Neuroprotective effects of genistein in Mongolian gerbils: estrogen receptor-β involvement.

Genistein is a naturally occurring plant-derived phytoestrogen, present in the human diet, known to possess some beneficial effects. The present study investigated the effect of genistein on neuroprotection evaluated through electroencephalographic and behavioural correlates in a model of global cerebral ischemia in gerbils. Over the dose range tested, genistein (3 and 10 mg/kg), given 5 min after recirculation antagonized the ischemia-induced electroencephalographic total spectral power decrease 7 days after ischemia; fully prevented ischemia-induced hyperlocomotion evaluated 1 day after ischemia; reversed ischemia-induced memory impairment evaluated through both nest building behaviour and object recognition test; decreased malondialdehyde overproduction in the brain, evaluated 7 days after reperfusion; and fully promoted the survival of pyramidal cells in the CA(1) hippocampal subfield.

Benefits and adverse effects of endocrine therapy.

Endocrine-responsive tumors that are small and without nodal involvement (i.e. tumors classified as pT1 pN0) are a heterogeneous group of tumors that are associated with a low risk of relapse in the majority of the cases.

Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy.

Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy (RT) and the clinical outcome among patients treated with adjuvant endocrine therapy.

Patients And Methods: Patient information was obtained from three International Breast Cancer Study Group trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy.

Neoadjuvant pegylated liposomal doxorubicin in combination with cisplatin and infusional fluoruracil (CCF) with and without endocrine therapy in locally advanced primary or recurrent breast cancer.

Purpose: To explore the activity of pegylated liposomal doxorubicin (PLD) as neoadjuvant therapy of breast cancer.

Methods: The combination of PLD with cisplatin and infusional fluorouracil (CCF) for 8 courses was investigated in patients with primary or recurrent T2-T4a-d N0-3 M0 breast cancer. Patients with ER and/or PgR ≥10% tumors also received letrozole (±triptorelin).

Pathological complete response after preoperative systemic therapy and outcome: relevance of clinical and biologic baseline features.

In order to evaluate the outcome of patients with breast cancer according to response after primary therapy and according to clinical and biologic baseline features, we identified patients who were treated with preoperative therapy and who underwent surgery at the European Institute of Oncology (IEO), Milan, Italy, between 1995 and 2006. The outcome of patients who achieved pathological complete remission (pCR) and patients with residual disease (RD) at final surgery was analyzed. Of the 687 patients treated with preoperative therapy, we identified 82 patients who achieved pCR (12%) and 605 patients with RD (88%).

Investigation of 18F-FDG PET in the selection of patients with breast cancer as candidates for sentinel node biopsy after neoadjuvant therapy.

Purpose: The main objective of this study was to determine the role of [(18)F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in the selection of patients with breast cancer as candidates for sentinel node biopsy (SNB) after neoadjuvant therapy.

Methods: Forty-four patients with primary breast cancer clinically classified as cT2, cT3 or cT4(a-c) cN0-N2 or cN3 M0 and with a baseline FDG PET scan positive both in the site of primary tumour and axillary lymph nodes underwent neoadjuvant therapy and then a second FDG PET scan. In the case of axillary FDG PET uptake, patients underwent axillary lymph node dissection (ALND).

A nomogram based on the expression of Ki-67, steroid hormone receptors status and number of chemotherapy courses to predict pathological complete remission after preoperative chemotherapy for breast cancer.

Background: Tools able to predict pathological complete response (pCR) to preoperative chemotherapy might improve treatment outcome.

Patients And Methods: Data from 783 patients with invasive ductal carcinoma treated with preoperative chemotherapy and operated at the European Institute of Oncology were used to develop a nomogram using logistic regression model based on both categorical (clinical T and N, HER2/neu, grade and primary therapy) and continuous variables (age, oestrogen receptor (ER), progesterone receptor (PgR), Ki-67 expression and number of chemotherapy courses). The performance of the resulting nomogram was internally evaluated through bootstrapping methods.

Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.

Purpose: Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.

Patients And Methods: Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone.

Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer.

Background: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women.

Patients And Methods: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer.

Results: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.

Timing of adjuvant systemic therapy and radiotherapy after breast-conserving surgery and mastectomy.

In the last two decades, systemic adjuvant treatment for breast cancer, in association with radiotherapy, has been shown to prolong disease-free survival and overall survival in patients with operable breast tumors. So far, the optimal sequence of systemic therapy and radiotherapy for breast cancer patients after conservative surgery or mastectomy is unclear. Several retrospective analyses showed a possible detrimental effect on local regional recurrence rates when radiation therapy is delayed after chemotherapy.

International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured?

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology-Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007.

Preoperative therapy with trastuzumab and oral vinorelbine (+/- endocrine therapy) in patients with HER2-positive breast cancer.

Background: Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/neu positive breast cancer.

Patients And Methods: We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.

Letrozole.

Importance Of The Field: Aromatase is an enzyme which converts adrenal androgens to estrogens in postmenopausal women. Given the importance of estrogens in breast cancer growth, aromatase inhibitors are used to treat breast cancer in different settings. This review focuses on letrozole, a third generation aromatase inhibitor, encompassing pharmacodynamic and pharmacokinetic aspects as well as its clinical efficacy and safety.

Perioperative serum VEGF and extracellular domains of EGFR and HER2 in early breast cancer.

Background: The prognostic role of serum levels of molecular biomarkers during the perioperative period in patients with early breast cancer is not clear.

Patients And Methods: Serum VEGF and extracellular domains (ECD) of EGFR and HER2 were prospectively determined in 119 consecutive patients with early breast cancer on the day before and after surgery.

Results: After a median follow-up of 93 months, the preoperative value and the absolute change from pre- to postoperative serum levels of VEGF and HER2 ECD did not predict disease-free survival (DFS).

Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab.

PURPOSE: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. EXPERIMENTAL DESIGN: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab.

Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen.

Purpose: To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2).

Materials And Methods: Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive.

Breast-conserving surgery in 201 very young patients (<35 years).

Introduction: Surgical treatment of breast cancer in very young patients (<35 years) is still a matter of debate, since age is a predictive factor of local recurrence after breast conservation.

Patients And Methods: We retrospectively evaluated outcome and prognostic factors of 201 consecutive patients treated with breast conservation followed by whole breast irradiation between 1997 and 2004 with special attention paid to local control. The average follow up was 72 months (range 13-133 months).

Lessons on responsiveness to adjuvant systemic therapies learned from the neoadjuvant setting.

Aims: Recommended principles for the choice of therapies in operable breast cancer include the recognition of diverse subtypes of breast cancer and, based on genetic signature and immunohistochemistry, the identification of targets and related factors predictive of response. We review recent developments in the knowledge of established predictive factors in the neo-adjuvant setting.

Methods And Results: Experimental and clinical studies have shown that the degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) of the primary tumor defines distinct biological entities that require a differentiated approach to neoadjuvant treatment and clinical trial investigation.

Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer.

Purpose: To assess the prognostic role of HER2 overexpression/amplification in patients with node-negative, pT1a-b breast cancers.

Patients And Methods: All patients with HER2-positive breast cancer were identified among a population of 2,130 patients whose diseases were staged as pT1a-b, pN0 and who underwent surgery at the European Institute of Oncology from 1999 to 2006. A matched cohort was selected by using variables of hormone receptor status, age, and year of surgery.

Murine models of human neuropathic pain.

Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, and autoimmune diseases are examples of diseases that may cause neuropathic pain. Unfortunately no satisfactory treatment is yet available for this type of pain.

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer.

Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer.

Patients And Methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years).

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure.

It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

Background: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial.

Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months).

The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up.

Background: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established.

Patients And Methods: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy.