Model-Based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.

Class III beta-tubulin isotype predicts response in advanced breast cancer patients randomly treated either with single-agent doxorubicin or docetaxel.

PURPOSE: To evaluate the role of microtubule-associated variables as potential predictors of response and clinical outcome in patients with advanced breast cancer receiving single-agent docetaxel or doxorubicin chemotherapy. EXPERIMENTAL DESIGN: The analysis was done on 173 tumor samples from patients with locally advanced or metastatic breast cancer who have participated in the TAX-303 phase III trial in which patients were randomly assigned to receive docetaxel or doxorubicin. Expression of total alpha- and beta-tubulin, classes II to IV beta-tubulin isotypes, and tau protein was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded tumors from the primary breast cancer. RESULTS: We observed that patients with "high" expression of class III beta-tubulin isotype had a higher probability of response to docetaxel than to doxorubicin treatment (odds ratio, 1.9; 95% confidence interval, 1.01-3.7; P = 0.05). No difference was observed in terms of time to progression or in terms of overall survival. CONCLUSIONS: This study suggests that the superiority of docetaxel over doxorubicin seems to be confined to the subgroup of patients with "high" expression of class III beta-tubulin isotype.

Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology.

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.

Progress and new standards of care in the management of HER-2 positive breast cancer.

The aim of this review article is to examine the available evidence regarding diagnosis and treatment of HER-2 positive breast cancer. This group of breast tumours (up to 30% of the total number of breast cancers) is known for having a more aggressive behaviour. The current recommendations for HER-2 positive tumour diagnosis are discussed since accurate identification of HER-2 amplification or overexpression is key for allowing a correct risk assessment and treatment. HER-2 positive tumours can be treated with trastuzumab (Herceptin, Hoffmann-La Roche, Basel, Switzerland), a monoclonal antibody targeted against the HER-2 receptor. The role of this drug in the metastatic, adjuvant and neoadjuvant setting is reviewed. The results of the recently reported adjuvant trials are commented, as the positive results of these trials changed the standard of care for patients with this particular type of breast cancer.

Monoclonal antibody-based targeted therapy in breast cancer: current status and future directions.

The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.

Metastatic melanoma: chemotherapy.

The incidence of cutaneous melanoma has been rapidly increasing, with an estimate of 47,700 new cases diagnosed in 2000 in the United States. In the early phase of its natural history, melanoma is cured in most cases by surgery, but once the metastatic phase develops, it is almost always fatal. The treatment of metastatic melanoma remains unsatisfactory. Systemic therapy has not been successful up to now, with very low response rates to single-agent chemotherapy. Polychemotherapy has increased the response rate (RR), without a significant improvement in overall survival. Immunotherapy alone is able to induce only a few durable complete responses (CRs). New chemotherapeutic and biologic agents are now available and promising combined approaches targeting the tumor by several different mechanisms are desirable and will probably represent the future modality of treatment.

Potential predictive value of Bcl-2 for response to tamoxifen in the adjuvant setting of node-positive breast cancer.

Approximately 50% of patients with estrogen receptor (ER)-positive breast cancer (BC) and 70%-80% of patients with ER-positive and progesterone receptor (PgR)-positive BC respond to hormonal therapy. Additional predictive markers are needed. A group of 287 patients with ER- and/or PgR-positive tumors was selected from 804 patients previously enrolled in a multicenter phase III trial. Bcl-2 expression was evaluated and correlated with response to adjuvant tamoxifen and survival. Estrogen receptor and PgR were determined by biochemical means and Bcl-2 by immunohistochemistry. With a median follow-up of 76 months (95 relapses and 60 deaths), of the 287 patients with, 187 (65%) had Bcl-2-positive tumors and 78 of these patients received tamoxifen. Of the 100 patients with Bcl-2-negative disease, 51 received tamoxifen and 49 regular follow-up. Using patients treated with tamoxifen as a reference, a univariate analysis of disease-free interval for patients who did not receive tamoxifen showed a hazard ratio (HR) of 1.42 (95% CI, 0.82-2.44; P = 0.21) for patients with Bcl-2-positive disease and a HR of 1.05 (95% CI, 0.55-1.99; P = 0.89) for patients with Bcl-2-negative disease (P = 0.48). After adjusting for number of positive lymph nodes, degree of receptor and PgR positivity, and type of surgery, the HRs were 1.54 (95% CI, 0.87-2.73; P = 0.14) for Bcl-2-positive disease and 1.05 (95% CI, 0.52-2.11; P = 0.88) for Bcl-2-negative disease. Despite its being a retrospective nonrandomized study with a relatively low number of patients, our results suggest that Bcl-2 deserves further evaluation as a predictive factor of sensitivity to tamoxifen.

Microtubule-associated parameters as predictive markers of docetaxel activity in advanced breast cancer patients: results of a pilot study.

Docetaxel is currently one of the most active agents for breast cancer. Predictive markers of docetaxel efficacy are clearly needed in order to avoid unnecessary toxicity in nonresponding or resistant patients and to improve the cost-effectiveness ratio of docetaxel. This pilot study correlates the clinical efficacy of docetaxel in 54 metastatic or locally advanced breast cancer patients with the expression of microtubule-associated parameters evaluated by immunohistochemistry in archival tumor samples. Among the 41 eligible patients (evaluable response to docetaxel and available predocetaxel treatment paraffin-embedded tumor tissue), response to docetaxel was: partial response 54%, stable disease 29%, and progressive disease 17%. Alfa- and b-tubulin and Tau protein were expressed in the majority of tumor samples. Class II, III, and IV b-tubulin isotypes were expressed in 56%, 65%, and 82% of samples, respectively. No clear association was found between response to docetaxel and the level of expression of Tau protein, a- and b-tubulin, and class III and IV b-tubulin isotypes. In patients with class II b-tubulin-positive tumors, the response rate was 39%, while in class II b-tubulin-negative tumors the response rate was 79% (P = 0.04). Therefore, we conclude that the class II b-tubulin isotype seems to be a promising predictive marker of docetaxel activity. Nevertheless, further investigations are needed due to the limited number of patients evaluated in this pilot study.

Management of head and neck cancer in elderly patients.

Head and neck cancer (HNC) represents a heterogeneous group of tumours requiring multimodality approaches. It is debatable whether HNC treatment in geriatric patients should be different to that delivered for younger patients. Furthermore, the risk of death seems to be higher in HNC patients with higher co-morbidity status. Despite the fact that there is no significant difference in outcome in younger versus older patients, older HNC patients are more likely to receive nonstandard, less aggressive therapies than younger patients. Age alone should not be the basis for selecting treatment options in older HNC patients. A thorough pretreatment evaluation of co-morbidities should always be performed, and radical surgical options should not be excluded in older HNC patients treated with curative intent, as postoperative complications occur no more frequently in older patients than in younger patients. Locoregional control and disease-free survival in older patients treated with radiation therapy (either with curative intent or in the palliative setting) are comparable to the results seen in younger HNC patients, with the same acute toxicity profile. In patients receiving systemic therapies, special attention must be given to modification of chemotherapy dosages according to renal and hepatic function. Molecular-targeted therapies appear to be very useful in such patients because of their favourable tolerability. In conclusion, once all physiological and biological risk factors have been addressed, a large proportion of geriatric patients can and should be offered the same HNC treatment as is offered to younger patients.

Chemobrain: is systemic chemotherapy neurotoxic?

PURPOSE OF REVIEW: The existence of chemobrain has become almost universally accepted, although many details of the concept are controversial. Data about the different types of cognitive impairment and their duration are not always consistent in the literature. We still do not know which cytotoxic agents are responsible, which characteristics make patients vulnerable, and which biologic mechanisms are involved. RECENT FINDINGS: Through this review of the recent literature, we provide an actualized definition of chemobrain including recent functional imaging data and we debate its controversial aspects. Potential causes such as oxidative stress and their potential clinical application in the prevention and treatment of chemobrain are also discussed. Eventually, the methodological aspects of published studies are questioned and propositions are provided in order to improve the design of future trials. SUMMARY: This issue is of clinical importance given the prevalence of breast carcinoma, the increased use of chemotherapy as adjuvant therapy, the increasing use of more aggressive dosing schedules, and the increasing survival rates. Better designed future trials should lead to a better definition and understanding of chemobrain and to future therapies.

Facts and controversies in systemic treatment of metastatic breast cancer.

The management of metastatic breast cancer remains an important and controversial issue. The systemic therapy, comprising endocrine, cytotoxic and biological agents, can be administered sequentially or in combination. Few drugs or combinations provide a significant improvement in survival and, therefore, in the great majority of cases, treatment is given with a palliative intent. With the exception of first-line therapy, for which general agreement exists, currently there is no consensual standard of care. This review will summarize the current knowledge and outline the controversial issues related to systemic therapy of metastatic breast cancer, with emphasis on treatment tailoring. The potential role of tumor molecular profile(s) in the selection of patients that could benefit the most from each strategy/agent will be discussed.