Germline DNA copy number variation in familial and early-onset breast cancer

Introduction: Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease." Methods: Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations. Results: The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer. Conclusions: This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-beta 1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1 beta- and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-beta 1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-beta 1, suggesting that it may have therapeutic use in CKD treatment.

Do the physical discomforts from breast cancer treatments affect the sexuality of women who underwent mastectomy?

The objective of this integrative review is to analyze the scientific production addressing the sexuality of women with breast cancer following mastectomy, focused on the effects that the physical discomfort due to cancer treatments have on their sex life. The search included articles published in the period between 2000 and 2009 on the MEDLINE, LILACS and PsycINFO databases, using the following descriptors: mastectomy, breast neoplasms, sexuality, sexual behavior, amputation, psychosexual development, and marital relations. Nine articles were selected, which addressed the effects of the physical discomfort from cancer treatments on the patients' sexuality. The findings revealed that, even when the patient's sex life is intense and fulfilling before the disease, factors such as stress, pain, fatigue, insult to body image, and low self-esteem due to the treatments may alter the sexual functioning of the affected woman. Healthcare professionals must be sensitized in order to welcome and include the topic in policies as well as in preventive, diagnostic, and therapeutic strategies.

Minimally invasive mastectomy: minimal incisions for better aesthetic quality of breast reconstruction

Background: Women with a family history of breast cancer who develop this disease are confronted with important situations regarding the increased risk for development of a second cancer in the contralateral breast. Prophylactic contralateral mastectomy (PCM) reduces by approximately 95% the risk for contralateral breast cancer. In spite of an increase in indications for PCM, the technical difficulties are many regarding the accomplishment of these procedures. The aim of this study is to describe the technique of mastectomy with preservation of the nipple-areola complex and a small incision, reducing surgical difficulties and complications attributed to this technique, thus allowing better aesthetic results in breast reconstruction. Methods: Forty-six patients with indications for PCM (28 bilateral) were submitted to minimally invasive mastectomy from March 2005 to November 2007. A small incision in the superior pole of the areola, sufficient to pass a liposuction 4 mm cannula is made. With the help of this cannula, detachment of the skin from the gland tissue is performed. Then a 3.5 to 4.5-cm long incision in the inframammary fold is made. Glandular detachment is completed using cautery in the sub,glandular portion and scissors in the upper breast portion cutting the restraints left by the cannula. The mammary gland tissue is removed through this incision. Results: Seventy-four breasts were operated on. The resected breast mass ranged from 285 g to 475 g. All 43 patients were reconstructed with prostheses. There was no necrosis of the nipple-areola complex or of the skin. Conclusions: This technique is an option for cases of patients with indications for PCM.

Thyroid hormone profile in breast cancer patients in postmenopause

Objective: The aim of this study was to determine thyroid hormone (TH) profile in postmenopausal patients with breast cancer (BC). Subjects and methods: 12 CaM patients stages I or II, without interventions that could interfere with tumor progression were selected, as well as and a control group with 18 postmenopausal women without CaM. We measured serum anti-thyroperoxidase antibody (TPOAB), thyroid-stimulating hormone (TSH), free thyroxine (T4L), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), before and after surgery, besides immunohistochemistry for estrogen (ER) and progesterone (PR) receptors. Results: Four patients with CaM showed changes in thyroid hormone profile: two had hyperthyroidism, one hypothyroidism, and one was positive for TPO-AB. All of them positive for ER and PR.TSH levels in breast cancer patients were not different from levels found in the control group (1.89 +/- 1.56 vs. 2.86 +/- 3.12 mIU/mL), but the levels of T4L in patients with CaM were statistically higher than those of the control group (1.83 +/- 0.57 vs. 1.10 +/- 0.20 ng/dL). Conclusion: These results reinforce the need for assessment of thyroid status in CaM patients, since in the absence of E2, changes in clinical HTs can act in E2-controlled processes. Arq Bras Endocrinol Metab. 2012;56(4):238-43

Glutathione Peroxidase 1 Pro198Leu Polymorphism in Brazilian Alzheimer's Disease Patients: Relations to the Enzyme Activity and to Selenium Status

Background/Aims: Oxidative stress plays a central role in Alzheimer's disease (AD). Pro198Leu cytosolic glutathione peroxidase (GPx1) polymorphism seems to be associated with a lower activity of this enzyme, but there are no studies with AD patients. Thus, the aim was to determine the frequency of the GPx1 Pro198Leu polymorphism in AD patients and to verify its relation to glutathione peroxidase (GPx) activity and selenium (Se) status. Methods:The study was carried out in a group of AD elderly (n = 28) compared to a control group (n = 29). Blood Se concentrations were measured through hydride generation atomic absorption spectroscopy. GPx activity was determined using a commercial kit, and the polymorphism using amplified DNA sequencing. Results:The distribution of genotypes was not different between groups. The variant allele frequency was 0.179 (AD group) and 0.207 (control group). Although no differences regarding GPx activity were found between individuals with different genotypes, lower blood Se levels were found in Pro/Pro AD patients compared to Pro/Pro control subjects, which was not found in the Pro/Leu groups. Moreover, the association between the erythrocyte Se concentration and GPx activity was affected by the Pro198Leu genotype. Conclusions: Results indicate that this polymorphism had apparently affected Se status in AD patients and that more studies in this field are necessary. Copyright (c) 2012 S. Karger AG, Basel

Toll-like receptor 3: implications for proinflammatory microenvironment in human breast cancer

Under many circumstances, the host constituents that are found in the tumor microenvironment support a malignancy network and provide the cancer cells with advantages in proliferation, invasiveness and metastasis establishment at remote organs. It is known that Toll like receptors (TLRs) are expressed not only on immune cells but also on cancer cells and it has suggested a deleterious role for TLR3 in inflammatory disease. Hypothesizing that altered IFN gamma signaling may be a key mechanism of immune dysfunction common to cancer as well CXCR4 is overexpressed among breast cancer patients, the mRNA expression of TLR3, CXCR4 and IFN gamma in breast cancer tumor tissues was investigated. No statistically significant differences in the expression of CXCR4 mRNA, IFN gamma and TLR3 between healthy and tumor tissues was observed, however, it was verified a positive correlation between mRNA relative expression of TLR3 and CXCR4 (p < 0.001), and mRNA relative expression of TLR3 was significantly increased in breast cancer tumor tissue when compared to healthy mammary gland tissue among patients expressing high IFN gamma (p = 0.001). Since the tumor microenvironment plays important roles in cancer initiation, growth, progression, invasion and metastasis, it is possible to propose that an overexpression of IFN gamma mRNA due to the pro-inflammatory microenvironment can lead to an up-regulation of CXCR4 mRNA and consequently to an increased TLR3 mRNA expression even among nodal negative patients. In the future, a comprehensive study of TLR3, CXCR4 and IFN gamma axis in primary breast tumors and corresponding healthy tissues will be crucial to further understanding of the cancer network.

Why Are Women With Cervical Cancer Not Being Diagnosed in Preinvasive Phase? An Analysis of Risk Factors Using a Hierarchical Model

Objective: To assess the risk factors for delayed diagnosis of uterine cervical lesions. Materials and Methods: This is a case-control study that recruited 178 women at 2 Brazilian hospitals. The cases (n = 74) were composed of women with a late diagnosis of a lesion in the uterine cervix (invasive carcinoma in any stage). The controls (n = 104) were composed of women with cervical lesions diagnosed early on (low-or high-grade intraepithelial lesions). The analysis was performed by means of logistic regression model using a hierarchical model. The socioeconomic and demographic variables were included at level I (distal). Level II (intermediate) included the personal and family antecedents and knowledge about the Papanicolaou test and human papillomavirus. Level III (proximal) encompassed the variables relating to individuals' care for their own health, gynecologic symptoms, and variables relating to access to the health care system. Results: The risk factors for late diagnosis of uterine cervical lesions were age older than 40 years (odds ratio [OR] = 10.4; 95% confidence interval [CI], 2.3-48.4), not knowing the difference between the Papanicolaou test and gynecological pelvic examinations (OR, = 2.5; 95% CI, 1.3-4.9), not thinking that the Papanicolaou test was important (odds ratio [OR], 4.2; 95% CI, 1.3-13.4), and abnormal vaginal bleeding (OR, 15.0; 95% CI, 6.5-35.0). Previous treatment for sexually transmissible disease was a protective factor (OR, 0.3; 95% CI, 0.1-0.8) for delayed diagnosis. Conclusions: Deficiencies in cervical cancer prevention programs in developing countries are not simply a matter of better provision and coverage of Papanicolaou tests. The misconception about the Papanicolaou test is a serious educational problem, as demonstrated by the present study.

HER-2, p53, p21 and hormonal receptors proteins expression as predictive factors of response and prognosis in locally advanced breast cancer treated with neoadjuvant docetaxel plus epirubicin combination

Abstract Background Neoadjuvant chemotherapy has been considered the standard care in locally advanced breast cancer. However, about 20% of the patients do not benefit from this clinical treatment and, predictive factors of response were not defined yet. This study was designed to evaluate the importance of biological markers to predict response and prognosis in stage II and III breast cancer patients treated with taxane and anthracycline combination as neoadjuvant setting. Methods Sixty patients received preoperative docetaxel (75 mg/m2) in combination with epirubicin (50 mg/m2) in i.v. infusion in D1 every 3 weeks after incisional biopsy. They received adjuvant chemotherapy with CMF or FEC, attaining axillary status following definitive breast surgery. Clinical and pathologic response rates were measured after preoperative therapy. We evaluated the response rate to neoadjuvant chemotherapy and the prognostic significance of clinicopathological and immunohistochemical parameters (ER, PR, p51, p21 and HER-2 protein expression). The median patient age was 50.5 years with a median follow up time 48 months after the time of diagnosis. Results Preoperative treatment achieved clinical response in 76.6% of patients and complete pathologic response in 5%. The clinical, pathological and immunohistochemical parameters were not able to predict response to therapy and, only HER2 protein overexpression was associated with a decrease in disease free and overall survival (P = 0.0007 and P = 0.003) as shown by multivariate analysis. Conclusion Immunohistochemical phenotypes were not able to predict response to neoadjuvant chemotherapy. Clinical response is inversely correlated with a risk of death in patients submitted to neoadjuvant chemotherapy and HER2 overexpression is the major prognostic factor in stage II and III breast cancer patients treated with a neoadjuvant docetaxel and epirubicin combination.

Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study

Abstract Background The main focus of several studies concerned with cancer progression and metastasis is to analyze the mechanisms that allow cancer cells to interact and quickly adapt with their environment. Integrins, a family of transmembrane glycoproteins, play a major role in invasive and metastatic processes. Integrins are involved in cell adhesion in both cell-extracellular matrix and cell-cell interactions, and particularly, β1 integrin is involved in proliferation and differentiation of cells in the development of epithelial tissues. This work aimed to investigate the putative role of β1 integrin expression on survival and metastasis in patients with breast invasive ductal carcinoma (IDC). In addition, we compared the expression of β1 integrin in patients with ductal carcinoma in situ (DCIS). Methods Through tissue microarray (TMA) slides containing 225 samples of IDC and 67 samples of DCIS, β1 integrin expression was related with several immunohistochemical markers and clinicopathologic features of prognostic significance. Results β1 integrin was overexpressed in 32.8% of IDC. In IDC, β1 integrin was related with HER-2 (p = 0.019) and VEGF (p = 0.011) expression and it had a significant relationship with metastasis and death (p = 0.001 and p = 0.05, respectively). Kaplan-Meier survival analysis showed that the overexpression of this protein is very significant (p = 0.002) in specific survival (number of months between diagnosis and death caused by the disease). There were no correlation between IDC and DCIS (p = 0.559) regarding β1 integrin expression. Conclusions Considering that the expression of β1 integrin in breast cancer remains controversial, specially its relation with survival of patients, our findings provide further evidence that β1 integrin can be a marker of poor prognosis in breast cancer. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6652215267393871

Pain and quality of life in patients undergoing radiotherapy for spinal metastatic disease treatment

Abstract Background Radiotherapy is an important tool in the control of pain in patients with spinal metastatic disease. We aimed to evaluate pain and of quality of life of patients with spinal metastatic disease undergoing radiotherapy with supportive treatment. Methods The study enrolled 30 patients. From January 2008 to January 2010, patients selection included those treated with a 20 Gy tumour dose in five fractions. Patients completed the visual analogue scale for pain assessment and the SF-36 questionnaire for quality of life assessment. Results The most frequent primary sites were breast, multiple myeloma, prostate and lymphoma. It was found that 14 spinal metastatic disease patients (46.66%) had restricted involvement of three or fewer vertebrae, while 16 patients (53.33%) had cases involving more than three vertebrae. The data from the visual analogue scale evaluation of pain showed that the average initial score was 5.7 points, the value 30 days after the end of radiotherapy was 4.60 points and the average value 6 months after treatment was 4.25 points. Notably, this final value was 25.43% lower than the value from the initial analysis. With regard to the quality of life evaluation, only the values for the functional capability and social aspects categories of the questionnaire showed significant improvement. Conclusion Radiotherapy with supportive treatment appears to be an important tool for the treatment of pain in patients with spinal metastatic disease.

Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain)

[EN] Background: All the relevant risk factors contributing to breast cancer etiology are not fully known. Exposure to organochlorine pesticides has been linked to an increased incidence of the disease, although not all data have been consistent. Most published studies evaluated the exposure to organochlorines individually, ignoring the potential effects exerted by the mixtures of chemicals. Methods: This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk.Results: The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024).Conclusions: This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk.

Evaluation of Antitumoral activity of bone targeted drugs/conventional chemotherapies and identification of biomarkers for the selection of patients with breast cancer for the bone targeted therapy in adjuvant setting

Bone metastases are responsible for different clinical complications defined as skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, hypercalcaemia, bone marrow infiltration and severe bone pain requiring palliative radiotherapy. The general aim of these three years research period was to improve the management of patients with bone metastases through two different approaches of translational research. Firstly in vitro preclinical tests were conducted on breast cancer cells and on indirect co-colture of cancer cells and osteoclasts to evaluate bone targeted therapy singly and in combination with conventional chemotherapy. The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Furthermore the combination Zoledronic Acid + Cisplatin induced a high antitumoral activity in the two triple-negative lines MDA-MB-231 and BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cisplatin doses. A co-colture system to test the activity of bone-targeted molecules on monocytes-breast conditioned by breast cancer cells was also developed. Another important criticism of the treatment of breast cancer patients, is the selection of patients who will benefit of bone targeted therapy in the adjuvant setting. A retrospective case-control study on breast cancer patients to find new predictive markers of bone metastases in the primary tumors was performed. Eight markers were evaluated and TFF1 and CXCR4 were found to discriminate between patients with relapse to bone respect to patients with no evidence of disease. In particular TFF1 was the most accurate marker reaching a sensitivity of 63% and a specificity of 79%. This marker could be a useful tool for clinicians to select patients who could benefit for bone targeted therapy in adjuvant setting.

Older Breast Cancer Survivors: Geriatric Assessment Domains Are Associated With Poor Tolerance of Treatment Adverse Effects and Predict Mortality Over 7 Years of Follow-Up

Purpose To evaluate geriatric assessment (GA) domains in relation to clinically important outcomes in older breast cancer survivors. Methods Six hundred sixty women diagnosed with primary breast cancer in four US geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island) were selected with disease stage I to IIIA, age ≥ 65 years at date of diagnosis, and permission from attending physician to contact. Data were collected over 7 years of follow-up from consenting patients' medical records, telephone interviews, physician questionnaires, and the National Death Index. Outcomes included self-reported treatment tolerance and all-cause mortality. Four GA domains were described by six individual measures, as follows: sociodemographic by adequate finances; clinical by Charlson comorbidity index (CCI) and body mass index; function by number of physical function limitations; and psychosocial by the five-item Mental Health Index (MHI5) and Medical Outcomes Study Social Support Survey (MOS-SSS). Associations were evaluated using t tests, χ2 tests, and regression analyses. Results In multivariable regression including age and stage, three measures from two domains (clinical and psychosocial) were associated with poor treatment tolerance; these were CCI ≥ 1 (odds ratio [OR] = 2.49; 95% CI, 1.18 to 5.25), MHI5 score less than 80 (OR = 2.36; 95% CI, 1.15 to 4.86), and MOS-SSS score less than 80 (OR = 3.32; 95% CI, 1.44 to 7.66). Four measures representing all four GA domains predicted mortality; these were inadequate finances (hazard ratio [HR] = 1.89; 95% CI, 1.24 to 2.88; CCI ≥ 1 (HR = 1.38; 95% CI, 1.01 to 1.88), functional limitation (HR = 1.40; 95% CI, 1.01 to 1.93), and MHI5 score less than 80 (HR = 1.34; 95% CI, 1.01 to 1.85). In addition, the proportion of women with these outcomes incrementally increased as the number of GA deficits increased. Conclusion This study provides longitudinal evidence that GA domains are associated with poor treatment tolerance and predict mortality at 7 years of follow-up, independent of age and stage of disease.

Longitudinal patterns in survival, comorbidity, healthcare utilization and quality of care among older women following breast cancer diagnosis

OBJECTIVES To compare longitudinal patterns of health care utilization and quality of care for other health conditions between breast cancer-surviving older women and a matched cohort without breast cancer. DESIGN Prospective five-year longitudinal comparison of cases and matched controls. SUBJECTS Newly identified breast cancer patients recruited during 1997–1999 from four geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island; N = 422) were matched by age, race, baseline comorbidity and zip code location with up to four non-breast-cancer controls (N = 1,656). OUTCOMES Survival; numbers of hospitalized days and physician visits; total inpatient and outpatient Medicare payments; guideline monitoring for patients with cardiovascular disease and diabetes, and bone density testing and colorectal cancer screening. RESULTS Five-year survival was similar for cases and controls (80% and 82%, respectively; p = 0.18). In the first follow-up year, comorbidity burden and health care utilization were higher for cases (p < 0.01), with most differences diminishing over time. However, the number of physician visits was higher for cases (p < 0.01) in every year, driven partly by more cancer and surgical specialist visits. Cases and controls adhered similarly to recommended bone density testing, and monitoring of cardiovascular disease and diabetes; adherence to recommended colorectal cancer screening was better among cases. CONCLUSION Breast cancer survivors’ health care utilization and disease burden return to pre-diagnosis levels after one year, yet their greater use of outpatient care persists at least five years. Quality of care for other chronic health problems is similar for cases and controls.