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Background: The aim of this study was to perform an independent review of the efficacy data and to determine whether the efficacy difference observed in a phase III randomised clinical trial that compared doxorubicin plus paclitaxel (AT) versus fluorouracil/doxorubicin/cyclophosphamide (FAC) in first-line chemotherapy of metastatic breast cancer was maintained after a longer follow-up period., Material and Methods: A blinded independent review of original radiological images and original case report forms (CRFs) was conducted by an expert radiologist and an expert medical oncologist, respectively. The analysis of the updated data included time to progression (TTP) and overall survival (OS)., Results: CRFs for all 267 patients randomised in the study were available for medical review. The results of the independent review were consistent with the original analysis. At a median follow-up of 69 months, the difference in median TTP and OS in favour of the AT arm remained significant (median TTP 8.1 vs. 6.2 months, (p = 0.036); OS 23.0 vs. 18.3 months, (p = 0.005), respectively)., Conclusions: This blinded independent review and analysis of updated data confirmed the advantage for AT over FAC with regard to TTP and OS in patients with metastatic breast cancer.

Taxanes are very effective agents in several types of cancer. However, their activity is counterbalanced by side effects that could represent a limitation of their use in older cancer patients. This review aims at evaluating whether or not there are data supporting a tailored use of standard taxanes i.e. docetaxel and paclitaxel in elderly patients with the aim to increase their therapeutic index. In addition, recent data on the role of nanoparticle albumine-bound paclitaxel in breast cancer are discussed in this paper.

The key to optimising our approach in early breast cancer is to individualise care. Each patient has a tumour with innate features that dictate their chance of relapse and their responsiveness to treatment. Often patients with similar clinical and pathological tumours will have markedly different outcomes and responses to adjuvant intervention. These differences are encoded in the tumour genetic profile. Effective biomarkers may replace or complement traditional clinical and histopathological markers in assessing tumour behaviour and risk. Development of high-throughput genomic technologies is enabling the study of gene expression profiles of tumours. Genomic fingerprints may refine prediction of the course of disease and response to adjuvant interventions. This review will focus on the role of multiparameter gene expression analyses in early breast cancer, with regards to prognosis and prediction. The prognostic role of genomic signatures, particularly the Mammaprint and Rotterdam signatures, is evolving. With regard to prediction of outcome, the Oncotype Dx multigene assay is in clinical use in tamoxifen treated patients. Extensive research continues on predictive gene identification for specific chemotherapeutic agents, particularly the anthracyclines, taxanes and alkylating agents.

Purpose: This manuscript reviews and discusses results from randomised clinical studies evaluating topoisomerase II alpha (topo II) as a marker predicting anthracyclines' activity in early breast cancer patients., Methods: A Medline search has led to the identification of six phase III clinical trials, in which topo II has been retrospectively evaluated as a marker predicting anthracyclines' activity in the adjuvant setting., Results: Rates of topo II gene aberrations, in particular gene deletion, seem to vary substantially between the studies. No extensive correlation has been found between topo II gene status and protein levels. Five of the six trials suggest that topo II gene amplification is associated with increased tumour sensitivity to anthracyclines. Two of the three studies evaluating topo II gene deletions suggest that topo II deleted tumours might also derive an increased benefit from anthracyclines., Conclusion: Current data suggest that topo II might become a predictive tool to identify patients candidate to receive anthracyclines in the adjuvant setting. Ongoing studies will likely address some pending issues which, at present, prevent the use of this marker in daily practice.

Purpose: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer., Patients and Methods: Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points., Results: Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative., Conclusion: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.

Purpose: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival., Patients and Methods: Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients., Results: Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival., Conclusion: Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide. Elderly individuals make up a large part of the breast cancer population, and there are important specific considerations for this population. The International Society of Geriatric Oncology created a task force to assess the available evidence on breast cancer in elderly individuals, and to provide evidence-based recommendations for the diagnosis and treatment of breast cancer in such individuals. A review of the published work was done with the results of a search on Medline for English-language articles published between 1990 and 2007 and of abstracts from key international conferences. Recommendations are given on the topics of screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and metastatic disease. Since large randomised trials in elderly patients with breast cancer are scarce, there is little level I evidence for the treatment of such patients. The available evidence was reviewed and synthesised to provide consensus recommendations regarding the care of breast cancer in older adults.

It is largely known that clinical activity of a given cytotoxic agent may vary between different patients. This suggests that breast cancer sub-types can be identified within the endocrine-resistant cohort, each of them with a specific degree of sensitivity to different cytotoxic drugs. Pre-clinical and early clinical data suggest that in the future some molecular markers might have practical value in predicting cytotoxics activity in the clinical setting. The most relevant evidence is summarized below according to the type of cytotoxic agent: (a) Anthracyclines Topoisomerase II alpha (topo II) gene aberrations (amplification or deletion) and/or topo II protein overexpression seem to predict response to topo II inhibitors such as anthracyclines. Of note, HER-2 amplified tumors have a concomitant topo II gene aberration in approximately 50% of cases. Moreover, the majority of hyper-proliferating tumors carry topo II protein overexpression. Early clinical data suggest the existence of a direct correlation between anthracyclines activity and the presence of topo II gene aberration or topo II protein overexpression. (b) Taxanes Microtubule-associated parameters (MTAP) such as the TAU protein, HER-2 gene amplification, and p-53 gene mutations, have been suggested as potential predictive markers for taxanes. Although early clinical data support pre-clinical experiments, the lack of large prospectively designed clinical studies makes it difficult to draw conclusions on the predictive value of these molecular markers. (c) DNA-damaging agents The BRCA 1 protein seems to play a major role in activating DNA repair mechanisms. Loss-of-function BRCA 1 mutations might lead to a substantial deficit in DNA repair mechanisms. This could ultimately translate into increased tumor sensitivity to DNA-damaging agents such as alkylating compounds and platinum-derivates. Pre-clinical and early clinical data seem to suggest that some BRCA 1 gene mutations might render the tumor more sensitive to DNA-damaging agents and clinical studies have recently been activated to investigate properly this hypothesis. A new generation of ongoing clinical studies and a "focused" use of the gene micro-array technology will hopefully clarify the complex interaction existing between molecular targets and cytotoxic drug activity. This "targeted" approach to chemotherapy might ultimately lead to a more effective strategy in breast cancer medical treatment.

Aromatase inhibitors and inactivators (AIs) have been/are being widely investigated as an alternative to tamoxifen in the treatment of postmenopausal breast cancer patients. In this paper we have reviewed data from phase III studies to define the role of AIs versus tamoxifen as first-line therapy in patients with metastatic breast cancer, as primary therapy for not operable or early breast cancers not suitable for conservative surgery and as adjuvant treatment for women with early breast cancer. An effort has been performed to evaluate whether specific recommendations were needed for older postmenopausal patients. AIs play a key role in the treatment of advanced breast cancer and represent the agent of choice in patients who are candidates to neoadjuvant hormone-therapy. Longer follow-up of already published trials and additional data coming from ongoing studies will better define when and how to use AIs in the adjuvant setting.

Metabolomics is the newest "omics" science. It is a dynamic portrait of the metabolic status of living systems. Metabolomics has brought new insights on metabolic fluxes and a more comprehensive and holistic understanding of a cell's environment. This burgeoning field promises to be a potential tool to fill the gap between genotype and phenotype. As its preceding "omics" sciences (ie, genomics and proteomics), metabolomics' aim is to dredge information hidden in a sea of data. This technology permits simultaneous monitoring of many hundreds, or thousands, of macro- and small molecules, as well as functional monitoring of multiple pivotal cellular pathways. In addition, elucidation of cellular responses to molecular damage, including evolutionarily conserved inducible molecular defense systems, could be achieved with metabolomics and could lead to the discovery of new biomarkers of molecular responses to functional perturbations. If metabolomic information could be translated into diagnostic tests, it might have the potential to impact on clinical practice, and it might lead to the supplementation of traditional biomarkers of cellular integrity, cell and tissue homeostasis, and morphological alterations that result from cell damage or death. In this review the concept and characteristics of metabolomics are introduced. Main current applications of metabolomics in cancer research are reviewed, including its potential in the drug discovery field, and, last but not least, its potential impact in the field of monitoring response and toxicity to anticancer agents. In the last section, research projects ongoing at our institution and future challenges for metabolomics will be presented and briefly discussed.

Adjuvant chemotherapy has led to improvements in relapse-free and overall survival in patients with breast, colon, and non-small-cell lung cancer, yet many older patients are not offered these potentially life-saving treatments. Moreover, older patients have been either excluded or under-represented in most adjuvant trials, limiting the generalizability of these treatments to older populations. Limited data in elders suggest that older patients derive significant benefits from adjuvant therapies provided they have life expectancies exceeding 5 years. Making treatment decisions in elders is challenging. Many have major comorbidities that may substantially limit life expectancy and minimize or negate the benefits of adjuvant chemotherapy. In this review, we discuss the potential benefits of adjuvant treatment in older patients with solid tumors with a focus on general principles involved in the selection of adjuvant therapy for patients with breast, colon, and non-small-cell lung cancer. In addition, we discuss the role of comorbidity and how it factors in treatment decisions. Finally, we discuss future research directions and funding for elders with cancer.

Tumors have usually been classified by their morphologic appearances. Unfortunately, these current classification schemes have serious drawbacks. They are not able to stratify similar histopathological appearances that will follow significantly different clinical courses or respond differently to chemotherapy. The information that a specific molecular profile correlates with important clinical endpoints should permit physicians to take treatment decisions based on the molecular characteristics of each tumor. Lessons from the metastatic setting have been translated to the adjuvant setting, and several strategies have been evaluated in clinical trials. The expression of estrogen receptors (ER) in breast cancer enables physicians to make treatment decisions related to the use of hormonal manipulations. In this context, the challenge is to define a suitable subgroup of patients who will benefit from the addition of chemotherapy. Otherwise, the lack of ER expression predicts no benefit from hormonotherapy. In this setting chemotherapy plays a central role. The selection of the most appropriate regimen based on HER-2 status remains an uncertain strategy. However, the expression of the oncoprotein HER-2 has been linked to the probability of response to the target-designed monoclonal antibody trastuzumab. The role of trastuzumab in the adjuvant setting is supported by the early results of three large clinical trials presented at the American Society Clinical Oncology meeting in 2005. These trials have shown a striking impact of trastuzumab on the main endpoints such as disease-free survival and overall survival. In this context, the integration of trastuzumab with taxane and anthracycline-based-chemotherapy seems to be the appropriate choice. This review will combine data from breast cancer biology with clinical evidence coming from large phase III trials in the attempt to propose a molecular targeted approach to the adjuvant treatment strategy of early breast cancer patients.

We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3-4 toxicity or antitumor activity and patients' baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m(2) every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.

Older women have unfortunately been underrepresented in breast cancer clinical trials, with the majority of studies being restricted to patients younger than 70 years. Elderly patients are an inhomogeneous group and frequently suffer from comorbidities and/or impaired organ functions. These facts may often lead to death from causes other than cancer, thus nullifying any possible benefit of adjuvant treatment; furthermore, they render extrapolation of standard treatment recommendations to the elderly potentially hazardous, particularly with respect to chemotherapy. Specific clinical trials are therefore needed to investigate adjuvant treatments tailored for the heterogeneous older population.

The elderly population has been neglected by the traditional approach to clinical breast cancer research. Elderly women have been underrepresented in breast cancer clinical trials, with the majority of studies being restricted to patients aged < 70 years. Elderly patients frequently have comorbidities and/or impaired organ function. These facts may often lead to death from causes other than cancer, thus nullifying any possible benefit of adjuvant treatment; furthermore, they render extrapolation of standard treatment recommendations to the elderly potentially hazardous, particularly with respect to chemotherapy. Therefore, specific clinical trials are needed to investigate adjuvant treatments tailored for the heterogeneous older population.

Purpose: To compare health-related quality of life (HRQOL) in patients with metastatic breast cancer receiving the combination of doxorubicin and paclitaxel (AT) or doxorubicin and cyclophosphamide (AC) as first-line chemotherapy treatment., Patients and Methods: Eligible patients (n = 275) with anthracycline-naive measurable metastatic breast cancer were randomly assigned to AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation of paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) was planned at cycle 2 to reach equivalent myelosuppression in the two groups. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the EORTC Breast Module at baseline and the start of cycles 2, 4, and 6, and 3 months after the last cycle., Results: Seventy-nine percent of the patients (n = 219) completed a baseline measure. However, there were no statistically significant differences in HRQOL between the two treatment groups. In both groups, selected aspects of HRQOL were impaired over time, with increased fatigue, although some clinically significant improvements in emotional functioning were seen, as well as a reduction in pain over time. Overall, global quality of life was maintained in both treatment groups., Conclusion: This information is important when advising women patients of the expected HRQOL consequences of treatment regimens and should help clinicians and their patients make informed treatment decisions.

Neutropenia is a significant hematologic complication induced by cytotoxic chemotherapy. The clinical consequences of chemotherapy-induced neutropenia are often severe and can be potentially life-threatening. Patients who develop febrile neutropenia often need to be hospitalized, reducing their quality of life and increasing costs. Neutropenia can also compromise the ability to deliver chemotherapy at the full dose and on schedule. To help prevent the occurrence of neutropenia, patients with a high risk of developing chemotherapy-related infections may be given prophylactic colony-stimulating factors. Filgrastim is a recombinant human granulocyte colony-stimulating factor that has been widely used (in over 3 million patients) for over 12 years in the management of neutropenia. Pegfilgrastim is an approved, long-acting, next generation of granulocyte colony-stimulating factor that has similar clinical benefits to filgrastim but has novel pharmacokinetic properties. Pegfilgrastim shows at least comparable safety and efficacy to filgrastim, with the added benefit of simplified once-per-chemotherapy-cycle dosing. In addition, two randomized, controlled pivotal trials have shown that a single dose of pegfilgrastim given once per cycle led to a lower observed incidence of febrile neutropenia following myelosuppressive chemotherapy, compared with daily injections of filgrastim. Clinical trials are currently expanding the clinical experience with pegfilgrastim in a variety of solid tumors and hematologic malignancies. In addition to prevention of chemotherapy-induced neutropenia in 21- and 28-day regimens, future studies are examining the suitability of pegfilgrastim in dose-dense therapy and other cancer settings.

Treatment regimens for solid tumours have been extensively investigated for their physical toxic effects, but far less is known about the potential impairment of cognitive function by anticancer treatment regimens. Here, we review published studies that examined cognitive function in adult patients receiving systemic therapy for solid tumours. Our review suggests that patients can experience cognitive changes related to their treatment. However, several studies had methodological limitations, such as use of a limited sample size, lack of baseline assessment, and lack of control for potential confounding factors. Better designed clinical trials are required so that the difficulties patients face in terms of reduced cognitive function as a result of anticancer treatment can be fully elucidated. These trials should have sufficient statistical power and, importantly, should also be prospective.

Purpose of Review: This review is intended to summarize the most up-to-date information in the field of chemotherapy for advanced breast cancer., Recent Findings: During the past year, the literature on chemotherapy for metastatic breast cancer has focused on three main areas of interest: the development of new cytotoxic agents with most studies addressing the taxane-pretreated population; the evaluation of new combination regimens, mainly incorporating a taxane; and the development of new trastuzumab-cytotoxic-agent combinations in the HER-2-positive population. In addition, interesting data regarding combination versus sequential single-agent chemotherapy and the optimal duration of chemotherapy have been published., Summary: Interesting new drugs have faced phase II development. Randomized trials will define their role in the daily management of metastatic breast cancer. New combination regimens, generally incorporating a taxane, improve short-term efficacy in comparison with standard anthracycline-based combinations or single-agent chemotherapy, but at the cost of increased toxicity. Trastuzumab can be safely combined with several cytotoxic agents.

Background: The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies., Methods: In a large multicenter Phase III trial, 275 anthracycline naive metastatic breast carcinoma patients were randomized to receive either doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3-hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600 mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six cycles. Close cardiac monitoring was implemented in the study design., Results: Congestive heart failure (CHF) occurred in three patients in the AT arm and in one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection fraction to below the limit of normal were documented in 33% AT and 19% AC patients and were not predictive of CHF development., Conclusions: AT is devoid of excessive cardiac risk among metastatic breast carcinoma patients, when the maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2)., (Copyright 2003 American Cancer Society.)

In the present article, an extensive review of the current knowledge regarding predictive molecular markers in breast cancer is presented. The main emphasis has been given to the adjuvant therapy setting, because of the lack of well-designed studies evaluating predictive markers in the metastatic setting. In the first part of the article some general concepts have been summarized, mainly to emphasize the difference between prognostic and predictive markers. In the second part of the article, studies evaluating molecular markers with predictive value for the most commonly used drugs or regimens (i.e., cyclophosphamide, methotrexate, 5-fluorouracil [CMF], anthracyclines, taxanes, and herceptin) have been reviewed and discussed. An attempt has been made to provide for each single predictive marker the currently available level of evidence, to allow the reader to have immediate information regarding the impact of the evaluated marker in daily clinical practice. In the last part of the article, the most important findings have been summarized and future avenues of research have been outlined.

Oral capecitabine is a useful chemotherapy for metastatic breast cancer, both as monotherapy and in combination with other cytotoxic drugs. The proven activity of capecitabine has provided the rationale to explore its use earlier in the course of the disease and in combination with other agents, particularly those known to further upregulate thymidine phosphorylase (TP) concentrations in tumor tissue. The efficacy and safety of capecitabine monotherapy compares favorably with cyclophosphamide/methotrexate/5-fluorouracil in chemotherapy-naïve patients and with paclitaxel in anthracycline-pretreated patients. Therefore, for patients whose disease has progressed during or following anthracycline treatment, but for whom capecitabine/docetaxel combination therapy or taxane monotherapy is not appropriate, capecitabine monotherapy is an attractive alternative to established i.v. treatments. In combination, capecitabine plus paclitaxel, which further upregulates TP in tumor tissue, has demonstrated high activity in two phase II studies in advanced/metastatic breast cancer. Similarly, combination with vinorelbine showed promising activity in pretreated metastatic breast cancer patients, and triple combinations with an anthracycline and a taxane or cyclophosphamide have proven to be highly active. In the future, capecitabine may be combined with novel biologic agents, such as trastuzumab and bevacizumab; the former combination has already shown encouraging results in a pilot trial. Confirmatory studies for many of these combinations and phase III trials versus standard therapy are now warranted.