Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

Undergoing chemotherapy can be one of the most terrifying things that you go through in your life. One of the most frightening things about chemotherapy is the lack of real information that most people have about it, and the unknown makes it so much more frightening as a result. This eBook, written by a young cancer survivor gives you the real story about what chemo is all about. The most valuable information you can get about chemotherapy is from someone that has already experienced it. This PDF eBook allows you to download and read it as soon as your order it. You can begin your journey of reassurance as soon as you want! Because that's what this is about: chemo does not have to be a terrifying unknown! Other people have gone through it before, and want to help you through it as well! This eBook is the guide through chemo that many people wish they could have had, and now you can have it yourself! Read more...

Chemo Secrets From a Breast Cancer Survivor Overview

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My Chemo Secrets From a Breast Cancer Survivor Review

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All of the information that the author discovered has been compiled into a downloadable pdf so that purchasers of Chemo Secrets From a Breast Cancer can begin putting the methods it teaches to use as soon as possible.

When compared to other ebooks and paper publications I have read, I consider this to be the bible for this topic. Get this and you will never regret the decision.

Metastasis Of Breast Cancer An Introduction

Breast cancer is the leading female cancer in Europe and in the USA and amongst the cancer types with high incidence in the rest of the world. In the UK and USA, approximately one in every ten women will contract the disease in their lifetime and it is amongst the leading cause of death in the female population in industrialised countries. The incidence of breast cancer increases with age and is generally peaked in the 50-60 age group. Metastasis, the spread of breast cancer to other locations in the body, is the main reason that leads to the mortality in the patients. The past decades have seen a significant progress in understanding the molecular and cellular mechanisms of cancer metastasis and development of new diagnostic, prognostic and predictive tools. Some of the new discoveries have been translated into clinical practice. This book aims at providing the current knowledge in the area of molecular and cellular basis of breast cancer metastasis, biological factors that influence...

Breast Cancer Metastasis Controlling Genes

These are the proteins that are implicated to influence critical steps in the metastasis of breast cancer resulting in promotion of metastasis. These critical steps and the genes involved are summarized in Table 1. of apoptosis of infiltrating Fas-immune cells providing a mechanism for tumor immune privilege (10). It was also observed that FasL in breast tissue is functionally active and that tamoxifen inhibits FasL expression, allowing the killing of cancer cells by activated lymphocytes (11). Fas exists in two forms, transmembrane and soluble (sFas). A study by Bewick et al. suggests that plasma levels of sFas may be a valuable clinical prognostic factor in predicting outcome for patients with metastatic breast cancer undergoing high-dose chemotherapy (12). sFas induces host lymphocyte apoptosis and impairs expression of NKG2D and T-cell activation. A study by Ueno et al. reports that compared with healthy female controls, breast cancer patients, especially those with liver...

Clinicopathological Features Of Brca1related Breast Cancer

The relevance of estrogen ERa to the etiology of BRCA1 -associated tumors has been a long-standing clinical conundrum. BRCA1 -associated tumors are largely ERa-negative (6) and their gene expression profile resembles that from basal epithelial cells in the mammary gland (94, 95). On the other hand, prophylactic oophorectomy, which removes the major source of circulating estrogen in premenopausal women, significantly reduces risk of breast cancer in BRCA1 -mutation carriers (96, 97). Consistent with the findings in human (96, 97), oophorectomy decreases the incidence of mammary tumor formation in the MMTV--BRCA1'' mouse model (98). In addition, tamoxifen has been shown to be effective in reducing the risk of contralateral tumors in BRCA1 -mutation carriers (99). Epidemiological evidence also suggests that hormonal exposure and obesity in adolescence, which are well-known risk factors for sporadic breast cancer, can significantly affect breast cancer onset for BRCA1 -mutation carriers...

Cell Motility And Breast Cancer Metastasis

Abstract Motility and invasion of breast cancer cells are the result of the concerted action of a number of cell activities directional migration underpinned by the dynamic organisation of cytoskeletal components (actin microfilaments and microtubules), establishment and disruption of cell-matrix and homotypic heterotypic cell-cell adhesions, and extracellular proteolysis. Metastasis formation is not only related to cancer cell motility, but also necessitates the collaboration of other, coined host cells. Newly discovered ligand-receptor interactions between cancer cells and these host elements offer a molecular explanation for Paget's seed and soil hypothesis, and indicate new targets for possible anti-metastatic therapeutic agents Keywords motility, metastasis, breast cancer, actin, microtubles, cytoskeleton, extra-ellular matrix, collagen, laminin, hyaluronate, cadherin, CXCL12 CXCR4 interaction, integrin, CD44, proteinases

Breast Cancer Cell Motility Molecular Targets For Possible Antimetastatic Agents

Insight into the molecular mechanisms of breast cancer cell motility has revealed a number of possible targets for the development of anti-metastatic drugs. Some of these targets were already indicated earlier in the text. In animal models for breast cancer metastasis, neutralizing antibodies against CXCR4 reduce the number of metastases (146). Furthermore, CXCR4 has been studied intensively in AIDS research, and CXCR4 antagonists from this research area such as T140, have shown to be capable of inhibiting cancer cell motility and pulmonary metastasis formation (147). In another study the synthetic inhibitor TN1 4003 was shown to reduce the number of metastasis in laboratory animals (148). Together with the RGD peptidomimetics already mentioned before, the CXCR4 antagonists are candidate molecules for anti-metastatic treatment. Cyclooxygenase-2 (COX-2) inhibitors have regained interest in oncology as well, since it was shown convincingly that they can inhibit cancer cell motility and...

Promising New Targets For Breast Cancer Diagnosis And Therapy

From the work outlined in section 4, it can be seen that changes in TJ molecule expression, such as occludin, claudin-1, claudin-2, claudin-3, claudin-4, claudin-5, claudin-7, and MAGUK proteins ZO-1, ZO-2, and MUPP-1. These provide potential prognostic indicators for breast tumours. The claudin family has caused considerable interest as an emerging target for cancer therapy (61) however, it remains to be seen how much of this potential can be translated into real treatments. Interestingly, levels of CAR have been found to be significantly correlated with long-term survival of patients with breast cancer with total CAR levels being elevated in primary breast cancers (132). This may have a bearing on its use as means of delivery for gene therapy. Agents that inhibit the effects of cytokines and growth factors such as TNF-a, TGF- , VEGf, and HGF, all of which are able to decrease tran-sepithelial transendothelial resistance and increase paracellular permeability,...

Chemotherapy Considerations

Agents such as adriamycin can affect cardiac function, and an assessment of functional status, a review of systems looking for decreased exercise tolerance, dyspnea, edema, orthopnea, etc., should be elicited. On physical examination, particular attention should be paid to signs of edema, tachycardia, or arrhythmias. At minimum, a 12-lead EKG should be done on any patient who has received adriamycin before undergoing a surgical procedure to look for conduction changes. An echocar-diogram for an evaluation of function should be done for any symptomatic patients before any major surgical procedure in patients who have received an adriamycin-based chemotherapy. An evaluation of respiratory symptoms should be elicited in patients who have undergone radiation to the thorax or treatment with bleomycin-based chemotherapy to evaluate for pulmonary fibrosis. Treatment with corticosteroids can lead to diabetes or adrenal insufficiency requiring monitoring of glucose levels postoperatively and...

Cell Adhesion Molecules In Breast Cancer Invasion And Metastasis

Abstract Metastasis occurs through a series of sequential steps, all of which a metastatic cell must successfully complete in order to establish growth at the secondary site. Cell adhesion molecules including the cadherins, immunoglobulin superfamily, selectins, and integrins play important roles in tumor metastasis. Mucins can also be involved in tumor cell adhesion. In this chapter we review the current knowledge of these groups of cell adhesion molecules in breast cancer.

The Role of Radiotherapy and Chemotherapy

Chemotherapy remains of uncertain value for low-grade astrocytomas that have not undergone anaplastic change. There is no clear evidence of efficacy in the literature and it is not widely used. With oligodendrogliomas 11,12 , especially those with anaplastic change, there is an increasing body of evidence that chemotherapy has a role to play. At the present time, opinions vary as to whether it should be considered as first-line or second-line treatment for such tumors.

Endocrine Resistance And Breast Cancer Invasion

Abstract Despite the initial success of endocrine therapies, a significant proportion of women will acquire resistance to such treatments. Furthermore, clinical relapse during anti-hormonal therapy has been linked to tumours that have gained an aggressive phenotype and enhanced metastatic capacity and is frequently associated with a poorer outlook for the patient. Recently, we have demonstrated that the acquisition of an endocrine resistant state in breast cancer cells is accompanied by a profound increase in invasive capacity. Tumour cell invasion is fundamental to the subsequent development of metastasis, the most significant factor that affects the survival of patients with cancer. Despite this, past therapeutic approaches have paid relatively little attention to these important issues thus a greater understanding of this process will lead to the identification of potential targets for anti-invasive intervention for such patients. To this end, we are currently addressing potential...

Prolonged Growth Factor Signalling Contributes To The Invasive Phenotype Of Ernegative Breast Cancer Cells

Certainly, a poor prognosis has invariably been reported for ER-negative clinical breast cancer (7,9,18,60,61), and invasiveness is substantial in de novo ER-negative breast cancer models such as MDA-MB-231 cells that exhibit extensive aberrant growth factor signalling. Moreover, our studies in ER-negative faslodex-resistant (FAS-R) cells also reveal that chronic exposure to more modest increases in EGFR kinase NFKB signalling during prolonged faslodex treatment can associate with morphological features characteristic of an epithelial-to-mesenchymal transition (EMT), together with very high levels of migratory and invasive activity in vitro alongside adaptive silencing of ER (4,59). In view of these observations, it is feasible that the chronic growth factor signalling that promotes ER negativity may culminate in parallel silencing of ER-regulated genes which play a central role in suppressing cellular invasion. In such cells, we are exploring whether there is a...

The Role Of The Hgf Regulatory Factors In Breast Cancer

Abstract Hepatocyte growth factor (HGF) plays a pivotal role in the invasion and motility of breast cancer cells, and is also a key angiogenic and lym-phangiogenic factor. The cytokine, which is primarily synthesised as inactive pro-HGF by stromal fibroblasts in breast tumours, requires activation to function as a biologically active factor. A number of pro-HGF activators have been identified in recent years, together with some naturally occurring activation inhibitors. This chapter discusses the impact of the HGF activators and activation inhibitors in the development and metastasis of breast cancer, and discusses their potential therapeutic value. Keywords breast cancer, hepatocyte growth factor, HGF activator (HGFA), HAI-1, HAI-2, matriptase, c-MET

The Insulinlike Growth Factor1 Ligand In Breast Cancer Management

Abstract The insulin-like growth factor-1 (IGF-1) system plays an important role in normal human development and is also a potent mitogen which can stimulate the development and progression of breast cancer cells. This review aims at looks at how measuring IGF-1 levels may be used in the clinical management of breast cancer patients. Many studies have shown that IGF-1 acts synergistically with oestrogen to stimulate breast cancer cells. Case-control studies have also shown that premenopausal women with high levels of serum IGF-1 have a high risk of developing breast cancer later in life which does not apply to postmenopausal women with correspondingly high serum levels. Serum IGF-1 levels can therefore potentially be used as biomarkers for predicting breast cancer risk while some studies have started using serum IGF-1 levels as a response bio-marker for chemopreventive drug trials. Measuring IGF-1 ligand expression in breast cancer tissue is not consistently associated with better or...

EGFR signalling in ERpositive acquired endocrineresistant breast cancer cells

There is now substantial in vitro and in vivo experimental evidence revealing that the control of endocrine-resistant breast cancer growth is a multifaceted event, involving signalling through many different growth factor receptor tyrosine kinases which provide a complex network of interacting signal transduction pathways impinging on tumour proliferation and cell survival parameters (6, 7, and references therein). For example, several studies have established that the intracellular signalling pathways associated with oestrogen-receptor (ER) and IGF-1R action are highly interactive. As such, anti-hormonal drugs can exert their anti-oestrogenic activity through disruption of oestrogen IGF-1R signalling cross-talk (6) in addition to their more classical effects of blockade of ER oestrogen response element (ERE) signalling. It follows that the growth inhibitory properties of such drugs are thus a combination of anti-oestrogenic and anti-growth factor activities (8-10). Similarly, members...

Lymphangiogenesis And Metastatic Spread Of Breast Cancer

Abstract Lymphangiogenesis, the growth and formation of new lymphatic vessels, has been extensively studied in recent years. With the identification of new lymphangiogenic factors and new lymphatic markers, the role of lymphangiogenesis in the progression of breast cancer and in the lymphatic spread of breast cancer cells have been recognized. The current chapter overviews the progress in this area. Keywords lymphangiogenesis, breast cancer, VEGF-D, lymphatic markers

Example of Breast Cancer Screening

The American Cancer Society estimated that, in 2004, 215,990 women would be newly diagnosed with breast cancer 40,110 would die of this disease.20 About 59,390 women will be diagnosed with carcinoma in situ of the breast, primarily by mammography.20 From 1996 to 2000, the age-adjusted incidence in nine Surveillance, Epidemiology, and End Results (SEER) registries was about 137 per 100,000 women the age-adjusted mortality during this period was about 28 per 100,000.21 The probability at birth of being diagnosed with breast cancer in 80 years of life is about 11 the probability at birth of dying of breast cancer by age 80 is about 2 .21 Breast cancer incidence for all women increased from 1980 to 2000, although the increase slowed considerably in the late 1990s. Between 1990 and 2000, breast cancer mortality for all women decreased by about 2.3 per year.22,68 The reasons for this decrease are not clear and may be due to a combination of screening and improved treatment.69 Three primary...

Breast Cancer Secreted Factors Alter The Bone Microenvironment

Abstract Bone is the most common site of breast cancer metastasis. Over eighty percent of patients with advanced breast cancer develop bone metastases. Once breast cancer has spread to bone, the cancer is incurable and patients develop mostly osteolytic, but also osteoblastic, or mixed bone lesions and suffer from extreme bone pain, skeletal fractures, hypercalcemia, and nerve compression. Current treatment is the use of antiresorptive bisphos-phonates, which reduces bone pain and skeletal fractures but does not improve overall survival. Mouse models of bone metastasis have led to an understanding of the complex interactions that occur within bone that contribute to the incurability of the disease. Once breast cancer cells enter bone, a vicious cycle develops between breast cancer cells and the other cells within bone. Breast cancer cells secrete factors that stimulate bone cells, causing them in turn to secrete factors back onto the cancer cells. Inhibiting the actions of...

Cyclooxygenase2 And Breast Cancer

Abstract Recent research suggests that the cyclooxygenase-2 (COX-2), an isoenzyme of the COX enzyme system has a fundamental role in breast cancer pathogenesis and metastasis. COX-2 appears to be expressed by a large proportion of invasive breast cancers and by DCIS, and levels seem to correlate with those of angiogenic factors such as VEGF, and with tumour-promoting systems such as aromatase. This is particularly important when we consider that COX-2 is amenable to suppression by simple medications such as aspirin and selective COX-2 inhibitors. This chapter reviews the research exploring the role of COX-2 in breast cancer, and studies investigating COX-2 inhibition. Keywords cyclooxygenase-2, breast cancer, ductal carcinoma in situ, prostaglandins, non-steroidal anti-inflammatory drugs (NSAIDs)

Chapter 1l Breast cancer

Genetics of breast cancer 3OO Breast cancer screening 306 Breast cancer presentation and staging 310 Management of non-invasive breast cancer 312 Management of early breast cancer 314 Management of locally advanced breast cancer 318 Management of metastatic breast cancer 320 Prevention of breast cancer 322 Much effort has been invested in this most common solid tumour occurring in women. The study of breast cancer has rewarded us with lessons in many aspects of oncological practice The benefits of this industry are now visible, with a fall in breast cancer deaths over the last decade.

Genetics of breast cancer

It is estimated that 5-10 of female breast cancer is due to inheritance of a mutated copy of either BRCA1 or BRCA2. Women who inherit a mutated copy of either gene have an elevated lifetime risk of breast cancer up to 87 by the age of 70 years. There is particular risk of pre-menopausal breast cancer, often before the age of 40 years there is an associated risk of ovarian cancer (greater with BRCA1) and male carriers are at risk of prostate cancer. Some ethnic groups are at particular risk for carriage of these mutations (estimated 2 of US Ashkenazi Jews). Other genes contribute less frequently to familial breast cancer. It is hypothesized that ataxia telangiectasia heterozygotes are at risk, but this is as yet unproven. Breast cancer occurs with mutation in PTEN (Cowden disease), MSH1 or MSH2 (HNPCC), and p53 (Li Fraumeni syndrome). The management of hereditary breast cancer is essentially that of non-hereditary disease. Less clear is how to manage asymptomatic female members of...

Breast cancer screening

The aim of screening for this disease is to identify pre-invasive disease or invasive disease before dissemination (through the lymphatics or blood). There is no evidence that simple breast self-examination is an effective means of screening for breast cancer. X-ray mammography is the most sensitive technique for detecting breast cancer and is also the most specific. Mammography is most sensitive once involution of the breast tissue has occurred (i.e. once the menopause has taken place). The test is less sensitive in women with dense breasts that is those with predominantly glandular tissue or residual stromal tissue. Screen-detected breast cancer Women thought to have strong family history of breast cancer are recommended to have genetic counselling and not assessment. If they are found to be at more than 16 risk, then mammographic screening is recommended. Meta-analysis of screening data of 40-50-year-olds suggests there is a non-significant benefit of mammography. At present,...

Breast cancerpresentation and staging

The diagnosis of breast cancer is made by 'triple assessment' This combined approach to assessment has > 90 sensitivity and specificity. The axilla is staged surgically. In the absence of locally advanced breast cancer or symptoms of metastatic disease or biochemical abnormality, routine radiological staging with CXR, CT scan, and isotope bone scan has not been found useful. The TNM staging system is commonly used.

Management of locally advanced breast cancer

Local control of the tumour and the prevention of fungation are of major importance to the quality of life of these women. A combination of primary systemic treatment and radiotherapy is commonly used. Many of these patients are elderly and have indolent ER-positive disease that responds to endocrine therapy with tamoxifen, aromatase inhibitors, or progestins. In younger women, particularly with aggressive 'inflammatory' breast cancer, primary chemotherapy is preferred. In patients with a good response to systemic treatment surgery may be feasible.

Prevention of breast cancer

The initial results of three tamoxifen studies in the prevention of breast cancer in 'high-risk' well women are controversial. An American study has shown a significant reduction in breast cancer with tamoxifen, but a UK and an Italian study have not confirmed this. The groups of women in each study were different, and it may be that the US study was positive because of the preponderance of older women (in whom tamoxifen may be more effective). 1. Early Breast Cancer Trialists' Collaborative Group. (1992) Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy Parts I and II. Lancet 339,1-15,71-85. 2. Early Breast Cancer Trialists' Collaborative Group. (1998) Tamoxifen for early breast cancer an overview of the randomized trials. Lancet 351, 1451-67. 3. Early Breast Cancer Trialists' Collaborative Group. (1998) Polychemotherapy for early breast cancer an overview of the randomized trials. Lancet 352,930-42.

Chemotherapy for advanced colorectal cancer

Indications for chemotherapy Timing of chemotherapy A single randomized study has demonstrated that chemotherapy given early imparts a small but significant survival advantage when compared to delaying treatment until symptoms arise. First-line chemotherapy First introduced in 1957, 5-FU is still the most widely used single agent. It acts, following conversion to active metabolites, as a false substrate for thymidylate synthase, preventing DNA synthesis. Several trials suggest a response rate of 10-20 . No increase in overall survival is seen when analyzing all patients treated. A number of small randomized trials, comparing chemotherapy to best supportive care, suggest that there may be an average survival benefit of around six months in favour of chemotherapy. Regional chemotherapy Second-line chemotherapy Further chemotherapy depends on patient wishes and performance status. For patients previously treated with 5-FU-based chemotherapy,

Highdose chemotherapy

In a Phase II study of 235 patients treated with ECF, 10 survival at four years was observed. One way to attempt to increase the proportion of long-term survivors is to use high-dose chemotherapy as consolidation in patients achieving a partial or complete remission. A previous study observed an 89 partial remission rate with high-dose etoposide and cisplatin. The lack of complete response was probably due to the fact that patients were not cyto-reduced with conventional chemotherapy prior to high-dose therapy. A randomized study is

Fdgpet In Metastatic Breast Cancer

In early stage breast cancer, the value of FDG-PET detection of micrometastatic disease and small lymph nodes is limited by the spatial resolution of PET imaging systems (about 5 mm). For initial staging of breast cancer, FDG-PET has limited additional value compared to conventional imaging and especially sentinel node analysis which allows relatively easy detection of micrometastatic disease (18). With regard to the value of FDG-PET for detecting and staging metastatic breast cancer (Figure 1), a number of reports exist. Moon et al. (19) assessed the accuracy of FDG-PET detection in 57 patients. Sensitivity was 85 , and specificity was 79 , when compared with routine imaging follow-up and histology as standard reference. False negative results in bone were particularly due to osteoblastic bone lesions. When FDG-PET was compared with magnetic resonance imaging (MRI with histology as standard reference) in 32 patients, sensitivity was 94 (versus 79 for MRI), and specificity was 72...

Sentinel Lymph Node Biopsy In Earlystage Breast Cancer

Abstract Sentinel lymph node biopsy (SLNB) is the current standard of care for nodal staging in early-stage breast cancer patients who are clinically node-negative. Data from three randomised controlled trials conclusively demonstrates that SLNB is associated with less arm morbidity and better quality of life than axillary lymph node dissection (ALND). Large observational studies have shown that SLNB is associated with low local recurrence rate and similar survival to ALND. Appropriately identified patients with negative results of SLNB need not undergo completion ALND. Micrometastasis and isolated tumour cells detected by pathologic examination of the SLN with use of immunohistochemical staining or RT-PCR are currently of unknown clinical significance and they are not a required part of SLN evaluation for breast cancer at this time. Keywords breast cancer, blue dye, isotope, lymphatic mapping, sentinel lymph node biopsy

Postchemotherapy surgery or residual masses

Where residual masses are present after chemotherapy for metastatic testicular teratoma, surgery should be performed to resect these. The majority of these will be in the retroperitoneum, and extensive and difficult surgery is often necessary for a complete resection. The residual masses may contain differentiated teratoma, fibrosis, or indeed viable tumour, and further chemotherapy may be indicated. Surgery should usually only be undertaken when markers have normalized.

Clinical Studies ofMLT and Breast Cancer

In addition to the studies in the rat model, the effects of MLT have also been investigated in human breast cancer. It has been reported that the nocturnal rise in MLT levels is significantly reduced in women with ER-positive breast tumors compared to women with ER-negative breast tumors and healthy age-matched controls (24). Another clinical study assessing pineal function in patients with breast cancer found that post-menopausal women with advanced breast cancer have diminished urinary levels of MLT compared to healthy controls (25). Based on these data, it has been suggested that depressed MLT secretion may be a predisposing factor for the development of breast cancer in humans (26). It has also been reported that a two-fold higher MLT level is associated with breast tumors with a low proliferative index compared to those with a high index, suggesting that hypersecretion of MLT may predict a more favorable prognosis (27). Clinical trials investigating the combined effects of MLT...

Retinoids and Breast Cancer

Studies using human breast cancer cell lines show that retinoids inhibit the growth of ER-positive but not ER-negative cell lines (54,55). This may be due to the fact that ER-positive breast cancer cells express higher levels of RAR than ER-negative breast cancer cells. For example, ER-positive MCF-7 breast cancer cells are RARa and P-pos-itive and respond to the growth-inhibitory effects of RA while ER-negative MDA-MB-231 breast cancer cells are RARa and P -negative and are unresponsive to the anti-mitogenic actions of RA. Several growth-regulatory pathways are affected when breast tumor cell lines are exposed to RA (56). For example, in MCF-7 cells, RA increases the activity of insulin-like growth factor binding protein one (IGF-BP-1), thereby reducing the mitogenic efficacy of IGF-1 (57). In addition, treatment of ERpositive MCF-7 and T47D human breast cancer cells with RA induces secretion of growth-related proteins, including TGF-P (59, and suppresses the expression of several...

Systemic Chemotherapy or Combined Modality Therapy

Chemotherapy is usually indicated for the more aggressive histologic subtypes of orbital lymphoma with potential for future systemic involvement or with existing disseminated disease. Indolent lymphomas are very sensitive to both single-agent and combination chemotherapy. Single-agent therapy is carried out with alkylating agents such as cyclophosphamide. For intermediate- to high-grade lymphomas, initial combination chemotherapy is usually with a doxorubicin-containing regimen such as cy-clophosphamide, doxorubicin, vincristine, and pred-nisone (CHOP) or cyclophosphamide, vincristine, dox-orubicin, and dexamethasone (CVAD). The most common life-threatening toxic effect from chemotherapy is myelosuppression, resulting in anemia, infection, and abnormal bleeding. Congestive heart failure secondary to decreased left ventricular function is another significant toxicity of these regimens. Combined chemotherapy and radiation therapy may be an appropriate option for intermediate- to...

Effects Ofthe Combination Of Mlt And Ra On Breast Cancer

Recent studies have suggested that MLT may be a ligand for the ROR receptors (13,57), and that the RORa and RARa receptors may cross-talk at the level of the hormone response element (70). We initiated a series of studies to examine the possible additive or synergistic effects of combined treatment with MLT and RA on breast cancer. As shown in Figure 1, ER-positive MCF-7 breast tumor cells showed significant growth-suppression after five days of treatment with either 10-9 M MLT (64 of control) or 10-9 M atRA (62 of control). Surprisingly, the simultaneous treatment of the cells with MLT and atRA had no inhibitory effect on cell proliferation. However, a sequential regimen of MLT (10-9 M) followed 24 h later by atRA (10-9 M) resulted in a cytocidal effect, decreasing the cell number to below the initial plating density after 5 days of treatment. Similar results were seen with the ER-positive T47D cell line in which both MLT and atRA, when used alone, inhibited cell proliferation by 60...

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy has been considered a relative contraindication to sentinel lymph node mapping as there are some concerns that this may adversely affect SLN localisation and false-negative rates. However, an increasing body of data suggests that SLNB accurately predicts the status of the axillary nodes in patients who have received preoperative chemotherapy. Overall, the studies of preoperative chemotherapy suggest that the failed localisation rates (85-96 ) and the false-negative rates (0-33 ) may be slightly higher in this setting (54-59). However, the SLNB is clearly not the major factor determining the use of adjuvant therapy in these patients, so the slightly increased false-negative rate is unlikely to cause harm. Neoadjuvant therapy may eradicate foci of disease in axillary lymph nodes, the long-term clinical significance of negative findings on SLNB after preoperative treatment is less clear. This potential loss of prognostic information may complicate clinical...

Surgical Management Of Patients With Metastatic Breast Cancer

Abstract Metastatic breast cancer can be a difficult problem to manage surgically as the sole mode of treatment. In certain cases, surgical management is the initial treatment of choice, such as sentinel lymph node mapping and nodal dissections for locoregional control. Other situations, such as metastatic breast cancer to solid organs, such as the brain, liver, and lung, are dictated by individual patient characteristics and the overall clinical situation. Clearly, surgery has become a part of the broader management schema in treating patients with metastatic breast cancer, with developing technologies, such as stereotactic radiosurgery, greatly enhancing our ability to treat such patients. Surgery is a single, but important, tool that should be combined with other modes of therapy, such as hormonal therapy and radiation therapy, to optimize treatment strategies and patient outcomes. There remains a fair amount of controversy as to the clinical significance of micrometastatic disease...

Patterns Of Breast Cancer Metastasis

For early stage breast cancer, the most common pattern of metastatic spread is to regional, ipsilateral draining lymph nodes. Identification and treatment of nodal disease with sentinel node mapping has resulted in a true paradigm shift in the staging and surgical management of early-stage breast cancer (15). For more advanced disease, breast cancer is readily capable of metastasizing to other organs of the body, with a particular prevalence for the bone, lung, liver, and brain. Autopsy studies of women dying of breast

Therapeutic Aspects Of Metastatic Breast Cancer Chemotherapy

Abstract The main treatment aims in managing metastatic breast cancer (MBC) are to relieve symptoms by controlling disease and prolonging survival while maintaining quality of life. Endocrine therapy is considered as a primary option for oestrogen-receptor positive MBC except in those with rapidly progressive visceral disease. Chemotherapy is considered for women with hormone-receptor-negative disease, and in those whose cancer is refractory to endocrine therapy or those with symptomatic or rapidly progressive visceral metastases. The major chemotherapy programmes routinely include anthracycline or taxane but capecitabine, gemcitabine, vinorelbine, and carboplatin are also increasingly used. For HER2- overexpressing breast cancer, trastuzumab-containing chemotherapy is used as a standard but see comments about safe combinations later. Compared with single agent chemotherapy, combination regimens show a greater tumour response rate and improved time to progression in women with...

Local Applications And Chemotherapy

One of the most interesting and potentially important minimally invasive therapies for brain tumors is the future potential for local applications of gene therapy and chemotherapy (also discussed in Chapters 13 and 14). Infusion technology with catheters in tumor or ventricles for convection-enhanced delivery is one example another is the application of cells or slow-release polymers to the tumor bed (57-59). It may be possible for the patient then to benefit from minimally invasive techniques for direct and local chemotherapy (60,61) and gene therapy (62,63).

The Diagnosis And Treatment Of Bone Metastases In Breast Cancer

Abstract Bone metastases from breast cancer can cause clinically relevant skeletal morbidity. These skeletal-related events (SREs) can undermine patient quality of life and functional independence. Early diagnosis of bone metastases could provide important benefits to patients. Although there is no clear consensus, some guidelines suggest bone scans for patients with advanced breast cancer. Skeletal scintigraphy should be the first choice for screening, and confirmation of diagnosis should be made with plain radiography, computed tomography, or magnetic resonance imaging. All patients with advanced metastatic disease should receive systemic anticancer therapy. Furthermore, supplementation of systemic anticancer therapy with bisphosphonates or other therapeutic approaches is suggested for prevention of SREs. Bisphosphonates have demonstrated significant reductions in the risk of SREs in patients with bone metastases from breast cancer. Zoledronic acid has demonstrated benefits beyond...

Growth Patterns and Angiogenesis in Cutaneous Breast Cancer Deposits

The most common tumor to metastasize to the skin is breast cancer. These skin deposits show remarkably different growth patterns with distinct angiogenic profiles. In a study of 51 surgically resected cutaneous deposits 7 , 26 cases had an infiltrative growth pattern The carcinoma cells infiltrated between preexisting dermal structures without significant disturbance of the dermal architecture. In nine cases, the growth pattern was expansive, the dermal deposit forming a well-circumscribed nodule consisting of carcinoma cells and reactive vascular tumor stroma. Preexisting dermal structures were pushed aside by the expansively growing nodule. The growth pattern was mixed infiltra-tive-expansive in the remaining 16 cases, meaning that these deposits consisted of a central expansive nodule surrounded by carcinoma cells showing an infiltrative growth pattern. The interobserver consistency of the assignment of the cutaneous deposits to the different growth pattern categories was 92...

Postmenopausal Women With Advanced Breast Cancer

Considering those patients having an aromatase inhibitor as mono-therapy in the adjuvant setting, first-line therapy in metastatic breast cancer could be tamoxifen-independent of the time frame between terminating treatment and time of relapse. For those being exposed to both treatment options in the adjuvant setting (e.g., tamoxifen followed by an aromatase inhibitor), provided they relapse > 1 year after terminating treatment with an aromatase inhibitor, one of these compounds could be explored as first-line treatment. For those relapsing within a time frame of 1 year or less after terminating adjuvant therapy or during therapy, while evidence is currently lacking, it may be reasonable to expect that some of these patients terminating tamoxifen several years earlier could still be sensitive to that treatment approach. While the final role of fulvestrant in metastatic disease remains to be settled, this drug certainly offers an interesting treatment approach. Although fulvestrant...

Premenopausal Women With Metastatic Breast Cancer

The potential benefits with respect to each individual treatment approach, the combination as well as interactions with chemotherapy-induced amenorrhea in the adjuvant setting has recently been discussed in detail elsewhere (85). In the metastatic setting, first-line therapy with either tamoxifen or ovarian ablation is associated with similar response rates (86, 87). Considering further treatment for premenopausal women, a natural choice should be treatment with a third-generation aromatase inhibitor. While we are left with an open question in adjuvant therapy regarding duration of treatment with an LH-RH analogue (85), based on the fact that metastatic breast cancer remains noncurable and, thus, patients responding to ovarian ablation may be candidates for subsequent aromatase inhibition, it seems reasonable to advocate permanent ovarian ablation (radiological or surgical) for those patients obtaining a clear response to treatment with an LH-RH analogue. Subsequently, such patients...

Polymorphisms Relevant To Cancer Chemotherapy

The basis of many forms of cancer chemotherapy involves the administration of maximum tolerated dosages with the goal of inflicting the greatest Growth factor receptors may be overexpressed in some tumors, potentially affecting the efficacy of chemotherapy. One example of this involves the humanized monoclonal antibody trastuzumab (Herceptin ), which was designed to target an oncogene (HER2 neu) that is overexpressed in some breast cancers and other cancers with poor prognoses. Trastuzumab, when given with paclitaxel and doxorubicin, enhances the cytotoxic effects of the anti-neoplastic agents in breast cancer tissues with high HER2 neu expression (Baselge et al., 1998). Some researchers suggest that an optimal approach to cancer chemotherapy would involve genotyping both malignant and normal cells when feasible (Sadee, 2000).

Synchronous chemotherapy

Chemotherapy delivered with radiotherapy may provide benefit over and above the addition of more cell kill. This may be due to the inhibition of DNA repair by the agent or some other mechanism of tumour radiosensitization. More clinical studies are required to define the optimal combination of chemotherapy and radiotherapy and to ensure this is a selective improvement for the tumour and does not just produce additive toxicity. The approach of targeted delivery of radiosensitizing agents selectively to tumours (e.g. via liposomes) may provide therapeutic gain.

Tj And Breast Cancer Metastasis

4.1 Role of TJs in Breast Cancer Metastasis Metastasis is the primary cause of fatality in breast cancer patients. Although there are believed to be numerous events contributing to the process of metastasis, it is widely accepted that the loss of cell-cell adhesion in neoplastic epithelium is necessary for invasion of surrounding stromal elements and subsequent metastatic events (10). Regulation of vascular permeability is one of the most important functions of endothelial cells, and endothelial cells from different organ sites show different degrees of permeability (114). Tumour blood vessels are more permeable on macro-molecular diffusion than normal tissue vessels. However, the cause and mechanism of hyperpermeability of human vessels had not been clear (114). Although, tumour-cell-conditioned medium increases endothelial cell permeability irreversibly. A timely discussion of the organization of TJs in mammary gland biology can be found in (65). 4.2 Expression of TJ Proteins in...

Bone Forming Breast Cancer Secreted Factors

About 15 of breast cancer bone metastases are osteoblastic (6). Endothelin-1 (ET-1) is a tumor-secreted peptide with a role in osteoblastic bone metastases (16). ET-1 stimulates osteoblast activity and new bone formation (41). It is secreted by breast cancers and cell lines that produce osteoblastic and mixed bone lesions in mouse models e.g., T47D, MCF-7, ZR75.1, and BT483 (16). Invasive breast tumors express higher ET-1 and ETA receptor than nonneoplastic tissue (42). Patients with breast cancer and lymph node metastases possess higher ET-1 serum levels than patients without lymph node metastases (42). Selective inhibition of the endothelin A receptor decreased osteoblastic metastases formed by ET-1-secreting ZR-75-1 breast cancer cells (16). An ETA receptor antagonist is currently in Phase III clinical trials in men with advanced prostate cancer. Adrenomedullin (AM) is another secreted peptide that may play a role in osteoblastic breast cancer bone metastases. AM is expressed by...

Early results in 1 breast cancer diagnosis

With a number of recent advances, contrast-enhanced MRI has emerged as a method with sensitivity approaching 100 for detection of invasive breast cancer 28, 29 . MRI is particularly valuable for detecting malignant lesions in mammographically dense breasts 30 . Studies are currently on going in the U.S., Canada, Germany, Netherlands, U.K., France and Italy to evaluate MRI as a possible screening method for women at high risk for breast cancer 13 . Since most invasive breast cancers are hypervascular, they typically show intense contrast enhancement. MRI for detecting breast cancer relies almost exclusively upon the presence of neovascularity. This vasculature is leaky and contains many arterio-venous shunts. Thus, breast cancerous tissue enhances rapidly and then washes out over the next several minutes, whereas normal breast parenchyma enhances more slowly. These washout time intensity curves are typical of most (but not all) cancers. With administration of contrast agents such as...

Case Study IV Tamoxifen and Breast Cancer

Breast cancer is the most common noncutaneous cancer among women in the United States.57 Although breast cancer mortality has declined in the United States over the past decade, it remains the second leading cause of cancer-related deaths in women, after lung cancer.58 Approximately 211,300 women in the United States were diagnosed with invasive breast cancer in 2004, and about 39,800 women will have died Hormonal therapy has an important place in the treatment and prevention of breast cancer. Because the antiestro-gen drug tamoxifen decreased contralateral breast cancer incidence, in 1992, the National Surgical Adjuvant Breast Cancer and Bowel Project (NSABP) started the Breast Cancer Prevention Trial (NSABP P-1) to test the hypothesis that tamoxifen could be used for the prevention of breast cancer in a group of healthy women at high risk for the disease.59-63 Before the Breast Cancer Prevention Trial, anecdotal evidence suggested that primary breast cancer could be prevented by...

Mammographic Density and Breast Cancer

Epithelium and stromal tissues that are strongly related to risk of breast cancer appear radiologically dense, whereas fat appears radiologically lucent.93 The proportion of the mammographic image occupied by radiologically dense tissue is a composite measure of breast tissue composition. At present, the role of mammographic density in breast cancer etiology is not clear.94 However, it has been established that mammographic density is an independent predictor of breast cancer risk, with associated relative risks between 4 and 6 for the highest vs. the lowest quartile of mammographic density. Evidence suggests that the magnitude of the increase in breast cancer risk is greater than that associated with nearly all other breast cancer risk factors after adjustment for age, body mass index (BMI), age at menarche, breast cancer family history, parity, menopausal status, and HRT use.93,95

Chemotherapy Induced Nausea Dexamethasone

10 mg m2 dose (max 20 mg) IV x 1, then 5 mg m2 dose (max 10 mg) IV q6h prn inj 4 mg mL, 10 mg mL -Dronabinol (Marinol) 5 mg m2 dose PO 1-3 hrs prior to chemotherapy, then q4h prn afterwards. May titrate up in 2.5 mg m2 dose increments to max of 15 mg m2 dose. cap 2.5, 5, 10 mg -Granisetron (Kytril) 10-20 mcg kg IV given just prior to chemotherapy (single dose) inj 1 mg mL Adults (oral) 1 mg PO bid or 2 mg PO qd tab 1 mg -Metoclopramide (Reglan) 0.5-1 mg kg dose IV q6h prn. Pretreatment with diphenhydramine 1 mg kg IV is recommended to decrease the risk of extrapyramidal reactions. inj 5 mg mL -Ondansetron (Zofran) 0.15 mg kg dose IV 30 minutes before chemotherapy and repeated 4 hr and 8 hr later (total of 3 doses) OR 0.3 mg kg dose IV x 1 30 minutes before chemotherapy OR

Combination Chemotherapy

The value of combination chemotherapy has been proved in humans. The combined use of two or more drugs often is superior to single-agent treatment in many cancers, and certain principles have been used in designing such treatments The chemotherapy of advanced Hodgkin's disease is one of the best examples of successful combination chemotherapy. Combination therapy with the MOPP regimen (mechlorethamine, Oncovin vincristine sulfate , procarbazine, prednisone), alternating with ABVD (Adriamycin doxorubicin hydrochloride , bleomycin, vinblastine, dacarbazine), has resulted in cure rates of 50 to 60 . The treatment of Hodgkin's disease also illustrates the use of combined modalities, that is, radiation plus chemotherapy. The combined modality approach to several childhood tumors (e.g.,Ewing's sarcoma,Wilms' tumor, and rhabdomyosarcoma) has dramatically increased the cure rates for these diseases. Adjuvant chemotherapy involves the use of antineo-plastic drugs when surgery or radiation...

The Genetic Control Of Breast Cancer Metastasis

Abstract Metastasis of breast cancer is a complex event involving coordinated cross-talk of several proteins. Genes that control the resultant metastasis can be broadly classified as metastasis promoter genes (MPGs) and metastasis suppressor genes (MSGs). There is an explosion of information in the studies that focus on these genes however, thus far, a very few of them are actually tested clinically and or in vivo functionally. In this chapter we will focus on the metastasis controlling genes that have been tested for clinical relevance or functional properties in breast cancer metastasis models.

Adjuvant chemotherapy of colorectal cancer

Nearly half the patients undergoing apparently curative resection of bowel cancer are destined to relapse and eventually die with either locally recurrent or distant metastatic disease. This is due to the presence of residual micro-metastases invisible at the time of surgery. The aim of adjuvant chemotherapy is to eradicate these micro-metastases and thereby prevent future relapse. Current available chemotherapy does not completely eradicate bulky, advanced metastatic bowel cancer. It does however eradicate micro-metastases in a proportion of patients. In view of the high incidence of colorectal cancer, even a small percentage benefit with adjuvant chemotherapy may have a significant impact in terms of prevention of death and morbidity. Adjuvant chemotherapy is an exercise in risk reduction. Questions to be considered after a potentially curative operation The risk that the patient has micro-metastases is estimated, after surgery, by examining the pathological features of the primary...

Principles of Chemotherapy

During World War II, sailors who were accidentally exposed to nitrogen mustard following the explosion of a ship developed marrow and lymphoid hypoplasia.1 This serendipitous discovery led to the first clinical trial conducted in 1942 using nitrogen mustard in patients with malignant lymphomas at Yale University.2 This marked the beginning of a new era of research in the quest for effective and safe drugs used in cancer chemotherapy. The term chemotherapy has been loosely applied to the myriad systemic therapeutic options in cancer treatment exclusive of irradiation and surgical approaches. In this chapter, we confine our discussion of chemotherapy to refer to the use of conventional cytotoxic agents. Use of targeted and biologic agents such as hormone or signal transduction manipulation and gene therapy is explored in other chapters.

Managing Chemotherapy

Initial therapy is usually empirical and the regimen is adjusted according to the results of culture and sensitivity testing. Physicians must select a drug, administration route, dosage, and dosing interval. These may be changed several times during therapy. For example, severe nausea and high severity of illness may necessitate initial par-enteral antibiotic administration. Several days later, when the nausea has abated and the patient is clinically stable, the patient may be switched to oral chemotherapy. Such an adjustment of therapy reduces the length of hospital stay while providing effective, safe treatment. Once a chemotherapy regimen has been selected, the next step in managing chemotherapy is to define the outcome measures that will define therapeutic success and those that will define unacceptable toxicity and necessitate discontinuation of the chosen drugs. For example, resolution of fever and purulent sputum production, normalization of the white blood cell count, reversal...

Using Serum Igf1 As A Surrogate Endpoint Biomarker Of Developing Primary And Secondary Breast Cancer

The strong association between breast cancer risk and serum IGF-1 has prompted clinical drug trials to use serum IGF-1 as a surrogate endpoint biomarker for predicting risk of developing primary breast carcinogenesis. In this way, circulating IGF-1 could be a cofactor in the development of breast cancer or it may be a by product of other processes that lead to carcinogenesis. As mentioned previously, several case-control studies have shown that serum IGF-1 in premenopausal women could potentially be used to predict risk of developing breast cancer later in life. In the clinical setting, serum IGF-1 could be used as a risk biomarker that could allow evaluation of risk of breast cancer in the general population or at least in groups of patients with high risk of developing early breast cancer such as BRCA1 and BRCA-2 gene mutation carriers or patients on exogenous oestrogen treatment. breast cancer patients who had completed breast cancer treatment, and then prospectively looked at...

Chemotherapy Approaches in the Management of Cancers

Cancer chemotherapy has principally been used in the management of advanced or metastatic disease, following failed local therapies, or in disease for which no alternative therapy is effective. Chemotherapy is curative for several advanced human cancers, such as gestational trophoblastic disease, certain hematologic malignancies, or germ cell testicular cancer. However, most common solid tumors are not curable with current chemotherapeutic regimens when metastatic (Table 2.1). The roles of chemotherapy are manifold induction chemotherapy denotes its use as primary therapy when there is no alternative treatment available or subsequently suitable even with tumor response, such as in hematologic malignancies, where disease is systemic. As an adjunct in combined modality therapy, chemotherapy is adjuvant when systemic treatment is applied after the tumor has been controlled by an alternative modality, such as surgery and or radiotherapy, or neoadjuvant (primary) chemotherapy when...

The Association Between Serum Igf1 And Breast Cancer Risk

Growth hormone and IGF-1 led to mammary gland hyperplasia (49). Animal studies suggested that high levels of circulating IGF-1 could be responsible for an increased risk of breast cancer in humans and this hypothesis prompted studies looking at the relationship between serum IGF-1 and risk of breast cancer in human subjects. The first prospective study on this relationship was performed by Hankinson et al. (18) who carried out a case-control study by retrospectively measuring serum IGF-1 on blood samples collected from 397 women who subsequently developed breast cancer against 620 age-matched controls. The results showed that when looking at the overall group, there was no relationship between serum IGF-1 and risk of developing breast cancer. However, on sub-analysis based on menopausal status, there was a significant association between elevated serum IGF-1 and breast cancer risk in women who were premenopausal at the time of blood collection (50). A subsequent larger case-control...

How Natural Compounds And Chemotherapy Drugs Inhibit Proliferation

Let us now pull together what has been presented about how natural compounds inhibit cancer cell proliferation and compare how natural compounds work to the way current chemotherapy drugs work, thus clarifying what natural compounds have to offer. As we will see, the cancer inhibitory effects of most natural compounds discussed are not due to direct DNA damage, whereas direct DNA damage is an important mechanism for many of the chemotherapy drugs used today. This distinction is important, in that natural compounds are therefore less likely than many chemotherapy drugs to induce DNA mutations in surviving cells. Moreover, natural compounds are more likely to act selectively on cancer cells and spare normal cells than are most chemotherapy drugs now in use. Targets of Natural Compounds Versus Targets of Chemotherapy Drugs Targets of Chemotherapy Drugs In contrast to natural compounds, the chemotherapy drugs in current use primarily target DNA. Several aspects of DNA are targeted,...

Desmosomes in breast cancer

Desmosomes are multifaceted intracellular junctions that participate in cell adhesion and maintenance of normal tissue structure. Desmosomes connect epithelial cells, myoepithelial cells, and the two cell types to each other. Despite the strong adhesion that desmosomes provide, the role of desmosomes in breast cancer metastasis is enigmatic. The loss of desmoplakin in breast cancers correlates with amplified proliferation and increased tumor size, suggesting that desmosomal proteins might be important in suppressing breast cancer progression. Desmoplakin levels are generally lower in metastases compared to primary tumors (67). Downregulation of DSC3 in breast cancer was first reported by Klus (68). Desmocollin 3 (DSC3), a p53 responsive gene, is expressed in normal breast while its expression is downregulated in both primary breast tumors and breast tumor cell lines (69). Decreased expression of DSC3 is partly due to cytosine hypermethylation and histone deacetyla-tion (70)....

Tight Junctions And Metastasis Of Breast Cancer

Although well known as functioning as a control for paracellular diffusion of ions and certain molecules, it has recently become apparent that the TJ has a vital role in maintaining cell integrity and that loss of cohesion of the TJ structure can lead to invasion and thus metastasis of breast cancer cells. Keywords TJ, metastasis, breast cancer, occludin

Effect Of Primary Breast Cancer Extirpation In Stage Iv Patients

Metastatic breast cancer is considered by many to be an incurable disease and therefore the treatment of such patients, whether with systemic therapy (chemotherapy, hormonal therapy), or with surgery is considered palliative (1). However, it has been suggested by others that there may be role for curative surgery in the treatment of selected patients with metastatic breast cancer (2, 3). Khan et al. were one of the first to describe an aggressive local surgical approach to metastatic breast cancer as a possible way of improving overall survival. They retrospectively examined over 16,000 patients with stage IV breast cancer derived from the National Cancer Data Base between 1990-1993, finding that 43 received either no operation or a variety of other diagnostic or palliative procedures and 57 underwent either a partial or total mastectomy (3). This study revealed that those patients who had free surgical margins had an improved overall 3-year survival compared to those not surgically...

In Vitro Effects of MLT on Breast Cancer

In addition to animal models, the effects of MLT on breast cancer have been investigated through in vitro studies using several different human breast tumor cell lines. Examination of MLT's effects on various breast cancer cell lines shows that MLT suppresses the growth of cells which express the estrogen receptor (ER-positive cell lines), but has no effect on ER-negative cell lines (13). One of the most extensively studied cell lines is the ER-positive MCF-7 human breast cancer cell line derived from the pleural effusion of a woman with metastatic adenocarcinoma of the breast (14). This breast cancer cell line expresses the ER and the estrogen-inducible progesterone receptor (PgR), as well as other steroid receptors, such as the androgen (AR) and glucocorticoid (GR) receptors (15,16). Studies investigating the effects of MLT on MCF-7 cells have shown that 10-9M MLT induces a 60 -80 inhibition of cell proliferation after 7 days of treatment (10). The effective growth-inhibitory...

Oncogenes in breast cancer

Abnormalities in a number of oncogenes have been associated with breast cancer including HER2, SRC, MYC and RAS. HER2 (also known as NEU or ERBB2) is involved in the regulation of normal breast development and over-expression has been associated with breast cancer and subsequently with ovarian cancer (Slamon et al., 1989). HER2 amplification has been seen in 20 -30 of breast cancers. The clinical utility of HER2 has received considerable attention over the last 15 years. Initial studies showed that amplification independently predicted a more aggressive disease and reduced overall survival and disease-free interval in node-positive patients (Slamon et al., 1987, 1989). Subsequently many studies have been carried out to try to confirm these findings. Multivariate analysis of over 15 000 patients from 47 studies has shown that, in the majority of studies and the majority of patients, HER2 amplification was associated with a worse prognosis in node-positive patients (Ross and Fletcher,...

Breast cancer screening with mammography

The currently recommended method for reducing breast cancer mortality is through a clinical breast examination and mammogram. The American Cancer Society recommends that these begin at age 40 for women at average risk 13 . Regular screening with mammography has been consistently shown in randomized controlled trials to provide long-term reduction in breast cancer mortality 13 . In order to achieve a 30 reduction in breast cancer mortality, 80 of women aged 50 to 70 should comply with these guidelines. However, compliance with screening guidelines is often inadequate to achieve this goal. This is particularly the case among women of lower socioeconomic levels and among ethnic minorities 14 . Concern over radiation from mammography represents one important barrier to compliance with screening recommendations 14-16 . This concern is especially relevant for women below the age of 50, where the balance between the number of breast cancer deaths prevented by screening compared with the...

Bone Resorbing Breast Cancer Secreted Factors

Breast-cancer secreted factors induce bone resorption by both indirect and direct actions on the osteoclast. Parathyroid hormone-related protein (PTHrP) is the most studied breast cancer-secreted factor. It indirectly activates osteoclastic bone resorption by stimulating osteoblasts and stromal cells to express RANKL, which in turn activates osteoclasts (20). PTHrP was first identified as a causal factor in humoral hypercalcemia of malignancy and was later shown to be a major factor in promoting osteolytic metastases (14). Breast cancer cells that have metastasized to bone express higher PTHrP mRNA levels than in soft tissue sites (21, 22). Inhibiting PTHrP with neutralizing antibodies decreased osteolytic bone metastases formed by MDA-MB-231 breast cancer cells in mice (23). A humanized PTHrP neutralizing antibody is currently in clinical trial for the treatment of breast cancer bone metastasis. Paradoxically, higher PTHrP expression in the primary breast tumor is correlated with a...

Highdose chemotherapy HDC with haematopoietic support

In the clinic, dose escalation within a 'conventional' range has an inconsistent effect on response rates, and with some exceptions, a negligible survival impact. Clinical dose escalation is complicated by a greatly increased toxicity, seen when these relatively non-specific toxins are administered to patients. Substantial advances in haematopoietic support have allowed investigation of very high doses of chemotherapy in the clinic. Autografting, using either autologous marrow or cytokine-mobilized peripheral blood progenitors, is seen to facilitate administration of very high doses of those drugs dose-limited by myelosuppression. 'High-dose chemotherapy' (HDC) is therapy administered in doses clearly outside the standard range and which, with exceptions, require some form of haematopoietic cellular support (some drugs, e.g. cyclophosphamide and etoposide are stem-cell sparing, and it is pos In early studies of HDC with bone marrow autograft support, high rates of objective response...

Mechanisms of Interaction with Conventional Chemotherapy

The concomitant use of conventional chemotherapy agents such as the fluoropyrimidines and the platinum analogues during radiation therapy is the standard of care for neoadju-vant, postoperative adjuvant and definitive therapy in the treatment of locally advanced cancers of the head and neck, lung, and throughout the gastrointestinal tract, including esophageal, gastric, pancreas, rectal, and anal cancers. The results of various Phase 3 clinical trials of concomitant combined modality therapy using these drugs are reviewed throughout this textbook under the disease-specific sites. Indeed, the success of these concomitant combined modality treatments for the locally advanced cancers is probably the most significant advances in cancer therapy during the past 10 to 15 years.65-67 Surprisingly, in spite of such success, the cellular and molecular mechanisms of interaction resulting in tumor radiosensitization remain poorly understood. Although an in-depth review of our current...

Lymphatic markers lymphangiogenesis and spread of clinical breast cancer

Early metastasis to lymph nodes is a frequent complication in human breast cancer. However, the extent to which this depends on lymphangio-genesis or on invasion of existing lymph vessels remains ill-defined. It has been suggested that breast carcinomas invade and destroy lymph vessels rather than promoting their proliferation and nodal metastasis can proceed via pre-existing lymphatics (151). In another study, it was postulated that lymphangiogenesis does not appear to be a feature of invasive breast carcinomas (151). However, the same study revealed that a proportion of the peritumoral lymphatics contained tumour emboli associated with hyaluronan, indicating a possible role for LYVE-1 hyaluronan interactions in lymphatic invasion or metastasis (151). Intra-tumoral lymphatic vessels have been demonstrated immunohistochemi-cally in breast cancer (152). Using a quantitative approach, the level of expression of a range of lymphangiogenic markers was analysed in a cohort of human breast...

Management of early breast cancer

Early breast cancer is defined as disease that can be completely extirpated by surgery, that is T1 3, N0-1 tumours. The management of this disease comprises Adjuvant therapy endocrine, chemotherapy, radiotherapy All patients require removal of the primary tumour with either wide local excision or mastectomy. Halsted mastectomy was the operation most extensively applied to breast cancer patients during the first half of the twentieth century, but it has gradually been replaced by a variety of less radical operations. Breast cancer patients who remain disease-free after local and regional treatment may eventually relapse and die of overt metastases. The current hypothesis ascribes the failure to obtain a cure to occult micro-metastases in distant organs, already present at the time of first surgery. The risk of harbouring occult metastases is low in cases with a small carcinoma and negative nodes and increases with the size of the primary carcinoma and number of axillary metastatic...

Bone A Fertile Soil For The Breast Cancer Seed

The mineralized matrix of the bone is a rich store of growth factors and calcium that are released during bone resorption (5). The released growth factors contribute to the growth of breast cancer cells in bone (6). Insulinlike growth factors (IGFs) I and II and transforming growth factor p (TGFP) are the most abundant growth factors in bone (5). A role of bone matrix IGF I and II in bone metastasis has not been completely demonstrated. Currently, only TGFp has been shown to be actively released from the bone matrix by osteoclast resorption (7). Expression of a dominant negative TGFp receptor subunit in MDA-MB-231 breast cancer cells blocked Actions of the two main bone cell types are coupled. The bone-forming osteoblast and the bone-resorbing osteoclast maintain bone homeostasis by a process of remodeling (13). Osteoclasts resorb bone, leaving a pit within which osteoblasts then form new bone (13). Osteoclast formation is regulated by cells of the osteoblast lineage that express...

Chemotherapy

A multitude of cytotoxic and cytostatic chemotherapeutic regimens have been used for the treatment of HGGs and, with the exception of PCV therapy (procarbazine, CCNU & vincristine) for AO and AOA, the results have been disappointing. A complete review of the various chemotherapy protocols is beyond the scope of this chapter but a recent meta-analysis, which drew on data from 12 randomized trials of chemotherapy for adult HGGs, demonstrated an increase in 1-year survival from 40 to 46 and an overall 2-month increase in median survival 17 . An important exception is the demonstrated durable response and prolonged survival for AO and AOA associated with deletions of the 1p and 1p+19q chromosomes (see Fig. 10.3 and text above) 15 .

Breast Cancer

Early results with ferumoxtran-10 MRI in breast cancer show a sensitivity of 78 , a specificity of 96 and a negative predictive value of 97 (Figure 3.4) (Michel et al. 2002). The sentinel lymph node procedure in breast cancer has a 3 to 10 false negative rate furthermore, positive internal mammary lymph nodes are missed in 17 . Finally, the sentinel lymph node is the only positive node in 61 lymph node positive patients. These patients all undergo axillary dissection, with subsequent high rate of clinically significant lymph edema. As a result from its high negative predictive value, in patients with a negative ferumoxtran-10 MRI, axillary dissection may potentially be avoided. Further studies are under its way to validate this statement. Figure 3.4. A 55-year-old patient with breast cancer and positive lymph node. Sagittal post-ferumoxtran-10 T2*-weighted MEDIC MR image shows one white (circle) and two dark nodes (arrows). The white node showed metastases on histopathology, the dark...

Breast Cancers

There is tremendous potential for more specific examination of gene expression and protein expression in already-recognized forms of breast cancers. Clinically cogent comparisons include estrogen receptor positive vs. estrogen receptor negative, HER2 neu positive vs. -negative, and familial BRCA 1 vs. familial BRCA 2 vs. sporadic breast cancers. It is practical to evaluate the influence of chemotherapy agents and chemopreventive agents on such tumors by sampling cells and proteins in ductal fluid from nipple aspirates. The most instructive clinical result to date is the development of Herceptin for advanced breast cancer (above).

NSCLCchemotherapy

Initial studies with alkylating agents in advanced NSCLC showed decreased survival with chemotherapy, and until recently no agents were available with objective response rates in excess of 20 . UK clinicians' attitudes to chemotherapy for NSCLC have remained negative, despite now wide acceptance of such treatment for small cell lung carcinoma. Recent developments indicate pessimism is misplaced. Despite this, use of chemotherapy in this setting is limited in UK, and it has been questioned whether the cost of non-surgical treatment for NSCLC (both financial and in terms of treatment-related toxicity) can be justified. However, a Canadian health economic analysis suggests that the cost of gaining a year of life for these patients is between 500 and 7000 small compared with 30 000 basic cost of diagnosis and supportive and terminal care. Combination chemotherapy and radiotherapy gives better survival than radiotherapy alone in unresectable disease 3-year survival, 13-23 v. 6 Poor...

SCLCchemotherapy

Prior to the introduction of systemic treatment with chemotherapy in the 1970s, the outlook for patients diagnosed with this disease was dreadful, with a median survival of six weeks for patients with extensive disease and three months for those with limited disease. Combination chemotherapy is now the standard treatment for both categories of disease. A much simplified staging system is used for SCLC as the vast majority of patients are initially treated with chemotherapy irrespective of disease extent. A two-stage system was drawn up by the Veterans Administration Lung Group Chemotherapy alone is not entirely responsible for improvement in survival, with developments in thoracic and cranial irradiation taking place in tandem. The wide range in survival rates between different clinical trials can be explained in part by differences in selection criteria. Intrinsic and emergent drug resistance are thought to underlie ultimate treatment failure in SCLC and a number of strategies have...

Male breast cancer

Carcinoma of the male breast is a relatively rare disease that accounts for less than 1 of all cases of cancer in men. Optimal management of breast cancer in men is unknown because the rarity of the disease precludes large randomised trials. Most information has been obtained from small, single-institution, retrospective studies or by extrapolation from breast cancer trials in women. There are increasing reports in the literature confirming the feasibility and accuracy of SLNB in male breast cancer patients with negative axillae, suggesting that SLNB may be offered as a surgical management option to male breast cancer patients by surgeons who are experienced with the technique (51, 52). Nine men with breast cancer underwent SLNB in the ALMANAC trial. SLN was identified in all of them and there was no false-negative result (53).

Multidisciplinary approach to cancer

With the development ofmore effective additional therapies for cancer (radiotherapy, chemotherapy), the management of cancer has become increasingly complex. No single clinician has all the skills needed to treat all cancers. This has led to the development of multidisciplinary teams that deal with certain types of cancer. Many professions allied to medicine have major roles to play in these teams (e.g. physiotherapists, stoma nurses, counsellors). The team may include individuals who are not directly involved in the treatment at presentation but have adjunctive roles at some stage in the course of the illness (e.g. palliative care). The composition of the team will vary considerably between institutions and disease states. There must be a sufficient range of expertise to allow for informed discussion of the management policy for individual patients. The team's various roles include To efficiently plan and deliver surgery, radiotherapy, and chemotherapy as appropriate.

Structural And Functional Features Of The Brca1 Protein

So far the only known enzymatic activity of BRCA1 is its ubiquitin (Ub) E3 ligase activity. The N-terminal RING domain of BRCA1 interacts with another structurally similar RING finger protein BARD1, and the BRCA1 BARD1 heterodimer confers strong Ub E3 ligase activity in vitro (19, 57). Importantly, missense cancer-predisposing mutations in the RING domain of BRCA1 abolish the Ub E3 ligase activity of the BRCA1 BARD1 complex, providing a compelling link between ubiquity-nation and breast cancer. The exact in vivo ubiquitination substrates of the BRCA1 BARD1 complex remain to be elucidated. However, recent studies have indicated that ubiquitination of the largest subunit of RNA polymerase II by BRCA1 BARD1 is responsible for DNA damage-induced inhibition of RNA processing (58, 59). In addition, BRCA1 BARD1 has been shown to ubiquitinate y-tubulin, which is involved in the control of proper centrosome duplication and chromosomal segregation (60). The construction of whole-body and...

Extracellular Proteinases

In the three-step hypothesis of Liotta (3), proteolysis is conceived as extracellular matrix (ECM) breakdown which creates a virtual gap to be continuously filled up by the leading edge of the moving cancer cell. Different classes of extracellular proteases have been associated with this phenomenon, of which matrix metalloproteinases (MMPs), the serine proteinases coined plasminogen activators (PAs) and the aspartic protei-nase cathepsine D have been studied in depth in breast cancer. One timely aspect of this type of motility regulation is the recent insight that synthesis and secretion of these proteinases is controlled via different pathways as a response to extracellular stimuli or inhibitors. Known examples of MMP upregulation relevant to metastasis are MMP-7 (matrilysin-1) upregulation as a result of Wnt pathway stimulation or cyclo-oxygenase-2 (COX-2) overexpression (25), and MMP-9 (gelatinase B) upregulation by integrin a 3 (26) or Src homology phosphatase (Shp-2) (27). Better...

Monitoring response to treatment

Successful chemotherapy is invariably accompanied by a fall in serial HCG and AFP levels. The serum half-life of AFP is 5-7 days. An initial rise in tumour marker levels may occur soon after starting the first course of chemotherapy, due to tumour lysis. Occasionally, a plateau or even a rise in AFP levels may occur, despite evidence of response from all other investigations. This is due to AFP production by the liver in response to toxicity, most commonly after hepatotoxic drugs such as methotrexate and ifosfamide.

Prognosis and response to treatment

Very high CA 125 levels prior to surgery are associated with a worse prognosis. In women with stage I disease a pre-operative level > 65 U ml is a powerful adverse prognostic indicator, and such patients are candidates for chemotherapy rather than surveillance. Elevated CA 125 levels after one, two, or three courses of chemotherapy are important adverse prognostic factors for survival. Serial changes in CA 125 are recognized as one of the best methods for monitoring therapy.

Palliative resection of the primary tumour

Up to 10 of patients with breast cancer will present with metastatic disease patients with visceral metastases have a poor prognosis but patients with the more frequent bone metastases have a median survival of 2 years. Resection of the primary tumour to achieve loco-regional control may improve patients' quality of life, preventing fungation or uncontrolled axillary metastases.

Physiologic Correlates Of Malignancy

They include the glycoprotein Carcinoembryonic Antigen (CEA), which may be elevated in gastrointestinal tumors, breast cancer, lung cancer, pancreas cancer, and ovarian cancer, and in cases of bronchogenic carcinoma and mammary carcinoma. Furthermore, CEA is excreted into the urine in papillary carcinoma of the bladder. There are six forms of CEAs. They are related glycoproteins in fetal intestinal epithelium that are expressed only in trace amounts in healthy adults. Another such tumor marker is the glycoprotein a-1-Fetoprotein (AFP), which is elevated in the blood in 60-90 of patients with hepatocellular carcinoma, 60 of patients with teratoid gonadal tumors, and 13 of patients with metastatic liver tumors. It is also expressed by some pancreas carci-nomata and gastrointestinal tumors. Physiologically, a-1-Fetoprotein is synthesized at high levels in fetal hepatocytes and plasma, but in barely detectable amounts in the adult liver. An isoenzyme of...

Other Cell Adhesion Molecules

EpCAM (epithelial cell adhesion molecule, EGP40, GA733-2, ESA, KSA, 17-1A antigen) is a 40kD glycoprotein on human epithelium that is involved in Ca++-independent homophilic intercellular adhesion and is not likely involved in cell-substrate adhesion (177). EpCAM is not thought to be related to the major families of cell adhesion molecules (cadherins, integrins, selectins, and the immunoglobulin superfamily) (178). It is localized to the lateral domain of polarized epithelial cells, but cells in suspension exhibit it on the entire cell surface (177). EpCAM is overexpressed 100- to 1,000-fold in primary and metastatic breast cancer (179). In a study of 205 patients Gastl etal. (180) found that 35.6 of invasive breast cancers had overexpression of Ep-CAM by immuno-histochemical staining, and there was an association with poor disease-free and overall survival (independent of tumor size, nodal status, histo-logical grade, and hormone receptor expression). A more recent study of 1715...

Summary And Perspectives

Women in the USA and most of the Western world have a 12 lifetime risk of developing breast cancer, which rivals lung cancer in being the most common cause of cancer-related deaths. Approximately 25 of women diagnosed with breast cancer die of the disease. There is a need for better prognostic markers for accurately predicting clinical outcome. As summarized above, adhesion molecules regulate several mechanisms that control tumor cell survival, proliferation, migration, invasion, and the ability to survive in various microenvironments. Therapeutics targeting various cellular invasive and migratory activities might be useful in treating pathologies that are associated with these cell phenotypes, such as metastasis and angiogenesis. Over the past several years, research has led to the development of integrin and protease inhibitors that are now being tested in clinical trials. As the underlying mechanisms and relevant key molecules become progressively identified, there are...

The Microenvironment Determines The Fate Of Transformed Cells

Breast cancer cells can colonize bone because they activate genetic programs that mediate cell-cell communication with osteoblasts and osteoclasts. Plasticity of the bone structure is maintained by a balance between osteoblastic and osteoclastic activities. This balance is regulated by various signals between the two cell types. Important interactions in the regulation of bone resorption include the induction and activation of osteoclastogenesis, induced by binding of RANK Ligand on osteoblasts to RANK on osteo-clast progenitors, and the suppression of osteoclasto-genesis, mediated by binding of RANKL to soluble Osteoprotegerin, which interferes with the engagement of RANK. Osteoprotegerin is a member of the TNFR family and a negative regulator of osteoclast function. Bone metastases of breast cancer typically express RANKL and thus activate bone resorption.

The Role Of Aromatase And Other Oestrogen Producing Enzymes In Mammary Carcinogenesis

Abstract There is a large and compelling body of epidemiological and experimental evidence that oestrogens are the fuel behind the aetiology of breast cancer. The local biosynthesis of oestrogens especially in postmenopausal women as a result of the interactions of various enzymes is believed to play a very important role in the pathogenesis and development of hormone-dependent breast carcinoma. The over-expression of such enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this chapter we shed light on CYP19 gene expression, aromatase enzyme activity and its role in mammary carcinogenesis. In addition, other oestrogen producing enzymes such as 17beta hydroxy steroid dehydrogenase 1, 2 and steroid sulphatase and their role in breast cancer development are discussed in details. The understanding of the mechanisms that regulate these enzymes is crucial to the development of new...

Monoclonal antibodies

The development of monoclonal antibodies that recognize human tumour-associated antigens has implications for nuclear medicine. Antibodies and fragments (Fab) can be labelled with 131I, 123I, mIn, and 99mTc for scintigraphy. In colorectal cancer, scintigraphy with monoclonal antibodies is potentially valuable in detecting occult disease, localizing recurrent disease when serum markers are elevated, and differentiating between viable tumour and post-surgical fibrosis. The potential roles for radio-immunoscintigraphy in ovarian cancer are in the evaluation of chemotherapy, of pelvic masses after therapy for the presence of viable tumour, and of raised serum markers.

Imaging of tumour tissue

Thallium-201 is widely used for myocardial perfusion imaging. Over the past few years there has been growing interest in the use of 201T1 in oncology. It may be useful in the differentiation between low-and high-grade glial tumours and between tumour recurrence and scar tissue. Thallium-201 scintigraphy can assess residual tumour viability after chemotherapy in bone and soft-tissue sarcomas.

CYP19 gene expression

The promoter I.7 was cloned by analyzing P450arom mRNA in breast cancer tissue levels. P450arom mRNA with exon 1.7 expression was significantly increased in breast cancer tissues and adipose tissue adjacent to tumours (37). This TATA-less promoter accounts for the transcription of 29-54 of P450arom mRNAs in breast cancer tissues. The in vivo cellular distribution and physiologic roles of promoter I.7 in healthy tissues, however, are not known. It is now known that the aromatase gene expression is regulated in a tissue-specific manner by the use of alternative promoters (37). Normal breast adipose tissue maintains low levels of aromatase expression primarily via promoter I.4 that lies 73 kb upstream of the common coding region. Promoters 1.3 and II are used only minimally in normal breast adipose tissue. By performing primer-specific RT-PCR analyses (38, 39, 40), it was revealed that the two major exons (I.3 and PII) are present in aromatase mRNAs isolated from breast tumours. These...

Role in mammary carcinogenesis

Cell line experiments have confirmed the role of aromatase in stimulating the growth of breast cancer cells (24, 59, 60, 61). Additionally, aromatase overexpression has been reported to be associated with a poor clinical outcome in women with breast cancer (62) (Figure 2). Such a relationship was not seen with the clinicopathological parameters of other tumour characteristics. The lack of correlation between aromatase The increasing evidence that aromatase inhibitors are superior to tamoxifen in postmenopausal women with ER positive early and advanced breast cancer is in keeping with our observation that higher aromatase expression correlates with poor clinical outcome (67, 68, 69). Figure 2. Kaplan-Meier analysis of disease-free survival of breast cancer patients depending on the expression of Aromatase mRNA (P 0.0105). (0 Low levels 1.00 High levels (cut-off point 10 000)).

Topoisomerase I inhibitors

The novelty of topoI as a cellular target for chemotherapy has resulted in the development of several analogues, such as irinotecan (CPT-11) and topotecan. Both CPT-11 and topotecan have greater aqueous solubility than CPT. Analogues of CPT with an amino group at the 9-position have enhanced activity, but are less soluble than topotecan or CPT-11. CPT and all CPT derivatives have a basic 5-ring structure. Reversible, pH-dependent non-enzymatic hydrolysis of the lactone ring of all CPT derivatives results in an open-ring carboxylate moiety. The two are in equilibrium in aqueous buffers, but the carboxylate form is a less potent inhibitor of topoI and a much less potent anti-tumour agent.

Therapeutic Potential Of Hai1 And Hai2 As Anticancer Agents

Figure 6. (A) Ribozyme transgenes were used to inhibit HAI-1 and HAI-2 expression in MDA-MB-231 breast cancer cells (Wild type control HAI-1 suppressed HAI-1 KO HAI-2 inhibited HAI-2 KO). HAI-1 KO and HAI-2 KO breast cancer cells revealed a dramatically more aggressive nature compared to the control group. (B) Crystal Violet Staining of Invaded Breast Cancer Cells. (i) Wild type breast cancer cell control group following 72 hour incubation. (ii) The elimination HAI-1 resulted in a significantly higher degree of breast cancer cell invasion. (iii) Suppression of HAI-2 expression dramatically influenced the nature of these cells, resulting in enhanced tumour cell invasion. (C) Wound Closure Migration Assay. The knockdown of HAI-1 or HAI-2 expression significantly increased the migratory nature of the breast cancer cells. (D) Recombinant HAI's were used to potently reduce, MRC5 fibroblast-induced, breast cancer cell invasion. (E) Retroviral Expression of HAIs within human MRC5 fibroblasts...

Pharmacological resistance

The underlying concept of pharmacological resistance is that the dose of chemotherapy that can be safely given is insufficient to result in an effective concentration of the active drug at its target site. This may be due to De novo resistance tumour does not respond despite full-dose chemotherapy Acquired resistance initial response to chemotherapy, then tumour fails to respond and regrows

Dose response and dose intensity

The strategy of therapeutic dose intensification in oncology has been largely driven by the incomplete chemotherapy sensitivity exhibited by many tumours. Experimental evidence suggests that the drug resistance of cancer cells is often relative it can be overcome by exposing the 'resistant' cell to higher concentrations of the drug to which it has become 'resistant'. In most laboratory models, extreme degrees of dose escalation are needed to overcome drug resistance. Results of studies indicate that arbitrary dose reduction should be avoided, and suggest that clinicians should consider use of prophylactic antibiotics, haematopoietic growth factors, etc. in situations where neutropenia and its complications threaten to undermine timely delivery of potentially curative chemotherapy.

Sequential combined therapy

The traditional approach to combining chemotherapy and radiotherapy has been to attempt to predict whether eradication of systemic disease or local tumour control is of most immediate concern, then deliver the appropriate treatment first the other treatment is delayed until completion of the first. The main difficulties are the uncertain behaviour of individual tumours and the inevitable delay in delivery of one treatment. Chemotherapy as the first-line treatment has the added potential benefit that in downstaging the tumour it may reduce both the volume of tissue which requires irradiation and the radiation dose required to control the tumour.

Concurrent combined therapy

Problems are avoided by delivering chemotherapy and radiotherapy together. This approach has advantages and some disadvantages (see Table 9.2). effects of chemotherapy because of their radiosensitizing effects. At least, in vitro, the interactions of chemotherapy and radiotherapy are complex and schedule-dependent e.g. irradiation of cells may lead to cell-cycle arrest and this may confer relative resistance to subsequent exposure to phase-specific cytotoxics such as taxanes conversely, exposure to taxanes can lead to radiosensitization.

The Insulinlike Growth Factor1 Ligand

The IGF-1 gene is located on chromosome 12q22 and codes for A and B domains which are homologous to the A and B chains of the insulin hormone. The liver produces the largest amount of IGF-1 as a result of GH stimulation and is the main contributor to serum IGF-1. Serum IGF-1 can stimulate normal breast cells and promote malignant transformation as well as breast cancer progression via an endocrine fashion (18). Many studies have also shown that stromal cells adjacent to breast cancer cells can produce IGF-1 locally to stimulate tumour cells via an paracrine or autocrine mechanism (19-23). In fact, several studies have suggested that local tissue production could be an important source of IGF-1 which may play a role in growth of normal tissue (24) as well breast cancer development and progression (20, 25-27).

Smallcell lung cancer and oesophageal cancer

Chemo-irradiation of intra-thoracic tumours is hindered by risk of serious morbidity, in particular pneumonitis and oesophagitis. Nonetheless, small cell-lung cancer is an excellent target for this approach although chemosensitive local failure is inevitable with chemotherapy alone, and even with conventional consolidation radiotherapy, 40-50 of these patients have locally recurrent disease. The results of combination etoposide, cisplatin, and thoracic irradiation are promising. Toxicity, especially oesophagitis, is considerable.

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