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This qualitative study investigated the attitudes, perceptions, and practices of breast cancer specialists with reference to the effect of patient age on management decisions in breast cancer, and attempted to identify national consensus on this issue. One hundred thirty-three relevant specialists, including 75 surgeons and 43 oncologists, participated in a virtual consultation using e-mailed questionnaires and openended discussion documents, culminating in the development of proposed consensus statements sent to participants for validation. A strong consensus was seen in favor of incorporating minimum standards of diagnostic services, treatment, and care for older patients with breast cancer into relevant national guidance, endorsed by professional bodies. Similarly, an overwhelming majority of participants agreed that simple, evidence-based protocols or guidelines on standardizing assessment of biological and chronological age should be produced by the National Institute for Health and Clinical Excellence and the Scottish Medicines Consortium, developed in collaboration with specialist oncogeriatricians, and endorsed by professional bodies. A further recommendation that all breast cancer patient treatment and diagnostic procedures be undertaken in light of up-to-date, relevant scientific data met with majority support. This study was successful in gauging national specialist opinion regarding the effect of patient age on management decisions in breast cancer in the U.K. [ABSTRACT FROM AUTHOR]

The association between breast cancer and benign thyroid disorders, in particular thyroid autoimmunity, has been debated for decades. Autoantibodies to thyroid peroxidase, the hallmark of thyroid autoimmunity, have a higher prevalence among patients with breast cancer compared with the general population. Furthermore a correlation between their positivity and a better prognosis of breast cancer was found in several independent small-scale studies, even if such observation was not confirmed in a subsequent retrospective study conducted on the largest patient cohort to date. The thyroid and mammary glands present several biological similarities, therefore the hypothesis of an immune response to shared thyroid/breast antigens could in part explain the association between thyroid autoimmunity and breast cancer. The sodium iodide symporter is expressed in both glands, however it seems unlikely to be the key common antigen, considering that autoantibodies targeting it are rare. Instead thyroid peroxidase, one of the major thyroid autoantigens, is also expressed in breast tissue and therefore represents the main antigenic link between thyroid autoimmunity and breast cancer. Furthermore lactoperoxidase, an enzyme of the same family that shares structural similarities with thyroid peroxidase, is expressed in neoplastic breast cells and is responsible for the cross-reactivity with some autoantibodies to thyroid peroxidase. Novel strategies for the diagnosis and treatment of breast cancer might take advantage of the antigenic link between thyroid and breast tissues., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome., Objectives: We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001)., Methods: TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1-3a, pN0-1, M0), with stored plasma ( n = 1,974), taken 15.5 (median; IQR 7.0-24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive ≥6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to-recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months., Results: No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78-1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79-1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82-1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments., Conclusions: No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date.

Background: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials., Methods: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug., Findings: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none)., Interpretation: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens., Methods: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779., Findings: START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group., Interpretation: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer., Funding: Cancer Research UK, UK Medical Research Council, UK Department of Health., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.

Background: Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients., Methods: In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed., Results: At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups., Conclusions: These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Background and Purpose: Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen., Materials and Methods: Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance., Results: Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred., Conclusions: At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

This qualitative study investigated the attitudes, perceptions, and practices of breast cancer specialists with reference to the effect of patient age on management decisions in breast cancer, and attempted to identify national consensus on this issue. One hundred thirty-three relevant specialists, including 75 surgeons and 43 oncologists, participated in a virtual consultation using e-mailed questionnaires and open-ended discussion documents, culminating in the development of proposed consensus statements sent to participants for validation. A strong consensus was seen in favor of incorporating minimum standards of diagnostic services, treatment, and care for older patients with breast cancer into relevant national guidance, endorsed by professional bodies. Similarly, an overwhelming majority of participants agreed that simple, evidence-based protocols or guidelines on standardizing assessment of biological and chronological age should be produced by the National Institute for Health and Clinical Excellence and the Scottish Medicines Consortium, developed in collaboration with specialist oncogeriatricians, and endorsed by professional bodies. A further recommendation that all breast cancer patient treatment and diagnostic procedures be undertaken in light of up-to-date, relevant scientific data met with majority support. This study was successful in gauging national specialist opinion regarding the effect of patient age on management decisions in breast cancer in the U.K.

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Background: The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size., Methods: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779., Findings: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5)., Interpretation: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Background: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy., Methods: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779., Findings: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy., Interpretation: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

Objectives: To develop a hitherto unavailable risk factor model for accurately predicting anemia development in cancer patients before chemotherapy (CT) administration., Methods: 2,070 nonanemic patients from the European Cancer Anaemia Survey (ECAS) with hemoglobin (Hb) > or =12 g/dl at enrollment who received their first CT during ECAS and underwent at least two CT cycles were divided randomly into split half (SH) 1 and SH2 (n = 1,035 each). The model was developed on SH1 using logistic regression to simultaneously evaluate predictive factors, and was validated using SH2 and an additional similar subpopulation of 5,901 ECAS patients. Anemia risk values were assigned to the predictive factors and the sum of the predictive factors gave the total anemia risk score; lower-, higher-, and highest-risk cutoff points of the total anemia risk score were determined., Results: Variables ultimately identified as significant predictive factors for anemia were: lower initial Hb (< or =12.9 g/dl in females, and < or =13.4 g/dl in males); having lung or gynecologic cancer versus gastrointestinal (GI)/colorectal cancer; cancer at any other site versus GI/colorectal cancer; treatment with platinum CT, and female gender., Conclusion: Using this evidence-based risk model, nonanemic patients who are at the highest risk of developing anemia prior to receiving CT can be identified clinically, allowing appropriate anemia management to be planned., (Copyright 2006 S. Karger AG, Basel.)

The estrogen receptor (ER) status and, to a lesser extent, progesterone receptor status have been recommended by recently published guidelines as important for routine prognostic and predictive evaluation of breast cancer. Although the clinical utility of ER status has been largely validated using biochemical ligand-binding assays such as the dextran-coated, charcoal ligand-binding assay, there has been the need to develop the ER immunocytochemical assay as a more accurate and practical alternative. In particular, ER status as determined on paraffin sections by immunocytochemical assay has been shown to be superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. The success of the paraffin-section assay is founded on two principles. The first relates to the advent of the heat-mediated, antigen-retrieval technique capable of restoring ER and progesterone receptor antigenicity in routinely prepared diagnostic formalin-fixed, paraffin-embedded tissue sections. The second is associated with the capacity for this substrate to provide more reliable and reproducible semiquantitative assessment of ER status in morphologically better-preserved tissue used routinely for histopathological diagnosis. The aim of this chapter is to describe the methodology currently used for optimal reproducible demonstration, scoring, and assessment of ER status in paraffin wax-embedded tissue sections in relation to the management of breast cancer in a routine or clinical-trial setting.

Adjuvant chemotherapy has been shown to provide survival benefits in patients with breast cancer, but some patients still relapse despite this. There is therefore a need for molecular markers present within the primary tumour that can predict for chemotherapy sensitivity or resistance. Until now, no single marker has emerged into routine clinical practice, but several candidate pathways are being extensively investigated. This paper summarises the current status of growth factor singalling and p53 function in this context. The data on human epidermal growth factor receptor-2, topoisomerase II and p53 expression in a variety of breast cancer treatment settings are discussed.

Anaemia is a common complication of cancer and cancer therapies, and fatigue is one of the most common symptoms of anaemia, disrupting functional performance and reducing overall quality of life. The positive effects of treating renal patients with recombinant human erythropoietin are well documented. This case report series details the specific effects of fatigue on individual patients with cancer and their way of life, and describes their significant improvement in lifestyle following the reversal of anaemia using recombinant human erythropoietin, epoetin alfa.

Cancer patients receiving cytotoxic chemotherapy often become anaemic and may require blood transfusions. A large-scale audit of patients with a variety of solid tumours receiving chemotherapy at 28 specialist centres throughout the UK was undertaken to quantify the problem. Data were available from 2719 patients receiving 3206 courses of cytotoxic chemotherapy for tumours of the breast (878), ovary (856), lung (772) or testis (213). Their mean age was 55 years (range 16-87). Overall, 33% of patients required at least one blood transfusion but the proportion varied from 19% for breast cancer to 43% for lung. Sixteen per cent of patients required more than one transfusion (7% for breast, 22% in lung). The mean proportion of patients with Hb < 11 g dl(-10 rose over the course of chemotherapy from 17% before the first cycle, to 38% by the sixth, despite transfusion in 33% of patients. Of the patients receiving transfusions, 25% required an inpatient admission and overnight stay. The most common symptoms reported at the time of transfusion were lethargy, tiredness and breathlessness. Further research is needed to evaluate the role of blood transfusions in patients receiving cytotoxic chemotherapy.

Background: Given as first- or second-line chemotherapy docetaxel appears to have great potential in advanced breast cancer., Patients and Methods: Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1-7). 342 patients (91%) had at least one prior anthracycline-based regimen., Results: Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients. 46% among the 299 patients who were anthracycline resistant and 35% among the 82 patients who were anthracycline refractory (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg m2 with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan-Meier survival analysis yielded a median survival of 194 days (95% CI: 178-218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis., Conclusions: The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an 'anthracycline refractory' population.

Several oncogenes seem to encode certain growth factors that may play a part in regulating cell growth in tumours. To assess whether such factors are synthesised endogenously by tumour cells the amounts of messenger RNA for several growth factors known to be synthesised by cancer cells of the breast in vitro were examined in biopsy specimens from 52 malignant and 15 non-malignant tumours of the breast and four samples of normal breast. Transforming growth factor beta messenger RNA was significantly more abundant in breast cancers (32 of 42 (76%) having appreciable amounts) than non-malignant breast tissue (five of 13 (38%) having similar amounts). Transcripts for both transforming growth factor alpha and its receptor, epidermal growth factor receptor, were found more commonly in carcinomas that were negative for oestrogen receptor (64% and 87%, respectively) than in those that were positive (27% and 30%, respectively). Insulin-like growth factor II messenger RNA was present in all 15 samples of non-malignant tissue but was found (in considerably lower amounts) in only 11 of 21 (52%) carcinomas. Epidermal growth factor receptor was also found in all non-malignant breast tissues, compared with 19 of 45 (42%) carcinomas. Platelet derived growth factor A and B chain transcripts coexisted in all normal and benign tissue and most carcinomas. This differing pattern of expression growth factors in tissue from malignant tumours compared with benign tumours and normal breast tissue suggests that some growth factors, particularly transforming growth factors alpha and beta, may have an important role in controlling growth of human breast cancers, particularly those that are hormone independent.

The importance of estrogen receptor (ER) determination in breast cancer is well established. Approximately 70% of ER-positive tumors are hormone responsive compared to 5-10% of ER-negative tumors. However, one-third of ER-positive tumors fail to respond, and the reasons for this are unclear. To further investigate these relationships we have determined levels of ER protein and mRNA in a number of human breast cancer biopsies. ER protein was estimated by the dextran-coated charcoal steroid binding method and by an ER immunocytochemical assay using a specific monoclonal antibody. A complimentary DNA clone (lambda OR3) encoding part of the human ER was used to determine mRNA levels. Dot blot analysis of twenty-seven tumors revealed a close agreement between ER mRNA and the dextran-coated charcoal assay (rs = 0.9; P less than 0.001). ER immunocytochemical assay staining also correlated with ER mRNA in twenty-five cases (rs = 0.75; P less than 0.001). Tumors from postmenopausal patients contained much higher levels of ER mRNA and ER protein than their premenopausal counterparts. ER-negative tumors produced no measurable ER mRNA. Northern blot analysis revealed a 6.4- and 3.7-kilobase species in ER-positive tumors and also in the human breast cancer cell line MCF-7. No differences in transcript sizes were found in tumors from hormone-responsive patients compared to nonresponding patients. We have also demonstrated, in tissue sections of normal and malignant breast, localization of ER mRNA by in situ hybridization to the same population of cells which exhibit immunoreactive ER.