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 here...

Chemo Secrets From a Breast Cancer Survivor Overview

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My Chemo Secrets From a Breast Cancer Survivor Review

Highly Recommended

I've really worked on the chapters in this ebook and can only say that if you put in the time you will never revert back to your old methods.

All the modules inside this e-book are very detailed and explanatory, there is nothing as comprehensive as this guide.

Finding the Breast Cancer Genes

Breast cancer is the most frequently diagnosed cancer worldwide, and is heavily publicized as the leading cause of cancer death for women in Britain and the second leading cause of cancer death for women in the United States.7 The news media, medical charities, and public health organizations in each country quote that a British woman has a 1-in-12 chance of developing invasive breast cancer during her lifetime, and that an American woman has a 1-in-8 chance. Although governments and medical charities (including the Imperial Cancer Research Fund and Cancer Research Campaign in Britain and the National Cancer Institute and American Cancer Society) have spent a considerable amount of money to look for a cause and to develop prevention and treatment strategies for the disease, neither an unequivocal cause nor a completely effective prevention, detection, or treatment strategy has yet been found. Mastectomy, which involves breast removal, not only has severe physiological and...

Induction Chemotherapy

A disappointing fact concerning the treatment of younger adults with AML is that the agents used for induction therapy now are much the same as three decades ago. Three days of an anthracycline (generally, daunorubicin or idarubicin) in conjunction with 7 days of continuous infusional cytarabine (100-200 mg m2 per day)17 remains the standard approach. It has been the practice in the Cancer and Leukemia Group B (CALGB) and other cooperative groups to perform a bone marrow examination approximately 2 weeks after the start of induction chemotherapy.1 If a sufficient degree of myeloblast reduction is not achieved, then 2 days of the same anthracycline and 5 days of cytarabine are administered as a reinduction cycle. Occasionally, serial bone marrows are necessary to clarify whether or not a reinduction cycle should be administered. Approximately 30 of younger adults with AML will require a second course (so-called 2 + 5 reinduction).1 Although not certain, the requirement for such a...

Maintenance Chemotherapy

Survival for adult ALL patients following matched sibling allo SCT in first remission is approximately 50 (range, 20-80 ).73 The International Bone Marrow Transplant Registry (IBMTR) compared 251 patients who received intensive postremission chemotherapy with 484 patients who received matched sibling allo SCT.74 Although 9-year DFS rates were similar 32 for chemotherapy and 34 for allo SCT a higher recurrence rate of 66 was observed for chemotherapy patients versus 30 for those receiving allo SCT, with treatment-related mortality being the main cause of failure in patients who received allo SCT. Allo SCT and autologous stem cell transplantation (auto SCT) in first remission were compared in a large French multicenter trial (LALA 87).75 Based on an intent-to-treat analysis, survival at 10 years was 46 for those receiving allo SCT compared to 31 for those receiving consolidation chemotherapy alone (p 0.04). The value of allo SCT was even more apparent after patients were classified into...

Chemotherapy Strategies

Variations on traditional induction therapy, usually including vincristine, prednisone, and an anthracycline intensified with cyclophosphamide and or L-asparaginase, are frequently used in the salvage setting. A second CR can occasionally be achieved in the subset of patients who had a long first remission or who developed recurrent disease after completing maintenance chemotherapy.10 Even one of the most favorable reports, however, achieved a CR in only 44 of the patients.11 Furthermore, the median survival for these patients was only 8 months, and 3-year survival was only 10 .

Chemotherapy For Acceleratedand Blastphase

Prior to the development of imatinib, the outlook for patients entering the advanced phases of CML was dismal. Chemotherapy was the mainstay for these patients, and the choice of chemotherapeutic agents generally followed the treatment plans for acute myeloid and lymphoblastic leukemia patients with accelerated or myeloid blast phase received cytarabine anthracycline-based regimens, while patients with lymphoid transformation received standard vincristine prednisone-based protocols. Although imatinib may now be considered the treatment of choice for patients with CML entering the accelerated or blast phase, most patients in the future will have already received imatinib as part of treatment for chronic-phase disease, and thus chemotherapy must still be considered as an important part of therapy. What has changed, however, is that patients entering advanced phases will have been treated with imatinib, and whether this changes the efficacy of chemotherapy is yet to be determined....

Review Of Published Prognostic Models In Breast Cancer Methodology

Papers were sought that presented new prognostic models for patients with operable breast cancer, or which evaluated a previously published model (validation study), or both of these. Medline , Embase , CancerLit , and other databases were searched late in 2001 (2). Some additional articles were identified after the main searches.

Importance of gene amplification in breast cancer

Recent studies using combination of cDNA array based expression profiling and comparative genomic hybridization have elucidated the role of gene amplification in the transcriptional program of breast cancer. In the study by Pollack et al. (2), copy number alteration and expression levels across 6691 mapped human genes were examined in 44 locally advanced breast cancer and 10 breast cancer cell lines. The data from this study suggest that at least 12 of all the variation in gene expression among the breast cancer is directly attributable to underlying variation in gene copy numbers. The total number of genomic alterations (gains and losses) correlated significantly with high grade (p 0.008), negative estrogen receptor (ER) (p 0.04), andp53 mutation (p 0.0006). Of 117 high-level amplifications (representing 91 different genes), 62 (representing 54 genes) were found to be associated with at least moderately elevated mRNA levels, and 42 (representing 36 different genes) with highly...

Breast cancer activism and consensus politics

Since the early 1990s 'lay' or 'patient' activism has had a profound and lasting impact in raising the public profile of breast cancer in Euro-American contexts (Kaufert 1998 Klawiter 2000, 2004). Although activism in relation to a range of health issues pertaining to women, particularly contraception and abortion, can be traced to the early 20th century (Weisman 1998), the recent upsurge in activities and interest in breast cancer is, in part, a legacy of the feminist politics of the 1970s and the successful lobbying activities of AIDS activist groups in the 1990s (Morgen 2002). Nevertheless, as Epstein points out, it is now the scope and reach of a culture of breast cancer activism which is informing and cross cutting the recent rapid growth in a diverse range of patient movements and lay groups active around the politics of health (2007). On the one hand, the recent visibility of a culture of activism around breast cancer has helped shape state or government instigated preventative...

Breast Cancer Activists

The Washington-based National Breast Cancer Coalition and the San Francisco-based Breast Cancer Action (by the mid 1990s the most influential advocacy groups involved in breast cancer politics at the national level) cautioned against the widespread availability of the new technology. They worried that the risk information generated by BRCA testing would provide ambiguous results, because of the risk, rather than certainty, of future disease incidence and the paucity of medical management options available. Therefore, both suggested that testing be offered in a highly regulated manner and only in conjunction with extensive clinical care. In fact, the Representatives of these patient advocacy groups began to express such opinions almost as soon as the BRCA gene discoveries were announced. In a front-page New York Times article announcing the BRCA gene discovery, Nancy Evans, president of BCA, noted It's a very mixed blessing to have this knowledge . . . it's the first step in a long...

Clients Journey through the Breast Cancer Activists System

After the genes were analyzed, the client returned to the clinic on an ongoing basis for post-test counseling and long-term follow-up.10 Both groups were careful, however, to note that both counseling and laboratory services should remain confidential unless the client decided otherwise. BCA urged that the array and number of unresolved issues related to genetic testing for susceptibility to breast cancer make compelling the need for written informed consent prior to such testing or to the release of the results of such testing to third parties.11 This confidentiality of genetic-test results was already standard practice at genetics clinics in the United States, who had responded to concerns that genomic information in the medical record could fall into the hands of insurers or employers and cause discrimination.

Having a family history of breast cancer

It was apparent that a number of those I met had undertaken a good deal of investigative work to explore in more detail the history of cancer in their family. Deborah talked about how after her mother's two sisters had developed breast cancer they had then uncovered what she termed an 'extensive' family history. We've done a bit more chipping away to see whether there has been more breast cancer back in other generations. We'd never looked into it until after her sisters Deborah's mother had breast cancer and then we were like hang on a minute oh yes auntie so and so died of cancer. It obviously is genetic to some extent it's just there is breast cancer down the female line on my mother's family and it strikes me that it must be related unless it's just a coincidence that my grandmother and mother had breast cancer. But they had very different lives it's an unlikely fluke because one lived in the country and did nothing for years and years and the other lived in the city and just...

Intensive chemotherapy using combination regimens

The first patients with CMML who were treated with combination chemotherapy used to manage acute myel-ogenous leukemia (AML) were probably those whose initial diagnosis was AML that was later reclassified as MDS or CMML. In later trials in patients with AML, patients with CMML were occasionally included, along with RAEB and RAEBt, as all three categories were considered high-risk MDS. More often than not, little information was given on the clinical and hematologic status of CMML patients, and in such prospective studies, selection bias toward treating younger patients with advanced disease was likely. With few exceptions, treatment regimens consisted of cytarabine (given at standard dosages for 5-7 days) plus anthracycline or anthracene-dione antibiotics (daunorubicin, mitoxantrone, or idaru-bicin). A review of six such studies conducted between 1980 and 1995 identified only 35 patients with CMML, 11 (31 95 confidence interval 15.9-47.0 ) of whom achieved a CR.18 Duration of...

Combination chemotherapy

In individual cases, complete responses to combination chemotherapy that included cytarabine have been reported. Although limited information is available, it appears that responses are lower than in CMML and that this approach should be saved for cases evolving into AML. Complete responses may be obtained in a minority of patients with such secondary AML or blast phase of aCML and, as in similar cases of AML secondary to MDS and CMML, the responses are short, and long-term disease-free survival is rarely obtained. Intensive chemotherapy may be considered as a cytoreductive approach before allo-geneic SCT.

Hydroxyurea and other singleagent chemotherapy

Other cytotoxic agents have occasionally been used empirically, mostly for patients with proliferative HES and evidence of end-organ damage. Case reports of successful treatment include use of cyclophosphamide in HES with recurrent eosinophilic colitis,92 vin-cristine,78 93 94 and, in hydroxyurea-resistant HES, cyto-sine arabinoside (100 mg m2 given subcutaneously or intravenously) daily for 5 days plus prednisone 100 mg orally, daily, for 5 days, every month (M. Beran, unpublished observations, 2003). Ameliorated clinical symptoms and suppressed eosinophilia were reported with each of the above treatments. The effect of chemotherapy on the natural course of the disease remains unknown.

Standard chemotherapy

When treatment is indicated, no particular chemotherapy regimen has clearly prolonged the survival of patients with advanced-stage follicular NHL compared with another. Extensive experience with single alkylating agents alone or combined with vincristine and prednisone e.g., cyclophosphamide, vincristine, and prednisone (CVP) , or CVP with adriamycin cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP) failed to demonstrate a major difference in outcome.17 20 Thus, until recently, a single alkylating agent or CVP was the standard. The use of CHOP is often reserved for patients for whom there is a concern of histologic conversion, or at the time of such conversion. Single-agent fludarabine is an active agent in previously treated and untreated patients,21-26 and fludarabine-based combinations with cyclophosphamide or mitoxantrone demonstrated high response rates in phase II trials.27 28 The regimen of fludarabine plus mitoxantrone has been...

Prognostic Value Of Circulating Tumor Cells In Metastatic Breast Cancer

Only three studies have correlated the presence of immunopurified CTCs with clinical outcome. The first by Gaforio et al. (30) evaluated a heterogeneous population of patients spanning the clinical contexts of neoadjuvant therapy, adjuvant therapy, and metastatic disease. Utilizing Kaplan-Meier analysis for progressionfree survival (PFS) and overall survival (OS), they found that patients with elevated CTCs prior to therapy had worse PFS (P 0.058) and OS (P 0.003). However, they did not stratify for disease stage, and at the time of publication neither of the medians for PFS or OS had been reached, making interpretation of the data difficult. The second study by Bauernhofer et al. (27) evaluated CTCs in 32 patients with metastatic breast cancer. They found that patients with detectable CTCs had a significantly shorter median OS of four months, compared with 13 months for patients without CTCs (P < 0.001). These authors did not specify the timing of the blood draws, and they did not...

Chemotherapy Regimens and Cancer Care

VADEMECUM Chemotherapy Regimens and Cancer Care LANDES BIOSCIENCE Georgetown, Texas U.S.A. Chemotherapy regimens and cancer care Alan D. Langerak, Luke P. Dreisbach. 1. Antineoplastic agents--Handbooks, manuals, etc. 2. Cancer--Chemo therapy--Handbooks, manuals, etc. I. Dreisbach, Luke P. II. Title. III. Series.

Systemic Chemotherapy

Systemic chemotherapy should be restricted to patients with advanced stage disease or with multiple relapsed and refractory plaques and tumors. Established treatment options include single-agent or multiagent chemotherapy such as steroids, methotrexate, chloram-bucil, vincristine, doxorubicin, cyclophosphamide, etoposide, and alkylators. Combination chemotherapy with CHOP or CHOP-like therapies has been shown to achieve higher response rates of approximately 70-80 .39 Eighty-one patients (46 primary CBCL and 35 CTCL) were treated with COP or CHOP regimens. The overall response rate was 40 in CTCL patients, with a CR in 23 of patients. The median response duration was 5.7 months and median survival was 19 months. A phase II trial with the etoposide, vin-cristine, doxorubicin, cyclophosphamide, and oral prednisone (EPOCH) regimen in 15 patients with refractory CTCL resulted in an overall response rate of 80 .40 Twenty-seven percent of patients achieved a CR, and 53 of patients achieved...

Conventional Chemotherapy

Treatment of the non-ALCL T-cell lymphomas with conventional chemotherapy designed for B-cell lymphomas has had only limited success. Common anthracycline-containing regimens result in low response rates and short durations of remission, and the vast majority of patients develop resistant disease. For example, Armitage et al. evaluated 134 cases of PTCL diagnosed at three centers from 1973 to 1986 80 patients had been treated with intensive regimens such as CHOP cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone with or without bleomycin, CAP-BOP (cyclophos-phamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone), COMLA (cyclophosphamide, vincristine, methotrexate, and cytosine arabinoside), and MACOP-B (methotrexate, doxorubicin, cyclophos-phamide, vincristine, prednisone, and bleomycin).21 While the median survival was 17 months and the 4-year survival was 28 for all 134 patients, for the 80 patients who received intensive...

Highdose Chemotherapystem Cell Transplant

Several groups have examined the impact of high-dose chemotherapy on T-cell lymphomas. Investigators at MD Anderson Cancer Center performed a retrospective analysis of 36 patients with relapsed or refractory PTCL who received high-dose chemotherapy and autologous (29 patients) or allogeneic (7 patients) hematopoietic transplantation.88 The 3-year overall survival rate was 36 , and progression-free survival (PFS) rate was 28 . The 3-year probabilities of survival for the autologous and allogeneic groups were 39 and 29 , respectively, while the PFS rates at 3 years were 32 and 14 , respectively. The pretransplant serum LDH level was the most important prognostic factor for both overall survival and PFS results. Furthermore, patients with an IPI score of < 1 had better overall survival, but not PFS rates, than those with greater IPI scores. At a median follow-up of 43 months, 13 patients (36 ) were still alive with no evidence of disease. These data were comparable to published studies...

Upa as a prognostic marker in breast cancer

Duffy et al. (40,41) first reported that breast cancer patients with high levels of uPA activity in their primary cancer exhibited both a shorter disease-free interval and shorter overall survival than those with low activity levels. These preliminary results have now been confirmed by approx 20 independent groups, worldwide (Tables 3 and 4). These singlecenter studies showed that the prognostic value of uPA was Different Groups Showing a Prognostic Value for uPA in Breast Cancer Different Groups Showing a Prognostic Value for uPA in Breast Cancer

Highdose Chemotherapy In First Or Partial Remission

The LNH87-2 trial by the GELA (Groupe d'Etude des Lymphomes de Adulte) group was a phase III trial that enrolled 916 patients with intermediate- and highgrade lymphoma in first CR with one or more unfavorable prognostic factors who received induction treatment using the LHN84 protocol.24 Only those patients who achieved a CR (61 , n 541) were randomized to receive sequential chemotherapy or proceed to autologous stem cell transplantation. Initial analysis revealed no difference in DFS and OS between the two consolidative treatment arms. However, a subset analysis of the higher risk population who had two or three risk factors favored the autologous stem cell

Challenging The Dogma Of Nodepositive And Nodenegative Breast Cancer

The first has four negative sentinel lymph nodes and the second has a 5.5 mm metastasis in one of several lymph nodes. Five years after diagnosis, the first patient develops a cerebral metastasis and the second patient has a mammographic density adjacent to the old partial mastectomy site that is fibrocystic change on biopsy. A curious pathologist performs deeper sections and cytokeratin immunohistochemistry (CK IHC) on the negative sentinel nodes prior to tumor board because these were not performed at the time of diagnosis. One of the sentinel nodes contains a 0.1 mm metastasis and another node contains five clusters of tumor cells ranging from one to six cells in the subcapsular sinus. Now imagine the discussion at tumor board. Someone is sure to suggest if we had only done the deeper sections and immunos five years ago . This, of course, is the sort of magical thinking that propagates oncological myths. What are we missing in these two scenarios Would the...

Purine Analog Based Combination Chemotherapy

Rituximab has shown greater activity when it was investigated in chemotherapy-naive patients. Rituximab at 375 mg m2 weekly for 4 wk produced partial responses in 8 of 14 (57 ) patients with CLL who had not received prior treatment (74). Thomas et al. (75) reported an overall response rate of 83 and a complete response rate of17 in patients with early-stage CLL treated with 8 wk of standard dose rituximab. Despite rituximab's modest single-agent activity in CLL, the combination of this antibody with chemotherapy appears to be a promising strategy. A combination of fludarabine, cyclophosphamide, and rituximab is being studied in patients with CLL. Fludarabine is given at a dose of 25 mg m2 and cyclophosphamide at a dose of 250 mg m2 for three consecutive days rituximab is given on the first day of each cycle. The rituximab dose is 375 mg m2 in the first cycle and 500 mg m2 in the subsequent cycles. Patients receive up to six cycles of treatment. The results of this ongoing study were...

Pai1 as a prognostic marker in breast cancers

Intuitively, it might be expected that high levels of an inhibitor of uPA in cancer tissue would correlate with a low probability of metastasis and thus with good outcome. Paradoxically, however, high levels of PAI-1 in breast cancer are also strongly and independently associated with poor outcome (Tables 5 and 6). Furthermore, the prognostic information available from PAI-1 is additional to that of uPA. Thus, the combined measurement of both proteins results in enhanced prognostic data over that available from either factor alone (65). Different Groups Showing a Prognostic Value for PAI-1 in Breast Cancer Different Groups Showing a Prognostic Value for PAI-1 in Breast Cancer

Organochlorine Compounds Polycyclic Aromatic Hydrocarbons and Breast Cancer

Environmental exposure to organochlorine compounds such as polychlorinated biphenyls (PCBs), 2,2'-bis (p-chlorophenyl)-1, 1, 1-tri-chloroethane (DDT) and its metabolite DDE, and organochloro pesticides has been suggested as a risk factor for breast cancer. The basis for this claim is that some of these are carcinogenic in animals, have estrogenic activity, and are inducers of cytochrome P-450 enzymes that metabolize drugs, hormones, and various xeno-biotics. Some epidemiological studies have suggested an association between this class of compounds and breast cancer risk, but these studies have been contradictory and inconclusive (reviewed in Reference 172). Because of a purported clustering of breast cancer on Long Island, New York, and a fair amount of political pressure, a 30 million Long Island breast cancer study project was launched to examine the relationship between exposure to environmental agents and breast cancer incidence. The study was carried out under the auspices of the...

The Heisenberg Uncertainty Principle Applied To Breast Cancer

Heisenberg postulated that the position and momentum of a particle could not be simultaneously known. His principle led to clearer understanding of the uncertainty inherent in scientific measurement. A similar paradox exists in assessing lymph node metastases with respect to knowing where they are but not knowing where they may have been going. Even if we could assess the biological potential of a single cell, cell cluster, or micrometastasis in a sentinel node, the node has already been removed from the patient anything removed has no capacity to harm only disease left behind has lethal potential. By assessing the disease removed from a patient, we infer from observational experience the risk of recurrence. Implicit in any risk prediction is the assumption and probability that some quantity of tumor with proliferative capacity remains in the patient. The failure pattern, or metastatic profile, for breast cancer has not changed over the course of our transition from radical mastectomy...

Abortion or Miscarriage and Breast Cancer

Some reports have suggested that incomplete pregnancies, terminated either by induced abortion or miscarriage, increases the risk of breast cancer (reviewed in Reference 184). A number of other studies have not shown an increased risk of breast cancer in women who have undergone induced abortions.184 A well-controlled study of the effects of induced abortion and miscarriage on breast cancer incidence, involving age-, parity-, and race-matched cases and controls, showed that neither induced abortion nor miscarriage increased breast cancer risk.184 This claim appears to be more of an issue of politics and religious beliefs than science.

Radiation therapy versus radiation therapy plus chemotherapy

Clinical trials of limited stage HL have more recently focused on the use of radiation therapy versus combined radiation therapy and chemotherapy. Decades ago, the specific chemotherapy regimen usually employed was MOPP. Given that MOPP has been replaced in the treatment of HL by ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), these pioneering studies are of only moderate relevance to today's practice. As a general statement, these studies included both pathologically staged and clinically staged patients, and generally compared subtotal lym-phoid radiation therapy or total lymphoid radiation therapy versus MOPP (or a variant of MOPP) combined with limited or extended field radiation therapy. Table 73.2 shows a summary of these studies. Two studies found an advantage (FFR) in combined modality therapy (CMT), whereas the others did not. There was no difference in OS in any study. Other findings of studies of this era are important. Multiple sites of disease were associated...

Chemotherapy Regimens Mopp and MOPP derivatives

The dosage, schedule, and frequency of MOPP chemotherapy are described in Table 73.6. Patients receive four drugs over a 2-week interval followed by a 2-week recovery period. A total of 4 weeks constitutes one cycle of treatment. Most patients receive six cycles. Historically, the dose of vincristine used in MOPP frequently exceeded the currently recognized dosage limit of 2 mg. Two updated mature studies with 1045 and 14 years46 follow-up, respectively, showed that 66 of patients have remained disease-free more than 10 years from the end of treatment. Forty-eight percent of advanced HL patients have survived between 9 and 21 years (median, 14 years) from the end of treatment. Nineteen percent of the complete remission cases have died of intercurrent illnesses, free of HL.45'46 Table 73.6 Main chemotherapy regimens used in advanced HL Table 73.6 Main chemotherapy regimens used in advanced HL

Can Hedgehog Signaling Antagonists Be Used for the Treatment of Breast Cancer

Hedgehog signaling inhibitors have been used successfully in vitro to inhibit growth of a variety of cancer cell lines and in vivo for the treatment of medulloblastoma (Berman et al. 2002 Romer et al. 2004). Amazingly, mice treated with these agents show little evidence of adverse side effects. If, indeed, activated hedgehog signaling plays a role in breast cancer development or progression, perhaps directly within the stem cells themselves or indirectly via a paracrine mechanism, small-molecule hedgehog signaling antagonists would appear to be attractive candidates for breast cancer treatment (Lewis and Veltmaat 2004). apoptosis, as well as to inhibit expression of a Gli-dependent luciferase reporter in sensitive cell lines (Mukherjee et al. 2006). These data have suggested that hedgehog signaling may be active in a subset of human breast cancer cell lines, and that hedgehog signaling antagonists might inhibit breast cancer growth in vivo. However, as aptly pointed out by Mukherjee...

Breast Cancer Molecular Subtypes

Unsupervised analysis and class discovery have identified several subtypes of breast cancer that differ systematically from one another and that may be considered as individual diseases under the umbrella term of breast cancer. Given the diversity in breast cancer outcomes that is incompletely explained by known prognostic factors, and the phenotypic diversity in biological factors such as histological grade, estrogen receptor (ER) status, progesterone receptor (PgR) status, and HER2 neu expression (HER2), it made sense to apply newly developed gene expression techniques to breast cancer samples to study the extent to which genetic diversity explained these differences. These studies revealed that not only do differences in gene expression lead to predictable differences in phenotypic and clinical features, but also that gene expression patterns among tumors group them in a way which suggests that breast cancer is more than one discrete disease. Initial evidence for molecular subtypes...

Pss And Breast Cancer

Occasionally, a worsening of the scleroderma was noted when the malignancy recurred, while improvement of skin changes occurred after treatment of the neoplasm 10 . (A similar finding was also noted in connection with bladder carcinoma 10 .) An incidence of breast cancer of up to 17 of all types of neoplasms in PSS is mentioned in several studies. In a number of cases the breast carcinoma was diagnosed after the onset of PSS, whereas, in others the scleroderma developed after the diagnosis and treatment of the malignancy (mastectomy lumpectomy and radio- or chemotherapy). There is no consistent connection between immunosuppressive therapy for scleroderma and the appearance of malignancy. Contrary, scleroderma (localized and systemic) has occasionally developed after radiotherapy for breast cancer. In these cases it is unclear whether the collagen disease may be connected to the malignancy itself, or to the radiation. The explanation suggested for the association of lung carcinoma and...

Use Of Microarrays To Identify Breast Cancer Subtypes

Could take tumor samples from 50 consecutive breast cancer patients, determine gene expression for each sample using microarray technology as described earlier, and then use statistical tools to divide the samples into subgroups based on similarities in gene expression. Whether these groupings would have clinical significance needs to be determined by further study. In contrast, class comparison studies start with two or more groups defined by clinically meaningful endpoints, such as whether the patients did or did not develop metastatic disease, or did or did not respond to a particular therapy. The genetic expression patterns of these two groups can then be compared to determine if there is a potential biological basis for the clinical difference, and, if so, determine which genes or gene groups appear to be involved. It is important to recognize that identification of gene expression differences at this level does not mean that the genes in question caused the differential...

Therapeutic Implications Of Breast Cancer Subtypes

The discovery of molecular subclasses of breast cancer provides further evidence that the biological diversity of breast cancer denies a one-size-fits-all approach to therapy. Existing knowledge of the biology of breast cancer provides crude clues to therapy luminal cancers are generally hormone receptor-positive and appropriate for endocrine therapy the HER2+ ER- subtypes is HER2-driven and appropriate for HER2-targeted therapy such as trastuzumab. Beyond this, the power of gene expression analysis and subclassification of breast cancer to answer the questions of response to therapy is only beginning to be evaluated. Work in this area can be divided into three broad areas efforts to understand differences in response to therapy based on recognized therapeutic targets such as ER, PgR, and HER2 efforts to identify gene expression signatures that predict response or resistance to specific therapies and efforts to identify novel targets within breast cancer subtypes. Increasingly, ER,...

Studies of Hormone Therapies in Metastatic Breast Cancer

Several studies evaluated the predictive role of c-erb-B2 to hormonal therapies in metastatic breast cancer. Because women with metastatic breast cancer require effective therapy, randomized clinical trials with a control group are not available. However, one can assume that in the absence of treatment the response rate of the tumor will be nil. Then, with the use of any therapy, response rates and other outcomes can be compared between women with tumors that are c-erb-B2 positive vs those whose tumors are c-erb-B2 negative. Most studies that investigated tissue c-erb-B2 status using IHC in patients with metastatic breast cancer reported that overexpression of the marker was associated with relative resistance to tamoxifen. In addition to differences in patient population and methods of c-erb-B2 detection, the studies are mostly small and may have included women with hormone receptor-positive and -negative tumors who may have received one of several hormone therapies. In one large...

Alkylating Agent Based Combination Chemotherapy

Large Randomized Studies of Alkylating Agent-Based Combination Chemotherapy Large Randomized Studies of Alkylating Agent-Based Combination Chemotherapy Alkylating agent-based combination chemotherapy, particularly with the inclusion of an anthracycline, appear to be more toxic and does not offer a significant advantage in previously untreated patients with CLL compared with single-agent chlorambucil. Among patients with CLL who have relapsed or are refractory to therapy with chlorambucil, combination chemotherapy produces responses in about one-third. Keating et al. (19) obtained responses (complete and partial) in 26 of previously treated patients with the multiagent regimen POACH (cyclophosphamide, Adriamycin, cytosine-arabi-noside, vincristine, and prednisone) the median survival was 15 mo. Similarly, the M-2 protocol produced responses in 35 of previously treated patients, with a median survival of 15 mo (17). Thus, responses are attainable with alkylating agent-based combination...

Cytotoxic Chemotherapy

Effects of age on the pharmacology of cytotoxic chemotherapy Table 5. Effects of age on the pharmacology of cytotoxic chemotherapy change, but the peak concentration of these agents is increased and the risk of toxicity enhanced as a results of volume of distribution (Vd) alterations. The effects of Vd changes may be ameliorated by correction of anaemia, when this is present. Several studies have shown that anaemia is an independent risk factor for chemotherapy-induced myelodepression 28 , as many agents bind to red blood cells consequently, anaemia is associated with increased concentration of circulating free drug. A decline in the glomerular filtration rate (GFR) is almost universal with aging, and may lead to an increased half-life of cytotoxic compounds, such as carboplatin, methotrexate, and bleomycin, whose parent compounds are excreted through the kidneys, and drugs that give origin to active or toxic metabolites excreted from the kidneys. For example, 80 of the...

Immunosuppression And Chemotherapy

Inimunosuppressed patients have impaired host defenses as a result ol an underlying immunodeficiency or drug administration (primarily related to organ transplantation or cancer chemotherapy).Because chemotherapy is often cytotoxic to bone marrow, destruction of platelets and red and white blood cells results in thrombocytopenia, anemia, and leukopenia. Inimunosuppressed individuals are al greatly increased risk for Initec tion, and even minor periodontal infections can become life threatening if immune suppression is severe. Intraoral , bacterial, viral, and fungal infections may manifest. Patients receiving bone marrow transplantation require special attention because these patients receive very high-dose chemotherapy and are particular ) susceptible to dissemination of oral infections. Treatment in these patients should be directed toward the prevention of oral complications that could be life threatening. The greatest potential for infection occurs during periods of extreme...

NX Chin M J McElrath and H C Neu Chemotherapy 34318 1988

Hohl, C. Hub-schwerlen, H. Richter, and R. L. Then, Proceedings of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, 1994, Abstr. F-153. 716. C. B. Ziegler, Y. Yang, P. Fabio, D. A. Steinberg, W. Weiss, M. J. Wildey, and K. Bush, Proceedings of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, 1994, Abstr. C-54.

Combination Chemotherapy With Concurrent Thalidomide

Six cycles of therapy, 46 of newly diagnosed patients had either a CR or nCR, a rate comparable to that seen with HDC ASCS.34 It remains to be seen whether the time to disease progression will be as long as that typically expected from HDC ASCS. The regimen is clearly more toxic than DVd alone, requiring prophylactic antibiotics because of high rates of infection, particularly pneumonia, and also daily aspirin because of a high rate of DVTs.109 The latter complication is not wholly unexpected, given the higher rate of throm-botic complications seen with TD.68' 69 Investigators at the University of Arkansas have published their extensive experience using combination chemotherapy with thalidomide in both the up-front and relapsed setting (Table 83.3).110-112 As in the other trials discussed, an increased rate of DVT was observed with these combinations, particularly during concomitant anthracycline and thalidomide administration.111, 112 Based on the results of the two randomized...

Artificial Nutrition as an Adjunctive Therapy in Patients Receiving Chemotherapy or Radiation Therapy

Twenty-seven randomised controlled trials (RCT) assessing the impact of TPN on a total of 1050 patients were reviewed 19 studied TPN in patients receiving chemotherapy, three investigated cancer patients being treated with radiation therapy, and four were on patients undergoing bone marrow transplantation. Results showed that there was no apparent effect of TPN on mortality in the overall series, even if a single RCT in patients undergoing bone marrow transplantation 75 showed an increase of survival in the fed patients. There was, however, a poorer response to chemotherapy in particular (absolute risk difference -7 confidence intervals -12 , -1 ) in TPN patients.

Breast Cancer Grading Identification of the Genomic Grade

Pathologists have traditionally used histological grade to describe distinct breast cancer phenotypes whereas, grade I or well-differentiated tumors are composed of polarized groups of cells that form tubular or duct-like structures grade III or undifferentiated tumors are associated with a high mitotic activity, nuclear pleo-morphism, and no tubular formation grade II tumors display intermediate characteristics. In addition, high- and low-grade tumors have been correlated with the expression of different biological markers, and several groups have also reported that mitotic apoptotic activity is higher in high grade poorly differentiated tumors (21). Finally, the recent results regarding the molecular classification of breast cancer have strongly pointed to an association of histological grade with particular gene expression tumor profiles (4,5). chromosome 16 is lost in 65 of grade I tumors compared to only 16 in grade III tumors, implying that the majority of well differentiated...

Systemic Cancer Chemotherapy

Cancers originating from different organs of the body differ in their behaviour and in their response to treatments. Primary surgery and or radiotherapy to a localised cancer offer the best chance of cure for patients. Drug treatments in the past were mainly restricted to patients with disseminated, metastatic ('advanced') disease, where a systemic effect is required. Cytotoxic chemotherapy for advanced disease offers cure for only certain types of cancer, e.g. testicular cancers, Wilms tumour. Most often, chemotherapy may prolong life, although patients ultimately die of their disease. Most treatments currently available are associated with unwanted effects of varying degrees of severity. The risk of causing harm must be weighed against the potential to do good in each individual case. Chemotherapy depends on developing drugs that kill malignant cells or modify their growth and leave those of the host unharmed or, and more usually, harmed but capable of recovery. When there is...

Classes of cytotoxic chemotherapy drugs

Cytotoxic chemotherapy drugs exert their effect by inhibiting cell proliferation. All proliferating cells, whether normal and malignant, cycle through a series of phases of synthesis of DNA (S phase) mitosis (M phase) and rest (G phase). Noncycling cells are quiescent in G0 phase (Fig. 30.1). Cytotoxic drugs interfere with cell division at various points of the cell cycle, e.g. synthesis of nucleotides from purines and pyrimidines, of DNA and RNA, and interference with mitosis. They are potentially mutagenic. Such drugs ultimately induce cell death by the process of apoptosis.3'4 This is a process by which single cells are removed from the midst of living tissue by fragmentation into membrane-bound particles and phagocytosed by other cells, without disturbing its architecture or function, or eliciting an inflammatory response. The instructions for the response are built into the cell's genetic material, i.e. 'programmed cell death'.5 In general cytotoxics are most effective against...

TABLE 81 Visible Signs of Breast Cancer

Breast Cancer Skin Dimpling

As breast cancer advances, it causes fibrosis (scar tissue). Shortening of this fibrotic tissue produces retraction signs, including dimpling, changes in contour, and retraction or deviation of the nipple. Other causes of retraction include fat necrosis and mammary duct ectasia.

Could Activated Hedgehog Signaling Regulate Breast Cancer Stem Cells

If, in fact, activated hedgehog signaling regulates behavior of normal mammary epithelial stem cells, it is entirely possible that it might also influence the behavior of breast cancer-initiating cells or breast cancer stem cells. In their study of hedgehog regulation of normal mammary epithelial stem progenitor cell self-renewal, Liu and colleagues explored this possibility (Liu et al. 2006). With CD44+ CD24- low Lin cells isolated from a xenograft of a metastatic human breast cancer, the subpopulation shown previously to be tumorigenic in xenografts in NOD Scid mice, showed increased expression of Ptch1, Gli1, Gli2, and Bmi1 mRNAs relative to all other cells isolated from the same tumor, as well as from the bulk tumor. These data suggested that hedgehog signaling might be activated in the tumorigenic subpopulation of cancer cells. In addition to these data in cancer xenografts, overexpression of either Gli1 or Gli2 in normal mammosphere-initiating cells led not only to increased...

Age And Hemopoietic Complications Of Cytotoxic Chemotherapy

At this point it is legitimate to ask whether myelosuppression following cytotoxic chemotherapy becomes more prolonged and severe with age, as a consequence of progressive reduction in hemopoietic reserve and whether the risk of increased toxicity may be ameliorated, in order of preserving the full dose and the full benefits of chemotherapy. The risk and severity of myelotoxicity was not increased in patients aged 65-70 and older in at least six large clinical trials (Table 1)75-80. While these studies demonstrate that the risk of myelosuppression is not increased in all older individuals, they shed little light on the risks of chemotherapy in the general aged population. The percentage of patients aged 80 and older was negligible, and also patients aged 70 and Several other studies support increased risk of myelodepression among the elderly 29-32. The risk of neutropenia was increased for women 65 and older receiving adjuvant chemotherapy for breast cancer with doxorubicin and...

Use of Radioprotective Agents in Radiotherapy and Chemotherapy of Cancers

Use of radioprotective agents to augment the effects of either radiotherapy or chemotherapy of various types of cancer has been investigated for 30 years or more, but until recently little positive benefit was observed. It is now clear that selective concentrations of protective agents can be realized in normal tissues, and that tumors are protected to a lesser extent. Favorable timing schedules for administering protective agents and anticancer therapies have played a significant role in the moderate success so far realized with radio-protector adjuvant treatments. Differential distributions of MEA released from its phosphorothioate and thiosulfate in various tissues have been found (330) the phosphorothioate of MEA had a lower concentration in sarcoma M-l than in the organs cf mice (331).The phosphorothioate of MEA also diminished symptoms of radiation sickness in human patients undergoing radiation therapy for breast cancer (332). Also, in cancer patients,...

CerbB2 as a Predictive Factor for Response to Chemotherapy Conclusions

Review of randomized clinical trials suggests that c-erb-B2 may indeed be predictive of response to specific chemotherapies. It is also possible that c-erb-B2 is a surrogate marker that reflects a more aggressive tumor biology and correlates with other factors that may predict for response to chemotherapy (e.g., lack of hormone receptors and worse grade). Based on the available data, systemic chemotherapy recommendations should be made

Myelosuppressive Chemotherapy

Several methods to mobilize PBSC from an extra vascular location into circulation have been described. Myelosuppressive chemotherapy was the first method described for stem cell mobilization.14 During the recovery phase after myelosuppressive chemotherapy, there was a 14- to 100-fold increase in peripheral blood CFU-GM above the baseline. The extent of this increase is proportional to the severity and duration of the cytopenia. High-dose cyclophosphamide (CY) is the most commonly used regimen since it is active against most tumors. However, there are several disadvantages to chemotherapy mobilization, including the length of time required, toxicity, neutropenic fever and or sepsis, bleeding diathesis, and the unpredictable timing of apheresis. In addition, little or no increase in peripheral blood CFU-GM was observed in some patients who had received extensive prior therapy and patients with marrow involvement with tumor.15 With the introduction of hematopoietic growth factors, it is...

Chemotherapy Plus Growth Factors For Stem Cell Mobilization

Although chemotherapy alone can produce increases in progenitors in PB, multiple phase II studies have shown that the addition of growth factors such as G-CSF and GM-CSF to myelosuppressive chemotherapy enhances mobilization and allows for more progenitors to be collected with fewer apheresis procedures while reducing myelotoxicity. Siena et al.37 reported that after highdose CY, an approximately 30-fold expansion of CFU-GM numbers was observed. This increase was further magnified, to over 100 times control values, when GM-CSF was given to accelerate post-CY hematopoietic recovery. These precursors were both increased in number and enriched in the more immature forms. In addition, there was an increase of the most immature CD34+ CD33- progenitors to multipotent and unipotent colony-forming cells (CD34+ CD33+) in PB. In a randomized cross-over trial reported by Koc et al.,38 high-dose CY plus G-CSF results in mobilization of more progenitors than GM-CSF plus G-CSF when tested in the...

Highdose Therapy For Highrisk Breast Cancer Phase II studies

The use of high-dose therapy with, initially, BM and, later, Peripheral blood progenitor cell(s) (PBPC) rescue was first explored and reported by Peters et al.25 at Duke University and by Gianni et al.26 at Milan. Each reported results that appeared superior to outcomes after conventional-dose chemotherapy using similar patient selection criteria. Specifically, Peters et al. reported a 72 5-year EFS in a prospective phase II trial of high-dose cyclophosphamide cisplatin BCNU in patients with 10 or more positive axillary nodes. These results have stood the scrutiny of time, with 61 EFS rate at 11-year follow-up.27 Gianni et al.26 used a sequential high-dose single-agent regimen in this patient population. At a median follow-up of 4 years, the observed EFS rate was 57 .

Randomized trials in highrisk breast cancer

Rodenhuis et al.28 randomized 885 patients with four or more involved lymph nodes to receive four cycles of conventional-dose chemotherapy followed by one more cycle of conventional-dose chemotherapy or one cycle of HDC. At a median follow-up of 57 months, there was a trend for an EFS advantage in favor of high-dose therapy (65 vs 59 , P 0.09), with no significant OS differences. The EFS of those patients randomized to high-dose therapy who were actually transplanted appeared superior to those in the control arm (P 0.03). Prospectively planned subset analysis showed that highdose therapy improved EFS among patients with 10 or more involved nodes (68 vs 49 , P 0.05). 10 or more positive nodes to receive four conventional-dose chemotherapy cycles followed by one cycle of cyclophosphamide cisplatin BCNU or by one additional cycle of those drugs at intermediate doses with granulocyte colony-stimulating factor support. Twenty-five patients who relapsed on the intermediate-dose arm (15 )...

Micronutrients Breast Cancer

To reduce the chances of developing breast cancer To reduce the chances of developing breast cancer Higher intakes can sharplyre-duce risk of breast cancer41 Fig. 5.30 Vitamin C intake and risk of breast cancer. In 12 studies of diet and breast cancer, vitamin C intake had the most consistent and significant inverse association with breast cancer risk. The risk was nearly one-third lower with the highest intakes of vitamin C, compared with lower intakes. The mean intake of the lowest quintile was the current recommended dietary allowance for vitamin C. (Adapted from Howe GR, et al. J Natl Cancer Inst. 1990 82 561)

S100A4 in Human Breast Cancer

Pedrocchi et al. (1994) first described the importance of S100A4 in breast cancer cell lines. Recently, Albertazzi et al. (1998b) have published a detailed study of S100A4 expression, not only in relation to the degree of aggressiveness of the disease, but also as to how it relates to other clinical markers such as the status of oestrogen and progesterone receptors and the degree of tumour differentiation. With this background, Albertazzi et al. (1998b) focused on the expression of S100A4 (h-mts1) as well as that of nm23 in human breast cancer. This was with a view to determining their individual abilities to serve as markers, and further to check whether a combination of the status of their expressions might enable one to obtain a more accurate assessment of the metastatic potential of the tumours. A further indication that S100A4 expression status might be related to the clinical aggressiveness of the tumour is provided by another line of evidence. Albertazzi et al. (1998b) have...

Relationship Between S100A4 S100A4v and nm23 Expression to Nodal Spread of Breast Cancer

The clinical data, together with the state of expression of steroid receptors and the expression levels of S100A4 and nm23 genes, were analysed using artificial neural networks (ANNs) for accuracy of prediction of nodal spread of the carcinomas. Naguib et al. (1997) previously had demonstrated that ANNs could be used to predict nodal involvement in breast cancer. In that study several established as well as experimental cancer markers had been analysed, and ANN techniques were found to be capable of dissecting and identifying the most powerful predictors of nodal metastasis. The ANN analyses, provided by Albertazzi et al. (1998b) as well as by Naguib et al. (1998), have also supported the conclusion that, overall, S100A4 expression is associated with and indicative of more aggressive forms of the disease. The investigation of Albertazzi et al. (1998b) does emphasise the view that when complemented with nm23, S100A4 could provide a powerful marker for predicting breast cancer...

The History Of Cancer Chemotherapy

The term chemotherapy refers to the treatment of cancer or other malignant diseases by using specific drugs that selectively destroy growing cells. Prior to the advent of chemotherapy, two main modalities were used in the treatment of cancer surgery and radiation. Both options, although effective for many types of cancer, are localized forms of therapy. Chemotherapy provided the first systemic form of treatment, using the bloodstream as a means of disseminating drug to both the tumor site as well as areas of metastasis. Additionally, this provided a major breakthrough in the treatment of hematologic malignancies, such as leukemia and lymphoma, which had previously been virtually untreatable with surgery or radiation. The advent of modern chemotherapy originated during World War I, with the observation that soldiers who had been exposed to mustard gas, or sulfur mustard, experienced significant decreases in their white blood cell counts, specifically their lymphocytes. Krumbaar first...

Chemotherapy Regimens

Regimens that often include agents belonging to separate classes of cytotoxic chemotherapy described in this chapter. Doses and scheduling have been determined over many years of experience and through use of evidence-based medicine through trial and error (experiments based on the inherently empirical way), classical cytotoxic agents have been developed (i.e., without direct reference to molecular mechanisms). Many cytotoxic chemotherapeutic agents are given via intravenous infusions. With regard to optimizing efficacy and reducing side effects, scheduling of administration can have significant effects. This aspect of clinical cancer trials is less widely appreciated than the effects of dose. The empirical effects of scheduling make developing combination regimens particularly challenging because complexities can mount exponentially with the addition of novel agents to an established regimen. To optimize ratios of efficacy to adverse effects (therapeutic window), historical...

Initial Use Of Aromatase Inhibitors In Metastatic Breast Cancer

Third-generation AIs were first evaluated in the management of metastatic breast cancer. Initial clinical trials, comparing anastrozole, letrozole, or exemestane with megesterol acetate as second-line therapy, showed that the AIs had equivalent or improved efficacy, with a favorable side effect profile (8-11). A meta-analysis of data from these studies demonstrated a survival advantage for the AIs, with a relative risk of death of 0.79 (95 CI, 0.69-0.91) (12). In the first-line metastatic setting, several large randomized trials have compared the various AIs with tamoxifen. A combined analysis of two studies comparing anastrozole with tamoxifen showed a significantly improved time to progression (TTP) among the women who received anastrozole, with less frequent thromboembolic events and vaginal bleeding (13-15). A mature survival analysis at 44 months showed no advantage of anastrozole over tamoxifen but confirmed the favorable tolerability profiles of both agents (16). First-line...

Expression of the egf family in breast cancer

Breast cancer cells are also able to synthesize EGF. In fact, EGF mRNA has been detected in a majority of human breast cancer cell lines, with the estrogen-receptor (ER)-positive breast cancer cell lines T47-D and ZR-75-1 showing higher levels of expression as compared to the ER-negative breast cancer cell lines (7). Progestins were found to specifically increase the levels of EGF mRNA in T47-D cells, while 17P-estradiol had no effect on EGF mRNA levels in this cell line (8,9). EGF mRNA was also detected in 83 of human breast tumors and in addition EGF protein has been detected in 15-30 of human primary invasive breast carcinomas (8,9). EGF is a crucial regulator of growth and differentiation in the mouse mammary gland, especially during pregnancy and lactation and during the spontaneous formation of mammary tumors (8,9). Transforming growth factor-a (TGF-a) was first identified in the culture media of virus-transformed cells and of human tumors cell. It shares 42...

Trastuzumab In Metastatic Breast Cancer Monotherapy

Single-agent trastuzumab was tested in phase I clinical trials since 1992. Subsequent phase II trials in patients pretreated with chemotherapy or without prior chemotherapy showed response rates of 12 to 26 and median time to progression from 3 to 5.1 months (9-12). administration (loading dose of 8 mg kg IV followed by 6 mg kg every 21 days) is active, tolerable, and increases patient convenience. However, as expected, mean trough trastuzumab concentrations were lower and peak levels were higher with three-weekly trastuzumab compared with weekly treatments (12,13). As it may take several weeks to achieve steady state levels with the every week regimen, it is advisable to start with the weekly approach especially in patients with symptomatic breast cancer. Regulatory approval of the every three weeks regimen has not been granted in the United States.

Breast Cancer Research Charity Science Activism and the Quest for Knowledge

Moving outside the clinical arena and the specific dynamic between patients and practitioners, the second half of this book examines the knowledge and technology associated with breast cancer genes in relation to a very different science society interface. Informed by the idea that the viability of scientific research is inseparable from social or institutional organisations and relations (Fujimura and Clarke 1992) and their particular 'scientific-body language' (Wynne 1991), Chapters 5-7 explore the dynamic interface between gendered health activism and the BRCA genes in the context of a breast cancer research charity in the UK. In the UK the character of this 'war' on cancer, through scientific research, and the nature of public support in fighting it, has been and continues to be refracted and forged through the history and social institution of charity. As this chapter illustrates, it is an institutional context for cancer research which has wide-ranging consequences for the kinds...

Human Epidermal Growth Factor Receptor 2 And Response To Chemotherapy

Women whose tumors overexpress HER2 appear to be relatively resistant to alky-lating agent-based adjuvant therapy and might derive greater benefit from anthra-cycline-based adjuvant therapy (42). Although the available data are far from conclusive, it is reasonable to assess HER2 status on all primary breast tumors at the time of diagnosis. Anthracycline-based therapy may be better in women with HER2-positive breast cancers in the adjuvant setting, unless such therapy is contra-indicated, or in women who received prior anthracycline therapy for a previous breast cancer (43). It has also been hypothesized that HER2 is to be viewed as a marker for the real anthracycline target, topoisomerase II a (TOP2A). The TOP2A gene is located next to the HER2 gene on chromosome 17q12-q21. In vitro studies have shown that amplification of TOP2A leads to overexpression of the topoisomerase II a and increased sensitivity to anthracyclines (44). In a retrospective analysis of topoi-somerase II a...

First Line and Refractory Metastatic Breast Cancer

Combination chemotherapy with trastuzumab is now standard of care for first line treatment of women with ErbB2-overexpressing breast cancer (51). With the potential benefits of small molecules being examined, there are a number of ongoing trials that will evaluate for potential increased efficacy, response to treatment when lapatinib is used alone, added to chemotherapy or hormonal therapy. As first line, EGF20009 is comparing two schedules of lapatinib alone in patients that have not had any prior therapy for their MBC and whose tumors were all ErbB2 FISH amplified. In that trial, lapatinib as a single agent demonstrated confirmed PRs in 5 of 13 patients (38 ), and stable disease greater than eight weeks in six of 13 patients (46 ) (52). This trial was recently updated by George Sledge at the San Antonio Breast Cancer Symposium (SABCS) in December of 2005. An interim analysis of the first 40 patients randomized to either 500 mg twice daily versus 1500 mg daily of lapatinib was...

Early Stage Breast Cancer

Given the high amounts of activity seen with lapatinib, the next step will be to incorporate its use in the treatment of early-stage breast cancer (ESBC). Although little data is available with regards to its long-term use, minimal to no cardiac and other toxicities have been seen with its use in MBC. Two large studies are being planned in the adjuvant therapy setting of ErbB2 overexpressing breast cancer. Both studies will incorporate standard anthracycline-taxane based chemotherapy in combination with either trastuzumab alone, lapatinib alone, or the combination of trastuzumab and lapatinib. Enrollment to both studies is scheduled to begin sometime in late 2006.

Monitoring Her2neu Ecd Levels In Mbc Patients Treated With Hormone Or Chemotherapy

In this section (summarized in Table 5), we reviewed 16 references (14 related to MBC and 4 related to PBC) representing 1148 breast cancer patients. The 1148 patients were divided into 499 MBC patients and 649 primary breast cancer patients. In these studies serial or longitudinal changes in serum HER2 neu ECD values were compared to the clinical course of disease in women with MBC. The clinical course of a patient's disease (defined as progression, response or stable disease) was determined by monitoring results of clinical tests such as X-ray films or CT scans. Patients were then classified as to whether changes in serum HER2 neu levels did or did not correspond to the clinical course of disease. For example, it was determined whether the serum value increased with progression or decreased with response to therapy to determine correspondence. In a report by Cook et al. (35), longitudinal monitoring was performed on 103 stage IV breast cancer patients who were being treated with...

Gefitinib in Breast Cancer

In the clinical setting, phase I trials of gefitinib have been generally well tolerated with the majority of events being that of grade 1 and 2 gastrointestinal or skin toxicities (64-67). Anti-tumor activity was demonstrated in a broad range of tumors including the observation of prolonged stable disease in patients with breast cancer. A phase II study by Albain et al. (68) evaluated the efficacy and safety of gefi-tinib in patients with metastatic breast cancer who had progressed on previous hormonal and cytotoxic agents. Gefitinib was delivered at 500mg day until disease progression or toxicity. The primary objective of the study was to evaluate the clinical benefit rate (defined as complete response plus partial response plus stable disease greater than or equal to six months). Sixty-three patients were enrolled. The median age of the patients was 52 years (range 34-81). Patient characteristics included 27 (43 ) patients with hormone receptor-positive disease and 17 patients (27 )...

Monitoring metastatic breast cancer patients treated with herceptinbased therapies

In studies presented in Table 5, women with MBC being treated with Herceptin and various chemotherapies (n 110) were monitored for changes in HER2 neu ECD levels. HER2 neu ECD levels were determined prior to treatment and then serially thereafter. Previous studies reported by Payne et al. have shown that Herceptin does not interfere with measuring ECD levels in the HER2 neu assay used in all three of these studies described below (74). In an initial report by Schwartz et al., in 2000, it was suggested that changes in serum HER2 neu during Herceptin-based therapy might parallel the clinical course of disease however, there were too few patients in the report to make a valid conclusion (65). In a report by Schoendorf et al. (64), 23 MBC patients treated with Herceptin and chemotherapy (for a median time of 13 mo, with a range of 4-22) were monitored serially for the change in serum HER2 neu ECD. The changes in HER2 neu ECD level were then evaluated in conjunction with response or lack...

Monotherapy Of Farnesyl Transferase Inhibitors In Breast Cancer And Other Diseases

Table 1 summarizes the results of a phase I-II trial of tipifarnib monotherapy in patients with ER-positive metastatic breast cancer who have failed second-line endocrine therapy, or with ER-negative disease (37). Seventy-six patients received either 400 mg (N 6) or 300 mg (N 35) twice daily on a continuous schedule, or 300 mg BID using a 3-week on, 1-week off intermittent schedule (N 35). The clinical benefit rate (partial response or stable for at least 24 weeks) was comparable in the continuous (25 ) and intermittent schedules (23 ). There was no statistical association between response to tipifarnib and tumor characteristics, such as the status of ER, HER2, and mutation in three ras genes. Sites of response occurred in liver, lung, pleura, lymph nodes, breast, and skin nodules. There was significantly less toxicity associated with the intermittent compared with the continuous schedule, including neutropenia, anemia, thrombocytopenia, and neurotoxicity. Although there was high...

Combining Farnesyl Transferase Inhibitors With Hormonal Therapy In Breast Cancer

The FTI tipifarnib has been evaluated in combination with the selective estrogen receptor modulators (i.e., tamoxifen), aromatase inhibitors (i.e., letrozole), and selective estrogen receptor down regulators (i.e., fulvestrant). Lebowitz et al. (71) reported the results of a phase I and pharmacokinetic trial evaluating tipifarnib in combination with tamoxifen in 12 patients with ER-positive metastatic breast cancer who previously had disease progression on hormonal therapy. Patients received tipifarnib (200 or 300 mg twice daily for 21 of 28 days) plus tamoxifen (20 mg once daily beginning one week of tipifarnib monotherapy). Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash and fatigue, and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen....

Combining Farnesyl Transferase Inhibitors With Cytotoxic Therapy In Breast Cancer And Other Diseases

Sparano et al. (39) performed a phase I trial of tipifarnib plus doxorubicin and cyclophosphamide (AC) in patients with metastatic breast cancer, followed by a phase II trial of four cycles of the tipifarnib-AC combination as preoperative therapy in patients with locally advanced breast cancer. The primary endpoint for the phase II trial was pathological complete response (pCR) in the breast at the time of definitive surgery pCR has been used as a surrogate marker for identifying active combinations because it has been shown to predict improved disease-free survival in several prospective trials in patients with operable breast cancer (80,81) and retrospective studies in patients with locally advanced breast cancer (82). The objective of the study was to determine whether the addition of tipifarnib to standard AC chemotherapy would increase the breast pCR rate to at least 25 , a result comparable to administering sequential docetaxel following AC for a total of eight cycles (81)....

Approach to Individual Diseases 221 Breast Cancer

Of the screening examinations promoted for early detection of breast cancer (mammography, clinical examination of the breast and breast self-examination) only screening mammography has proved effective in randomized clinical trials (level 1 evidence) 125-130. With one exception 126, all these trials, reported a 20-30 reduction in breast cancer mortality in the screened population. Screening mammography has been the object of a recent controversy. A meta-analysis of randomized trials claimed that the six positive trials were fraught by so many biases to make the results unreliable, and only the two negative studies were free of bias 131. This position has not found general acceptance however, because one of the negative studies, the Malmo trial, turned positive at the last analysis 132, and the other negative study, the Canadian trial, was criticized because it had used single view mammography, that appears less sensitive 125, 126. The unbalanced randomization in the Edinburgh trial,...

Clinical Studies In Patients With Metastatic Breast Cancer Phase 2 Study

Because chemotherapy is typically given at the highest tolerated dose, the maximum tolerated dose achieved in the phase 1 trial (300 mg m2) was chosen for further study in a phase 2, multicenter study (11). This trial included 63 women with histologically confirmed, measurable disease who had not received taxane therapy in the past six months. These women received a median of six cycles of nab-paclitaxel 300 mg m2 by intravenous infusion over 30 minutes every three weeks without antihistamine or corticosteroid premedication. Treatment was generally well tolerated with an acceptable level of dose interruptions and delays (Table 1). Dose reductions were primarily due to hematologic toxicities, and most delays were from four to eight days. TABLE 1 Summary of Dose Interruptions, Dose Delays, and Safety in a Phase 2 Trial of nab-Paclitaxel in 63 Patients with Metastatic Breast Cancer

Being scientists of breast cancer genetics

Talking about communicating their work to fundraisers, as well as participating on the tours, the discussions undertaken with a group of scientists working at the centre, revealed a dense nexus of reciprocities in their relationship with fundraisers, the charity they were funded by and the kind of science being pursued.3 The second section of this chapter explores the uneven 'benefits and burdens' for those carrying out basic science genetic research, who are funded by a specific disease-focused research charity with its own unique historical, and institutional links to a culture of gendered breast cancer activism.

Evidence Supporting The Role Of Angiogenesis In Breast Cancer

Angiogenesis has been shown to be critical in the growth and development of many solid tumors, including breast cancer (3). Many tumors also rely on this process for malignant transformation and the development of distant metastases (4). Transla-tional work has confirmed these mechanisms in breast cancer, lending merit to the pursuit of antiangiogenesis targets in the treatment of this disease. Both hyper-plastic murine breast papillomas and normal breast lobules develop new blood vessels when adjacent to malignant breast tissue (5,6). Studies such as these suggest that angiogenesis may in fact precede the transformation from mammary hyperplasia to malignancy. Further support for the role of angiogenesis in breast cancer has been shown in the correlative studies linking micro-vessel density (MVD) and the risk of malignant transformation. Fibrocystic lesions with the highest MVD have an increased risk for the development of invasive breast cancers (7). High MVD has also been linked to...

Detection of Occult Metastases in the Bone Marrow in Patients with Early Stage Breast Cancer Clinical Significance

The presence of OMBM has been correlated with pathologic Tumor-Node-Metastasis (TNM) stage in breast cancer. Several other investigators have obtained similar results. In the original study from the Ludwig Institute (11), the presence of OMBM was correlated with the tumor stage (p 0.05), and vascular invasion (p < 0.01), both of which are known predictors of poor prognosis. While the presence of OMBM appears to be correlated with known features of disease progression, the ultimate utility of this test will be determined by whether it can predict breast cancer recurrence. Several studies now show that, in fact, the presence of occult metastases in the bone marrow identifies a population of patients at high risk for recurrence (Table 1) (14,71-76). Our own studies (14) have revealed that the presence of occult metastases in the bone marrow significantly predicts recurrence the 2-yr recurrence rate for patients with no evidence of OMBM was 3 compared with 33 for patients with...

Bevacizumab and Breast Cancer

Following initial phase I trials evaluating dosing and tolerability in a variety of advanced solid tumors, investigators looked at the safety and efficacy of single agent bevacizumab in a phase II trial (33). In this study, 75 women with previously treated, metastatic breast cancer (70 receiving two or more prior chemotherapy regimens) were assigned to receive single-agent bevacizumab at escalating doses starting at 3 mg kg IV every other week, up to 20 mg kg every other week. The overall response rate in this pretreated population was 9.3 (confirmed response rate 6.7 ), with a median duration of confirmed response of 5.5 months, and a reported 17 of patients with stable disease or better after five months of therapy. The drug was well tolerated at all doses, with increased incidence of headache, nausea, and vomiting at the 20 mg kg dose. The most substantial toxicity was hypertension (seen in 23 of participants, 18.6 requiring treatment) and proteinuria (1+ in 12.5 , 2+ in 2.7 , and...

On The Applied Sidemammacaredetection And Prevention Of Breast Cancer

About 180,000 American women develop breast cancer each year. The disease kills an additional 46,000 women. Every women is a potential victim and about 12 of women will develop breast cancer at some time in their lives. In addition to loss of life, victims of breast cancer often undergo disfiguring surgery that may physically and emotionally disable them. Early detection of a malignant tumor in the breast is a major weapon in the fight against breast cancer. At present, doctors do not know how to prevent breast cancer, but early detection significantly improves a woman's chances of survival. Importantly, the victims of the disease are almost always the first ones to detect the tumor. In most cases, however, women only detect the tumor after the cancer has reached an advanced stage. Regular and proficient self-examination by young women could substantially improve the detection of small tumors. Early detection would dramatically increase survival and lower the likelihood of disfiguring...

Clinical Significance of OMLN in Patients with Breast Cancer

Investigators from the Ludwig Institute and International Breast Cancer study group have performed a definitive study of the importance of occult lymph node metastases in patients with node-negative breast cancer (87). They examined serial sections of 921 node-negative breast cancer patients by routine histological methods. Nine percent of these patients were found to have OMLN these patients had a poorer disease-free (p 0.003) and overall survival (p 0.002) after 5 yr median follow-up, compared with patients whose nodes remained negative after serial sectioning. Six-year median follow-up data give even more conclusive evidence of the prognostic significance of occult lymph node metastases. Another large-scale study was performed (88). These investigators studied the lymph nodes from 1121 patients with primary operable breast cancer, by serial macroscopic sectioning they found single OMLN in 120 patients. A significant difference in recurrence (p 0.005) and survival (p 0.04) was found...

The Enrolment of Patients Visibility Voice and Breast Cancer Activism

In total 17 women were interviewed for this component of the research. All were 'unaffected' women (i.e. they did not and had not had breast cancer), most were between 30 and 45 years old and were presumed to be at 'moderate risk' on the basis of their referral letter. A feature of breast cancer referrals noted by GPs more generally (Ruston 2004). The forms used asked for information about the patient themselves, the patient's sister(s) mother's brother(s) father father(s) sister(s) father's brother'(s) grandchildren grand-father and grandmother. Details requested include name, date of birth, date of death (if a relative has died), where cancer was diagnosed, the site of the cancer and when it was diagnosed.

Epigenetics and Breast Cancer Progression

In breast cancer, multiple genes are methylated compared to noncancerous tissue. DNA methylation, acquired over time, leads to silencing of genes that are critical in several pathways. For example, genes involved in growth (estrogen receptor, progesterone receptor) evasion of apoptosis (HOXA5, DAPK, Twist), tissue invasion and metastasis (E-cadherin), and limitless replicative potential (cyclin D2, p16, BRCA1, GSTP1,14.3.3 sigma, and RAR-beta) can be methylated in breast cancers (7). The prevalence of methylation in specific genes in normal and malignant breast tissue has been evaluated. Some investigations have focused on a single candidate gene, whereas others evaluated methylation status of several genes. Using a panel of seven genes with the MSP assay in a variety of breast cancers, investigators have demonstrated that virtually all invasive breast carcinomas examined contained at least one hypermethylated gene, 80 contained two, and 60 contained three or more methylated genes...

Inhibition Of Dna Methylation And Histone Acetylation In Breast Cancer

Promoter methylation has been identified in several key genes that are important in breast cancer initiation and progression. Among others, p16, retinoic acid receptor, BRCA1, APC, E-cadherin, GSTP1, and RASSF1A are frequently methylated. Several HDAC inhibitors and DNMT inhibitors have been investigated in preclinical models in breast cancer and are reviewed subsequently however, the clinical experience is limited. Preclinical studies suggest that agents that modulate epige-netic changes may have single agent activity or may have synergy in combination with standard treatments.

Diviners and Pastoral Keepers Working in Clinical Breast Cancer Genetics

There are a number of different models for calculating breast cancer risk, some of which include other lifestyle 'risk factors' (e.g. Gail et al. 1989) however, the one used in the cancer genetic clinics was generally based solely on a person's family history (e.g. Claus et al. 1994). 2. Significantly there were no designated 'genetic counsellors' for those at risk of breast cancer in either of the cancer genetic clinics where I carried out research. That is to say nearly all staff I encountered had moved into the field of cancer genetics from a background in clinical training.

Prevalence Of Circulating Her2neu Levels In Breast Cancer

We reviewed a total of 55 publications from which data on the prevalence (7,8,22-73) of elevated levels of circulating HER2 neu could be extracted. The data are summarized in Fig. 2 and represent circulating HER2 neu ECD measurements in more than 6500 patients with breast cancer. A review of 24 references used to evaluate ECD levels in primary breast cancer showed that approx 18.5 of the 1923 patients had circulating HER2 neu ECD levels that were above the control cutoff described in each publication. In contrast, a review of 45 references and 4622 patients with metastatic breast cancer (MBC) showed that 43 of the patients had circulating HER2 neu ECD values above the normal cutoff for the control group. In 15 of the 45 publications ECD levels were elevated above the control group in over 50 of the patients studied. It is interesting to note that the data in Fig. 2 came from essentially six different assays. The automated Immuno-1 HER2 neu test (manufactured by Bayer Health Care,...

Genetic And Environmental Associations With Breast Cancer Subtypes

Much work has gone into identifying genetic and environmental risk factors for breast cancer. Based on the recognition that breast cancer is more than one disease, it is possible that different risk factors may contribute to the development of different types of breast cancer. One of the clearest examples of this phenomenon is the predisposition for basal-like breast cancers among carriers of BRCA1 genetic mutations. Patients with BRCA1 mutations are at high (up to 80 ) lifetime risk for developing breast cancer (15). It has long been known that breast cancer arising in BRCA1 mutation carriers possess certain characteristics including ER-negativity, HER2-negativity, and certain histological characteristics (16). It has also become clear that when patients with inherited BRCA1 mutations develop breast cancer, it is virtually always basal-like (8,17-19). The reason for this segregation has not been determined, however, sporadic basal-like breast cancers also may have decreased...

Metronomic Chemotherapy

The basis of several preclinical studies, the notion of metronomic chemotherapy as an antiangiogenic strategy was proposed (58), and the idea has received renewed interest in light of the success of other angiogenesis inhibitors in the treatment of cancer. Metronomics is based on the premise that continuous delivery of low-dose cytotoxic agents without a prolonged drug-free interval will selectively inhibit proliferating endothelial cells in the tumor, thus disrupting the blood supply and arresting malignant growth (59). In addition, this technique has also been shown to decrease circulating endothelial progenitor cells (CEPs) that would otherwise be incorporated into forming tumor vasculature (60). There are several potential advantages to this strategy over the more traditional method of administering higher dose cytotoxic regimens (34). This strategy reduces treatment related toxicity as drug efficacy will not require administering the maximally-tolerated dose of a single agent in...

Physiological Basis of Breast Cancer Prevention

The above-described epidemiological observations indicating that pregnancy significantly reduces the lifetime risk of developing breast cancer provide a window of opportunity for learning how and why this physiological condition exerts such a protective effect. Due to the complexity of the carcinogenic process, this event does not explain all the aspects of this complex disease nevertheless, data obtained in experimental models have served as a blue print for developing a new paradigm in breast cancer prevention (I.H. Russo and J. Russo 1993, 1994, 1996 I.H. Russo et al. 1990a, b J. Russo et al. 1977 Srivastava et al. 1998 Mgbonyebi et al. 1996 Tahin et al. 1996 J. Russo and I.H. Russo 2000 Alvarado et al. 1993, 1994). Our studies have unraveled the biological principle underlying the protection conferred by an early first full-term pregnancy, demonstrating experimentally that it induces in the breast the expression of a specific signature in response to the differentiation of this...

The Role of Breast Architecture and the Pathogenesis of Breast Cancer

Stage of development of the mammary parenchyma, the Lob 1. This observation is supported by comparative studies of normal and cancer-bearing breasts obtained at autopsy. It was found that the nontumoral parenchyma in cancer-associated breasts contained a significantly higher number of hyperplastic terminal ducts, atypical Lob 1 and ductal carcinomas in situ originated in Lob 1 than those breasts of women free of breast cancer. These observations indicate that the Lob 1 is affected by preneoplastic as well as by neoplastic processes (J. Russo and I.H. Russo 1998 J. Russo et al. 1994, 2000 J. Russo and I.H. Russo 1994, 2004 Vorherr 1974). The finding that the Lob 1, which are undifferentiated structures, cause the most aggressive neoplasm, acquires relevance in light of the fact that these structures are more numerous in the breast of nulliparous women, who are in turn at a higher risk of de veloping breast cancer. The Lob 1 found in the breast of nulliparous women never went through...

Expression of the egfr family in breast cancer

The EGFR family is involved in the regulation of mammary growth and differentiation. The female mammary gland undergoes extensive postnatal development under the influence of systemic hormones, including EGF family ligands and their cognate receptors. All four erb-B family receptors are expressed in mammary glands of adult females, but the EGFR and c-erb-B2 are preferentially expressed in young females (17-19). The first postnatal episode of mammary development occurs at puberty, and leads to elongation and branching of the mammary ducts to extend throughout the fatty mesenchyme. EGFR and c-erb-B2 are present both in the stroma and the epithelium and are tyrosine phosphorylated, which is indicative of signaling activity (18,19). The EGFR is important at puberty, because expression of dominant-negative EGFR impairs ductal morphogenesis (20). The second wave of activation of erbB family receptors occurs in pregnancy (18,19). Dominant-negative c-erb-B2 and c-erb-B4 transgenes interfere...

Established singleagent oral chemotherapy

In patients who have CMML with a significant myelo-proliferative component, high WBC count, or organomegaly, treatment with single-agent chemotherapy has been the standard of care. Oral agents such as busulfan, 6-mercaptopurine, hydroxyurea, and oral etoposide have been used empirically with some success, but a prospective randomized study conclusively determined the superiority of hydroxyurea over etopo-side in terms of overall survival in patients with mostly advanced proliferative disease (i.e., splenomegaly, mild thrombocytopenia, and increased bone marrow blasts) 24 months for hydroxyurea versus 9 months for etoposide.10 This is the only prospective randomized study to date that has compared two treatment regimens in patients with CMML. Although neither regimen induced complete remission (CR) or affected the natural history of the disease, the results supported the idea of using hydroxyurea plus supportive care as the standard-of-care arm in any future randomized trials. No...

Chemotherapy In Combination With Wbxrt

Chemotherapy in combination with WBXRT, or combined modality therapy, has been used to treat PCNSL for over two decades. Initially, chemotherapy regimens used to treat systemic NHL were employed. Systemic administration of CHOP or CHOD (with dexametha-sone), either before or after WBXRT, has been studied in two phase II and one randomized phase III trial.26 38 39 In the phase II, trials the reported median survivals of 10 and 13 months were no better than historical controls using WBXRT alone, and were associated with high toxicity and a 15 mortality. The randomized trial of WBXRT followed by CHOP or no further treatment showed no difference in failure-free or OS between the two arms, although the study was terminated early due to poor accrual. These data demonstrate that there is no role for CHOP-type therapy in the treatment of PCNSL. The BBB is a unique obstacle to the successful treatment of brain tumors because high-molecular-weight or polar compounds cannot cross an intact BBB....

Upa and pai1 in breast cancer

Several groups have related levels of both uPA and PAI-1 in breast cancers to tumor and patient characteristics. In a pooled analysis of 8175 primary breast cancers, uPA levels were not significantly associated with patient age, menopausal status, or lymph node status. Levels however, were positively correlated with tumor grade, negatively with hormone receptors and higher in pT2 and pT4 tumors than pT1 and pT3 samples (30). Conflicting reports have been published on the cell type(s) expressing uPA and PAI-1 in breast cancer. Early work using immunohistochemistry suggested that uPA protein was mostly located in malignant cells (15,31,32). Christensen et al. (33), however, reported that uPA immunostaining was present in a number of different cell types, being most intense in macrophages and mast cells but showing moderate intensity in epithelial, fibro- Factors Shown to Regulate Expression of uPA Levels in Cell Lines Derived from Breast Cancers Factors Shown to Regulate Expression of...

Bone Marrow Micrometastasis In Breast Cancer

Ninety-five percent of patients who present with breast cancer apparently have local disease without evidence of distant metastatic spread on pretreatment staging by conventional methods (1). Despite improvements in surgical techniques, radiotherapy and drug treatment, one third of all patients relapse and die within ten years, and this proportion has not changed significantly. It is accepted that this group of patients has micrometastatic disease at presentation that cannot be detected by current standard methods (2-5). Therefore, indirect prognostic criteria, such as lymph node metastasis, tumor size, and the presence of tumor emboli in lymphatic or vascular spaces associated with the primary tumor, are used in an attempt to identify a group of patients at high risk of developing distant metastases, who would perhaps benefit from adjuvant systemic treatment. Though axillary lymph node status in breast cancer patients remains the single most important predictor of outcomes, our...

Special considerations for chemotherapy in cNS tumors

Drugs that penetrate the BBB have the capacity to produce neurotoxicity as a dose-limiting side effect, which may compound other treatment-related neurotoxicities (e.g., methotrexate and RT). The use of chemotherapy, especially in high doses, in patients with CNS tumors carries additional hazards linked primarily to the infectious risks of ventricular- or lumbar-peritoneal shunts, central venous lines, and frequent episodes of fever, which cause difficulties in discriminating between shunt infections and febrile neutropenia. A recent publication analyzing tolerance of chemotherapy in patients with medulloblastoma showed that patients age 10-20 years were more likely to suffer toxicity and require modifications in treatment than individuals 5-10 years of age 102 . These data suggest that adolescent and young adult patients would benefit from a modification of the aggressive chemotherapy regimens often utilized in children.

Adverse Effects Of Chemotherapy And Rheumatic Symptoms

Tamoxifen is widely used in the therapy of breast cancer patients and may be associated with rheumatic symptoms. For example, in Warner et al.'s 9 report, 9 out of the 23 patients developed rheumatic symptoms shortly after starting tamoxifen. Furthermore, 3 patients developed an inflammatory symmetrical polyarthritis between 2 weeks and 1 year of commencing tamoxifen which resolved on tamoxifen withdrawal 16 . The mechanism by which tamoxifen may induce rheumatic symptoms is unclear but could be related to its antioestrogenic effects. However, against this argument is that raloxifene, a newly licensed selective oestrogen receptor modulator for postmenopausal women, has not so far been associated with these symptoms 17 . Many combination chemotherapy regimens include corticosteroids, often in high doses and osteoporotic vertebral and hip fractures may occur which may be mistaken for pathological fractures from metastatic deposits. Similarly, steroid induced myopathies may initially be...

Prenyl Protein Protease Is a New Chemotherapy

The protein called p21ras or simply Ras is a small GTP-binding protein involved in cell signaling pathways that regulate growth and cell division. Mutant forms of Ras cause uncontrolled cell growth, and Ras mutations are involved in one third of all human cancers. Because the signaling activity of Ras is dependent on prenylation, the prenylation reaction itself, as well as the prote-olysis of the -AAX motif and the methylation of the prenylated Cys residue, have been considered targets for development of new chemotherapy strategies. Mutations that inhibit prenyl transferases cause defective growth or death of cells, raising questions about the usefulness of prenyl transferase inhibitors in chemotherapy. However, Victor Boyartchuk and his colleagues at the University of California, Berkeley, and Acacia Biosciences have shown that the protease that cleaves the -AAX motif from Ras following the prenylation reaction may be a better chemotherapeutic target. They have identified two genes...

Breast Cancer Classification Based On Gene Expression Profiling

By detailing the expression levels of thousands of genes simultaneously from tumor cells and their surrounding microenvironment, gene expression profiles have provided molecular portraits of breast cancer, distinguished by extensive differences in gene expression in breast cancer samples that were once considered homogeneous by classical diagnostic methods (1-5) (Table 1). Using cDNA microarrays, the Stanford researchers (1,2) were the first to identify, in a series of 42 and 78 patient samples, respectively, a new molecular classification of breast cancer based on the expression levels of nearly 500 genes, called the intrinsic gene subset because they were found to be highly variable between different patient samples and less variable between samples taken from the same patient before and after treatment. This new classification consisted of at least five distinct subtypes of tumors the basal-like, the erbB2, and the normal-like subgroups, which were mostly estrogen receptor...

Rationale for cytotoxic chemotherapy

Cytotoxic chemotherapy began with sulphur mustards (oily vesicant liquids) which had been developed and used as chemical weapons in World War I (1914-18). Amongst their actions depression of haemopoiesis and of lymphoid tissues were observed. Preparations for World War II (1939 5) included research to increase the potency and toxicity ('efficacy') of these odious substances. Substitution of a nitrogen atom for the sulphur atom, i.e. making nitrogen mustards, had the desired result. The disappearance of lymphocytes and granulocytes from the blood of rabbits was a useful marker of toxicity and gave rise to the idea of possible efficacy in lymphoid cancers. cancer cell killing. Even so, cytotoxic chemotherapy agents remain the mainstay of systemic anticancer treatment, since an understanding of their pharmacology has enabled clinicians to exploit the benefits of these drugs by various means (see below).

The morality of breast cancer research

Several of those I met, discussed how working in this particular area of basic science had a particular moral 'value' compared to other areas of research. This was linked, in part, to the public profile of cancer research, particularly breast cancer research, which conferred a certain significance to the science they studied Gillian I didn't select it because it was breast cancer, I didn't choose it but I am glad I did as it is good to know you are doing something to help everyday. It has meaning to it rather than just working in a lab. The 'meaning' of working in the field of breast cancer research was apparent in other ways. Many of those I met were aware of the degree of public or media criticism and concern that had been directed towards other types of genetic research, particularly in relation to GM food, or Pre-natal genetic testing. From the perspective of some of these scientists, the ethical value of being part of a breast cancer research charity I think if you were to say to...

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