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Breast cancer screening, outside the population-screening program, of women from breast cancer families without proven BRCA1/BRCA2 mutations: a simulation study.

PURPOSE: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based. METHODS: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated. RESULTS: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative. CONCLUSION: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members.

Adult↗

Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice.

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products.

Animals↗

The effects of green tea consumption on incidence of breast cancer and recurrence of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Green tea is widely used by women for the prevention and treatment of breast cancer. The authors aimed to determine the efficacy of green tea ingestion on the risk of breast cancer development and the risk of breast cancer recurrence. METHODS: The authors conducted a systematic review and meta-analyses of observational studies from systematic searches of 8 electronic data sources and contact with authors. They included studies assessing breast cancer incidence and recurrence. RESULTS: Results: The pooled relative risk (RR) of developing breast cancer for the highest levels of green tea consumption in cohort studies was 0.89 (95% confidence interval [CI], 0.71-1.1; P= .28; I(2)= 0%), and in case control studies, the odds ratio was 0.44 (95% CI, 0.14-1.31; P= .14; I(2)= 47%). The pooled RR of cohort studies for breast cancer recurrence in all stages was 0.75 (95% CI, 0.47-1.19; P= .22; I(2)= 37%). A subgroup analysis of recurrence in stage I and II disease showed a pooled RR in cohort studies of 0.56 (95% CI, 0.38-0.83; P= .004; I2= 0%). Dose-response relationships were evident in only 3 of the 7 studies. CONCLUSION: To date, the epidemiological data indicates that consumption of 5 or more cups of green tea a day shows a non-statistically significant trend towards the prevention of breast cancer development. Evidence indicates that green tea consumption may possibly help prevent breast cancer recurrence in early stage (I and II) cancers. However, conclusions as to the potential therapeutic application of green tea are currently impossible to make due to the small number of studies conducted, the lack of any clinical trial evidence, the lack of a consistent dose-response relationship, and the potential for interaction with standard care.

Anticarcinogenic Agents↗

Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer Symposium, December, 2001).

This paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium. The preliminary results of the ATAC study have shown that Arimidex is superior to tamoxifen in postmenopausal women with ER-positive early breast cancer in terms of DFS, adverse effects and prevention of contralateral breast cancer. However, longer follow up is required to assess the drug safety regarding bone mineral density and cognitive function. Letrozole seems to be superior to tamoxifen as a first-line therapy in ER-positive advanced breast cancer in postmenopausal women. Although the incidence of acute myeloid leukaemia is significantly increased (cumulative incidence at 5 years = 1.1%) in breast cancer patients receiving cyclophosphamide and anthracyclines, the risk of this complication is easily outweighed by the benefits of chemotherapy. Adjuvant clodronate was found to be associated with a significant reduction in the incidence of bone metastases during the treatment period. A randomised trial comparing axillary dissection and axillary radiotherapy (RT) for early breast cancer reported no significant difference in survival at 15 years. However, axillary recurrence was significantly increased in the RT group. hTERT protein expression by IHC was found to correlate significantly with breast cancer-specific survival. There is no evidence to support the use of IHC of the sentinel node in routine clinical practice. LCIS is currently considered as a non-obligate precursor to breast cancer rather than just a risk factor.

Antineoplastic Combined Chemotherapy Protocols↗

Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic.

PURPOSE: Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status. PATIENTS AND METHODS: Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, a polymerase chain reaction-based heteroduplex analysis, or direct sequencing. RESULTS: Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P <.0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P <.0016; OR, 1.69; 95% CI, 1.23 to 2.38). CONCLUSION: These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.

Adult↗

High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer.

PURPOSE: Women with a hereditary predisposition for breast cancer have an extremely high risk of developing invasive breast carcinoma, and many women consider prophylactic mastectomy to avoid this risk. The use of prophylactic mastectomy is still debated. Identification of frequent premalignant lesions in mastectomy specimens would support the preventive concept of prophylactic mastectomy. PATIENTS AND METHODS: We performed a prospective study of breast specimens from 67 women at extremely high genetic risk of breast cancer, with or without previous breast cancer, who were undergoing prophylactic mastectomy (66% were carriers of a BRCA1 or BRCA2 mutation). Breast specimens were studied by radiographic and macroscopic examination of 5-mm tissue slices, with subsequent histology of suspicious lesions and random samples from each quadrant of the breast and the nipple area. RESULTS: In 57% of the women, one or more different types of high-risk histopathologic lesions were present: 37% atypical lobular hyperplasia, 39% atypical ductal hyperplasia, 25% lobular carcinoma-in-situ, and 15% ductal carcinoma-in-situ. A 4-mm invasive ductal carcinoma was found in one woman with ductal carcinoma-in-situ. None of these lesions was detected at palpation or mammography, which were performed before the mastectomy. The presence of high-risk lesions was independently related to age older than 40 years (odds ratio, 6.6; P =.01) and to bilateral oophorectomy before prophylactic mastectomy (odds ratio, 0.2; P = 0.02). CONCLUSION: Many women at high risk of hereditary breast cancer develop high-risk histopathologic lesions, especially after the age of 40 years. Surveillance does not detect such high-risk histopathologic lesions.

Adult↗

Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis.

PURPOSE: Surgery of the primary tumor usually is not advised for patients with metastatic breast cancer at diagnosis because the disease is considered incurable. In this population-based study, we evaluate the impact of local surgery on survival of patients with metastatic breast cancer at diagnosis. METHODS: We included all 300 metastatic breast cancer patients recorded at the Geneva Cancer Registry between 1977 and 1996. We compared mortality risks from breast cancer between patients who had surgery of the primary breast tumor to those who had not and adjusted these risks for other prognostic factors. RESULTS: Women who had complete excision of the primary breast tumor with negative surgical margins had a 40% reduced risk of death as a result of breast cancer (multiadjusted hazard ratio [HR], 0.6; 95% CI, 0.4 to 1.0) compared with women who did not have surgery (P = .049). This mortality reduction was not significantly different among patients with different sites of metastasis, but in the stratified analysis the effect was particularly evident for women with bone metastasis only (HR, 0.2; 95% CI, 0.1 to 0.4; P = .001). Survival of women who had surgery with positive surgical margins was not different from that of women who did not have surgery. CONCLUSION: Complete surgical excision of the primary tumor improves survival of patients with metastatic breast cancer at diagnosis, particularly among women with only bone metastases.

Adult↗

Breast hypoplasia following irradiation of the female breast in infancy and early childhood.

The occurrence and the degree of breast hypoplasia were studied in 129 women irradiated with ionizing radiation in infancy or childhood for hemangioma located in the breast region. The patients were born between 1934 and 1943 and were treated at Radiumhemmet before 4 years of age. Dosimetry was based on treatment data. The mean absorbed dose to the breast anlage was 2.3 Gy. Breast asymmetry was estimated by a mailed questionnaire to all patients and by a clinical examination of 53 patients living in Stockholm County. Breast hypoplasia on the treated side was reported by 57% of the patients and on the contralateral side by 8%. A breast hypoplasia exceeding 10% was found in 53% of the clinically examined patients on the treated side and in 9% on the contralateral side. The frequency and the severity of impaired breast development increased with the absorbed dose. The possibility of a threshold dose for the occurrence of breast hypoplasia could neither be established nor ruled out.

Breast↗

Indications for breast conservation in early stage breast cancer.

Breast conservation, utilizing limited excisional breast surgery and axillary lymphadenectomy followed by radiation therapy can achieve excellent local/regional control and survival in many breast cancer patients. With average sized tumors, where larger volume resections are performed the results can equal that of the modified radical mastectomy. However, smaller tumors do very well with breast removal so it is a challenge to demonstrate that the long-term results of breast conservation in earlier stage disease are equivalent to mastectomy. Small or occult tumors do not always indicate localized disease and suitability for breast conservation depends on a combination of factors: tumor size and ratio of tumor to breast volume, cell type, location of tumor, obtaining clear margins, the mammographic picture, multicentricity, and the probability of axillary lymph node involvement. It is important to select patients for conservation where an equivalent survival can be expected. Recurrence in the radiated breast usually is diagnosed and treated at a more advanced stage than the disease which was initially treated conservatively. It is difficult to manage and carries a poorer prognosis.

Breast Neoplasms↗

The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer.

BACKGROUND: The risks and benefits of hormone replacement therapy (HRT) are of considerable interest and importance, especially in terms of whether they differ among subsets of women. OBJECTIVE: To determine whether HRT is associated with increased risks for breast cancer and total mortality in women with a family history of breast cancer. DESIGN: Prospective cohort study. SETTING: Population-based sample of midwestern post-menopausal women enrolled in an observational study of risk factors for cancer. PARTICIPANTS: Random sample of 41,837 female Iowa residents 55 to 69 years of age. MEASUREMENTS: Incidence rates of and relative risks for breast cancer (n = 1085) and total mortality (n = 2035) through 8 years of follow-up were calculated by using data from the State Health Registry of Iowa and the National Death Index. RESULTS: A family history of breast cancer was reported by 12.2% of the cohort at risk. Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate of 61 cases per 10,000 person-years (95% CI, 28 to 94 cases); this rate was not statistically significantly higher than the rate in women who had never used HRT (46 cases per 10,000 person-years [CI, 36 to 55 cases]). Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]). The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]). CONCLUSIONS: These data suggest that HRT use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate.

Aged↗

Treatment of estrogen deficiency symptoms in women surviving breast cancer. Part 2: Hormone replacement therapy and breast cancer.

There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 59 breast cancer experts and patient advocates participated. The proceedings of the conference will be published in six installments in successive issues of ONCOLOGY. The first part, published last month, defined the problem and explored its magnitude and ramifications for patient management. This second part focuses on the benefits and risks of hormone replacement therapy (HRT) in patients with breast cancer.

Antineoplastic Agents↗

Primary non-Hodgkin's lymphoma of the breast: breast conservation therapy in two patients.

We report two patients with primary non-Hodgkin's lymphoma of the breast who were treated with breast conservation therapy. These two patients were diagnosed with primary breast lymphoma by fine-needle aspiration cytology and underwent tumorectomy followed by adjuvant chemoradiation therapy. Follow-up studies showed that the two patients were free of disease for two and three years, respectively. To date, there exists no therapeutic standard for this disease and there is no survival advantage for patients who undergo radical mastectomy. Despite the rarity of lymphoma in the breast, a preoperative accurate diagnosis is essential so that unnecessary, extended breast ablation or delayed treatment is avoided. Cytologic diagnosis of breast lymphoma is an easy procedure and provides guidance for appropriate preoperative management. Early diagnosis combined with breast conservation therapy and systemic adjuvant therapy results in a favorable outcome for patients with breast lymphoma.

Adult↗

The Van Nuys Breast Center: the first free-standing multidisciplinary breast center.

This article describes the author's 30-year experience with the design and development of breast centers. It describes the author's initial attempt at developing a breast center at UCLA, the history of the Van Nuys Breast Center (its patient population, philosophy, problems, finances, and demise), and the development of the Harold E. and Henrietta C. Lee Breast Center. Breast centers are defined as focused multidisciplinary facilities of excellence, dealing with the complete range of breast problems. The main focus of this article is the Van Nuys Breast Center, which was the prototype model for most breast centers developed in the United States.

Breast Neoplasms↗

Breast cancer risks and prevention: implications of the Breast Cancer Prevention Trial results.

Breast cancer is a major health concern for women in the U.S. Several factors determine a woman's risk for developing breast cancer including age, genetics, hormonal exposure and others. It is possible to estimate a woman's risk for developing breast cancer by using a statistical model known as the Gail model. Using this model, the Breast Cancer Prevention Trial (BCPT) found that women at high risk for breast cancer could have their incidence of breast cancer reduced by 49% by taking tamoxifen. The serious side effects of tamoxifen therapy were almost exclusively seen in women over age 50. Women under 50 with a high risk of breast cancer are, therefore, most likely to benefit from taking tamoxifen for five years. Thus, a benefit-to-risk estimate should be made for each woman before advising her to take tamoxifen. A new trial (Study of Tamoxifen And Raloxifene, STAR) will compare tamoxifen with raloxifene for their effectiveness in reducing breast cancer and for side effects. West Virginia women participated in the BCPT and will be able to participate in the STAR trial through centers in Morgantown and Charleston.

Aged↗

Risk factors for benign breast biopsies: a nested case-control study in the Alberta breast screening program.

A nested case-control study was conducted to identify risk factors for benign breast biopsies in 382 cases (women with a benign biopsy result) and 399 controls (women who had not undergone a biopsy) who were sampled from the Alberta breast cancer screening program. The breast biopsy specimens of the cases were reviewed by a panel of pathologists, and percent fibroglandular tissue density was assessed. The multivariable odds ratios for the risk of open benign breast biopsy associated with current cigarette smoking was 2.04 (95% CI 1.32-3.13), for ever regular smoking was 1.61 (1.20-2.16), and for passive smoking was 1.41 (0.99-2.02). A risk reduction was found for ever alcohol consumption (0.61 [0.44-0.85]). Some risk reductions were found when the highest and the lowest quintiles of total aerobic recreational activity were compared (0.71 [0.42-1.20]), stair climbing (0.61 [0.37-1.01]) and walking pace (0.13 [0.02-0.741). Lifestyle risk factors may be implicated in the continuum between detection of an abnormality on a screening mammogram and a breast biopsy specimen. By considering these risk factors, breast screening programs may be better able to identify those women who require a breast biopsy and reduce the number of benign breast biopsies.

Aged↗

Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer.

PURPOSE: Determination of meaningful prognostic indicesremains a high priority for women diagnosed with node-negative primary breast cancer. Currently, 30% of these women relapse, and there is no reliable means of predicting this group of patients. This study investigates whether the level of expression of versican, an anticell adhesive proteoglycan, in the peritumoral stromal tissue of women with node-negative, primary breast cancer predicts relapse-free survival. This study also examines whether breast cancer cells regulate the secretion of versican by mammary fibroblasts. EXPERIMENTAL DESIGN: Immunoreactive versican was measured in breast cancer tissue sections of 58 node-negative patients by video image analysis. Primary isolates of mammary fibroblasts were cultured in medium conditioned by the breast cancer cell lines ZR-75-1, MCF-7, BT-20, and MB231. Changes in versican secretion were measured by immunoblotting and enhanced chemiluminescence. RESULTS: Cox analyses indicated that peritumoral versican level was the sole predictor of relapse-free survival. The relapse rate in patients with low versican levels was lower than in patients with high versican levels (Kaplan-Meier: 83% relapse free at 5 years for versican mean integrated absorbance <14 versus 33% for > or = 14, P = 0.0006). Accumulation of versican in medium of mammary fibroblasts was increased after culture in conditioned medium from breast cancer cell lines. CONCLUSIONS: Relapse in women with node-negative breast cancer is related to the level of versican deposited in peritumoral stroma by mammary fibroblasts. Versican secretion appears to be regulated by breast cancer cell mediators. Neoplastic remodeling of extracellular matrix through increased versican deposition may facilitate local invasion and metastasis.

Adult↗

Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma.

The Wnt genes encode a family of related, secreted proteins which initiate a signal cascade upon binding to cell surface receptor molecules. The signaling pathway has been shown to be critical for normal growth and development in model organisms and is implicated in the genesis of numerous human cancers. Wnt proteins regulate mammary development in the mouse but their precise role in normal breast development and malignant transformation in humans remains poorly defined. In this study, we have examined the expression of several Wnt ligands by in situ anti-sense RNA hybridization in normal and malignant human breast tissue, as well as in several estrogen-responsive and estrogen-independent human breast cancer cell lines. The specific Wnt genes tested included Wnt1, Wnt2, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7b and Wnt10b. We have also studied the expression of frizzled receptors 1 and 2 by immunohistochemistry in these tissues. Our results indicate that several of the Wnt ligands, especially Wnt1 and Wnt6, are strongly expressed in both normal and malignant breast tissue and that Wnt7b is down-regulated in breast cancer, compared to normal breast epithelium. The expression of frizzled 1 and 2 receptors was found to be up-regulated in breast cancer. These studies provide additional support to the hypothesis that the Wnt signaling pathway is involved in human breast cancer.

Breast Neoplasms↗

[Breast conserving treatment in patients with early detection of breast cancer].

OBJECTIVES: Kujawsko-pomorskie province is a region with high morbidity and death-rate from breast cancer. One method of detected less advanced forms of breast cancer and increased number of patients with BCT having prophylactic medical examination. DESIGN: The aim of the study was the treatment evaluation of patients with noninvasive and invasive cancer treated with BCT, screening-detected and non-screening detected. MATERIALS AND METHODS: Prophylactic mammography for breast cancer was taken in three medical centers. First one so called "mobile" was localized in the health service center, second one in the bus with the mammography reaching distant areas and third one was performing examinations locally. There were 63401 people examined for breast cancer (age 35 -79), detected 288 breast cancers (0.54% of examined population). 260 of them were operated on. 1149 breast cancers were detected in non-screening group. The number of detected noninvasive cancers, their sizes and methods of treatment were analysed. RESULTS: Twelve of 260 (4,62%) cancers detected in screening patients were carcinoma noninvasive and 34 invasive cancers treated with BCT. In non-screening patients 20 carcinoma noninvasive and 104 invasive cancers were found and treated with BCT The number of patients with noninvasive and invasive cancers treated with BCT in prophylactic group is statistically higher. Sizes and clinical stages of malignant tumours detected in both groups were not different CONCLUSIONS: 1. Prophylactic breast cancer examinations increase the number of noninvasive cancers. 2. Breast cancer prophylactic examinations increase the number of patients treated with BCT.

Adult↗