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Substantial progress has been made in the diagnosis and treatment of primary and metastatic breast cancer in the last 20 years. New technical instruments and laboratory tools have emerged in recent years that expand the options for the study of breast cancer at different stages. Such an improved platform requires a departure from standard approaches and prompts testing of the innovative tools in the workup of women with breast cancer, with the aim of investigating at which stage, in the natural history of breast cancer, they should be applied to optimize clinical management. It is known that the widespread use of routine mammography has led to an increase in the early detection of primary breast lesions that significantly contributes to the decrease of mortality from breast cancer that is now measurable in Europe and North America. The dramatic shift in the stage of breast cancer at diagnosis has been associated with the successful application of less mutilating surgical procedures, with the widespread resort to breast-conserving surgery and, more recently, with avoidance of useless surgical staging of the axillary lymph node status through the use of sentinel node biopsy. In addition, adjuvant and preoperative systemic therapy has been optimized in terms of drug availability and activity and refinement of the criteria for administration, thus significantly contributing to prolongation of survival in women with early breast cancer. The challenge at this time is to define procedures and tools that allow easy characterization of the tumor, its aggressiveness and its pattern of sensitivity/ resistance to drug therapy, so that treatment can be tailored to individual needs rather than to the average risk of the average patient. The technological development of the diagnostic imaging has been impressive in the field of radiology and nuclear medicine allowing for the dependable detection of small lesions. These tools have generated new approaches permitting the successful differential diagnosis of doubtful lesions and the rapid identification of systemic metastases, and are providing a means for the non-invasive characterization of biology of cancer tissue. It is likely that these advances will provide further contributions to the optimization of therapeutic strategies, considering that the metabolic information offered by nuclear medicine procedures, combined with the anatomical data provided by conventional radiological techniques, should find a place in predicting tumor response and monitoring the outcome of patients. It is difficult to formulate conclusive diagnostic guidelines for application in the workup of breast cancer, since while the role of some examinations, such as mammography and US, is well established, that of others, such as MRI and PET, is still a matter of investigations. New technical instruments and laboratory tools have emerged in recent years that expand the options for the study of breast cancer at different stages. Such an improved platform requires a departure from standard approaches and prompts testing of the innovative tools in the workup of women with breast cancer, with the aim of investigating at which stage, in the natural history of breast cancer, they should be applied to optimize clinical management. Assessment may be simplified by evaluating their role: (1) in screening for and in diagnosing of breast cancer; (2) for loco-regional staging; (3) for extensive staging and follow-up; (4) for better characterization of the tumor; (5) for monitoring/predicting patterns of sensitivity or resistance to therapy. Clinical observation is the mainstay of evaluation in each phase of the patient's management, and histopathological analysis is the gold standard for diagnosis, but laboratory tests, radiological imaging and nuclear medicine imaging are assuming a growing role in the workup of patients with breast cancer (Table 22.1). [ABSTRACT FROM AUTHOR]

Metastases to the skeleton occur in approximately 75% of patients with advanced breast carcinoma, and skeletal metastases are present in >90 % of patients who die from breast carcinoma (Coleman and Rubens 1987; Hortobagyi 1991). Bone disease is most often lytic or mixed lytic/blastic, determining a series of disease-related events that have the most significant impact on quality of life in these relatively long-surviving patients (Kakonen and Mundy 2003). The symptomatic treatment of skeletal pain due to metastases from breast cancer is a complex task that may require administration of drugs, including bisphosphonates and analgesics, and external beam radiotherapy (Lipton 2000; Hoskin 2003). Bisphosphonates target osteoclast-mediated bone resorption and reduce the skeletal complication rate arising from osteolytic metastases in breast cancer (Coleman 2000). External beam radiotherapy allows an effective pain control with a relatively low dose and a low toxicity if the metastatic disease is not extensive, but the toxicity rapidly increases with wide irradiation fields (Hoskin 1995). Systemic radioisotope therapy with radionuclides linked to a bone seeker agent may be the option of choice for the radiation treatment of patients with multiple skeletal localizations due to its efficacy, low cost and low toxicity (Dearnaley et al. 1992). Nonetheless, it still appears to have a low priority among medical oncologists and remain underutilized. Physician education regarding radioisotope therapy should be improved, and clinical trials to evaluate newer treatment paradigms including radionuclides should be strongly encouraged (Damerla et al. 2005). Radionuclides suitable for systemic metabolic radiotherapy of bone pain, and commercially available, include 89Sr, 186Re chelated by HEDP and 153Sm chelated by EDTMP (Serafini 1994; McEwan 1997; Serafini 2001). The main physical characteristic of the three radionuclides are illustrated in Table 21.1. Beta emitters with short half-lives, such as 186Re and 153Sm, deliver their radiation dose at higher dose rates, which may be more therapeutically effective than equivalent doses given at lower dose rates. The short range of 153Sm beta emission, actually the shortest of the three available radionuclides, may be of advantage limiting red marrow irradiation (Serafini 2000, 2001). 153Sm-EDTMP was developed by Goeckeler at the University of Missouri as a 1:1 chelation complex of radioactive 153Sm and a tetraphosphonate, (ethylenediamine-tetramethylene phosphonate), also known as lexidronam (Goeckeler et al. 1987). 153Sm-EDTMP shows high selective skeletal uptake like conventional 99mTc bone scanning agents: its bone localization is by chemiabsorption of the tetraphosphate by hydroxyapatite and by the formation of samarium oxide involving oxygen of the hydroxyapatite. The therapeutic effect is due to the irradiation by the short range beta emission of 153Sm. Early phase I/II studies were published over 10 years ago (Turner et al. 1989; Podoloff et al. 1991; Eary et al. 1993; Turner and Claringbold 1991), and since then this agent has been clinically used for pain palliation in symptomatic bone metastases from several cancers, mainly prostate and breast carcinoma. This review will address the characteristics of 153Sm-EDTMP as a radiopharmaceutical and its clinical applications for bone pain palliation in breast carcinoma. [ABSTRACT FROM AUTHOR]

Metastases in the skeleton are the most common of all bone neoplasms. The ultimate prognosis for patients suffering from bone metastases is poor. Therapy such as hormonal manipulation (for carcinomas of the breast and prostate) and cytotoxic chemotherapy (for breast cancer and lung cancer) may result in control of both the disease and the accompanying pain for months or possibly years, and it may improve the quality of life. In clinical practice pain caused by bone secondaries is a common cause of cancer pain, because the incidence of patients with bone metastases is very high. Common malignancies including breast, prostate and lung cancer frequently spread to the skeleton. Approximately 65% of patients with bone metastases suffer from bone pain. Two-thirds of patients with breast cancer will develop metastatic bone disease. The average survival time following the appearance of bone metastases varies between 2 and 4 years. Whereas osteoblastic metastases predominate in prostate cancer, patients with breast cancer usually present with mixed (osteoblastic and osteolytic) bone lesions. Bone metastases are seldom solitary. They most commonly affect the spine, pelvis, ribs, proximal thigh and upper arm bones and skull. The therapeutic options are rarely (if ever) curative, and at some point in time the vast majority of patients suffering from osseous metastases will develop progressive disease. Patients with progressive disease require palliation for painful bone metastases. Current options for palliation of bone pain in this group of patients include conventional analgesics, external beam radiotherapy, chemotherapy and bisphosphonates. An alternative approach to the relief of multifocal bone pain is the systemic administration of a radionuclide, which concentrates at sites of increased bone turnover. Bone metastases from breast cancer will excite an osteoblastic response in bone, leading to an increased uptake of the radiopharmaceutical. In this way therapeutic doses of radionuclides may be localized close to the tumor by utilizing uptake mechanisms in adjacent non-tumor tissue. Boneseeking radiopharmaceuticals have traditionally been used to image tumors in bone, but, depending on the carrier ligand and energy of the radioactive label, these agents can also be used to treat primary or metastatic tumors in bone (Lewington 1993). [ABSTRACT FROM AUTHOR]

Breast cancer represents a major health problem with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of increasing incidence, breast cancer mortality is declining in the majority of developed countries. This is the combined result of better education, widespread screening programs and more efficacious adjuvant treatments. The better knowledge of breast cancer biology nowadays allows sparing the cosmetic, physical and psychological consequences of radical mastectomy to the majority of breast cancer patients. The sentinel node technique is rapidly expanding and will further reduce the extent and the consequences of surgery. Several clinical and pathologic factors are used to discriminate among patients at low (<10%), average (10-40%) and high risk of relapse, and international guidelines have been established to help clinicians to choose the appropriate postoperative treatments. Nodal status, tumor size, tumor grade, age and HER2 expression are universally accepted as important factors to define risk categories. Newer factors such as uPA/PAI-1, cyclin-E and other proliferative indices and the gene expression profile are promising and will allow a better discrimination among patients at different risk. Their generalized use is, however, not yet recommended because of lack of reproducibility, necessity of fresh tumor samples, limited data and follow-up. Endocrine manipulation with tamoxifen, ovarian ablation or aromatase inhibitors is the preferred option in case of endocrine-responsive tumors. Tamoxifen administered for 5 years has been considered for many years the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen with a different safety profile. At the present time aromatase inhibitors represent the preferred option for postmenopausal patients. Chemotherapy is the treatment of choice in case of steroid receptor negative tumors. Polychemotherapy is superior to single agents, and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. These agents are currently approved for adjuvant therapy in the US and European countries. Chemotherapy followed by endocrine therapy represents the standard adjuvant treatment of highrisk patients with endocrine responsive tumors. For Her2-neu overexpressing tumors, the addition of trastuzumab, a monoclonal antibody directed against the extra-membrane portion of the Her2 receptor, significantly reduced the risk of recurrence and death. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer. The upfront administration of chemotherapy significantly increases the rate of breast-conserving surgery and allows an in vivo chemosensitivity testing. A proportion of patients achieve a pathologic complete response, and these patients have signifi-cantly better long-term outcomes. Twenty-five to 40% of breast cancer patients eventually develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice.… [ABSTRACT FROM AUTHOR]

Bone scintigraphy with radiolabelled phosphonates shows a high sensitivity in detecting breast cancer metastases. For this reason it has been considered the most useful tool for early diagnosing and monitoring the metastatic spread of breast cancer. In the past years, there has been wide debate on its impact on survival time, morbidity and quality of life. The results of some studies on the asymptomatic patients during follow-up have led to the adoption of an almost minimalist policy for breast cancer surveillance including only a few procedures (breast self-examination, history, physical examination, patient education on symptoms, and abdomen ultrasonography). The routine use of additional tests, such as tumour markers, chest X-rays, bone scintigraphy, and computed tomography (CT), has not been recommended, except in those cases with clinical suspicion or in patients at high risk of metastases. On the other hand, the early diagnosis of bone involvement may reduce the risk of skeletal-related events, thus leading to a significant improvement in quality of life and opening the options of the new therapy choices in order to plan more aggressive systemic treatments whose efficacy could have impact even on survival. Besides this, the recent development of nuclear medicine modalities, the evolution of PET and PET/CT systems has brought new elements of discussion in this area, since at present the depiction of skeletal metastases can be carried out with 99mTcphosphonates and also with 18F-PET, 18F-FDG-PET, and 18F-FDG-PET/CT. Therefore, the clinical problem today is not only when and whether bone scans should be used, but the question has also become which diagnostic modality can be used? In our opinion the choice of the modality has to consider different general and local factors such as the diagnostic accuracy, the availability, the economic costs, and so on. The most important issue is that every new diagnostic approach should be validated by large randomised prospective clinical trials with the goal to measure the effective impact on the course of the disease and on patient management. Nowadays, we do not have a sufficient amount of this kind of data, in spite of much clinical evidence that demonstrates the excellent sensitivity of bone scintigraphy in discovering skeletal metastases. [ABSTRACT FROM AUTHOR]

During the last decade, the application of positron emission tomography (PET) has remarkably improved the management of cancer patients. The radiotracer most widely used in clinical practice is the glucose analogue 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). FDG-PET is showing increasing usefulness in the distinction between malignant and benign lesions, in disease staging, re-staging and therapy planning. Due to the lack of precise anatomic landmarks, PET may present limitations in lesion localization. In contrast, PET/computed tomography (CT), by directly combining functional and morphological aspects, provides more reliable anatomical details. The main advantage of combined PET/CT imaging is, in fact, its ability to accurately correlate abnormal metabolic changes detected on PET imaging to anatomic structures defined at CT imaging (Townsend 2001). With this chapter, the impact in breast cancer diagnosis of PET/CT will be evaluated and compared with PET alone, visually correlated with morphologic imaging obtained in a separate session. [ABSTRACT FROM AUTHOR]

F-18 FDG PET in breast cancer was evaluated for the characterization of primary breast tumors, lymph node staging and the follow-up of patients after surgery, chemotherapy and/or external radiotherapy. Despite the low sensitivity and moderate specificity of FDG PET in the initial detection and characterization of breast cancer and the low lesion-based sensitivity for lymph node staging, the results from using FDG PET in re-staging breast cancer patients are very promising. A major advantage of FDG PET imaging compared to conventional imaging is to screen the entire patient for local recurrence, lymph node metastases and distant metastases during a single whole-body examination using a single injection of activity with a reported average sensitivity and specificity of 96% and 77%, respectively. In most studies the sensitivity of FDG PET is higher than that of a combination of conventional imaging methods. Limitations of FDG PET in the follow-up of breast cancer patients include the relatively low detection rate of bone metastases, especially in case of sclerotic subtype, and the relatively high rate of false-positive results. The rather low specificity of FDG PET can be improved/increased by utilizing combined anatomical-molecular imaging techniques, such as a PET/CT tomograph. First results using PET/CT imaging in the follow-up of breast cancer patients demonstrate increased specificity compared to FDG PET alone. Both imaging modalities, however, offer the detection of recurrent and metastatic breast cancer disease at an early stage and thus continue to demonstrate the efficacy of molecular imaging in patient management, despite the limited therapeutic options in recurrent and metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Circulating tumour markers for breast cancer can be classified in different groups: mucins such as CA 15.3, CA 27.29 and CA 549, carcinoembryonic antigen (CEA), cytokeratins (TPA, TPs, Cyfra 21.1), enzymes (LDH), hormones and their subunits. All of them have been proposed over the years for the diagnosis and monitoring of breast cancer at different stages. It is well known that tumour marker tests lack in sensitivity at the earliest stage of cancer and also in specificity. False-negative results are rare in patients with advanced disease and metastases; on the contrary they are most frequent in the first stages. Besides this, false-positive results can be due to different nonmalignant conditions. At present CA 15.3 is the most widely used tumour marker in breast cancer patients. Its use follows the general concepts everywhere accepted for mucinic markers: the CA 15.3 test is not useful in screening and early diagnosis; it has an established role in the diagnosis of recurrences; it has an established role in therapy monitoring, alone or in association with other diagnostic tools; it is still under study as a predictor of response to therapy. Several international guidelines help physicians in using tumour markers giving practical recommendations for the appropriate interpretation of circulating tumour markers. CEA and cytokeratins markers are so far less specific than mucinic markers; therefore, they are sometimes tested for evaluating breast cancer patients. The association of tumour marker tests with a diagnostic imaging modality such as FDG-PET today is of great interest, because sometimes the patients present with a tumour marker increase and do not show clinical symptoms or signs of cancer, or on the contrary some others subjects present with some doubtful symptoms or signs of cancer, and the association with a biochemical test for malignancy can be helpful to make the final diagnosis. FDG-PET is known as a metabolic imaging modality, that, contrary to radiological techniques, reveals cancer not on the basis of morphology like the radiological methods, but because of the uptake and/or processing of a radioactive tracer in cancer tissue. The visualization of cancer by PET depends on the viability and activity of the tumour, and this requirement is very close to the function of synthesis and secretion of tumour markers as products of cell metabolism. One can say that FDG-PET and tumour marker tests describe cancer activities in different ways, and their diagnostic added value takes advantage of this combination. This chapter overviews the results of the association of FDG-PET with elevated or progressively increasing tumour markers. Tumour-marker-guided PET has demonstrated a diagnostic effectiveness in detecting cancer lesions with variable sensitivity, both at presentation (staging) and during the follow-up (discovery of relapses, metastases and re-staging). It is well known that tumour marker increase is a reliable signal of the presence of occult disease, and this suspicion can be explored by FDG-PET. For this reason some authors have proposed that whole body PET may become the method of choice for the assessment of asymptomatic patients with elevated tumour marker levels. The recent development of hybrid systems, allowing the concomitant examination of the patient by combining PET with CT, has increased the accuracy of diagnostic imaging, and several papers support the evidence that PET/CT is able to add incremental diagnostic confidence to PET and detects more lesions than CT or PET alone. A discussion is still open about the question if FDG-PET or PET/CT can substitute the entire battery of tests routinely used for staging breast cancer or detecting relapse in all breast cancer patients.… [ABSTRACT FROM AUTHOR]

Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used successfully for the staging and re-staging of breast cancer. Another significant indication is the evaluation of therapy response. There are only few data on FDGPET in breast cancer after radiation therapy. The same holds true for chemotherapy. Only the therapy response in locally advanced breast cancer after chemotherapy has been investigated thoroughly. Histopathologic response could be predicted with an accuracy of 88-91% after the first and second course of therapy. A quantitative evaluation is of course a prerequisite when FDG-PET is used for therapy monitoring. Only few studies have focussed on hormone therapy. Here, a flare phenomenon with increasing SUVs after initiation of tamoxifen therapy has been observed. More prospective multicenter trials will be needed to make FDG-PET a powerful tool in monitoring chemotherapy in breast cancer. Whole body imaging with fluorine-18 deoxyglucose PET (FDG-PET) has gained widespread acceptance for the staging and restaging of breast cancer (Biersack et at. 2001; Kostakoglu and Goldsmith 2003; Grahek et al. 2004). Another significant indication for FDG-PET is the evaluation of therapy response. Above that the proof of viability of tumour tissue after termination of chemotherapy is another indication for PET. The evaluation of therapy response is usually done by CT, sonography or MRI (Biersack and Palmedo 2003). These imaging procedures allow the detection of changes of the tumour size or volume. Because the majority of cells within a tumour mass are in a resting state, reduction of tumour volume requires time and might be masked by unspecific effects (edema as a result of necrosis). In contrast, cellular uptake of FDG is a function of cell viability and seems to be associated with the increased cell turnover. Animal models have shown that, after therapy, the amount of tumour FDG uptake reflects the number of viable tumour cells present (Haberkorn et al. 1987). Already in 1989, Minn et al. (1989) studied patients with breast cancer before and after therapy using FDG-PET. Even using a planar gamma camera equipped with thick lead collimators, they could show that increasing FDG uptake over time was associated with tumour progression. These data make evident that new cumbersome sophisticated FDG imaging procedures may further increase the diagnostic significance of FDG-PET in therapy monitoring. [ABSTRACT FROM AUTHOR]

In this chapter the findings of response-monitoring studies in breast cancer, using [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET), are summarised. These studies indicate that there is a strong relationship between response and decrease in FDG signal even at an early stage of therapy. The review concentrates on methodological aspects of monitoring response with FDG: timing of serial scans, ROI definition approach, method of quantification, pitfalls of FDG and future directions in functional imaging. For the sake of optimal clinical applicability there now is need to standardise methodology. This is necessary to establish firm cut-off values for discriminating responders from non-responders, which in turn will provide a means for optimal treatment for as many patients as possible. [ABSTRACT FROM AUTHOR]

PET and PET/CT have revealed a good diagnostic accuracy in visualizing both primary cancer and metastatic lesions, and many clinical studies demonstrate that they can compete with the morphological conventional diagnostic modalities mainly in staging, detecting tumor relapses, evaluating tumor response to therapy and giving useful prognostic indications. Data about the usefulness of PET to stage axillary nodes in breast cancer patients are controversial, also considering that another nuclear medicine technique, the sentinel lymph nodes biopsy (SLNB) after localization with lymphoscintigraphy, is very reliable for this indication. It is well known that SLNB today is considered the standard nuclear medicine method for staging axilla. This chapter is focused on the diagnostic potential of PET in studying lymph node axillary metastases that are one the most important prognostic factors affecting the therapeutic strategies. The diagnostic results of the most important clinical trials carried out with FDG-PET in axillary staging of breast cancer patients have been examined and reported. However, the position of FDG-PET in studying the loco-regional lymph nodal involvement still has to be completely evaluated, since the main problem is the absence of long-term prospective studies able to evaluate the outcome of the patients after FDG-PET staging and treated or not with ALND according to FDG negative or positive uptake. The main reason for the discussions in the field is the limitation of FDG-PET in depicting the small metastases spread to axillary lymph nodes. This lack in sensitivity has become particularly evident since the introduction of very aggressive pathologic techniques with SLNB, such as multi-slice sectioning and immunocytochemistry staining. These approaches have significantly increased the rate of detection of micrometastases shown in the biopsies from the studies on the clinical validation of SLNB and ALND. On the contrary, the detection of micrometastases with FDGPET is very critical, being limited by the spatial resolution of the PET scanner. Any discussions about this indication for PET in clinical oncology should take into consideration the fact that at present the standard method for staging axilla remains the ALND, which does not entail any intrinsic risk of downstaging the axillary status. The SLNB plays an important role in selecting patients that should undergo ALND due to its high sensitivity, also for micrometastases, even if the SLNB also has a non-negligible false-negative rate in almost all studies. The combined used of SNLB and FDG-PET is a new strategy that has been recently proposed. According to the conclusions of some recent studies, this means that FDG-PET does not have to be considered as an alternative diagnostic tool instead of SLNB, but in those patients with clinically negative axillary lymph nodes, PET could discriminate patients eligible for ALND from the patients who should undergo SLNB. This is based on the FDG axillary uptake and on the high positive predictive value of PET. Therefore, breast cancer patients with FDG-positive uptake should directly undergo ALND rather than SLNB for axillary staging. On the contrary, those cases without FDG uptake in the axilla should be examined with SLNB in order to select candidates for ALND. This approach of course has to be validated through adequate large prospective studies with a follow-up evaluation, but it is important to stress the fact that in this way it is possible to take advantage of the strength of the two methods. Probably the role of PET, even in this new clinical perspective, should be reconsidered due to the improvements of the scanner technology, such as with the hybrid system PET/CT or other more sophisticated advances in the detectors and/or dedicated software. [ABSTRACT FROM AUTHOR]

Cancer produces major biochemical changes in the cell's energy metabolism, altering utilization of glucose and other substrates, protein synthesis and expression of receptors and antigens. Tumor growth also leads to hypoxia, with heterogeneity in blood flow owing to focal necrosis, neoangiogenesis, as well as disruption of transport mechanisms of substrates across cell membranes and other physiological boundaries. Molecular changes result in cell cycle dysfunction, altered apoptosis and cell differentiation, neovascularization, and tumor cell migration and invasion. Understanding tumorigenesis is crucial for developing molecular therapeutic targets that can overcome current therapeutic limitations. As our understanding of the molecular nature of cancer improves, better methods are being developed to monitor cancer progression and regression in response to treatment. Insights from research into disease-specific biochemical processes have advanced the development of molecular biomarkers as targets for molecular imaging. A biomarker can be defined as a measurable variable of a molecular, biological or functional process that can also be used as a measure of pharmacologic response to treatment. Biomarker imaging reflects endogenous molecular/genetic processes in normal and pathologic tissues, making it a particularly attractive technique to obtain molecular information that can be rapidly translated into clinically useful information. Biomarkers have proven highly useful for identifying malignant lesions and staging disease extent. In some cases, they can also be used as sensitive indicators of treatment response. Complementary to biopsy and circulating biomarkers assay, biomarker imaging is applied to stage patients and to assess therapeutic response repeatedly in single lesions, as well as to evaluate the global tumor burden at any stage of disease. Many potential imaging targets have been discovered through research in modern genomics and proteomics. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) was first applied to the evaluation of breast parenchyma in the late 1980s, mainly in women with proven carcinomas. Heywang and coworkers (1986) discovered that breast cancer is associated with significant enhancement following the intravenous injection of contrast medium (gadolinium dimeglumine, e.g., Gd-DTPA). The pathophysiological basis of this enhancement has been extensively investigated. Folkman first described the biological rule of capillary vessels for the nutrition of normal tissues and arrived at the discovery that malignant tissues need a supplementary inflow of nutritional factors. For this reason, they are able to release some specific proteins that induce new vessel growth (vascular endothelial growth factor, VEGF) (Folkman 1985, Folkman et al. 1987; Folkman 2002; Weidner et al. 1991; Hanahan et al. 1996; Gimbrone et al. 1972). [ABSTRACT FROM AUTHOR]

The risks of unjustified use of such techniques and the lack of rational clinical application have increased with the availability of many diagnostic techniques. Errors of this nature would affect the diagnostic accuracy and therefore reduce the possibilities for treatment. It is not uncommon for women and also for general practitioners to be misinformed about which is the most suitable technique, or rather what is the best combination of the various techniques; for this reason, inappropriate tests are often requested or tests which would in fact make a useful contribution to safeguarding the women's health. This work has the following aims: to state precisely the real diagnostic contribution of each method, both radiological and otherwise, and suggest methods of application and indications consistent with the state of the art and to suggest the most effective and rational blends of the various techniques and organisation of diagnostic activities. [ABSTRACT FROM AUTHOR]

Sentinel lymph node (SLN) localisation and biopsy represent one of the most important developments in surgery and have already produced important changes in the management of patients affected by early infiltrating breast carcinoma. Sentinel lymph node biopsy (SLNB) was first applied in melanoma patients by Morton and colleagues (Morton et al. 1992); they intra-operatively injected the patent with vital blue dye close to the primary lesion, and the blue-stained SLN was later found by dissection, following tracer diffusion. [ABSTRACT FROM AUTHOR]

Scintigraphic in vivo evaluation of complex cellular processes such as proliferation, apoptosis, receptor/ligand interactions, transport of substrates and metabolism of nutrients in human cancers is a wide and continuing evolving area of investigation in nuclear medicine (Denoyer et al. 2006; Been et al. 2004; Corsten et al. 2006; Weissleder 2006). A major purpose in this area is the non-invasive detection of well-known biochemical, molecular and histological markers of tumor aggressiveness, invasiveness and resistance to therapy, which may provide rational criteria for a fine tuning of therapeutic strategies in individual patients. [ABSTRACT FROM AUTHOR]

Carcinoma of the breast is the commonest form of cancer in women in most western countries: in the USA, it represents 32% of all invasive tumours in the female population. It is the second leading cause of death for women following lung cancer, accounting for 15% of all cancer deaths among women in the USA. In 2005, the American Cancer Society estimated 211,240 new cases and 40,410 female deaths from this disease (Jemal et al. 2005). Trends in incidence and mortality show that there has been a small, but steady annual increase in breast cancer (BC) incidence over the last 30 years, whereas the mortality rate has declined steadily since the beginning of the 1990s (Jemal et al. 2005). Early diagnosis is of the utmost importance to improve prognosis. Mammography (MM) is currently the best imaging modality for early detection of BC, and the results of several trials have demonstrated that mammographic screening can decrease the death rate due to BC (Daniel and Kopans 2004; Tabar et al. 2001). Nevertheless, this technique has some limitations that reduce its accuracy (Berlin 2001): not all BCs are evident on mammograms, especially in dense or dysplastic breasts (Birdwell et al. 2001), even palpable cancer may not be seen mammographically (Holland et al. 1983), it lacks of adequate specifi city in differentiating between malignant and benign lesions (Kopans 1992; Monusturi et al. 1991) and sometimes deciding which lesions require a biopsy may represent a challenge (Adler and Whal 1995). Excisional biopsy is the most effective method to determine the nature of breast abnormalities; however, the high number of biopsies in patients with benign breast lesions is a result of the low positive predictive value of MM (Kopans 1992). Breast ultrasound is largely used, but there are a few valid indications for this imaging technique, primarily involving the differentiation between cystic and solid masses and the evaluation of palpable lesions not visible on MM (Jackson 1990; Kopans 2004). Multiple areas of research have therefore been sought in order to select patients for biopsy and spare unnecessary surgical procedures. Among new imaging modalities, breast magnetic resonance imaging (MRI) and nuclear medicine breast imaging seem to be the most promising. Breast scintigraphy, also called, is a supplemental breast exam that may be used in some patients to investigate a breast abnormality. This nuclear medicine test is not a primary investigative tool for BC, but can be helpful in selected cases after mammography has been performed (Schillaci and Buscombe 2004; Schillaci 2005a). [ABSTRACT FROM AUTHOR]

The correct assessment of axillary lymph node status represents the most important goal in the preoperative phase of breast cancer patients since the presence of lymph node metastases together with primary tumor size can be considered, in the absence of distant metastatic localizations, the single most significant parameter to guide the therapeutic strategy and to better determine disease prognosis as well as serving as an indicator of the tumor ability to spread (Carter et al. 1989). In particular, the number of axillary metastatic nodes when it exceeds three is associated with a worse prognosis (Fisher et al. 1983; Carter et al. 1989; Saez et al. 1989). To date, the procedure of choice for pathological axillary status evaluation is represented by axillary lymph node dissection (ALND), which has a routine use in patients with newly ascertained invasive breast cancer in spite of its invasiveness and morbidity. However, ALND may not be necessary in many cases, in particular in early stage carcinomas with tumor size <10 mm and even more so when axillary clinical examination is negative, since in this case the percentage of lymph node metastases is very low. Moreover, even when axillary lymph node metastases are present, ALND may not affect the choice of adjuvant therapy and, apart from this, a change of treatment may give only a small survival benefit. Eventual complications and the costs of the procedure also have to be considered when the indication is equivocal. Thus, at present, the routine use of ALND is questionable. [ABSTRACT FROM AUTHOR]

A large number of markers have been proposed for breast cancer, but among them only CA 15.3, CEA and cytokeratins (i.e. TPA, TPS and Cyfra 21.1) are currently used in clinical practice. Serum marker levels reflect tumour burden, and for this reason they are not sensitive enough to be used for screening and early diagnosis of primary breast cancer. By contrast, the role of tumour markers is established in the diagnosis of recurrent disease and in the evaluation of response to treatment. In the former case, however, prospective randomised studies are required to demonstrate any survival benefit when earlier therapeutic interventions are instituted upon elevation of serum markers. In the second case, tumour marker evaluation represents a simple, objective method for monitoring of therapeutic response that seems to offer significant advantages over conventional imaging methods (e.g., objectivity and modifications in tumour biology). Furthermore, research studies are ongoing to identify and validate new biochemical parameters that can be of use not only in advanced disease, but also in other stages of the diagnostic workup of breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer heterogeneity represents a major hurdle to improve patient survival. Notwithstanding its potential curability due to the availability of treatment modalities that are effective in the presence of favourable clinical or patho-biologic features, there is still a great deal of controversy in its clinical management. In the last decades, tumour biomarkers that are indicative of or related to cell traits characterising malignancy, such as self-sufficiency in proliferative growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, activation of pathways leading to neo-angiogenesis, invasion and metastasis, have provided information that have proved to be associated with disease progression. However, when singly analysed, their prognostic relevance was modest, and the only clinically useful biomarkers that remained are cell proliferation and plasminogen activationrelated factors for prognosis, steroid hormone receptors and HER2/neu for prediction of response to hormonal or to the novel targeted anti-HER2/neu therapy, respectively. It therefore remains necessary to reduce the intrinsic complexity of breast cancer in order to improve its clinical outcome. One way to achieve this objective derives directly from the concept that cancer is a genetic disease at the somatic level and from the recent availability of high-throughput post-genomic analytical tools such as gene and protein expression techniques for global gene expression analysis. The knowledge derived from gene expression-profiling studies is impressive and challenges currently used breast cancer classification and existing theories about metastatic progression and breast cancer biology. Several studies employing this technology have been consistent in reproducing a molecular classification for breast cancer in which: (1) oestrogen receptor status and tumour grade are the most important discriminators of gene expression subgroups; (2) tumours can be grouped into at least four subsets according to steroid receptor and HER2/neu status; (3) each subset of tumours has a distinct clinical outcome and may therefore respond differentially to various treatments. Additionally, prognostic gene expression signatures have been proposed that outperform traditional clinical risk classification systems, suggesting the possibility to reduce over-treatment in early breast cancer, notwithstanding that the identification of high-risk patients still needs to be improved. A number of recent studies have been directed to answer different clinical and biological questions. However, despite initial enthusiasm doubts have been raised recently regarding the reliability of gene expression profiling for clinical applications, and the outcome of these novel studies still needs to be validated with the cooperation of different specialists and the integration between all the different skills involved in translational research in oncology. [ABSTRACT FROM AUTHOR]

Cancer of the breast is one of the most common human neoplasms, accounting for one quarter of all cancers in females. It is associated with the western life style. Risk factors include early menarche and late childbirth. Breast cancer is further characterized by a marked genetic susceptibility. The typing of invasive breast cancer, its histological variants and their grading systems are well established. More difficult is the classification of the pre-invasive breast lesions that are now increasingly detected by mammography. [ABSTRACT FROM AUTHOR]

This book is a multidisciplinary textbook dealing with the diagnosis of breast cancer and at the same time considering the most important modalities to study breast tumours. Besides the different options among the imaging modalities, other aspects are overviewed including the biology and histology of breast cancer as well as the available laboratory tests and treatments. One chapter is dedicated to the histological classification of breast cancer and another to biomolecular features of clinical relevance. The routine use of tumour marker assays is discussed, with a critical evaluation of their clinical usefulness, interpretation criteria and diagnostic limits. The most important nuclear medicine procedures are described and the most remarkable results published in the recent literature are analysed. A number of chapters focus on nuclear medicine procedures: scintimammography, sentinel lymph node biopsy after lymphoscintigraphy, bone scintigraphy with 99mTc-labelled phosphonates and positron-emission tomography (PET) with 18F-fluorodeoxyglucose (FDG). [ABSTRACT FROM AUTHOR]