis in AA women with TNBC. TNBC, triple-negative breast cancer; AA, African-American; RCTs, Randomized Controlled Trials; SES, socioeconomic status.

In general, early BC detection (via screening), prompt diagnosis, and comprehensive treatment, as well as reduction of tobacco smoking, have improved the health condition of numerous women with BC [21]. However, in spite of these efforts, several AA women still have a lover probability to receive a state of the art diagnostic workup and therapy, compared to their EA (or NHW) counterparts [22]. To rectify this situation, innovative approaches, beyond the current standards, will be necessary to actively promote BC prevention, improve healthcare path, augment survival, and reduce BC mortality.

A SPOTLIGHT ON THE FAMILY HISTORY AND GENETIC MUTATIONS: THE IMPACT OF ETHNICITY ON MOLECULAR MAKE-UP IN TNBC

Family history (FH) of BC depends on the number of family members affected, the age at diagnosis, and the number of unaffected women in the pedigree [23]. A woman’s BC risk is increased if she has a first-degree relative with BC at a young age or if she has multiple relatives with BC [23]. Approximately 5–10% of BCs have been attributed to heredity [24]. In particular, the BRCA (breast cancer gene) 1 and BRCA 2 gene mutations, which are located on chromosomes 17 and 13, respectively, are responsible for the majority of autosomal dominant inherited BCs. BRCA1 and BRCA2 genes produce tumor suppressor proteins, which allow to repair DNA damages and reinforce the stability of cellular genetic material [24]. If BRCA1 and BRCA2 are mutated, cells may create genetic abnormalities, often leading to cancer development.

Such mutations are related to some degree to the woman’s ethnic background. In particular, BRCA1 mutations, are encountered mostly in Ashkenazi Jewish women (8.3%). In contrast, they are less prevalent in Hispanic women (3.5%), NHW women (2.2%), AA women (1.3%), and Asian women (0.5%) [25]. In addition, over a half of women with inherited harmful BRCA1 mutation, and slightly less than a half of those with the inherited BRCA2 mutation, will develop BC by the age of 70 [14, 26].

Also, about 40% of females with inherited a BRCA1 mutation and 11–17% of women with inherited a harmful BRCA2 mutation will develop ovarian cancer by the age of 70 [26].

Likewise, women diagnosed with BC, associated with harmful BRCA1/2 mutations have a higher probability for developing a second BC (e.g., in the ipsilateral or the contralateral breast) compared to those, without BRCA1/2 mutations [14, 26].

Notably, many patients with BCs, who carry a BRCA1 mutation, may have a TNBC subtype that frequently has a worse outcome, than other BC subtypes [14, 26]. Therefore, it has been recommended that women with early-onset BC and women with a positive FH for BRCA1/2 mutations should undergo genetic testing, at the time of BC diagnosis [14, 26].

It should be highlighted that the BRCA1/2 mutations are responsible for BC in almost 50% of families with several cases of BC, while some other mutations, which are linked to a smaller increase in BC risk include PALB2, PTEN, TP53, ATM, CDH1, CHEK2, and STK11 genes [14, 26, 27]. In particular, mutations in the PALB2 tumor suppressor gene are associated with a risk of BC similar to the one related with BRCA1/2 mutations, since the PALB2 protein collaborates with the BRCA1/2 proteins in repairing DNA breaks [28]. Notably, more than one-third of women with the PALB2 mutation will develop BC by age 70, and this risk is doubled in women with the FH of BC and the PALB2 mutation [28].

SOCIOECONOMIC DISPARITIES IN BC – A LINK BETWEEN THE ECONOMIC DEPRIVATION AND DYSFUNCTIONAL HEALTHCARE PATH

BC risk factors, incidence, prevalence, survival, and mortality rates that are different in particular ethnic groups, can also vary, depending on socioeconomic conditions [9, 29]. For instance, the key socioeconomic parameters that influence disparities in BC mortality, include poverty, social injustice, and disadvantaged educational or occupational aspects of life [30]. In particular, poverty has been linked with decreased rates of BC screening, late-stage diagnosis, inadequate therapy, or incomplete follow up care, as well as increased death rate from BC [9, 31, 32]. A cascade of challenges that economically disadvantaged AA women often experience include lack of health insurance, difficulties in access to well-trained healthcare practitioners, modern medical equipment and infrastructures, as well as insufficient education and support [3, 9, 33].

This, in turn, often leads to lower rates of mammography screening and greater probability of advanced-stage BC at diagnosis, and delayed or substandard therapy [9, 34]. Moreover, common metabolic comorbidities, such as obesity, diabetes mellitus type 2 (T2DM), arterial hypertension (HTN), and cardiovascular disease (CVD)) are more prevalent in economically deprived women (e.g., AA) [35]. Also, in the underserved populations, there is limited access to fresh and healthy alimentary products, and lack of safe space for physical exercises [2, 5, 36]. This, in turn, often contributes to central (abdominal) obesity with an abnormal carbohydrate and lipid metabolism, which can be linked with subsequent worse prognosis of BC [2, 5, 19, 36, 37]. In essence, poverty and related to it cluster of factors, including lack of primary care physician, untreated comorbidities, lack or limited health insurance, unhealthy lifestyle (e.g., tobacco smoking, inadequate nutrition, and lack of regular physical activity), insufficient health information or lower literacy level, as well as maladaptive responses to overwhelming daily stressors contribute to BC disparities among women. A cluster of these conditions is commonly seen in AA women (Fig. 3) [9, 19, 38].

Furthermore, long-term exposures to many environmental toxic agents, including endocrine-disrupting chemicals (EDC), which are present in several commercial, industrial, and personal care products are almost unavoidable, especially for women with the low socioeconomic status (SES) [39]. The most hazardous EDC involve polycyclic aromatic hydrocarbons (PAH), organochlorines (e.g., polychlorinated biphenyls (PCBs) and dioxins), phenols (e.g., bisphenol A (BPA)), phthalates, parabens, benzene, ethylene oxide, pesticides (e.g., organo-halogenated agents, and dichlorodiphenyltrichloroethane (DDT) that was withdrawn from the market), and certain metals (e.g., cadmium) [40, 41]. Notably, EDC, and different forms of hormone replacement therapy, which act upon breast tissue, have an impact on BC risk or development (Table 1) [40, 41].

Regretfully, certain attitudes of medical personnel may also aggravate disparities in BC mortality rates (e.g., negative perceptions or manners exhibited towards AA or low SES women vs. positive or neutral attitudes, displayed towards EA (or NHW) and high SES women) [42]. In particular, the Carolina Breast Cancer study has shown that the aggressive subtypes of BCs, which are less responsive to standard treatments and characterized by poor survival (e.g., TNBC), are more prevalent in younger AA, and Hispanic women living in low SES areas [43]. In addition, many AA women rely more on their breast self-examination, as an effective method for BC detection, compared to EA (or NHW) women [44]. Unfortunately, such a habit can decrease the rates of mammography testing among AA women, and may lead to overlooking some underlying pathologies of breast tissue [44].

BEHAVIORAL AND CULTURAL FACTORS ACCOUNTING FOR BC DISPARITIES IN AA WOMEN

Behavioral Patternsand Belief Systems differ considerably among AA and EA (or NHW) women, with relation to their attitudes toward BC screening procedures. In particular, AA women may be prone to avoiding mammography, since they can be afraid of pain, discomfort, embarrassment, and unknown consequences of exposure to radiation (during this procedure) [45, 46]. Since many AA women can experience anxiety about the findings of the test, it is crucial to provide clear and practical educational information that will be well-adjusted to a woman’s belief system [47, 48].

Table 1An interplay between inherited and acquired risk factors or causes, which can affect outcomes of the TNBC in AA compared to EA (or NHW) patients.INHERITED/BIOLOGIC RISK FACTORS FOR TNBCGenetics Women born with BRCA mutation are > to develop TNBC; 70% of all BCs diagnoses in women with the BRCA mutation are TNBCsAncestry TNBC is more likely to be diagnosed in AA & Hispanic women (vs. NHW & Asians)Obesity & its comorbidities Insulin resistance dysglycemia, dyslipidemia, diabetes mellitus type 2 (T2DM), hypertension (HTN), cardiovascular disease (CVD)Hormonal imbalance due to reproductive cycle & pre-menopause in younger women (< 50 years of age)ACQUIRED/BEHAVIORAL ENVIRONMENTAL/NON-BIOLOGIC RISK FACTORS FOR TNBCSocioeconomic status (SES) Unemployment, or insecure workplace, low income, lack of medical insurance, scarcity of nutritious food, unsafe neighborhood lack of places for exercisesAccess to healthcare services Limited (or none) access leading to delays in BC screening, diagnosis, therapyBehavioral, educational, and cultural issues Low education & specific behaviors or beliefs influence decision-making about BC prevention, diagnosis & treatment, or participation in RCTsEnvironmental toxicity The elevated burden of exposure to chemical & physical toxins in the air/water, soil pollutions, and heavy metals: cadmium, lead & arsenic)OVERLAPPING AREAS OF COMMON BIOLOGIC & NON-BIOLOGIC RISK FACTORS FOR TNBCGenetics, ancestry & low SES: sub-standard living/working conditions dysfunctional healthcare pathReproductive issues very young age at 1st childbirth, short breast –feeding period, multi-parity, use of oral contra- ceptives for >1 yearMetabolic complications of central obesity metabolic syndrome, prediabetes, a combination of hormonal, metabolic & pro-inflammatory dysfunctionsUncontrolled stress response poverty, injustice, violence, insecurity, processed food (< quality, > quantity), sedentary lifestyleSTAGES OF TNBCStage 0 isolated in one part of the breast (e.g