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Breast cancer is a devastating illness that affects tens of thousands of American women each year. Although it is impossible to predict who will develop breast cancer, clinicians can identify women who are at increased risk for breast cancer and provide them with options to reduce their risk. A number of validated, quantitative risk-assessment models incorporate features of a patient's medical and family history to help women more accurately estimate their individual risk and thus aid them in decision-making. Over the years, research has focused on the development of both surgical and medical methods for breast cancer risk reduction in high-risk women. This chapter will emphasize the importance of identifying and educating women at increased risk for breast cancer, and then providing them with a comprehensive breast cancer risk management plan. We will also discuss the surgical and medical options available and offer a management summary for breast cancer risk reduction. [ABSTRACT FROM AUTHOR]

The development of breast-conserving therapy (BCT) using whole-breast irradiation (WBI) to eradicate residual disease following nonablative resection of breast cancer was one of the great success stories of twentieth-century oncology. Approximately 70-80% of patients with stage I or II invasive breast cancers are estimated to be potential candidates on technical grounds for BCT. [ABSTRACT FROM AUTHOR]

Oncologists typically thought of systemic therapies for breast cancer as belonging to one of two categories: either cytotoxic chemotherapy or hormonal therapy. Though this simple approach served well for decades, the recent development of trastuzumab showed its inadequacies. Trastuzumab, neither broadly cytotoxic nor a classic hormonal manipulation, didn't fit. Thus, a third category, biologic therapy, or alternatively, targeted therapy, emerged. Targeted therapy is a type of medication which blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells. Though we tend to think of targeting growth signals in cancer as recent developments, perhaps they are not so novel after all. First proposed as adjunctive therapy by Schinzinger in 1889, Beatson introduced ovariectomy into clinical practice in 18961. While hormonal therapy is not traditionally categorized as targeted therapy, the estrogen receptor remains arguably the most important growth factor receptor identified for breast cancer, as adjuvant hormonal therapies have a bigger impact on recurrence and survival than any other treatment. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women in the Western world, and is essentially incurable when distant metastases are detected. Despite an increasing incidence, breast cancer mortality has fallen, largely due to the advent of widespread screening programs, but also partly due to the increasing use of adjuvant systemic treatment and advances in loco-regional control. This chapter will review the advances in gene expression profiling, made possible with microarray technology, as new tools for assessing breast cancer recurrence. It will discuss the molecular classification of breast cancer subtypes, as well as the various molecular signatures with their prognostic and predictive implications. Two prospective randomized trials, MINDACT and TAILORx, designed to validate this new technology, will be briefly discussed. [ABSTRACT FROM AUTHOR]

Neoadjuvant (preoperative) chemotherapy was initially developed as a treatment strategy for patients presenting with locally advanced breast cancer, as a means of improving resectability and locoregional control. This treatment sequence has now become standard, conventional practice for patients with bulky cancers of the breast and axillae. Two important advantages identified from this experience have resulted in extension of the neoadjuvant therapy approach to include early-stage breast cancer patients as potential candidates: (i) primary disease downstaging, thereby increasing lumpectomy eligibility (ii) earlier assessment of chemosensitivity versus identification of patients with resistant disease, thereby providing opportunities to individualize therapy Furthermore, several studies have documented the finding that response in the breast correlates with survival, thereby demonstrating that primary tumor downstaging is an excellent surrogate marker for systemic therapy effectiveness. Many breast cancer patients will benefit from systemic therapy to control occult micrometastases in distant organs. As insights broaden regarding the heterogeneity of tumor biology, and as we learn more about treatment toxicity, it has become abundantly clear that expansion of the systemic therapy armamentarium is warranted. Assessment of novel therapies in the prospective adjuvant randomized clinical trial setting typically requires several thousand patient-years of follow-up, and these studies are extremely costly. Ability to evaluate new regimens in the neoadjuvant setting offers the promise of determining chemoeffectiveness within a few months, by using pathologic extent of tumor response from surgery as a surrogate for results achieved in distant organs. Neoadjuvant chemotherapy has therefore become an advantageous treatment sequence for many reasons, and may be considered for application in any breast cancer case where the multidisciplinary oncology team is confident that chemotherapy is a necessary component of the patient's comprehensive therapy. The decision to proceed with neoadjuvant chemotherapy is accompanied by several special considerations that must be handled by the surgeon, and these considerations involve the pre-treatment/diagnostic phase as well as local and regional management. [ABSTRACT FROM AUTHOR]

Adjuvant hormonal therapy is standard treatment for all patients with hormone receptor-positive early stage breast cancer following primary surgery. Hormonal therapy benefits patients whose breast cancer expresses estrogen or progesterone receptors, but not those with hormone receptor-negative disease.1 The goal of adjuvant hormonal therapy is to prevent breast cancer cells from receiving endogenous estrogen stimulation. There are multiple options for adjuvant hormonal therapy in early-stage breast cancer patients. Beatson first observed the role of estrogen deprivation in treatment of breast cancer over 100 years ago after observing the regression of advanced breast cancer following oophorectomy. After Beatson's historic observation, ovarian ablation by either oophorectomy or irradiation became standard for patients with advanced breast cancer. Ovarian ablation has gradually been replaced by pharmacologic hormone therapy. Selective estrogen receptor modulators such as tamoxifen block the action of estrogen at the estrogen receptor. Luteinizing hormonereleasing hormone agonists act centrally to suppress estrogen synthesis, and aromatase inhibitors prevent the peripheral conversion of androgens to estrogen leading to estrogen deprivation. Recommendations for adjuvant hormonal therapy for pre -and postmenopausal early-stage breast cancer patients will be discussed in this chapter. [ABSTRACT FROM AUTHOR]

Since the first edition of this text adjuvant therapy for early stage breast cancer has changed in several important ways. Several trials have further elucidated the impact of adjuvant chemotherapy for breast cancer. Several trials have confirmed the promise of aromatase inhibitors for adjuvant endocrine therapy. A new targeted therapy, trastuzumab, has been shown to be highly effective as part of adjuvant therapy for HER2-positive breast cancer.An updated meta-analysis of the benefits of adjuvant therapy of breast cancer has appeared. Because of these advances adjuvant therapy options available to women today are quite different than those of just 5 years ago. The purpose of this chapter is to review where our current therapy options have succeeded and where adjuvant therapy options have limited effectiveness or other associated problems. As a starting point we will review the results of the most recently published EBCCTG meta-analysis. [ABSTRACT FROM AUTHOR]

Breast cancer is an increasing global public health burden with more than one million new cases anticipated worldwide1 and more than 200,000 new cases anticipated in the United States in 2007 (www.cancer.org). Early stage disease accounts for an increasing proportion of these incident breast cancer diagnoses, largely as a result of improvements in public education, screening programs, technology and treatment However, despite the increasing proportion of early stage diagnoses, a significant proportion of women will experience a distant relapse leading to death from recurrence-related complications. These distant treatment failures indicate that some women have clinically undetectable micrometastatic disease at diagnosis which cannot be cured with locoregional therapy alone. Systemic chemotherapy aimed at eradicating these clinically occult micrometases is thus an integral component of the adjuvant treatment strategy for many women with early stage disease. Over the last several decades, investigators have endeavored to optimize disease specific outcomes and thus, improve patient survival through therapeutic innovation, while minimizing treatment-related toxicity. These efforts have manifested as refinements of the adjuvant chemotherapy prescription; innovations in scheduling, drug delivery and dosing; and the incorporation of biologic/targeted therapies. Specific advances in the adjuvant chemotherapy strategy for women with early stage breast cancer will be reviewed here. [ABSTRACT FROM AUTHOR]

An estimated 178,480 people in the United States will be diagnosed with and 40,460 will die from breast cancer in 2007.With the institution of screening mammography guidelines between 1980 and 1987, there was a doubling in the incidence of small breast cancers (≤ 2 cm) with a concomitant decrease by 27% in the incidence of larger breast cancers (≥ 3 cm). As a greater percentage of breast cancers are being diagnosed at an earlier stage, the medical community has been challenged to develop diagnostic and treatment modalities that maximize benefit from therapy while reducing the morbidity associated with treatment. The management of breast cancer has changed dramatically in the last two decades with improvements in systemic therapy and advances in surgical techniques. The single greatest predictor of overall survival for women diagnosed with operable breast cancer is the presence or absence of lymph node metastasis. Traditionally, axillary staging was performed with Level I and II axillary lymph node dissection (ALND). This identified women with poorer prognosis and greater risk of recurrence while helping direct their adjuvant therapy. Unfortunately, ALND for axillary staging in breast cancer carries a relatively high risk of secondary lymphedema as well as other morbidities such as parethesias and limited arm mobility. The concept of the sentinel lymph node (SLN) is based on the knowledge that there is an orderly progression of lymph drainage from the tumor via the lymphatic system to the dominant lymph basin of the affected area. Sentinel lymph node biopsy (SLNB) was established by Morton et al and was found to be an accurate technique in identifying nodal metastasis in malignant melanoma. The authors were able to avoid the associated morbidities of complete lymphadenectomy for early stage extremity melanoma. In breast cancer, tumor cells shed from the primary breast lesion progress along the lymphatic channels to the first draining lymph nodes in the axilla. By mapping the lymphatic drainage of the breast, the sentinel node can be identified, removed and evaluated for evidence of metastatic disease. As the number of tumors detected by imaging modalities alone increases, patients are being diagnosed with early stage breast cancer and therefore have a lower probability of axillary metastasis. The development of a less invasive method to evaluate the axilla and thereby reduce the risk of the morbidities associated with ALND was a logical next step in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the second most common cancer among women and the second leading cause of cancer death in the US. In 2006, more than 214,000 new breast cancer cases were diagnosed. It is estimated that close to 50,000 women died of the same disease in 2006. Breast cancer develops in about 12% of women who live to age 90. A positive family history is reported by 15-20% of women with breast cancer. Studies of twins suggest that heritable factors accounts for 25 to 30% of all breast cancers. However, less than 7% of all breast cancers are associated with known inherited high penetrance gene mutations. The first two major susceptibility genes for breast cancer, BRCA1 and BRCA2, were identified in 1994 and 1995, respectively. Other tumor susceptibility genes such as TP53 are known to increase breast cancer risk to an even greater level than BRCA1 and BRCA2. Nonetheless, deleterious mutations of TP53 are rare and therefore accounts for a much smaller proportion of breast cancer cases.We will review recent developments in the search for additional breast cancer susceptibility genes, recommendations for genetic counseling referral as well as follow-up of BRCA- gene mutation carriers. [ABSTRACT FROM AUTHOR]

Even though the majority of breast cancer occurs in postmenopausal women, a substantial number of very young women are afflicted each year. For the purposes of this chapter, the definition of "very young women" will be those 35 years of age and under; however, in the literature "young age" ranges anywhere from less than 25 to less than 50 years of age. In the USA, women less than 40 years old account for approximately 6.5% of all newly diagnosed cases of breast cancer, with those under 30 years representing 0.6% of the total new cases. Each year there are approximately 1,200 new cases of breast cancer diagnosed in women under 30 years, and there are nearly 250,000 women in the USA under the age of 40 years currently living with breast cancer [22]. [ABSTRACT FROM AUTHOR]

Tailoring cancer treatment can be defined in various ways, but it is generally accepted that this approach refers to situations where well-identified subcategories of cancer patients may obtain the greatest benefit from some type of treatment on the basis of specific predefined conditions such as clinical prognostic or predictive factors and/or biological or molecular characteristics. This is not really a new concept, however, since it has been applied for decades within the development of all cancer therapeutic modalities. Indeed, anticancer drugs have usually been tested on all tumor types and all indications until they found their niches or the category of patients for which they brought the most significant contribution. [ABSTRACT FROM AUTHOR]

The worldwide incidence of breast cancer is approximately 500,000 patients per year. It is the leading cause of death in women between the ages of 40 and 79 years, and the second leading cause of cancer death for women of all ages. Breast cancer mortality has declined over the past 10 years due largely to improved education and earlier detection by mammographic screening, but also in part due to the increasing use of adjuvant systemic therapy. Decisions related to the use of adjuvant systemic therapies have relied on traditional clinicopathologic staging, including histologic appearance, identification of specific tumor subtype, tumor grading, assessment of lymph-node status, and presence of metastases. These are useful for the initial workup and general information related to prognosis, but are limited in their ability to predict response to treatment and/or risk of adverse events to such therapies. Clinically validated predictive tools have classically included evaluation of hormonal receptors (estrogen and progesterone receptors, ER and PR, respectively) and most recently HER2. Although histologic grade is generally considered prognostic, it has not been added to staging systems due to concern over reproducibility. Data to support the inclusion of special newer techniques (such as serial sectioning, immunohistochemistry (IHC), and/or reverse transcriptase-polymerase chain reaction, RTPCR) to detect micrometastases in hematoxylin-and-eosin-negative lymph nodes also serve to provide general ideas related to prognosis, but their independent contribution is a matter of debate. [ABSTRACT FROM AUTHOR]

Depressive disorders (or clinically significant levels of depressive symptoms) hinder a woman's compliance with antineoplastic therapy [64, 24], reduce her quality of life [29], and diminish her survival [56, 63, 119]. Unfortunately, depressive syndromes and major depression are exceedingly common in women with breast cancer, with prevalence rates ranging from 5 to 50%, in comparison to 5-9% of women without cancer interviewed in the community [69]. Undoubtedly, heterogeneous study methodologies have contributed to the wide variability in rates of depression observed in women with breast cancer, including the use of "inclusive" or "exclusive" depression diagnostic criteria (see below), differences in time of psychiatric assessment after diagnosis of breast cancer, stage of breast cancer, and the type or intensity of ongoing antineoplastic treatment. As might be expected, the prevalence of depression increases with neoplastic progression. The 11% prevalence rate of major depression associated with early stage, node-negative breast cancer [97] is in marked contrast to the markedly elevated prevalence rates (as great as 50%) of women with metastatic breast cancer undergoing palliative therapies [4], accompanied by the psychological stresses of coping with an unpredictable (and often prolonged) progression of their breast cancer, associated pain and increasing disability, and the physiologic challenges of tumor burden and recent antineoplastic therapies [12]. To evaluate the importance of psychological factors in women with breast cancer, many epidemiologic investigators have utilized self-report instruments to assess the severity of depressive symptoms in women with breast cancer. [ABSTRACT FROM AUTHOR]

Understanding preferences is essential for optimal decision making. Preferences are judgments of the best option among several. Divergence of opinions and choices about treatments is common in medicine. Nowhere is this more apparent than in the choice of treatments for breast cancer. Some seek toxic treatments that are unlikely to help, while others avoid well-tolerated treatments that may cure. Studies of preferences can help us understand why people in similar circumstances make different decisions, and how best to support people facing difficult decisions. [ABSTRACT FROM AUTHOR]

The earliest reference to breast cancer (BC) in men dates from 3000-2500 BCE, on an Egyptian papyrus [11], and the first clinical report was described in the 14th century by John of Arderne [71]. [ABSTRACT FROM AUTHOR]

Hormone replacement therapy with either estrogen alone (ERT) or estrogen plus progesterone (HRT) has, in the past, been recommended to healthy women at menopause mainly for relief of short-term menopausal changes, particularly vasomotor symptoms or hot flashes. Recommendations were, however, also based on the documented long-term benefits on bone density [1] and fracture prevention [2], as well as genitourinary symptoms, perceived reduction of coronary artery disease (CAD) [3], and dementia [4]. [ABSTRACT FROM AUTHOR]

Historically, both breast cancer diagnosed during pregnancy and that diagnosed in the 1 st year postpartum have been considered to be pregnancy-associated. It has been estimated from 32 case series over several decades that 0.2-3.8% of breast cancers occur during pregnancy [1]. This incidence may rise as women delay their pregnancies until later in life and as the number of premenopausal women with breast cancer continues to grow [2, 3]. The management of pregnant patients with breast cancer is complex, involving a balance between optimizing maternal treatment to maximize the chances of survival, whilst minimizing the risks to the fetus. However, the rarity of the condition means that few breast surgeons or oncologists will develop an expertise in this area, a fact that is compounded by lack of clinical trial evidence. Nonetheless, over the years a considerable experience of managing pregnancy-associated breast cancer has accumulated and is presented in this chapter. [ABSTRACT FROM AUTHOR]

Apoptosis is a programmed cell death process that plays an important role in tissue homeostasis as well as elimination of abnormal cells [86, 119]. Apoptotic cell death is morphologically characterized as cells with chromatin condensation, nuclear fragmentation, cell shrinkage, and membrane blebbing. Apoptotic cells break into small membrane-bound fragments called apoptotic bodies, and are removed by phagocytosis without induction of an inflammatory response in the tissues [120]. It has been shown that apoptosis is involved in several stages of normal breast development, such as during the formation of the intraductal lumen, at the end of the menstrual cycle, and in the involution of mammary glands after cessation of lactation [4, 19, 33, 105]. For example, the epithelial cells in mammary duct glands rapidly proliferate to develop additional ductal branching and lobuloalveolar growth during pregnancy. After lactation, breast ducts undergo an involution stage with massive apoptosis and reconstruction of breast ducts, leading to the return of the primary breast duct structure [50]. Apoptosis also occurs in the lobular unit of terminal duct with proliferation of the gland epithelial cells several days before the menstrual cycle and a peak in apoptosis close to the end of the cycle [4]. Regulated apoptosis therefore maintains a balance between cell proliferation and cell death in normal breast tissues. [ABSTRACT FROM AUTHOR]

We know that many human breast cancers are dependent upon the steroid hormones, estrogen and progesterone for their growth, and that their effects are mediated through the estrogen receptors (ERs α and β) and progesterone receptors (PRs A and B). Targeted therapy directed at reducing the mitogenic effects of estrogen through blockade of the ERs was the first [4], and remains the most frequently prescribed form of systemic therapy, especially for postmenopausal human breast cancer. The recent clinical success of the aromatase inhibitors (AIs) [114], and the potential for sequencing of these agents with antiestrogens [10] has further enhanced our management of the disease. But while these targeted strategies are initially useful in many breast cancer patients, acquired hormonal resistance (HR) eventually develops with the appearance of metastatic lesions in patients. An emerging hypothesis is that the ERs remain central to the problem of resistance, due to their molecular crosstalk with growth factors, or possibly other intracellular signaling molecules. Recent information concerning the molecular basis for HR and the molecular mechanisms associated with receptor function has helped elucidate potential new therapeutic strategies and treatment combinations with promise for the clinic. The aims of this chapter will be to review the role of the ER signaling network as the integral foundation for assessing clinical outcome and selecting appropriate therapies for ER-positive breast cancer. [ABSTRACT FROM AUTHOR]

Aberrant signaling is a key characteristic of cancerous cells that frequently leads to continuous proliferation and suppressed apoptosis. To correct deregulated signaling pathways and thereby eliminate cancer cells, many biological and chemical agents have been developed and used for breast cancer therapy that specifically target oncogenic signaling molecules. In the past two decades, significant advances have been made in the prevention, diagnosis, and treatment of breast cancer that can be attributed largely to the identification and understanding of the aberrant signaling network critical in the development and progression of breast tumors. These pathways include those of the ErbB family of receptor tyrosine kinases (RTKs), estrogen receptors (ERs), BRCA1/2, c-myc, TGF-?, and Wnt [1, 2]. However, to further accelerate the development of more efficient therapy for breast cancer, there is a continuous and urgent need for a better understanding of the malignant, chemoresistant, and metastatic biology of breast tumors. Specifically, to best fulfill this need, we will require to: (1) gain knowledge about the biological activities of the aberrant signaling network, (2) identify and characterize novel signaling modules important for mammary glands, and (3) fully address the complexity (i.e., pathway crosstalk), of the oncogenic signaling pathways. The goal of this chapter, therefore, aims to describe recent research findings in all three of these aspects of signaling pathways, focusing on their involvement in breast cancer development, progression, and metastasis. [ABSTRACT FROM AUTHOR]

With the advent and evolution of the era of molecular research into cancer, the hallmark of cancer has been conclusively established as the failure of cancer cells to repair and maintain the integrity of their genome. It is generally true that in this respect breast cancer is a clonal disease arising from one aberrant cell having dysregulated growth-control signals. However, within the expanding population of daughter cells there is ever greater heterogeneity in terms of accumulated mutations in the inherited background parent genome. Naturally, each subsequent round of cell division accelerates the destabilization of the genome which, in turn, expresses itself in greater derangements of cellular biology, ultimately leading to the emergence of the most feared phenotype: that of the metastatic cancer cell. [ABSTRACT FROM AUTHOR]

Rowinsky The number of rationally designed, target-based systemic therapeutics undergoing development in the treatment of breast cancer and other malignancies is unprecedented. Targets that principally confer autonomy, which is the hallmark of the malignant phenotype, are being thwarted, in contrast to nonspecific cytotoxic agents that rely primarily on the proliferative rate of malignant cells to confer a therapeutic advantage. Novel targets include those that are involved in aberrant signal transduction, cell-cycle dysregulation, evasion of apoptosis, sustained angiogenesis, tissue invasion, metastasis, and immune tolerance [1-4]. Based on the results of preclinical studies and early clinical trials to date, more selective therapeutics are likely to result in less cytotoxicity to normal tissues, and hence more "breathing room" to maximize the therapeutic indices of multiagent regimens. It is anticipated that therapeutic agents capable of differentiating between malignant and normal tissues will more readily achieve high therapeutic indices. However, since most new targets for antiproliferative therapies have not yet been validated in clinical practice, prioritizing the long list of rationally designed, target-based therapeutics entering clinical evaluations, so that those with a high potential for improving clinical outcome are accurately identified for further study, is a formidable challenge. In this chapter, a variety of rationally derived, targeted-based systemic therapeutics that are currently under evaluation and may confer incremental therapeutic advantages in treating patients with breast cancer, as well as several innovative nonspecific cytotoxic agents against novel targets, will be discussed. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the major health threats for women all over the world. It is the most commonly diagnosed cancer in women and the second leading cause of cancer death in women in Western society (unpublished data from the Comprehensive Cancer Monitoring Program Meeting in Europe, 2003). In recent years, the mortality rate of breast cancer has declined slightly [80], thanks to early detection programs and the advances in therapy, and especially improvements in systemic therapy, such as new chemotherapeutic agents and aromatase inhibitors. However, even localized diseases will relapse locally or distantly in a significant proportion of patients. When disease progresses to the metastatic stage it becomes essentially incurable and the median survival time is about 2 years. Chemotherapy is the main treatment at this stage. The response rate of combined chemotherapies ranges from 35% to 67%, and the median response duration is short, usually approximately 9 months [6]. Therefore, finding alternative therapies for patients whose disease is refractory to chemotherapy or hormone therapy is critical. Gene therapy is one of the alternative therapies. [ABSTRACT FROM AUTHOR]

Angiogenesis, the development of new vessels from pre-existing vasculature, is a crucial mechanism for tumor growth [1]. Tumor cells may be in a state of dormancy from months to years until "the angiogenic switch," which is promoted by releasing soluble factors. It can occur at different stages of the tumor progression pathway, depending on the tumor type and the environment [2]. The microenvironment can provoke a shift toward proangiogenic factors via metabolic changes (low oxygen tension, low pH, hypoglycemia), mechanical stresses (pressure generated by proliferating cells), the immune/inflammatory response, and mutations [3, 4]. Some oncogenes and tumor-suppressor genes operate and contribute by causing upregulation of endogenous angiogenesis stimulators or downregulation of inhibitors [2]. Recently, other mechanisms of enhancing vasculature have also been described. These pathways differ sufficiently from normal tissues to be considered as therapy targets, but with so many it is perhaps unlikely that one alone will be suitable for all patients, all stages, and all sites of metastasis. This review describes the pathways and mechanisms so far relevant to breast cancer, but in many cases pathways have not yet been studied in this disease. Current antiangiogenic therapy is beginning to fulfill its promise and will be reviewed, highlighting potential problems in conducting trials in this area. [ABSTRACT FROM AUTHOR]

Tumorigenesis is a multistep process involving serial genetic alterations that drive the progressive transformation of normal epithelial cells into malignant cancer cells. The dynamic changes of the genome associated with neoplastic transformation involve mutations that produce dominant increases in the function of oncogenes and recessive loss of function in tumor suppressor genes [1]. During the last 20 years, improved genetic and molecular techniques have provided a greater understanding of the molecular events underlying normal development as well as neoplastic transformation. An increased understanding of cellular regulation processes is enabling rational identification of therapeutic targets. Recognition of these targets has allowed the development of effective cancer therapies. This is an ongoing process. Based on our current knowledge, several key attributes of a good target protein have been identified. Two of these attributes are that the target is preferentially expressed (or activated) in tumor but not in healthy tissue and that it confers a selective growth advantage to the tumor cells. Furthermore, inhibition of the function suppresses the transformed phenotype and halts tumor progression without adversely affecting normal cells. [ABSTRACT FROM AUTHOR]

The greatest hope for long, active lives for people with breast cancer rests in the creation of highly sensitive and specific tools to further optimize early diagnosis and treatment. Mammography is the international gold standard for breast cancer screening. It has positively affected our ability to detect small noninvasive breast cancer. However, this test has a high false-negative rate and a positive predictive value of only 25% [27]. The utility of mammography is even more questionable in young women, particularly those with dense breasts and with risk factors for the development of breast cancer. The inadequate sensitivity and specificity of mammograms provokes unnecessary anxiety and increases healthcare costs through the need for additional testing [12]. It is logical to expect that successful earlier detection should be possible, since it is estimated to take 6-8 years for a breast tumor to reach the 0.5 cm size threshold needed for detection by mammography [17]. [ABSTRACT FROM AUTHOR]

At present, the biology of breast cancer remains poorly understood. Currently, lymph node metastases, tumor grade, and size, and expression of hormone receptors provide the only true prognostic and predictive factors related to clinical outcome and response to treatment, respectively. Many other potential candidates have been suggested but, due to their limited predictive power, have not been widely accepted by the general oncological community. These histopathological features do not allow us any insight into breast cancer biology, however, and these prognostic classifications are far from perfect. At present, due to these limitations many clinicians consider prescribing adjuvant treatment to many women with early breast cancer to reduce the risk of relapse, only to benefit a few, thus exposing many patients to unnecessary toxicity. Since the publication of the complete sequence of the human genome however, a new era of research has begun [1]. More than 3 billions base pairs form the 30,000-40,000 genes that code all the required genetic information of a particular individual. The functions of the vast majority of these genes are still unknown. [ABSTRACT FROM AUTHOR]

Pain perceptions and pain behavior following acute injury are time dependent. At the first experience of pain a nocifensive reflex response develops, which is followed by the experience of an aversive, noxious quality, resulting in a negative affect and motivational response. Relief of noxious pain is achieved through counter-irritant measures (rubbing the painful site). A third response phase is defensive; the affected part is flexed and cradled, protected from stimulation due to hypersensitivity. Fortunately pain intensity diminishes with time, but hypersensitivity may persist. The hyperkinesis of the initial pain experience evolves into a quiescent phase and, in some, anorexia and sleep [1]. The demarcation of these phases is determined by the severity of the pain. The evolving response pattern changes from a spinal reflex to supraspinal and cerebral centered pain modulation [1]. [ABSTRACT FROM AUTHOR]

According to the literature, 30-90% of patients with advanced cancer will develop skeletal metastases. Carcinomas of the breast (47-85%) and of the prostate (33-85%) are the tumors most commonly associated with bone metastases [31]. The skeleton is in fact the most common site of metastatic disease in breast cancer and the most common site of first distant relapse [21]. These patients have a longer survival after the diagnosis of bone metastases compared to patients with visceral metastases. Their median survival is usually beyond 20 months, and about 10% of them are still alive 5-10 years after the first diagnosis of skeletal dissemination [21]. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer, even if it appears to be limited to a single organ, is generally considered to be a disseminated disease that requires systemic, rather than local therapy. However, it has been reported that 5-12% of these patients have metastases that are confined to the liver [1-4]. Most of these patients are treated palliatively, with a median survival after the detection of liver metastases of only 2-14 months [3-9]. However, modern systemic treatments can achieve response rates of approximately 60% [10] and, in some cases, can control tumor progression, albeit temporarily [9, 10]. For most of these patients, the clinical course consists of a succession of more or less prolonged remissions followed by repeated relapses. As proposed by Greenberg and colleagues [9] as well as by Pocard and colleagues [11-14], remission consolidation strategies are needed for patients with metastatic breast cancer to the liver that responds to chemotherapy. It is in this context that several groups have started to consider surgical options in the management of this selected group of patients [11-22]. Liver surgery offers the only chance for cure in patients with a variety of primary and metastatic liver tumors. Furthermore, there is an increasing role for surgical cytoreduction in multimodality treatments for cancer. In this chapter we summarize the available data and the different therapeutic options for the surgical management of liver metastases in patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

The treatment of brain metastases has progressed during these last years; new techniques have emerged and treatment indications have evolved. In this chapter we will review the clinical features of brain metastases in patients with breast cancer, and discuss the potential therapeutic modalities, focusing on the expanding role of radiosurgery. [ABSTRACT FROM AUTHOR]

The medical care of the aging population is becoming an increasing issue in healthcare. In Europe the number of people aged 60 years or more is growing at a rate of 0.8 million, or 1%, per year [1]. This figure is predicted to increase from 21 to 40% by 2050, by which time one-third of the elderly population might be 80 years old or more [1]. The average life expectancy in Western Europe for women and men aged 75 years is currently 11.1 and 8.5 years respectively [4]. Breast cancer incidence increases with age, and currently 48% of breast cancer cases occur in women 65 years and above, with over 30% occurring in those over 70 years [2]. The EUROCARE II program showed the relative risk (RR) of death for women with breast cancer aged 65-69 years compared with younger patients (55-64 years) was 1.7 at 1 year, but became similar at 5 years (RR = 1.09) [1]. This program therefore confirmed that elderly cancer patients have a large survival disadvantage and that this was seen particularly in women and at 1 year [1]. These findings are also reflected in cancer mortality rates in the elderly in the USA [3]. [ABSTRACT FROM AUTHOR]

Until about a decade ago, the standard endocrine therapy for all women with hormone-receptor positive breast cancer was tamoxifen, regardless of age, menopausal status, or stage of disease. The only molecularly tailored aspect of the use of tamoxifen was the recognition that it was only effective against breast cancers that expressed estrogen receptors (ERs). Patient-tailored therapy might otherwise be termed "good clinical judgment" regarding who was treated with an endocrine agent and when. However, the approval of third-generation specific aromatase inhibitors (AIs) saw a paradigm shift because efficacy considerations could now also be taken into consideration. In addition, the simple mode of action exhibited by AIs as a class gave rise to new insights into the molecular basis of estrogen-dependent malignancies. This chapter summarizes the current clinical literature, with an emphasis on how molecular insights might translate into new treatment approaches. Our abilities to tailor, at the molecular level, endocrine treatments for advanced disease through molecular biomarkers remains rudimentary, but progress in the analysis of breast cancer at the genomic level may make truly tailored therapy a reality. [ABSTRACT FROM AUTHOR]

The term "locally advanced breast cancer" (LABC) encompasses a heterogeneous group of clinical scenarios. Historically, this has included patients with tumors larger than 5 cm in size and/or tumors that involve the skin or chest wall. Advanced nodal involvement also is included in this definition; patients with matted axillary lymph nodes, involvement of the ipsilateral supraclavicular, infraclavicular, or internal mammary lymph nodes are also included in this group description. The American Joint Committee on Cancer (AJCC) TNM staging system includes all patients with clinical and pathologic stage III disease as well as a subgroup of stage IIB (T3N0) patients in this locally advanced group [1]. Inflammatory breast cancer has often been included in this group; however, this disease has distinct biologic behavior and clinical presentation that separates it into a distinct category from patients described as being advanced purely by tumor size or nodal status. [ABSTRACT FROM AUTHOR]

The clinical rationale for considering neoadjuvant chemotherapy in breast cancer originated from studies in patients with locally advanced inoperable disease, in whom neoadjuvant chemotherapy was used to render them operable. In those studies, neoadjuvant chemotherapy induced clinical responses and conversion to operability in a significant proportion of patients [1-4]. The rationale for neoadjuvant chemotherapy expanded further to include patients with large operable breast cancer in an effort to convert mastectomy candidates to candidates for breast-conserving procedures. Evaluation of neoadjuvant chemotherapy in operable breast cancer was further facilitated, when lumpectomy was established as the surgical treatment of choice in the majority of such patients [5-9] and when adjuvant chemotherapy was found to significantly prolong disease-free and overall survival not only in node-positive patients, but also in those with negative nodes [10, 11]. [ABSTRACT FROM AUTHOR]

Today, the typical woman with a new diagnosis of breast cancer is postmenopausal, 60-65 years of age, and in relatively good health. This woman, plus women over the age of 65 years comprise approximately half of all women facing adjuvant breast cancer decisions. Understanding the current data (and its limitations) available to guide decision making in this older cohort will serve as the focus of this chapter. Studies relevant to the older woman with breast cancer will be reviewed, and tools currently available to facilitate individualized patient decision making will be presented. [ABSTRACT FROM AUTHOR]

The heterogeneity of breast cancer is well understood both biologically and in the practice setting. On one hand, it is not uncommon for some patients to survive for years despite the presence of widely advanced or metastatic disease. In contrast, patients with localized tumors may relapse rapidly despite adequate surgical and medical treatment. Age has long been considered to have a strong association with this varying clinical behavior, with older patients being more likely to have indolent disease, and younger patients tending to have a more aggressive course. Recognizing the unique nature of the disease in this younger population, in 1993 the National Institutes of Health (NIH) sponsored a conference to discuss the various aspects of breast cancer in younger women. The consensus statements were published in the Journal of the National Cancer Institute Monographs [99]. Since then, multiple consensus panels have acknowledged young age as an adverse prognostic factor [29, 43, 45, although controversy regarding treatment still exists. Thus, it is appropriate to consider the special scenario of breast cancer in the young, premenopausal patient, with a specific focus on whether therapy should be tailored in a different manner than in older premenopausal or postmenopausal patients. [ABSTRACT FROM AUTHOR]

Selecting the optimal systemic adjuvant therapy for an individual with hormone-responsive breast cancer can be a challenging task for the medical oncologist. Many patients with estrogen (ER)- and/or progesterone receptor (PR)-positive breast cancer will benefit from some form of hormonal therapy. The number of hormonal agents with proven efficacy in the adjuvant setting has increased in recent years. At the same time, there is still considerable uncertainty about the optimal approach in many situations. The decision to use chemotherapy in patients with hormone-receptor-positive breast cancer is even more challenging, and there are many unresolved questions. The difficulty over the decision to use chemotherapy arises from several features of hormone-responsive breast cancer. First, patients with hormone-responsive breast cancer will, on average, obtain a substantial reduction in their risk of recurrence from hormonal therapy, leaving the absolute risk reduction from chemotherapy less pronounced. The situation is further complicated by the mounting evidence that hormone-responsive breast cancer is, on average, less sensitive to chemotherapy than its hormone-unresponsive counterpart. As a result, the average benefit of chemotherapy is often not substantially greater than the risk of treatment. The patient and her oncologist are faced with a difficult decision, weighing the side effects and risks of chemotherapy versus the benefits. New prognostic and predictive tests are needed to assist with decision making. [ABSTRACT FROM AUTHOR]

Breast cancer is a common disease among the elderly. The median age at the time of diagnosis of breast cancer is 63 years, with 30% of women being 70 years of age or older [1]. The term elderly is defined variably in different studies ranging from greater than 60 years to greater than 80 years of age. For the purposes of this review it will be defined as 70 years or greater, which has been used in most studies. As our population in the western hemisphere continues to age, the percentage of women with breast cancer ≥ 70 years of age will increase [2]. [ABSTRACT FROM AUTHOR]

Breast irradiation is an essential component in the breast-conserving treatment of early breast cancer, either invasive [1-9], or in situ [10-12]. Numerous studies have provided evidence of the negative impact of young age on the risk of locoregional recurrences, which raises the issues of the potential radiation resistance of breast cancer in young patients, ways to predict this radioresistance in groups of patients, and the ways to overcome this resistance. [ABSTRACT FROM AUTHOR]

In the era of molecular medicine, the clinical application of molecular and genetic markers in the diagnosis, staging, and management of breast cancer continues to expand rapidly. Immunohistochemical staining techniques allow the pathologist to determine whether tumors express specific proteins. Fig. 13.1 demonstrates positive immunhistochemical staining of estrogen receptor (ER), progesterone receptor (PR), P53 and Her2/neu in breast cancer sections. Although the use of molecular markers as they relate to the tailored use of radiotherapy in local-regional management is only beginning to evolve, there is a growing body of literature supporting the potential for molecular and genetic factors in clinical decision making regarding the application of radiation therapy in the local-regional management of breast cancer. As with conventional clinical and histopathologic factors, data regarding molecular and genetic factors are often conflicting and are subject to the usual limitations of predominantly retrospective studies. There are, however, some consistent data suggesting associations between local-regional control of disease and several molecular markers, including hormone receptor status, Her2/neu, P53, proliferative markers, and others. Interpretation of these data and how to use this information in clinical practice remains challenging. In this chapter we will present an overview of the tailored use of radiotherapy in breast cancer with specific focus on molecular and genetic markers. [ABSTRACT FROM AUTHOR]

For most breast surgeons, the resection of any breast malignancy in the operating theatre appears a galaxy away from the molecular biological aspects of the cancer. The surgical adagium is simple: the breast cancer should be removed with clear margins with the best possible cosmetic result [1]. So why bother with biological markers, immunohistochemistry, gene profiling, and other sophisticated techniques to improve outcome of the surgical act in itself? [ABSTRACT FROM AUTHOR]