Showing papers in "Breast Cancer Research and Treatment in 2007"

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.

Abstract: Background Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death.

Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study

Abstract: Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02-1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative" breast cancer cell lines growing in vitro.

Abstract: Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-to-mesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 mICROM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (chi2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with "triple-negative" breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

MDA-MB-435 cells are derived from M14 melanoma cells--a loss for breast cancer, but a boon for melanoma research.

Abstract: Background The tissue of origin of the cell line MDA-MB-435 has been a matter of debate since analysis of DNA microarray data led Ross et al. (2000, Nat Genet 24(3):227–235) to suggest they might be of melanocyte origin due to their similarity to melanoma cell lines. We have previously shown that MDA-MB-435 cells maintained in multiple laboratories are of common origin to those used by Ross et al. and concluded that MDA-MB-435 cells are not a representative model for breast cancer. We could not determine, however, whether the melanoma-like properties of the MDA-MB-435 cell line are the result of misclassification or due to transdifferention to a melanoma-like phenotype.

Significance of interleukin-6 (IL-6) in breast cancer (review)

Abstract: Cytokines are factors that are known to have both tumor-promoting and inhibitory effects on breast cancer growth depending presumably on their relative concentrations and the presence of other modulating factors. Different cytokines play an important role in controlling the immune system. Interleukin-6 (IL-6) is a pleiotropic cytokine with obviously tumor-promoting and tumor-inhibitory effects. Here, we review the role of IL-6 in in vitro experiments of breast tumor cells, in breast tumor tissues (BTs) and assess its potential as a prognostic indicator in breast cancer patients. A literature search was conducted using PubMed, restricted to articles published in English language. In summary, results regarding the effect of IL-6 on breast tumor cells and on BTs are not unique indicating both tumor-promoting and inhibitory effects of IL-6. Concerning patients' serum IL-6 levels, data are surprisingly unique showing IL-6 to be a negative prognosticator in breast tumor patients.

Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy

Abstract: Purpose To explore the relationship of regional cerebral blood flow and metabolism with cognitive function and past exposure to chemotherapy for breast cancer. Patients and methods Subjects treated for breast cancer with adjuvant chemotherapy remotely (5–10 years previously) were studied with neuropsychologic testing and positron emission tomography (PET), and were compared with control subjects who had never received chemotherapy. [O-15] water PET scans was acquired during performance of control and memory-related tasks to evaluate cognition-related cerebral blood flow, and [F-18] fluorodeoxyglucose (FDG) PET scans were acquired to evaluate resting cerebral metabolism. PET scans were analyzed by statistical parametric mapping and region of interest methods of analysis. Results During performance of a short-term recall task, modulation of cerebral blood flow in specific regions of frontal cortex and cerebellum was significantly altered in chemotherapy-treated subjects. Cerebral activation in chemotherapy-treated subjects differed most significantly from untreated subjects in inferior frontal gyrus, and resting metabolism in this area correlated with performance on a short-term memory task previously found to be particularly impaired in chemotherapy-treated subjects. In examining drug-class specific effects, metabolism of the basal ganglia was significantly decreased in tamoxifen + chemotherapy-treated patients compared with chemotherapy-only breast cancer subjects or with subjects who had not received chemotherapy, while chemotherapy alone was not associated with decreased basal ganglia activity relative to untreated subjects. Conclusion Specific alterations in activity of frontal cortex, cerebellum, and basal ganglia in breast cancer survivors were documented by functional neuroimaging 5–10 years after completion of chemotherapy.

Psychological distress and fatigue predicted recurrence and survival in primary breast cancer patients.

Abstract: This study examined whether psychological distress in newly diagnosed breast cancer patients was associated with their survival. We analyzed data from 1,588 breast cancer patients who filled in the EORTC QLQ-C30 questionnaire and the Hospital Anxiety and Depression Scale (HADS) 2 months after their primary operation. The median follow-up time was 12.9 years. Psychological distress (EORTC QLQ-C30 emotional function; HADS anxiety; HADS depression) and EORTC fatigue, physical function, and overall ratings were used to predict recurrence-free and overall survival, controlling for the known clinical and histopathological prognostic factors (biological model) using Cox multivariate regression analysis. Low levels of psychological distress (good EORTC emotional function) and low fatigue independently predicted longer recurrence-free and overall survival, controlling for biological factors. Lack of anxiety (HADS) also predicted longer recurrence-free survival. When added in combination to the biological model, fatigue remained a significant predictor of recurrence-free survival (P = 0.0004; risk ratio 1.32 (1.13-1.54)) and emotional function remained a significant predictor of overall survival (P = 0.0074; risk ratio 0.81 (0.70-0.95)). Low psychological distress and a low level of fatigue may cause a greater cancer resistance or may reflect underlying mental and physical robustness.

Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature.

Abstract: Background Metaplastic carcinoma of the breast is a rare form of breast cancer and has an uncertain prognostic significance. The purpose of the present study was to compare the clinical course, and prognosis, between this type of tumor and poorly differentiated ductal carcinoma. Patients and methods We analyzed 37 cases of metaplastic carcinoma of the breast treated at our institution (European Institute of Oncology in Milan, Italy) between 1997 and 2004, comparing them with 72 cases (control group) of poorly differentiated ductal carcinoma. All 109 patients had negative receptors and were G3 at final histology. The control cases were matched according to year of surgery, pT (pT1 vs. pT2/ 3/4), and pN (absent vs. present). Results Of the 37 patients, eleven died from disease progression, eight developed metastatic disease and two experienced local recurrence. In the control group (72 patients) we observed three deaths due to disease progression, 13 distant metastases, and two local recurrences. Conclusion The overall survival in the metaplastic carcinoma group was significantly worse than in the control group. As regards to disease-free survival, there was no statistically significant difference between the two groups.

BRCA1 and BRCA2 germline mutation analysis in the Indonesian population.

Abstract: Specific mutations in BRCA1 and BRCA2 genes have been identified in specific populations and ethnic groups. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast cancers in the Indonesian population. One hundred-twenty moderate to high risk breast cancer patients were tested using PCR-DGGE, and any aberrant band was sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed on all samples to detect large deletions in the two genes. Twenty-three different mutations were detected in 30 individuals, ten were deleterious mutations and 20 were “unclassified variants” with uncertain clinical consequences. Three of seven (c.2784_2875insT, p.Leu1415X and del exon 13–15) and two of four (p.Glu2183X and p.Gln2894X) deleterious mutations that were found in BRCA1 and BRCA2 respectively, are novel. Several novel, pathogenic BRCA1 and BRCA2 germline mutations are found in early onset Indonesian breast cancer patients, these may therefore be specific for the Indonesian population.

Weight gain and recovery of pre-cancer weight after breast cancer treatments: evidence from the women's healthy eating and living (WHEL) study.

Abstract: Purpose To examine predictors of weight gain following breast cancer diagnosis and subsequent return to pre-cancer weight.

Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma.

Abstract: Alternative and complementary therapeutic strategies need to be developed for metastatic breast cancer. Virotherapy is a novel therapeutic approach for the treatment of cancer in which the replicating virus itself is the anticancer agent. However, the success of virotherapy has been limited due to inefficient virus delivery to the tumor site. The present study addresses the utility of human mesenchymal stem cells (hMSCs) as intermediate carriers for conditionally replicating adenoviruses (CRAds) to target metastatic breast cancer in vivo. HMSC were transduced with CRAds. We used a SCID mouse xenograft model to examine the effects of systemically injected CRAd loaded hMSC or CRAd alone on the growth of MDA-MB-231 derived pulmonary metastases (experimental metastases model) in vivo and on overall survival. Intravenous injection of CRAd loaded hMSCs into mice with established MDA-MB-231 pulmonary metastatic disease homed to the tumor site and led to extended mouse survival compared to mice treated with CRAd alone. Injected hMSCs transduced with CRAds suppressed the growth of pulmonary metastases, presumably through viral amplification in the hMSCs. Thus, hMSCs may be an effective platform for the targeted delivery of CRAds to distant cancer sites such as metastatic breast cancer.

Elevated tissue sodium concentration in malignant breast lesions detected with non-invasive 23Na MRI.

Abstract: The hypothesis that physiological and biochemical changes associated with proliferating malignant tumors may cause an increase in total tissue sodium concentration (TSC) was tested with non-invasive, quantitative sodium (23Na) magnetic resonance imaging (MRI) in patients with benign and malignant breast tumors. 23Na and 1H MRI of the breast was performed on 22 women with suspicious breast lesions (≥1 cm) at 1.5 Tesla. A commercial proton (1H) phased array breast coil and custom solenoidal 23Na coil were used to acquire 1H and 23Na images during the same MRI examination. Quantitative 3-dimensional 23Na projection imaging was implemented with negligible signal loss from MRI relaxation, or from radio-frequency field inhomogeneity, in less than 15 min. Co-registered 1H and 23Na images permitted quantification of TSC in normal and suspicious tissues on the basis of 1H MRI contrast enhancement and anatomy, with histology confirmed by biopsy. Sodium concentrations were consistently elevated in (N = 19) histologically proven malignant breast lesions by an average of 63% compared to glandular tissue. The increase in sodium concentration in malignant tissue was highly significant compared to unaffected glandular tissue (P < 0.0001, paired t-test), adipose tissue, and TSC in three patients with benign lesions. Elevated TSC in breast lesions measured by non-invasive 23Na MRI appears to be a cellular-level indicator associated with malignancy. This method may have potential to improve the specificity of breast MRI with only a modest increase in scan time per patient.

Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases

Abstract: Conflicting theories of epithelial carcinogenesis disagree on the clonal composition of primary tumors and on the time at which metastases occur. In order to study the spatial distribution of disparate clonal populations within breast carcinomas and the extent of the genetic relationship between primary tumors and regional metastases, we have analyzed by comparative genomic hybridization 122 tissue samples from altogether 60 breast cancer patients, including 34 tumor samples obtained from different quadrants of 9 breast carcinomas, as well as paired primary-metastatic samples from 12 patients. The median intratumor genetic heterogeneity score (HS) was 17.4% and unsupervised hierarchical clustering analysis comparing the genetic features to those of an independent series of 41 breast carcinomas confirmed intratumor clonal divergence in a high proportion of cases. The median HS between paired primary breast tumors and lymph node metastases was 33.3%, but the number of genomic imbalances did not differ significantly. Clustering analysis confirmed extensive clonal divergence between primary carcinomas and lymph node metastases in several cases. In the independent series of 41 breast carcinomas, the number of genomic imbalances in primary tumors was significantly higher in patients presenting lymph node metastases (median = 15.5) than in the group with no evidence of disease spreading at diagnosis (median = 5.0). We conclude that primary breast carcinomas may be composed of several genetically heterogeneous and spatially separated cell populations and that paired primary breast tumors and lymph node metastases often present divergent clonal evolution, indicating that metastases may occur relatively early during breast carcinogenesis.

The discovery and mechanism of action of letrozole

Abstract: Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara®) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

Changes in shoulder muscle size and activity following treatment for breast cancer.

Abstract: Morbidity of the shoulder after breast cancer is a well-known phenomenon. MRI studies have shown muscle morbidity in cervical cancer and prostate cancer. In breast cancer clinical observations and patient reports include muscle morbidity in a number of muscles acting at the shoulder. Several of these muscles lie in the field of surgery and radiotherapy. Timed interaction between muscles that stabilise the shoulder and those acting as prime movers is essential to achieve a smooth scapulohumeral rthythm during functional elevation of the arm. Seventy-four women treated for unilateral carcinoma of the breast were included in the study. All patients filled out the Shoulder Pain and Disability Index (SPADI). EMG activity of four muscles was recorded during scaption on the affected and unaffected side. Muscle cross sectional area and signal intensity was determined from MRI scans. The association between EMG and covariates was determined using multiple linear regression techniques. Three of the 4 muscles on the affected side demonstrated significantly less EMG activity, particularly when lowering the arm. Upper trapezius demonstrated the greatest loss in activity. Decreased activity in both upper trapezius and rhomboid were significantly associated with an increase in SPADI score and increased time since surgery. Pectoralis major and minor were significantly smaller on the affected side. Muscles affected in the long term are the muscles associated with pain and disability yet are not in the direct field of surgery or radiotherapy. Primary muscle shortening and secondary loss of muscle activity may be producing a movement disorder similar to the ‘Dropped Shoulder Syndrome’. Exercise programmes should aim not only for range of movement but also for posture correction and education of potential long-term effects.

Predictive factors for late normal tissue complications following radiotherapy for breast cancer.

Abstract: Radiotherapy after breast-conserving surgery is commonly applied to reduce recurrence of breast cancer but may cause acute and late side effects. To identify prognostic factors for the development of late toxicity after radiotherapy, we conducted a prospective study of breast cancer patients. We assessed late complications of radiotherapy and collected information on epidemiologic factors in a cohort of breast cancer patients who had received radiotherapy after breast-conserving surgery. Among 416 patients with complete follow-up data, the association between possible risk factors and development of late complications was evaluated using multivariate logistic regression analysis. After a median follow-up time of 51 months, 131 (31.4%) patients presented with telangiectasia and 28 (6.7%) patients with fibrosis. We observed a strong association between development of telangiectasia and fibrosis (p < 0.01). Increasing age of the patient was a risk factor for both telangiectasia and fibrosis (p-value for trend <0.01 and 0.03, respectively). Patients with acute skin toxicity (odds ratio (OR) 1.8, 95% confidence interval (CI) 1.0–3.1) were at higher risk to develop telangiectasia. Long-term smoking was associated with a significant increase in risk of telangiectasia compared to non-smokers (OR 2.3, 95% CI 1.2–4.6). Our study revealed several factors other than radiation dose that may predispose to late complications following radiotherapy. Further understanding of differences in response to irradiation may advance individualized treatment and improve cosmetic outcome.

The neonatal splice variant of Nav1.5 potentiates in vitro invasive behaviour of MDA-MB-231 human breast cancer cells.

Abstract: Upregulation of functional voltage-gated Na+ channels (VGSCs) occurs in metastatic human breast cancer (BCa) in vitro and in vivo. The present study aimed to ascertain the specific involvement of the ‘neonatal’ splice variant of Nav1.5 (nNav1.5), thought to be predominant, in the VGSC-dependent invasive behaviour of MDA-MB-231 cells. Functional activity of nNav1.5 was suppressed by two different methods targeting nNav1.5: (i) small interfering RNA (siRNA), and (ii) a polyclonal antibody (NESO-pAb); effects upon migration and invasion were determined. nNav1.5 mRNA, protein and signalling were measured using real-time PCR, Western blotting, and patch clamp recording, respectively. Treatment with the siRNA rapidly reduced (by ∼90%) the level of nNav1.5 (but not adult Nav1.5) mRNA, but the protein reduction was much smaller (∼30%), even after 13 days. Nevertheless, the siRNA reduced peak VGSC current density by 33%, and significantly increased the cells’ sensitivity to nanomolar tetrodotoxin (TTX). Importantly, the siRNA suppressed in vitro migration by 43%, and eliminated the normally inhibitory effect of TTX. Migrated MDA-MB-231 cells expressed more nNav1.5 protein at the plasma membrane than non-migrated cells. Furthermore, NESO-pAb reduced migration by up to 42%, in a dose-dependent manner. NESO-pAb also reduced Matrigel invasion without affecting proliferation. TTX had no effect on cells already treated with NESO-pAb. It was concluded that nNav1.5 is primarily responsible for the VGSC-dependent enhancement of invasive behaviour in MDA-MB-231 cells. Accordingly, targeting nNav1.5 expression/activity may be useful in clinical management of metastatic BCa.

The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers.

Abstract: Background Estrogen receptor (ER) and/or progesterone receptor expression occurs in ∼50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study.

Male breast cancer: a review of clinical management

Abstract: Male breast cancer incidence is 1% of all breast cancers and is increasing. We aim to present an overview of male breast cancer with particular emphasis on clinical management. Studies were identified by an online search of literature in the MEDLINE database till June 2006 followed by an extensive review of bibliographies. Increased risk factors include genetic predisposition as in BRCA2 families; testicular dysfunction due to chromosomal abnormality such as Klinefelter’s syndrome or environmental factors such as chronic heat exposure and radiation. Clinical assessment with biopsy is the hallmark of diagnosis. Earlier presentations are becoming commoner but there are wide geographical differences. Surgical treatment involves simple or modified radical mastectomy along with surgical assessment of the axilla, either via sentinel node biopsy in clinically node-negative disease or axillary sampling/clearance in node-positive disease. Reconstructions for restoring body image have been recently reported. Indications for adjuvant therapies are similar to that in women. For metastatic disease, tamoxifen is still the mainstay for oestrogen receptor positive disease. For oestrogen receptor negative disease, doxorubicin based chemotherapy regimens are used. In addition, the oft neglected psychological aspects of men having a “cancer of women” are increasingly being recognised. There is, thus, need for further increasing awareness among men to reduce stigma associated with presentation of symptoms related to breast. This should be in addition to stressing to clinicians the ways of earlier detection and tailor-made “gender oriented” treatment of breast cancer in men.

Long-term management of breast cancer-related lymphedema after intensive decongestive physiotherapy.

Abstract: Background Treatment of lymphedema is based on intensive decongestive physiotherapy followed by a long-term maintenance treatment. We analyzed the factors influencing lymphedema volume during maintenance treatment.

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

Abstract: Background A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2.

Over-expression of genes and proteins of ubiquitin specific peptidases (USPs) and proteasome subunits (PSs) in breast cancer tissue observed by the methods of RFDD-PCR and proteomics.

Abstract: The ubiquitin-proteasome system facilitates the degradation of damaged proteins and regulators of growth and stress response. Alterations in this proteolytic system are associated with a variety of human pathologies. By restriction fragment differential display polymerase chain reaction (RFDD-PCR) and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-TOF MS) based on two-dimensional polyacrylamide gel electrophoresis (2-DE), differentially expressed genes and proteins of ubiquitin specific proteases (USPs), proteasome subuinits (PSs) and ubiquitin protein ligase E3A (UBE3A) were analyzed between breast cancer and adjacent normal tissues. Some of them were further verified as over-expression by immunohistochemical stain. Five genes of proteasome subunits (PSs), including PSMB5, PSMD1, PSMD2, PSMD8 and PSMD11, four genes of USPs, including USP9X, USP9Y, USP10 and USP25, and ubiquitin protein ligase E3A (UBE3A) were over-expressed (>3-fold) in breast cancer tissue compared to adjacent normal tissue, and over-expression (>4-fold) of proteins of PSMA1 and SMT3A were observed in breast cancer tissue. PSMD8, PSMD11 and UBE3A were further verified as over-expression by immunohistochemical stain. The action of ubiquitin-proteasome system were obviously enhanced in breast cancer, and selectively intervention in action of ubiquitin-proteasome system may be a useful method of treating human breast cancer.

Body size, weight change, fat distribution and breast cancer risk in Hispanic and non-Hispanic white women

Abstract: Introduction The incidence of breast cancer varies among women living in the Southwestern part of the US. We evaluate how body size influences breast cancer risk among these women. Methods Cases (n = 2,325) diagnosed with breast cancer between October 1, 1999 and May 2004 residing in Arizona, Colorado, New Mexico, or Utah were matched to controls (n = 2,525). Participants were interviewed; height, weight, waist, and hip circumference were measured at the time of interview; blood was drawn. Results A large body mass index (BMI) at age 15 was inversely associated with pre-menopausal breast cancer risk in both non-Hispanic white (NHW) and Hispanic women (Odds ratio, ORs 0.68 95% CI 0.44, 1.04, and 0.65 95% CI 0.39, 1.08, respectively); BMI at age 15 also had an impact on subsequent breast cancer associated with obesity after menopause. Among postmenopausal women, recent exposure to hormones was an important modifier of risk associated with body size. Among women not recently exposed to hormones risk associated with obesity was 1.61 (95% CI 1.05, 2.45) for NHW women; gaining ‡25 kg between 15 and age 50 was inversely associated with breast cancer among Hispanic women (OR 0.51, 95% CI 0.23, 1.14). A large weight gain and a large waist-tohip ratio (WHR) was associated with an increased odds of having an estrogen receptor negative tumor among NHW only (OR 1.81, 95% CI 1.07, 3.08, and 2.04 95% CI 1.20,3.50). Conclusions These findings suggest that the metabolic consequences of obesity on breast cancer risk differ between NHW and Hispanic women living in the Southwest.

MR-determined metabolic phenotype of breast cancer in prediction of lymphatic spread, grade, and hormone status

Abstract: The purpose of the study was to evaluate the use of metabolic phenotype, described by high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS), as a tool for prediction of histological grade, hormone status, and axillary lymphatic spread in breast cancer patients. Biopsies from breast cancer (n = 91) and adjacent non-involved tissue (n = 48) were excised from patients (n = 77) during surgery. HR MAS MR spectra of intact samples were acquired. Multivariate models relating spectral data to histological grade, lymphatic spread, and hormone status were designed. The multivariate methods applied were variable reduction by principal component analysis (PCA) or partial least-squares regression-uninformative variable elimination (PLS-UVE), and modelling by PLS, probabilistic neural network (PNN), or cascade correlation neural network. In the end, model verification by prediction of blind samples (n = 12) was performed. Validation of PNN training resulted in sensitivity and specificity ranging from 83 to 100% for all predictions. Verification of models by blind sample testing showed that hormone status was well predicted by both PNN and PLS (11 of 12 correct), lymphatic spread was best predicted by PLS (8 of 12), whereas PLS-UVE PNN was the best approach for predicting grade (9 of 12 correct). MR-determined metabolic phenotype may have a future role as a supplement for clinical decision-making-concerning adjuvant treatment and the adaptation to more individualised treatment protocols.

A cognitive behavioral therapy intervention to promote weight loss improves body composition and blood lipid profiles among overweight breast cancer survivors.

Abstract: Overweight or obesity is an established negative prognostic factor in breast cancer Co-morbidities associated with obesity, including cardiovascular disease (CVD), may negatively impact quality of life and survival in this population Our purpose was to determine the effect of a cognitive behavioral therapy (CBT) intervention for weight loss through exercise and diet modification on risk factors for recurrence of breast cancer, and risks for CVD associated with obesity Eighty-five overweight or obese breast cancer survivors were randomly assigned to a once weekly, 16-week intervention or wait-list control group The intervention incorporated elements of CBT for obesity, addressing a reduction in energy intake, as well exercise, with a goal of an average of 1 h a day of moderate to vigorous activity Body weight, total and regional body fat (by dual energy X-ray absorptiometry), waist and hip circumference, and blood lipids were assessed at baseline and following 16 weeks of intervention Results: Seventy six women (894%) completed the intervention Independent t-test to evaluate group differences at 16 weeks showed significant differences in weight, body mass index, percent fat, trunk fat, leg fat, as well as waist and hip circumference between intervention and control groups (P ≤ 005) Furthermore, levels of triglycerides and total cholesterol/high density lipoprotein cholesterol levels were also significantly reduced following the intervention These results indicate that 16 weeks of a CBT program for weight management may reduce obesity and CVD risk in overweight breast cancer survivors

Possible socioeconomic and ethnic disparities in quality of life in a cohort of breast cancer survivors

Abstract: This paper describes the ethnic and socioeconomic correlates of functioning in a cohort of long-term nonrecurring breast cancer survivors. Participants (n = 804) in this study were women from the Health, Eating, Activity, and Lifestyle (HEAL) Study, a population-based, multicenter, multiethnic, prospective study of women newly diagnosed with in situ or Stages I to IIIA breast cancer. Measurements occurred at three timepoints following diagnosis. Outcomes included standardized measures of functioning (MOS SF-36). Overall, these long-term survivors reported values on two physical function subscales of the SF-36 slightly lower than population norms. Black women reported statistically significantly lower physical functioning (PF) scores (P = 0.01), compared with White and Hispanic women, but higher mental health (MH) scores (P < 0.01) compared with White and Hispanic women. In the final adjusted model, race was significantly related to PF, with Black participants and participants in the “Other” ethnic category reporting poorer functioning compared to the White referent group (P < 0.01, 0.05). Not working outside the home, being retired or disabled and being unemployed (on leave, looking for work) were associated with poorer PF compared to currently working (both P < 0.01). These data indicate that race/ethnicity influences psychosocial functioning in breast cancer survivors and can be used to identify need for targeted interventions to improve functioning.

Accuracy of fine needle aspiration cytology (FNAC) of axillary lymph nodes as a triage test in breast cancer staging

Abstract: Introduction Axillary node fine needle aspiration cytology (FNAC) has the potential to triage women with operable breast cancer to initial nodal surgical procedure. Because of variability in the reported accuracy of this test its role and clinical utility in pre-operative staging remains controversial.

Simultaneous two-color spectral fluorescence lymphangiography with near infrared quantum dots to map two lymphatic flows from the breast and the upper extremity

Abstract: Due to their small size and poor access, the lymphatic function has been difficult to study in vivo. Especially difficult is the mapping of lymphatic drainage from two basins into the same node. Quantum dots can be used to perform multicolor images with high fluorescent intensity and are of a nano-size size suitable for lymphatic imaging via direct interstitial injection. Here we show simultaneous two-color in vivo wavelength-resolved spectral fluorescence lymphangiography using two near infrared quantum dots with different emission spectra, which allow non-invasive and simultaneous visualization of two separate lymphatic flows draining the breast and the upper extremity and variations in the drainage patterns and the water sheds within the axillary node. Two-color spectral fluorescence lymphangiography can provide insight into mechanisms of drainage from different lymphatic basins that may lead to sentinel lymph nodes detection of the breast cancer as well as prevention of complications such as lymphedema of the arm.

Accuracy and underestimation of malignancy of breast core needle biopsy: the Florence experience of over 4000 consecutive biopsies.

Abstract: Breast core needle biopsy (CNB) is used for sampling breast lesions in both the screening and diagnostic context. We present the accuracy of breast CNB from a consecutive series of 4035 core biopsies, using methods that minimise selection and verification bias. We calculate accuracy and underestimation of malignancy for both automated (14G) and directional vacuum-assisted (11G) CNB performed under stereotactic or sonographic guidance. Overall sensitivity of CNB is 94.2% (92.9-95.5%) and specificity is 88.1% (86.6-89.6%), positive and negative predictive values are 84.8% (82.9-86.7%) and 95.6% (94.6-96.6%), respectively. In sampling microcalcification, the overall underestimation of malignancy is 26.6% (22.9-30.3%): underestimation is significantly higher for automated CB relative to VAB (chi2 ((df = 1)) = 8.90 , P = 0.002), the absolute difference in underestimation being 14% (5-23%); sensitivity is higher for VAB than automated CB (chi2 ((df = 1)) = 3.28, P = 0.06) but specificity is significantly higher for automated CB (14G) relative to VAB (11G) (chi2 ((df = 1)) = 6.37, P = 0.01), and the overall accuracy of the two methods is similar. Sensitivity of CNB improved with experience (over time and in relation to caseload). Accuracy was not substantially affected by lesion palpability or image-guidance method, and was similar for both masses and calcification but lower for lesions depicted as distortions on mammography. Inadequacy was very low and decreased with greater operator caseload, and was not associated with core gauge or image-guidance method. False negatives occurred in 4.4% (3.4-5.4%) of cases, and where core histology was benign but discordant with (suspicious) imaging and/or clinical findings the likelihood of malignancy was 33.1% (18.5-47.7%), emphasising the importance of correlating all test information in breast diagnosis.

A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of BMP4 and BMP7

Abstract: Bone morphogenetic proteins (BMPs) regulate diverse cellular processes, such as proliferation, differentiation, and apoptosis. The BMPs have been studied in several cancers, but thus far contradictory results have been obtained and, especially in breast cancer, information on BMPs is still limited. We performed a systematic expression survey of BMPs and their receptors in breast cancer. mRNA expression was studied of seven BMP ligands (BMP2-BMP8) and six receptors (ACVR1, BMPR1A, BMPR1B, BMPR2, ACVR2A, and ACVR2B) that specifically mediate BMP signals. Expression levels were determined in 22 breast cancer cell lines, 39 primary breast tumors, normal human mammary epithelial cell line, and normal mammary gland using semiquantitative RT-PCR. The expression frequencies and expression levels of different BMPs varied considerably in breast cancer with BMP4 and BMP7 being most frequently expressed and showing highest expression levels. The BMP specific receptors were more uniformly expressed and indicated that breast cancer is fully capable of transmitting BMP signals. Expression frequencies and levels for both the ligands and the receptors were in good concordance between the breast cancer cell lines and primary tumors. We can conclude that breast cancers possess functional BMP signaling machinery on the cell surface with distinct differences in the expression of various BMP ligands. Our survey focuses the attention particularly toward BMP4 and BMP7 and suggests their importance in breast cancer. Breast cancer cell lines and the data generated here serve as a good resource for further studies on BMP function in breast cancer.