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Dose- and time-response for breast cancer risk after radiation therapy for benign breast disease.

Exposure of the breast to ionising radiation increases the risk of breast cancer, especially among young women. However, some issues remain controversial, for instance the shape of the dose-response curve and the expression of time-related excess. The main purpose of this report was to examine the dose-response curves for radiation-induced breast cancer formulated according to radiobiological target theories. Another purpose was to analyse the time-related excess of breast cancer risk after exposure when dose and age at first exposure were held constant. Breast cancer incidence was analysed in a cohort of 3090 women diagnosed with benign breast disease during 1925-61 (median age 37 years). Of these, 1216 were treated with radiation therapy. The dose range was 0-50 Gy (mean 5.8 Gy). The incidence rate as function of dose was analysed using a linear-quadratic Poisson regression model. Cell-killing effects and other modifying effects were incorporated through additional log-linear terms. Additive and multiplicative models were compared in estimating the time-related excess. The analysis, which was based on 278 breast cancer cases, showed a linear dose-response relationship at low to medium dose levels with a cell-killing effect of 5% Gy-1 (95% confidence interval 2-9%). For a given absorbed dose and age at first exposure the time-related excess was proportional to the background rates with a suggestion that the excess remains throughout life.

Adolescent↗

Human breast cancer cells contain a phosphoramidon-sensitive metalloproteinase which can process exogenous big endothelin-1 to endothelin-1: a proposed mitogen for human breast fibroblasts.

Endothelin-1 (ET-1) levels are elevated in human breast tumours compared with normal and benign tissues, and in the presence of insulin-like growth factor 1 (IGF-I) ET-1 is a potent mitogen for human breast fibroblasts. In this study we have examined the ability of intact human breast cancer cell lines to process exogenously added big ET-1 (1-38) to the active mature ET-1 peptide by using a specific radioimmunometric assay. In both hormome-dependent (MCF-7, T47-D) and hormone-independent (MDA-MB-231) breast cancer cell lines the putative endothelin-converting enzyme (ECE) exhibited apparent Michaelis-Menten kinetics when converting added big ET-1 to ET-1. Both basal ET-1 production and exogenously added big ET-1 to ET-1 conversion were greatly reduced in all three cell lines in response to the metalloproteinase inhibitor phosphoramidon but were insensitive to other classes of protease inhibitors. Inhibition was also observed when cells were incubated in the presence of the divalent cation chelators 1,10-phenanthroline and EDTA. In MCF-7 cells the optimal pH for the ECE activity using a saponin cell permeabilisation procedure was found to residue within a narrow range of 6.2-7.26. Our results indicate that human breast cancer cells contain a neutral phosphoramidon-sensitive metalloproteinase which can process big ET-1 to ET-1. In the breast this conversion could contribute substantially to the local extracellular levels of this proposed paracrine breast fibroblast mitogen.

Aspartic Acid Endopeptidases↗

Breast cancer incidence subsequent to surgical reduction of the female breast.

The incidence of breast cancer among 1240 women who were treated surgically for breast hypertrophy in Copenhagen, Denmark between 1943 and 1971 was determined and compared with age- and calendar period-specific rates for the Danish female population. A total of 32 cases of breast cancer had developed by the end of 1990; the expected number was 52.55, yielding a relative risk (RR) of 0.61 [95% confidence interval (CI) 0.42-0.86]. The greatest reduction in risk was observed for women who had 600 g or more of breast tissue removed (RR=0.30; 95% CI 0.10-0.69). This suggests that the number of potential foci is important for cancer development in the female breast. In the group of women who were operated on before the age of 20, four cases of breast cancer developed, compared with 2.23 expected cases, to give an RR of 1.79, suggesting that the aetiology of their breast hypertrophy may be different from that for the rest of the group.

Adult↗

Autotransplants in men with breast cancer. ABMTR Breast Cancer Working Committee. Autologous Blood and Marrow Transplant Registry.

The purpose of this study was to determine the outcome of high-dose therapy with autologous hematopoietic stem cell support (autotransplants) in men with breast cancer. We studied 13 men receiving autotransplants for breast cancer and reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) by 10 centers. Six men had stage 2 breast cancer, four had stage 3, and three had metastatic breast cancer. Of twelve tumors tested, all were estrogen receptor positive. Median age at transplant was 50 years. The most common conditioning regimen was cyclophosphamide, thiotepa and carboplatin (n = 5); the remaining eight men received other alkylator-based regimens. Three men received bone marrow, eight received blood stem cells, and two received both for hematopoietic support. All patients had hematopoietic recovery. There were no unexpected regimen-related toxicities. Of 10 men receiving autotransplants as adjuvant therapy, three relapsed 3, 5 and 50 months post-transplant and died 16, 19 and 67 months post-transplant. Seven of 10 are disease-free with median follow-up of 23 months (range 6-50 months). Of three men treated for metastatic breast cancer, one had progressive disease and two recurrent disease at 6, 7 and 16 months post-transplant. In conclusion, results of autotransplants for male breast cancer appear similar to those reported for women receiving autotransplants for breast cancer.

Adult↗

Breast cancer genome anatomy: correlation of morphological changes in breast carcinomas with expression of the novel gene product Di12.

To determine which genes may be activated or inactivated during breast cancer development, we employed two cloning strategies (subtractive hybridization and differential display) using RNA samples from a human breast tumor and its matching normal breast cell line. Of 950 clones isolated, 102 cDNA inserts were analysed by DNA sequencing and database searching. We found 30 clones that were obviously unidentified, with no significant homology to any listed human gene. We focused upon one of the novel genes, Di12, that is differentially expressed as a 1.35 kb RNA in breast cancer tissues and cell-lines, and in several normal tissues. A full length cDNA of this gene was cloned, and its DNA sequence revealed an open reading frame of 339 amino acids. Antibodies to the ten N-terminal amino acids were developed to investigate the expression of Di12 in breast cancer cell-lines and tumors. The Di12 protein was found in tissue sections of infiltrating ductal carcinomas (IDCs), but not in benign or normal breast specimens. RT-PCR analysis confirmed expression of Di12 in 80% of infiltrating ductal carcinomas (IDCs). As IDC constitutes approximately 70% of breast cancers seen clinically, the level of Di12 expression may be predictive of disease progression.

Amino Acid Sequence↗

Two erbB-4 transcripts are expressed in normal breast and in most breast cancers.

ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT-PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which amplified a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the 'full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with different intracellular signalling pathways and therefore influence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the C-terminal transcripts as CT-a (full-length) and CT-b which lacks the P13K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.

Alternative Splicing↗

bFGF and aFGF induce membrane ruffling in breast cancer cells but not in normal breast epithelial cells: FGFR-4 involvement.

Acidic and basic fibroblast growth factors (aFGF and bFGF) are growth factors which may have a physiological role in the normal breast and in breast cancer. A study of the effects of aFGF and bFGF on a variety of breast cell lines and epithelial cells purified from normal breast organoids showed that whereas normal breast cells did not exhibit membrane ruffling in response to either of these growth factors, some breast cancer cell lines did. This difference was not due to lack of receptor since all the cell lines tested were mitogenically stimulated by bFGF. Dominant negative mutations of FGF receptor 3 (FGFR-3) and the small GTP-binding protein p21rac inhibited membrane ruffling, showing that receptor dimerization and phosphorylation and p21rac activation are prerequisites for membrane ruffling in response to aFGF and bFGF. Transient transfection of individual FGFRs into cos-7 cells showed that FGFR-1, FGFR-2 and FGFR-3 could not mediate a membrane ruffling response whereas FGFR-4 could. These studies elucidate one signalling mechanism of FGF and point to differences in the response of normal and cancer breast epithelial cells which may be important in cell motility.

3T3 Cells↗

Delayed breast cellulitis following breast conserving operation.

A complication of breast conservation, which has been increasingly reported in the literature, is 'delayed cellulitis' in the treated breast. This is to be distinguished from wound infection in the breast following lumpectomy. This study reports 16 cases diagnosed with delayed cellulitis following breast conserving surgery, unresponsive to antibiotic therapy. Diagnostic criteria included: pain, erythema and edema in the operated breast. Symptoms appeared up to 10 months after surgery and time to resolution was seven and a half months. No patients had positive cytology and bacteriology tests were negative. Thirteen patients were observed, and three patients were treated with antibiotics with no apparent immediate effect. The appearance of breast cellulitis after surgery poses a problematic diagnostic and management dilemma. It is important to distinguish between this entity and infection, or inflammatory carcinoma. The picture may be attributed to impairment or occlusion of the lymphatic circulation in the breast. This seems to be a newly defined complication with an incidence of 3-5%.

Adult↗

Modulation of oestrone sulphate formation and hydrolysis in breast cancer cells by breast cyst fluid from British and Hungarian women.

Women with gross cystic breast disease may have an increased risk of breast cancer. In this study the ability of breast cyst fluid (BCF), obtained from British or Hungarian women, to modulate oestrone sulphate (E1S) formation or hydrolysis, has been examined. For this, oestrogen receptor-positive (ER+) MCF-7 or MDA-MB-231 (ER-) breast cancer cells were employed. The formation and hydrolysis of E1S was measured using radiometric techniques. BCF from British and Hungarian women mainly inhibited E1S hydrolysis in MCF-7 cells while stimulating hydrolysis in MDA-MB-231 cells. The extent of inhibition or stimulation of E1S hydrolysis in these cells was related to the Na+/K+ ratio of the BCF. There was a significant inverse relationship between the extent to which BCF samples inhibited hydrolysis in MCF-7 cells and stimulated it in MDA-MB-231 cells. BCF stimulated E1S formation in MCF-7 cells while inhibiting formation in MDA-MB-231 cells. No difference in the ability of BCF from British or Hungarian women to inhibit or stimulate E1S hydrolysis was detected in ER+ or ER- breast cancer cells. In contrast, BCF from British women stimulated E1S formation in ER+ cells (median 82%) to a significantly greater extent (P < 0.01) than BCF from Hungarian women (median 33%). The role that E1S has in breast cancer development remains unclear. The greater stimulation of E1S formation by BCF from British women, who have a higher risk of breast cancer than Hungarian women, suggests that it may act as a storage form of oestrogen within cells that can be activated by oestrone sulphatase.

Breast Neoplasms↗

[Ultrasound examination of the breast with 7.5 MHz and 13 MHz-transducers: scope for improving diagnostic accuracy in complementary breast diagnostics?].

AIM: Complementary diagnostic methods in early diagnosis of breast cancer are used to increase diagnostic accuracy and minimize unnecessary invasive diagnostic procedures. Aim of the following prospective, open multicenter clinical study was to define the value of high-frequency breast ultrasound with 13 MHZ transducers compared to standard breast ultrasound with 7.5 MHz. METHOD: Data of 810 female patients, aged 45 to 60 years, with 819 suspicious breast lesions evaluated by four participating centres between October 1996 and December 1997. Standardised breast ultrasound was performed uniformly using a AU4 IDEA diagnostic ultrasound system by Esaote-Biomedica in addition to a standardised procedure of clinical examination and standard-2view-mammography. Analysis of all aquired data and the correlating histopathological findings was done by means of descriptive statistics on the basis of an access datafile (Version 2.0). RESULTS: The histopathological evaluation showed 435 benign and 384 malignant findings. Overall sensitivity and specificity of the clinical examination were 71.1 % and 88.9 % and for mammography 84.7 % and 76.5 %, respectively. Standard ultrasound with 7,5 MHz reached a sensitivity of 82,6 % and a specificity of 80.8 % high-frequency ultrasound with 13 MHz came to 87.2 % and 78.4 %, respectively. Regarding tumour size, mammography gave the highest sensitivity in detection of pre-invasive cancers (DCIS). High-frequency breast ultrasound (13 MHz) proved to have a higher diagnostic accuracy compared to standard breast ultrasound (7,5 MHz) regardless of tumour size. Sensitivity was especially improved in case of small invasive tumours (pT1a) with 78 % versus 56 %, respectively. CONCLUSIONS: We conclude that high-frequency ultrasound is a valueable additive tool especially in the diagnosis of small tumours, improving diagnostic safety and reducing unnecessary invasive diagnostic procedures.

Breast Diseases↗

[Angiosarcoma of the breast after conservatively operated breast carcinoma--a sequela of adjuvant radiotherapy?].

Angiosarcoma represents only 2.4% of soft tissue malignancies. Primary angiosarcoma of the breast is also a rare neoplasm. The incidence of this disease has been reported to be 0.04% of all breast malignancies. The aetiology is unknown. Angiosarcoma associated with chronic lymphoedematous arm of a postmastectomy woman was described by Stewart and Treves. In this paper we describe a 62-year-old female who underwent wide excision, axillary node dissection and adjuvant radiotherapy for primary breast cancer. After 5 years she noticed a purple discolouration of the treated left breast. Biopsy of these areas confirmed an angiosarcoma. No haematogenous dissemination was found. She underwent simple mastectomy without systemic therapy. A chest X-ray 3 months later revealed diffuse bilateral lung metastases. The incidence of breast conserving therapies is growing fast. Until now we have no evidence on the role of irradiation as an aetiological reason for angiosarcoma after breast-conserving surgery and axillary node dissection. Therefore, we have to pay increasing attention to these patients. A patient with history of radiotherapy after breast conserving therapy and skin discolouration must undergo a biopsy of these areas. The only therapy of angiosarcoma is an early mastectomy. The success of chemotherapy is uncertain. Possibly adjuvant chemotherapy with actinomycin D for the group with poorly differentiated tumours appears beneficial. Prospective studies might help to resolve this question.

Breast↗

Breast lymphedema after breast conserving treatment.

The authors aimed to evaluate breast lymphedema after breast conserving therapy (BCT) and sentinel node biopsy (SNB) or axillary clearance (AC). Fifty-seven breast cancer patients with BCT underwent SNB only and 103 underwent AC (57 with tumor negative and 46 with positive axillary nodes). Clinical examination and breast ultrasonography (US) were performed one year after surgery. Clinical examination revealed breast edema in 48% of patients in the AC node positive group, in 35% in the AC node negative group, and in 23% in the SNB group (p<0.05 between SNB and AC node positive). US revealed subcutaneous edema in the operated breast in 69-70% of the patients in the AC groups and in 28% in the SNB group (p=0.001-0.0001 between the SNB and the AC groups). Breast lymphedema was less common one year after BCT in patients with SNB only than in those with more extensive axillary treatment.

Adult↗

Breast lymphoma associated with breast implants: two case-reports and a review of the literature.

Breast lymphoma is a rare entity consisting mostly of B-cell lymphomas that affects older women. Very few cases of breast lymphomas of T-cell origin have been reported. Even fewer cases of breast lymphomas have been reported in women who have received breast implants. Silicone, a frequent component of breast implants, has been extensively investigated as a possible etiologic agent for some neoplasias and autoimmune disorders, including non-Hodgkin's lymphoma. We herein report two unusual cases of anaplastic large cell lymphoma of T-cell phenotype developing in the breasts of women who had received breast implants.

Aged↗

Circulation in the breast after radiotherapy and breast conservation.

OBJECTIVE: To investigate the breast circulation after radiotherapy and breast conservation. DESIGN: Open clinical study. SETTING: University hospital, Sweden. SUBJECTS: 24 patients with breast cancer (mean age 54 years, range 41-64). INTERVENTIONS: The glandular and the subcutaneous circulation in the breast were measured by Xenon (133Xe) clearance and the skin circulation by laser Doppler fluxmetry (LDF) two to five years after radiotherapy (50 Gy) following lumpectomy. The subcutaneous circulation was measured 2 cm above and medial or lateral to the areolar border and the glandular circulation 2 cm below and medial or lateral to the areolar border in the quadrant not previously operated on for carcinoma. The skin circulation was measured at the corresponding sites. MAIN OUTCOME MEASURES: Circulation in the subcutaneous and glandular tissue measured by 133Xe clearance and in the skin by LDF. RESULTS: The subcutaneous circulation, expressed as the ratio of 133Xe clearance in the operated irradiated: non-operated non-irradiated breast, was 0.88 (0.94) (median, interquartile range) and the glandular circulation 0.93 (0.75). The skin circulation ratios over the corresponding areas were 1.00 (0.37) and 1.00 (0.38), respectively. CONCLUSION: Radiotherapy after breast conservation surgery does not lead to long-term changes in basal glandular, subcutaneous, or skin circulation in the breast.

Adult↗

Usefulness of technetium-99m tetrofosmin scintimammography to detect breast cancer in mammographically dense breasts.

The purpose of this study was to assess the usefulness of techentium-99m tetrofosmin (Tc-TF) scintimammography to detect breast cancer in 32 female Taiwanese patients with indeterminate mammograpic probability of malignancy because of mammographyically dense breasts. All breast masses were removed and final histopathological diagnoses were obtained in all cases. The results showed that Tc-TF scintimammography findings were true-positive in 20 cases, false-positive in 1 case, true-negative in seven cases, and false-negative in four cases. The diagnostic sensitivity, specificity, and accuracy were 83, 88, and 84%, respectively, for detecting breast cancer in mammographically dense breasts. In conclusion, Tc-TF scintimammography is a useful tool for detecting breast cancer in patients with indeterminate mammograms because of mammographically dense breasts.

Adult↗

Usefulness of thallium-201 SPECT scintimammography to differentiate benign from malignant breast masses in mammographically dense breasts.

The purpose of this study was to assess the usefulness of thallium-201 (Tl-201) single-photon emission-computed tomography (SPECT) scintimammography to differentiate benign from malignant breast masses in 32 female Taiwanese patients with indeterminate mammographic probability of malignancy because of mammographically dense breasts. All breast masses were removed, and final histopathological diagnoses were obtained in all cases. The results showed that thallium-201 SPECT scintimammography findings were true-positive in 22 cases, false-positive in 1 case, true-negative in 7 cases, and false-negative in 2 cases. The diagnostic sensitivity, specificity, and accuracy were 91.7%, 87.5%, and 90.6%, respectively, for detecting breast cancer in mammographically dense breasts. In conclusion, thallium-201 SPECT scintimammography is a useful tool for differentiating benign from malignant breast masses in patients with indeterminate mammograms because of mammographically dense breasts.

Adult↗

Risk of contralateral breast cancer: associations with factors related to initial breast cancer.

A case-control study was conducted to assess the risk factors associated with the development of a contralateral primary breast cancer among women who had had a first primary breast cancer. Hospital records were reviewed for 292 women who had an incident contralateral breast cancer, diagnosed in one of eight Connecticut hospitals between July 1, 1975 and December 31, 1983, and for a comparison group of 264 surviving unilateral breast cancer patients previously diagnosed in the same hospitals. All subjects were identified through the records of the Connecticut Tumor Registry. A family history of breast cancer in any first- or second-degree relative was associated with an almost threefold increased risk of developing a contralateral cancer (adjusted odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.6-4.9). Further, this relation was modified by the time elapsed since the initial cancer diagnosis (ratio of OR = 1.9, 95% CI = 1.2-3.0 for a five-year differential in time since initial diagnosis). A delay of 10 years in first full-term pregnancy was associated with a 36% decrease in risk (adjusted OR = 0.6, 95% CI = 0.3-1.2); this estimate excluded the magnitude of increased risk usually observed in studies of initial breast cancer. A conceptual framework is presented for assessing the study findings in the context of previous studies that have examined the corresponding associations for initial primary breast cancers.

Adult↗

Cystic disease and fibroadenoma of the breast: natural history and relation to breast cancer risk.

Approximately 25% of all 'discrete' breast lesions are fibroadenomas or breast cysts and they more commonly cause a breast lump than breast cancer. Despite their frequency, their natural history and relationship to subsequent breast cancer have not been clearly defined, although it would appear that palpable breast cysts, but not fibroadenomas, are associated with some increased risk of breast cancer. The diagnosis of these two entities is now possible by fine needle aspiration and excision of these lesions is only indicated in certain circumstances.

Adenofibroma↗