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Detection bias and relation of benign breast disease to breast cancer.

The relation between benign breast disease and breast cancer was investigated in a case-control study of postmenopausal patients selected either by diagnostic procedure sampling (mammography 150 cases and controls, breast biopsy 107 cases and controls) or by conventional sampling procedures (257 controls to match total number of cases). For mammography patients, the odds ratio for association between benign breast disease and breast cancer was 0.9; for biopsy patients the odds ratio was 0.8; but by use of conventional methods, the odds ratio was elevated to a "causal" and statistically significant 2.6. When patients were classified according to cancer stage, benign breast disease was present in 56/147 patients with localised cancer compared with 24/107 patients with non-localised cancer (odds ratio 2.3). Evidence that benign breast disease is a risk factor for breast cancer may therefore be misleading if choice of control groups makes no provision for bias produced by inequalities in detection of disease.

Aged↗

Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line.

To evaluate whether leptin plays a putative role in breast tumorigenesis, we studied the expression of its long and short receptor isoforms in various tumoral breast tissues. We applied semiquantitative RT-PCR method to RNA extracted from 20 breast cancer biopsies and two human breast cancer cell lines (T47-D and MCF-7). Our results showed the expression of both leptin receptor transcripts in all tumoral tissues examined. By in situ hybridization experiments, we localized leptin receptors in proliferating epithelial cells. Study of leptin effects on human breast cancer cells growth was performed by [3H]-thymidine incorporation method and colorimetric MTT assay. We demonstrated that leptin (50-100 ng/ml) significantly stimulates proliferation of the human breast cancer cell line T47-D (P<0.05). Western blot analysis indicated that leptin induces a time-dependent activation of mitogen-activated protein kinases (MAPKinase) 1 and 2 in T47-D cell line. Moreover, the specific MAPK-inhibitor PD 98059 blocked cell proliferation induced by leptin. In conclusion, we demonstrate that leptin receptors are expressed in breast cancer and that leptin induces proliferation in the T47-D cell line via activation of the MAPKinases pathway. These data suggest that leptin and its receptors may be implicated in mammary cell proliferation and in breast cancer pathogenesis.

Blotting, Western↗

Relationship of family history and outcome after breast conservation therapy in women with ductal carcinoma in situ of the breast.

PURPOSE: The purpose of this study was to evaluate the relationship between a family history of breast or ovarian cancer and outcome after breast-conserving surgery and radiation in women presenting with an initial diagnosis of ductal carcinoma in situ (DCIS) of the breast. METHODS AND MATERIALS: A total of 146 consecutive women with a pathologic diagnosis of ductal carcinoma in situ as their first diagnosis of any breast cancer were identified; 28 (19%) had a positive family history of breast or ovarian cancer in a first-degree relative, 27 (19%) had a positive family history in a second-degree relative, and 91 (62%) had no family history. Pathologic, clinical, and treatment factors, and clinical outcomes for each family history group were compared. Cosmesis and complications were recorded at each follow-up. Patients were treated between 1978 and 1995, and the median follow-up was 7.1 years. RESULTS: Patients with a positive family history in a first- or second-degree relative each had an 8% incidence of local failure at 10 years, while the negative family history group demonstrated a 16% local failure rate (p = 0.33). Overall survival at 10 years for patients with a positive family history in a first- or second-degree relative was 100% and for those with a negative family history was 91% (p = 0.08). The negative family history group had a higher median age that may account for the difference in overall survival. Cause-specific survival (CSS) was 97%, 100%, and 99%, respectively, at 10 years (p = 0.25). There were no differences in the cosmetic results or complication rates between women with a positive or negative family history. CONCLUSION: We have shown that a family history of breast and/or ovarian cancer is not associated with an adverse outcome for women treated with breast conservation therapy for DCIS. Local recurrence, cause-specific survival, overall survival, cosmesis, and complication rates were comparable to that of similarly treated women with negative family histories. Therefore, a positive family history is not a contraindication for breast conservation therapy in women with DCIS.

Adult↗

The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer.

BACKGROUND: With the general acceptance of lumpectomy, axillary staging, and radiotherapy as local treatment for infiltrating breast cancer, an appreciation is evolving for the spectrum of vascular lesions that occur in the mammary skin after this treatment. Most of these lesions develop within the prior radiation field after breast conservation treatment. STUDY DESIGN: A retrospective chart and slide review was conducted, consisting of five patients with cutaneous vascular lesions after breast conservation treatment for infiltrating breast cancer. RESULTS: The latent time interval from definitive treatment of breast cancer to the clinical recognition of vascular lesions ranged from 5 to 11 years. Two patients did not have either arm or breast edema, two patients had breast edema, and the fifth patient had arm edema. Lesions arising in the irradiated mammary skin included extensive lymphangiectasia (one), atypical vascular lesions (two), and cutaneous angiosarcoma (four). CONCLUSIONS: Atypical vascular lesions at the skin margins of mastectomy may be predictive of recurrence after resection of angiosarcoma. Excision of skin from the entire radiation field may be necessary to secure local control of the chest wall in patients with cutaneous angiosarcoma after therapeutic breast radiotherapy.

Aged↗

Demonstration of aromatase activity and its regulation in breast tumor and benign breast fibroblasts.

Breast tumors from post-menopausal women contain higher amounts of estradiol than would be predicted from levels circulating in plasma. This observation raised the hypothesis that tumors may synthesize estradiol in situ and increase their tissue estradiol levels via this mechanism. The key enzyme involved in tissue estrogen synthesis, aromatase, is present in breast tumors but, according to some investigators, not in sufficient concentration to be biologically meaningful. We postulated that foci of cells in breast tumors might contain high amounts of aromatase and this locally produced estrogen might act in a paracrine or autocrine fashion. To test this hypothesis, we utilized immunohistochemistry to localize the aromatase enzyme, an histological scoring system to quantitate it, and culture of isolated breast cells to demonstrate its potential regulation. In 26 archival breast tumors, 16 (62%) contained aromatase by radiometric assay. With the immunohistochemical method, we detected areas with staining in the stroma as well as tumor epithelial cells. Staining ranged from the intensity approaching that seen in placenta to levels just distinguishable from background. We adopted an histological scoring system (H-score) from that used to quantitate progesterone receptor levels in tissue and used it to quantitate aromatase activity. A higher histologic score was found in stromal spindle cells (13) than in tumor epithelial cells (4.8). The biochemical aromatase results correlated with the H-score of stromal but not epithelial cells. To further study stromal cells from tumors, we isolated stromal cells from breast tumors and the benign areas of breast distal to the tumor and grew them in culture. Addition of dexamethasone, phorbol esters, and cyclic AMP analogues stimulated aromatase enzyme and messenger RNA levels substantially. Use of aromatase enzyme inhibitors such as letrozole blocked estrogen production but did not alter aromatase message levels. Epithelial cells, whether nonmalignant or cancer derived, exhibited no regulation by dexamethasone, phorbol esters, or cAMP analogues. These data, taken together, suggest that stromal cells may be more important than epithelial cancer cells for estrogen production in breast tumors. The ability to stimulate aromatase activity substantially with various enhancers of aromatase provides further credence for an important biologic role of estrogen production in tumor tissue.

Aromatase↗

Polyamine profiles in tumor, normal tissue of the homologous breast, blood, and urine of breast cancer sufferers.

Polyamines are involved in the development of breast cancer. We assayed polyamines in erythrocytes, urines, and breast tissues (tumor tissue and histologically normal breast tissue close to the tumor) of patients with invasive breast cancer (n = 174) and benign breast disease (n = 71, used as controls). Polyamine levels in red blood cells and urine were similar to the polyamine concentrations found in healthy subjects, and thus cannot be used as diagnostic markers of breast cancer. In cancer tissue, polyamines were significantly increased in comparison with the polyamine concentrations in controls, and were correlated to the tumor aggressiveness as evaluated by histological grade and Ki-67 proliferative index. On the other hand, correlation was found between polyamine levels in the tumor and the status of the hormone receptors. In the mammary tissue close to the cancer, polyamines dramatically decreased in comparison with the polyamine levels of tissue samples removed around the histologically proven benign tumors. The changes of the polyamine concentrations in the histologically normal breast tissue in the vicinity of the cancer could play a role in the cancer development and need further studies, especially if polyamines are considered as a potential therapeutic target in breast cancer.

Adenocarcinoma↗

The relation of breast size to breast cancer risk in postmenopausal women (United States).

OBJECTIVE: Breast size has been hypothesized to predict a woman's risk of breast cancer although studies in the main have not supported an association. In a large, population-based case-control study we examined whether breast size might emerge as a significant risk factor among very lean women in whom breast size might be a truer reflection of the volume of gland mass at risk for malignant change. METHODS: The data derive from a population-based case-control study of women aged 50 to 79 years conducted in several New England states and Wisconsin. Incident cases of invasive breast cancer (n = 2015) were identified through state tumor registries and controls (n = 2556) were selected at random within age strata from population lists. Telephone interviews were conducted to obtain information on known and suspected risk factors which included bra dimensions (cup and back size) prior to a first birth, or at the age of 20 for nulliparous women. RESULTS: We observed a significant positive association for cup size which was limited to women who were the most lean as young adults based on chest circumference. Among those reporting a chest size under 34 inches multivariate-adjusted relative risks were 1.34 (95% CI: 1.04 to 1.74) for cup size B, and 1.76 (95% CI: 1.04 to 3.01) for cup size C and larger, compared to a cup size smaller than B, and the trend for increasing cup size was statistically significant (P = 0.005). There was no relation with breast size among women reporting an average or larger back circumference (34 inches or larger). CONCLUSION: Breast size before a pregnancy is a positive predictor of postmenopausal breast cancer, but this association is limited to those who were especially lean as young women.

Adipose Tissue↗

Is male breast cancer similar or different than female breast cancer?

OBJECTIVE: To determine if male breast carcinogenesis was similar to its more common female counterpart, we compared incidence patterns among men and women with breast cancer. METHODS: Breast cancer records were obtained from the SEER database. Women were stratified by age < 50 and > or = 50 years to simulate premenopausal and postmenopausal breast cancer. RESULTS: Age-adjusted incidence trends were stable among men but increased among women. Male to female breast cancer ratio was higher for blacks than for whites. Favorable prognostic factors reflective of tumor biology (nuclear grade and hormone receptor expression) were more common for men and postmenopausal women than for premenopausal women. For example, low nuclear grade, estrogen and progesterone receptor-positive expression were more common among men and postmenopausal women than among premenopausal women. The age-specific incidence rate curve for men increased steadily for all ages with a constant slope. On the other hand, age-specific rates for women increased rapidly until age 50 years then rose at a slower rate for postmenopausal women. Age-frequency distribution for male breast cancer was unimodal, with peak incidence at age 71 years. Age-frequency distribution for women was bimodal with early-onset and late-onset incidence at 52 and 71 years, respectively. CONCLUSIONS: Gender-specific incidence trends differed, most likely reflective of female-related changes in surveillance and/or reproductive risk factors. On the other hand, similar prognostic factor profiles reflective of tumor biology, age-specific incidence rate patterns, and age-frequency distributions suggested that male breast cancer was more like postmenopausal than premenopausal female breast cancer.

Age Factors↗

Breast tissue organochlorine levels and metabolic genotypes in relation to breast cancer risk Canada.

Genes that metabolize the rate of clearance of environmental carcinogens may be candidate genes for cancer susceptibility. There is some data to suggest that exposure to environmental pesticides and other organochlorine pollutants is a risk factor to breast cancer. It is therefore reasonable to ask if variants in the genes responsible for the metabolic activation of organochlorines are associated with different tissue burdens of organochlorines and if these variants modify the risk of breast cancer in the population. We conducted a case-control study of women who underwent an excision biopsy for suspected breast cancer in a Toronto hospital from 1995 to 1997. Patients are residents of the Greater Toronto Area and are primarily Caucasian of European descent. Cases were women with invasive breast cancer (n = 70) and controls (n = 69) were women diagnosed with benign disease, frequency matched by age to cases. Levels of organochlorines were measured in benign breast tissue and seven polymorphisms in five candidate genes were genotyped. In general, women who carried inactive alleles of the GSTM1 had higher levels of breast organochlorines, and were at modestly increased risk of breast cancer (odds ratio = 2.2; 95% CI = 1.1-4.4). However, multiple comparisons were made and generally our data do not support the hypothesis that organochlorines increase the risk of breast cancer among subgroups of women with specific metabolic genotypes.

Adult↗

Is there an increased risk of breast cancer in women who have had a breast cyst aspirated?

A consecutive series of 644 women who presented with breast nodularity between 1976 and 1982 have been followed up to determine their rate of subsequent breast cancer. Fifteen women have developed breast cancer, 14 of these were among 352 women with an aspirated cyst (relative risk 4.4). Women with multiple cysts had the highest risk and women with breast nodularity had no excess risk. Review of histology specimens from those women who had undergone biopsy showed an excess of florid epithelial hyperplasia in women who subsequently developed breast cancer and women with multiple aspirated cysts were more likely to have florid epithelial hyperplasia. Multiple cysts are clinical markers of histological breast proliferation and women who have had multiple breast cysts aspirated have an increased risk of breast cancer and should be advised to practice regular self examination.

Adult↗

Breast self-examination and death from breast cancer: a meta-analysis.

Breast self-examination (BSE) is widely recommended for breast cancer prevention. Following recent controversy over the efficacy of mammography, it may be seen as an alternative. We present a meta-analysis of the effect of regular BSE on breast cancer mortality. From a search of the medical literature, 20 observational studies and three clinical trials were identified that reported on breast cancer death rates or rates of advanced breast cancer (a marker of death) according to BSE practice. A lower risk of mortality or advanced breast cancer was only found in studies of women with breast cancer who reported practising BSE before diagnosis (mortality: pooled relative risk 0.64, 95% CI 0.56-0.73; advanced cancer, pooled relative risk 0.60, 95% CI 0.46-0.80). The results are probably due to bias and confounding. There was no difference in death rate in studies on women who detected their cancer during an examination (pooled relative risk 0.90, 95% CI 0.72-1.12). None of the trials of BSE training (in which most women reported practising it regularly) showed lower mortality in the BSE group (pooled relative risk 1.01, 95% CI 0.92-1.12). They did show that BSE is associated with considerably more women seeking medical advice and having biopsies. Regular BSE is not an effective method of reducing breast cancer mortality.

Adult↗

Breast cellulitis complicating breast conservation therapy.

Breast conservation therapy has gained acceptance as treatment for limited disease due to breast cancer. Unfortunately, a minority of patients who undergo this therapy will develop cellulitis of the breast, often recurrently, months to years later. A definitive pathogen has not been identified in the large majority of cases reported to date. Whilst some patients develop systemic toxicity with local skin changes of cellulitis, others manifest no fever, chills or leukocytosis. Local breast findings gradually clear with antibiotic treatment: when breast changes persist, non-inflammatory causes, including tumour recurrence, of the breast should be considered. More study is needed to define risk factors for the development of breast cellulitis complicating breast conservation therapy.

Acute Disease↗

Outcome of radiotherapy after breast conserving surgery in screen detected breast cancers.

The treatment outcomes were reviewed for all the patients at this institute who underwent breast irradiation after breast conserving surgery in 1991. Of a total of 643 patients treated, 194 (30%) had presented with tumours detected by screening mammography. The breast was irradiated with a tangential pair of fields, giving a dose of 40 Gy in 15 fractions over 3 weeks in 97% of these patients. A boost was not used. With a median follow-up of 4.7 years, there was better cancer related survival in patients with screen detected cancers compared with those that were non-screen detected (94% versus 84% at 5 years; P = 0.002). The breast recurrence rate at 5 years was 1% for screen detected cancers compared with 6% for those that were non-screen detected (P = 0.01). Factors additional to screen detected status that were found to be significant for cancer survival were pathological stage (P = 0.03) and histological grade (P = 0.01). In a Cox multivariate analysis, only two factors were significant for breast recurrence: screen detected status (P = 0.023) and histological grade (P = 0.016). This study suggests that breast irradiation with 40 Gy given over 3 weeks after breast conserving surgery for screen detected breast cancer gives a high level of local control out to 5 years.

Aged↗

Radial scars of the breast and breast carcinomas have similar alterations in expression of factors involved in vascular stroma formation.

We recently reported that radial scars are an independent histologic risk factor for breast cancer. The reason for this association is not known. Given the importance of stromal-epithelial interactions in the pathogenesis of breast cancer, we studied radial scars for the expression of a number of factors known to be involved in the formation of vascular stroma in breast cancer. In situ hybridization was performed on formalin-fixed paraffin sections using (35)S-labeled riboprobes for collagen type 1, total fibronectin, extra domain A (ED-A)+ fibronectin, thrombospondin 1, vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF), and one of its endothelial receptors, kinase insert domain-containing receptor (KDR) (vascular endothelial growth factor receptor [VEGFR-2]). Expression levels in radial scars (9 cases) were compared with those in normal breast tissue (15 cases) and infiltrating ductal breast carcinoma (4 cases). Factor VIII-related antigen immunostaining was used to define the distribution of microvessels in radial scars, carcinoma, and normal breast tissue. Compared with normal breast tissue, the radial scars showed focally increased numbers of blood vessels and focally increased expression of messenger RNA (mRNA) for collagen type 1, total fibronectin, ED-A+ fibronectin, thrombospondin 1, VPF/VEGF, and KDR. This pattern of mRNA overexpression was similar to that seen in the 4 invasive cancers. We conclude that there are similarities between radial scars and invasive breast cancers with regard to the level of mRNA expression for several factors involved in the formation of vascular stroma. These results suggest that a similar disturbance in stromal-epithelial interactions is present in both lesions.

Adult↗

Expression of a prostate-associated protein, human glandular kallikrein (hK2), in breast tumours and in normal breast secretions.

The recent demonstration of human glandular kallikrein (hK2) expression in a breast carcinoma cell line has suggested that this putatively prostate-restricted, steroid hormone-regulated protease may also be expressed in breast epithelium in vivo and secreted into the mammary duct system. Given that the only substrate yet identified for hK2 activity is the precursor of prostate-specific antigen (PSA), the expression of which in breast carcinomas may be associated with favourable prognosis, our purpose was to examine the expression pattern of both hK2 and PSA in breast tumour tissues. Cytosolic extracts of 336 primary breast carcinomas prepared for routine oestrogen receptor (ER) and progesterone receptor (PR) analysis, as well as 31 nipple aspirates from six women with non-diseased mammary glands, were assayed for hK2 and PSA using immunofluorometric assays developed by the authors. In the tumour extracts, measurable hK2 and PSA concentrations were detected in 53% and 73% of cases respectively, and were positively correlated to each other (r = 0.59, P = 0.0001). Higher concentrations of PSA and hK2 were found in tumours expressing steroid hormone receptors (P = 0.0001 for PSA and P = 0.0001 for hK2, by Wilcoxon tests for both ER and PR), and both PSA (r = 0.25, P = 0.0001) and hK2 (r = 0.22, P = 0.0001) correlated directly with PR levels. A negative correlation between patient age and PSA (r = -0.12, P = 0.03) was also found. Both proteins were present in nipple aspirate fluid at relatively high concentrations which were positively correlated (r = 0.53, P = 0.002). The molecular weights of the immunoreactive species quantified by the hK2 and PSA assays were established by high-performance liquid chromatography (HPLC) and were consistent with the known molecular weights of hK2 and PSA. Together these data provide the first evidence, to our knowledge, that both malignant breast tissue and normal breast secretion contain measurable quantities of hK2, and that the degree of hK2 expression or secretion is directly proportional to the expression of PSA and steroid hormone receptors. hK2 expression may therefore be a marker of steroid hormone action in breast tissue.

Breast↗

Risk factors for breast cancer in women with proliferative breast disease.

To assess the importance of various risk factors for breast cancer in women with benign proliferative breast lesions, we reevaluated 10,366 consecutive breast biopsies performed in women who had presented at three Nashville hospitals. The median duration of follow-up was 17 years for 3303 women, 1925 of whom had proliferative disease. This sample contained 84.4 per cent of the patients originally selected for follow-up. Women having proliferative disease without atypical hyperplasia had a risk of cancer that was 1.9 times the risk in women with nonproliferative lesions (95 per cent confidence interval, 1.2 to 2.9). The risk in women with atypical hyperplasia (atypia) was 5.3 times that in women with nonproliferative lesions (95 per cent confidence interval, 3.1 to 8.8). A family history of breast cancer had little effect on the risk in women with nonproliferative lesions. However, the risk in women with atypia and a family history of breast cancer was 11 times that in women who had nonproliferative lesions without a family history (95 per cent confidence interval, 5.5 to 24). Calcification elevated the cancer risk in patients with proliferative disease. Although cysts alone did not substantially elevate the risk, women with both cysts and a family history of breast cancer had a risk 2.7 times higher than that for women without either of these risk factors (95 per cent confidence interval, 1.5 to 4.6). This study demonstrates that the majority of women (70 per cent) who undergo breast biopsy for benign disease are not at increased risk of cancer. However, patients with a clinically meaningful elevation in cancer risk can be identified on the basis of atypical hyperplasia and a family history of breast cancer.

Adult↗

Selection criteria for breast conservation in breast cancer.

Breast conservation, comprising limited excision of the breast and axillary lymphadenectomy followed by irradiation, yields survival equal to mastectomy with the advantage of preservation of the breast for properly selected patients. When breast conservation therapy is competently done it achieves highly satisfactory cosmetic results and acceptably low rates of local recurrence. However, numerous controversies surround the selection criteria, the relative importance of some of them, and the treatment. Four critical elements in selecting patients for breast conservation therapy are: history and physical examination, careful mammographic evaluation, histological assessment of the resected specimen, and assessment of the patient's needs and expectations. Today, it is estimated that breast conservation can be recommended to 50%-75% of all women with operable breast cancer. However, this treatment is not widely used. In this article we review the generally accepted principles and controversies about the selection of patients for breast conservation.

Actuarial Analysis↗

CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies.

Previous studies of families with multiple cases of breast cancer have indicated that a frameshift alteration in the CHEK2 gene, 1100delC, is associated with an elevated frequency of breast cancer in such families, but the risk associated with the variant in other situations is uncertain. To evaluate the breast cancer risk associated with this variant, 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in five countries were genotyped. CHEK2*1100delC was found in 201 cases (1.9%) and 64 controls (0.7%) (estimated odds ratio 2.34; 95% CI 1.72-3.20; P=.0000001). There was some evidence of a higher prevalence of CHEK2*1100delC among cases with a first-degree relative affected with breast cancer (odds ratio 1.44; 95% CI 0.93-2.23; P=.10) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis (P=.002). These results confirm that CHEK2*1100delC confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results are consistent with the hypothesis that CHEK2*1100delC multiplies the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.

Adult↗