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

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. 

Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) (that is estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative), can further be divided into AR-negative TNBC (also known as quadruple-negative breast cancer (QNBC), a more frequent TNBC subtype) and AR-positive TNBC. The paucity of treatment targets makes QNBC very difficult to manage. Moreover, in the absence of AR expression, many breast cancers (BCs) often display aggressive behavior, leading to negative outcomes in afflicted women. At present, some novel therapeutic targets have emerged, and hopefully, the relevant targeted strategies will improve the survival of patients with QNBC. This chapter briefly outlines the main TNBC subtypes and focuses on the AR expression (its presence vs. absence), and potential treatment approaches, including AR antagonists (ARA). In addition, this chapter overviews certain molecular characteristics of TNBC and presents recently approved targeted therapies. 

 The ability to identify the molecular features of metastatic breast cancer (BC) provides a unique insight into a patient's therapeutic options and the opportunity to follow the BC progress over time. A classical tissue biopsy remains the standard procedure to describe tumor biology and guide treatment choices. However, a liquid biopsy, which can provide medical practitioners with the opportunity to detect genomic mutations and monitor therapeutic effects, can play a prominent role in the diagnosis, therapy, and prognosis of patients with different malignancies, including metastatic BC. In fact, the liquid-biopsy-based therapeutic interventions led to the approval of alpelisib (a PI3K inhibitor) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor2 (HER2)-negative, advanced or metastatic BC, in whom BC had progressed on or after therapy with an aromatase inhibitor (AI). This chapter describes a liquid biopsy in BC. It explores its potential for clinical applications in early diagnosis, monitoring treatment response, detecting minimal residual lesions, predicting risk of progression or recurrence, and estimating prognosis. It compares a liquid biopsy with a tissue biopsy, and outlines the benefits and limitations of each of these procedures, focusing on patients with metastatic BC. Moreover, this chapter analyses the results from recent studies relevant to liquid biopsies in BC (e.g., circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA)). 

During a metastatic progression of breast cancer (BC), and upon application of various antineoplastic therapies, the initial status of biomarkers can be altered. Awareness of changes in hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) is very important, because they may have an impact on patient management. However, the procedures for monitoring these changes in women with metastatic BC still remain unclear. According to the guidelines for clinical practice from the American Society of Clinical Oncology (ASCO), the reevaluation of metastatic BC lesions, is of great importance, and it has been recommended that the biopsies of multiple metastatic lesions need to be performed. The aim of this chapter is to highlight the role of retesting receptor status in BC metastases and the impact that this approach may have on the selection of therapeutic strategies, in the individualized management plans for patients with metastatic BC. In addition, this chapter concisely presents some novel biomarkers linked with targeted therapies for metastatic BC. 

Three recently approved therapies for the treatment of triple-negative breast cancer (TNBC), including poly(ADP-ribose) polymerase (PARP) inhibitors, immunotherapy, and antibody-drug conjugates (ADC) have changed the management of several patients with advanced, metastatic, and even early-stage TNBC. PARP inhibitors, such as olaparib and talazoparib, have been approved as therapies for BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). Immunotherapy has been approved for patients with programmed death ligand 1 (PD-L1)-positive, metastatic TNBC. Immune checkpoint inhibitors (ICIs), such as atezolizumab and pembrolizumab demonstrated a significant improvement in progression-free survival (PFS) (in combination with chemotherapy). An antibody-drug conjugate (ADC), sacituzumab govitecan (SG) (that targets trophoblast cell surface antigen 2 (Trop-2)), has shown efficacy and prolonged PFS and overall survival (OS) in patients with metastatic TNBC. The goal of this chapter is to briefly review some of the most promising therapies available for the treatment of TNBC, including PARP inhibitors, ICIs, and ADCs. Considerations of choosing these therapeutic options and their sequence, in the context of the BRCA mutation and the PD-L1 positivity, in patients with TNBC have been discussed.

Patients with Breast cancer (BC) often experience a spectrum of adverse, anticancer therapy-related symptoms, which deteriorate their quality of life (QoL). Therefore, effective strategies for BC are needed. Personalized medicine offers many therapeutic options (e.g., targeted therapies) that can be tailored to the individual needs of a given patient. This chapter aims to briefly present typical side effects of current anticancer treatments, which often reduce the QoL of patients with BC and survivors. In particular, it addresses pain (including chemotherapy (CHT)-induced peripheral neuropathy (PN) and lymphedema), depression, cognitive dysfunction, premature menopause, and CHT-induced menopause. It focuses on the adverse effects of the BC therapies, such as chemotherapy (CHT), immunotherapy (IT), and some targeted therapies. In addition, several issues related to cardiovascular toxicity induced by anticancer treatments and cardioprotective measures for women with BC are addressed. This chapter also touches on the recent advances in precision medicine and provides some future directions, aimed at fulfilling unmet needs of patients with BC. The described approaches may be helpful in planning personalized treatment, facilitating the patient’s tolerability of many available anticancer therapies, optimizing the medication selection, and improving the patient’s QoL.

A constellation of specific personal characteristics of the patients have been described as personomics, which involves an individual patient’s personality type, set of personal values, priorities, preferences, health-related beliefs, goals, economic status, and different life circumstances, which can affect when and how a certain disease (e.g., breast cancer (BC)) can be manifested in a given woman. As a consequence, personomics can be considered to be a novel clinical instrument that is helpful for making a connection between the standard and the emerging, more individualized model of medical care. This plays an essential role in patients diagnosed with the most aggressive and difficult-to-treat malignancies (e.g., BC subtypes, such as triple-negative breast cancer (TNBC). At present, many biological properties in the forms of different “omics” platforms (such as genomics, proteomics, transcriptomics, metabolomics, epigenomics, and pharmacogenomics) have emerged. They have been incorporated into precision medicine. However, to optimally tailor diagnostic and therapeutic approaches to a given patient, the biological characteristics need to be integrated with the personal ones. This chapter aims to address some practical research ideas of personalized medicine, relevant to personomics that can incorporate individual patient issues into the comprehensive therapeutic plan.

Stress is an inevitable part of life. It constantly bombards our lives, and these explosions range from minor daily frustrations to overwhelming fear brought on by the adverse prognosis of serious diseases, like triple-negative breast cancer (TNBC). In patients with cancer, distress has been defined as “a multifactorial unpleasant experience of a psychological (e.g., cognitive, behavioral, emotional), social, spiritual, and physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. However, even in such a difficult health-related situation, it is encouraging that some consequences of distress are not inevitable. Some natural questions for every woman with cancer (e.g., TNBC) are: “What are the normal limits of distress?” and “What to do when distress becomes more serious?” This chapter will briefly address the above questions and will present some tools that can be used to measure distress. In addition, a few simple strategies that are easily accessible and effective in Distress Management and its complications will be suggested (e.g., “Do's and Don'ts” list of recommendations).

In spite of a very difficult situation, women with triple-negative breast cancer (TNBC) need to realize that some consequences of the cancer-related distress can be alleviated. Moreover, it is possible to counteract, to some degree, the damaging effects of this distress. In particular, the relaxation response, as the opposite, “calming version“ of the “typical” stress response can be achieved by a given patient with cancer, with some simple, intentional, and conscious efforts. In fact, modern stress management offers a whole armamentarium of tools and strategies that are necessary to reduce negative results of stress-related reactions. Since many warning signs of stress are connected with certain activities of the autonomic nervous system (ANS), it should be beneficial to patients to learn some basic information about the ANS functions. This chapter will explain how to elicit the relaxation response as the “common denominator” to counterbalance the “typical” stress response. It will also teach how to use diaphragmatic breathing, and the most feasible to adopt elements of the mindfulness-based interventions, as well as cognitive-behavioral approaches, to more effectively combat distress daily.

Mindfulness and compassion meditation have a positive impact on cognition, mood, behavior, and general health, based on recent studies in neuroscience. However, the research methodology is still insufficient to determine and measure different mental states during meditation, especially in minority populations. Intersectional Neuroscience, which is an innovative research model, may provide some solutions since it adapts modern research procedures to include disadvantageous groups of participants (e.g., ethnic minorities, patients with chronic diseases, like cancer, heart disease, or depression). Evaluating Multivariate Maps of BODY Awareness (EMBODY) is a task designed to accommodate diverse neural structures and functions, using the multi-voxel pattern analysis (MVPA) classifiers, with functional magnetic resonance imaging (fMRI). The EMBODY task applies individualized artificial intelligence algorithms to the fMRI data, in order to identify mental states during breath-focused meditation, a basic skill that stabilizes attention. This chapter describes a potential application of the Intersectional Neuroscience (IN) approach to developing useful metrics of meditation practice, including participants from disadvantageous groups. Hopefully, these findings can be explored in-depth, and possibly applied to patients with triple-negative breast cancer (TNBC), in the future. 

To emphasize on the suffering of women with breast cancer (BC), it is necessary to identify and deeply understand many aspects of BC etiology, development, and complex management. However, the strategies for achieving these goals for individual patients often need to be refocused, or redirected, based on personal expectations, needs, and circumstances that can differ considerably among women with very aggressive BC, such as triple-negative breast cancer (TNBC). The main goal of cognitive-behavioral interventions is to change some specific thoughts, emotions, and behaviors and teach constructive coping skills and behavioral modifications, which will aid in building an individual activity plan, coordinated with cancer-related therapies. This chapter will present the concept of the “third-wave” cognitive and behavioral therapies (CBT) and the importance of psychological processes of change, in supportive care interventions, for patients with TNBC. Adding such processes of change should facilitate the development of personalized care solutions for better outcomes for many patients suffering from BC, despite their poor prognosis. This should encourage the patients, caregivers, and their medical care teams to learn, and then, apply these safe interventions in their individualized contexts. 

Patients with cancer, who have achieved an unexpectedly favorable and long-term clinical response are commonly known as exceptional responders (ER). Such patients have often experienced extraordinary responses to some oncology therapies, which have been ineffective for other individuals with similar malignancies. These unusually positive responses may be partially due to some unique genetic and molecular mechanisms, which can be further studied. This, in turn, could provide some directions to a better understanding of why the specific therapy works for only a small number of patients with cancer, but not for everybody. To further elucidate these issues, the National Cancer Institute (NCI) has been conducting various research projects to explain biological processes, which can be responsible for these remarkable responses. A recent pilot study, known as the Exceptional Responders Initiative (ERI), has evaluated the feasibility of identifying exceptional responders retrospectively, by obtaining pre-exceptional response treatment tumor tissues and analyzing them with modern molecular tools. The promising findings of this study can inspire many women with breast cancer (BC) and their medical teams. This chapter presents a synopsis of the ERI. It suggests some possibilities to adjust this concept for patients with breast cancer (BC) (e.g., advanced or metastatic triplenegative breast cancer (TNBC)). 

Many women with aggressive BC subtypes are devastated, due to metastatic spread, resistance to therapy, and poor prognosis. However, there is a growing body of scientific evidence that some patients have been able to defy the odds of advanced malignancy and recover, in spite of their fatal prognosis and dismal oncology statistics. Also, these “better than expected” clinical effects were not totally rare. To explore this fascinating subject, future research is undoubtedly necessary. In line with this challenge, the innovative “Radical Remission Project” was created, which allows collecting cases of Radical Remissions for research studies. It also connects survivors with patients, who actually struggle with aggressive cancers. Since there is a concern about giving false hope to patients with advanced malignancies, they need to be professionally informed that the cases of Radical Remissions must be first explored in detailed research studies, before making any conclusions about their potential applicability to patients with similar prognoses. This is necessary to protect the most vulnerable patients, who must not be given any false expectations, and the practical communication skills of the cancer care teams are crucial to accomplish it. In addition, Complementary and Integrative Medicine (CIM), which manages the physical, mental, emotional, and spiritual needs of patients with cancer, regardless of their prognosis, appears to be helpful in an attempt to meet these needs. CIM is gradually becoming a part of each stage of the cancer journey, from active to supportive and palliative oncology care. Similarly, integrative oncology that uses evidence-based, lifestyle modifications, mind-body techniques, and specific natural products in combination with conventional anticancer treatments is in line with patients’ safety. This chapter briefly addresses some universal factors, which can make a genuine difference to help in recovery from cancer, based on the Radical Remission Project and CIM-related research. It focuses on the role of open and precise communication between patients and cancer care teams. The ongoing Radical Remission Project can inspire many women with breast cancer (BC) and their medical teams to consider introducing some safe and useful approaches to their standard oncology management. 

There is a need to practically redefine the future way of life, among numerous patients with breast cancer (BC). In fact, spirituality, hope, and gratitude may play a remarkable role in a possible transformation into a “new life”. Also, these invisible, positive “forces” recognize patients as individual human beings, which should be connected with their families, caregivers, friends, and medical professionals, as functional “units”. This chapter provides some suggestions for practical approaches to help design a functional “new life”, especially for women with aggressive BC (e.g., triple-negative breast cancer (TNBC)). In addition, medical care teams may consider incorporating such supportive modalities into the main therapeutic oncology plan.

It has been demonstrated that one of the components of mindfulness meditation, called self-kindness, plays a prominent role in alleviating distress perception, and reducing depressive symptoms, especially among younger women with breast cancer (BC), who represent a particularly vulnerable patient population, often struggling not only with a serious illness but also with numerous family and work-related obligations. This chapter will describe in detail self-kindness as a technique to help ease distress, anxiety, and depressive feelings, as well as enhance resilience and establish objective health-related expectations or goals for patients with cancer, including women with an aggressive subtype of BC, such as triple-negative breast cancer (TNBC).

Compassion-focused therapy (CFT) integrates techniques from cognitivebehavioral therapy with concepts from psychology and neuroscience. The main objective of CFT is to use compassionate mind training to help individuals develop and maintain the experiences of inner warmth and stability, through the cultivation of compassion (including self-compassion). This chapter will describe in detail self-compassion as a technique to help ease distress, anxiety, or depressive feelings, as well as enhance resilience and establish objective health-related expectations and goals for patients with serious chronic diseases, such as cancer, including triple-negative breast cancer (TNBC). 

Compassion in the medical field differs from its traditional meaning in daily life. In medicine, compassion includes a desire to understand an individual’s suffering, together with a wish to relieve it. In essence, compassion offers a unique concept, according to which, the modern science of compassion can be practically applied to suffering people, in many circumstances. This is particularly important for some vulnerable groups of patients (e.g., ethnic minorities), such as women with breast cancer (BC) (e.g., in advanced or metastatic stages, with comorbidities and socioeconomic problems). This chapter presents some suggestions (based on recent research reports) for helpful strategies that medical professionals can use daily, to help maintain compassion for their patients with serious diseases, including some aggressive cancers (e.g., Triple-Negative Breast Cancer (TNBC)).