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Breast irradiation in women with early stage invasive breast cancer following breast conservation surgery. Provincial Breast Disease Site Group.

GUIDELINE QUESTIONS: 1) Should breast irradiation be given to women with early stage invasive breast cancer (stage I and II) following breast conservation surgery (lumpectomy with clear resection margins and axillary dissection)? 2) Is there an optimal schedule for breast irradiation? 3) What is a reasonable interval between definitive surgery and the start of breast irradiation? 4) Are there patients who can be spared breast irradiation after lumpectomy? OBJECTIVE: To make recommendations about the use of breast irradiation in women with early stage invasive breast cancer following breast conservation surgery. OUTCOMES: Local control is the primary endpoint of interest. Survival, quality of life (addressed through the adverse effects of radiotherapy) and cosmesis are also considered. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 6 members of the Breast Disease Site Group (Breast DSG) of the Ontario Cancer Treatment Practice Guidelines Initiative. Earlier drafts of the evidence-based recommendation were reviewed, discussed and approved by the Breast DSG, which comprises medical oncologists, radiation oncologists, surgeons, epidemiologists, pathologists and a medical sociologist. There was no participation by a community representative in the development of this guideline. QUALITY OF EVIDENCE: There are 5 randomized controlled trials (RCTs) and 1 meta-analysis comparing breast irradiation with no breast irradiation following breast conservation surgery; 6 randomized trials comparing breast conservation surgery plus breast irradiation with mastectomy are also included, as well as several retrospective studies. BENEFITS: All of the 5 RCTs showed a significant decrease in local recurrence rates among patients receiving radiotherapy. In the 4 trials with a median follow-up of 5 years or longer, the relative risk reduction with breast irradiation ranged from 69% to 88%. The absolute differences ranged from 16% (p < 0.001) to 25% (p < 0.001). Despite the effect on local recurrence, no difference in survival was detected in any of the 5 trials. Most of the patients with local recurrence in these trials underwent mastectomy. HARMS: Major adverse effects of breast irradiation occur very infrequently. PRACTICE GUIDELINE: Women with early stage invasive breast cancer (stage I and II) who have undergone breast conservation surgery should be offered postoperative breast irradiation. The optimal fractionation schedule for breast irradiation has not been established, and the role of boost irradiation is unclear. Outside of a clinical trial, 2 commonly used fractionation schedules are suggested: 50 Gy in 25 fractions to the whole breast, or 40 Gy in 16 fractions to the whole breast with a local boost to the primary site of 12.5 Gy in 5 fractions. Shorter schedules (e.g., 40 or 44 Gy in 16 fractions) have also been used routinely in some centres. The enrollment of patients in ongoing clinical trials is encouraged. Women who have undergone breast conservation surgery should receive local breast irradiation as soon as possible after wound healing. A safe interval between surgery and the start of radiotherapy is unknown, but it is reasonable to start breast irradiation within 12 weeks after definitive surgery. For women who are candidates for chemotherapy, the optimal sequencing of chemotherapy and breast irradiation is unknown. It is reasonable to start radiotherapy after the completion of chemotherapy, or concurrently if anthracycline-containing regimens are not used. For further information, please refer to Ontario Cancer Treatment Practice Guidelines Initiative's practice guideline "Surgical Management of Early Stage Invasive Breast Cancer (stage I and II)."

Breast Neoplasms↗

Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer.

BACKGROUND: The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). METHODS: Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. FINDINGS: Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p=0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p=0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast cancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. INTERPRETATION: The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

Adult↗

Variability in surface antigen expression of human breast epithelial cells cultured from normal breast, normal tissue peripheral to breast carcinomas, and breast carcinomas.

Single-cell heterogeneity and variability in expression of several surface antigens on human mammary epithelial cells in short-term culture were studied with immunofluorescence techniques, using polyclonal and monoclonal antibodies. The cultures, derived from normal breast, a fibroadenoma, a gynecomastia, normal breast tissue peripheral to breast carcinomas, and breast carcinomas and their metastases, were studied after one passage in vitro. The percentage of positive cells varied considerably from one tissue sample to another in all categories from normal to malignant, although there was an overall trend toward a decreasing percentage of positive cells of malignant tissues. The relative antigen content varied 3- to 8-fold among individual samples of cells from normal, peripheral, and carcinoma tissue, while the mean values in the three categories were similar. The single-cell variability in relative antigen content was considerable in all individual samples of normal, peripheral, and carcinoma tissues, as reflected in the high coefficients of variation. However, the coefficients of variation were significantly higher for cells from carcinoma and peripheral tissues [69 +/- 10% (S.E.) and 75 +/- 9%, respectively] than for cells from normal breast (48 +/- 5%). By analyzing in clonal colonies the appearance of quantitative variants in expression of a specific surface antigen, detected with a monoclonal antibody, the carcinoma cells were found to have a 10-fold higher rate of phenotypic variability (mean, 1.21 X 10(-2)/cell/generation) than did cells from normal breast (mean, 0.119 X 10(-2)) and one gynecomastia (0.045 X 10(-2)). Mammary epithelial cells from apparently "normal" tissue peripheral to a carcinoma had an intermediate rate of phenotypic variability (mean, 0.310 X 10(-2)) that was significantly higher than that of the normal tissue.

Adenofibroma↗

Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer.

A (modified) radical mastectomy (RM) was compared with breast-conserving therapy (BCT) in stage I and stage II breast cancer patients. Treatment of the study arm comprised lumpectomy, axillary clearance and radiotherapy to the breast (50 Gy in 5 weeks external irradiation and a boost with iridium implant of 25 Gy). 902 patients were included. There were 734 TNM stage II patients. Patients with microscopically incomplete excision of the tumour were not excluded. After a median follow-up of 6 years, overall survival and local recurrence rates do not differ significantly between the two study arms. Actuarial survival at 8 years was 73% after RM and 71% after BCT; actuarial local recurrence at 8 years was 9% and 15%, respectively. In the mastectomy group tumour size did not affect local relapse, but after BCT the incidence of local recurrences was higher for tumours of 2-5 cm (16%) than for smaller tumours (7%) (at 8 years, P = 0.08). Results of salvage treatment for local recurrence so far were similar in both the BCT and the mastectomy group.

Aging↗

Western blotting and enzymatic activity analysis of cathepsin D in breast tissue and sera of patients with breast cancer and benign breast disease and of normal controls.

Increased total antigen amounts of cathepsin D in breast tissue have been reported to be associated with increased disease recurrence, more frequent metastasis, and increased mortality in breast cancer patients. In the present study, Western blotting analysis has been used for the first time to determine the relative amounts of precursor and processed forms of cathepsin D in sera and breast tissue of patients with breast cancer, benign breast disease, and normal controls. Sera gave similar blots for breast cancer patients and controls with two major forms of cathepsin D (M(r) 52,000 and 27,000). Malignant breast tissue contained the two forms of cathepsin D found in sera and an additional M(r) 31,000 form which was found in significantly increased (P < 0.001) relative amounts in breast tissue from 43 breast cancer patients [24 +/- 12% (SD)] when compared to 51 benign breast disease patients (13 +/- 8.9%) and 23 normal controls (1.8 +/- 4.4%). Preliminary analysis of subgroups of benign breast disease patients suggested no significant difference (P = 0.41) in relative amounts of the M(r) 31,000 form of cathepsin D between proliferative-type and non-proliferative-type fibrocystic breast disease. A cathepsin D assay has been optimized for human breast tissue and used to demonstrate for the first time significantly increased (P < 0.001) amounts of pepstatin-inhibitable, cathepsin D-specific activity in breast tissue from 36 breast cancer patients (2.2 +/- 1.4 units/mg of protein) when compared to 47 benign breast disease patients (0.63 +/- 0.43) and 23 normal controls (0.24 +/- 0.21). Preliminary analysis of subgroups of benign breast disease patients suggested no significant difference (P = 0.21) in pepstatin-inhibitable, cathepsin D-specific activity between proliferative-type and nonproliferative-type fibrocystic breast disease. The positive correlation (r = 0.82) of increased amounts of the M(r) 31,000 form of cathepsin D and increased pepstatin-inhibitable, cathepsin D enzymatic activity in malignant breast tissue suggests that the M(r) 31,000 form is the proteolytically active form of the enzyme which may be involved in the development and/or metastatic spread of breast cancer.

Adult↗

Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.

BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. METHODS Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. FINDINGS The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95 percent CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90 percent of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons...

Adolescent↗

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

Adult↗

Relative effect of steroid hormone receptors on the prognosis of patients with operable breast cancer. A univariate and multivariate analysis of 3089 Japanese patients with breast cancer from the Study Group for the Japanese Breast Cancer Society on Hormone Receptors and Prognosis in Breast Cancer.

In a retrospective multicenter study to investigate the correlation between estrogen (ER) and/or progesterone receptors (PgR) in primary breast cancer with patient prognosis, 3118 patients with operable breast cancer (International Union Against Cancer Stages I, II, and III) were investigated from ten hospitals in Japan who underwent surgery from October 1972 to December 1982; 3089 were evaluable. The ER-positive and PgR-positive cancers were found in 56% and 34% of patients, respectively. The positivities decreased as the tumor size increased but were independent on lymph node metastasis. There were no significant differences in relapse-free survival (RFS) in relation to receptor status (median follow-up, 89 months [ER], 84 months [PgR]). However, in patients with four or more positive nodes, those with PgR-positive cancer had a longer RFS. The patients with ER-positive cancer survived significantly longer than ER-negative ones, with the greatest difference seen in those with four or more positive nodes. There was a significantly longer postrelapse survival (PRS) for patients with ER-positive cancer because of the different distribution of the major metastasis and better responses to first-line and subsequent treatments. Cox's multivariate analysis showed that overall survival but not PRS was affected by ER (and more weakly by PgR) because of the longer PRS in patients with ER-positive cancer.

Adult↗

Ten-year results of the treatment of early-stage breast carcinoma in elderly women using breast-conserving surgery and definitive breast irradiation.

PURPOSE: The optimal management of breast cancer in elderly women is not well established. Therefore, the present study was undertaken to evaluate the outcome of breast cancer in elderly women treated with breast-conserving surgery and definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 558 women age > or = 50 years treated with breast-conserving surgery and definitive breast irradiation for Stages I-II invasive carcinoma of the breast. Of the 558 total women, there were 173 elderly women > or = 65 years and a comparison group of 385 women age 50-64 years. Treatment for all women included complete gross excision of the primary tumor, pathologic axillary lymph node staging, and definitive breast irradiation. Adjuvant systemic chemotherapy was used in 18% (102 out of 558) of the overall group. Adjuvant tamoxifen was used in 17% (94 out of 558) of the overall group. The median follow-up after treatment was 6.2 years (mean = 6.4 years; range = 0.1-15.4 years). RESULTS: Elderly patients age > or = 65 years and patients age 50-64 years were both found to have tumors with adverse prognostic features, including clinical T2 lesions (43 vs. 34%, respectively; p = 0.055), estrogen receptor negativity (9 vs. 16%, respectively; p = 0.13), and progesterone receptor negativity (17 vs. 21%, respectively; p = 0.50). Pathologic axillary lymph node staging showed that 24% of the elderly women were node positive, including 8% with four or more positive nodes, which was not different from women age 50-64 years (p = 0.23). There was no difference between the two age groups for the rate of deaths from breast cancer at 10 years (13 vs. 13%, respectively; p = 0.71). However, there was a significant difference between the two age groups for the rate of deaths from intercurrent disease at 10 years (11 vs. 2%, respectively; p = 0.0006). There were no differences between the two age groups for the 10-year rates of overall survival (77 vs. 85%, respectively; p = 0.14), relapse-free survival (64 vs. 70%, respectively; p = 0.16), freedom from distant metastases (83 vs. 78%, respectively; p = 0.45), or local failure (13 vs. 12%, respectively; p = 0.60). CONCLUSIONS: These results have shown that breast carcinomas in elderly women are not indolent and have a number of adverse prognostic features. Breast-conserving surgery and definitive breast irradiation in elderly women age > or = 65 years achieves good outcomes for survival, freedom from distant metastases, and local control, which are comparable to women age 50-64 years. The causes of deaths in elderly women age > or = 65 years are from both breast cancer and intercurrent disease. Breast-conserving surgery and definitive breast irradiation should continue to be considered as a standard treatment option for appropriately selected elderly women with early-stage breast cancer.

Aged↗

Breast cancer and family history: levels of lipid-associated sialic acid in plasma and absent family history of breast cancer in women who have breast tumors.

BACKGROUND: Breast cancer has a strong genetic component, and at least two breast cancer genes exist. But these genes probably play little role in most breast cancers. Other factors, such as environmental estrogens and diet, may cause the genetic changes involved in the genesis of sporadic breast cancer. A method of observing genetic changes indirectly might be to measure tumor markers known to be associated with breast cancer. METHODS: We measured, by biochemical extraction and partition, lipid-associated sialic acid in plasma (LASA-P), a circulating tumor marker, in a group of 239 women with benign or malignant breast tumors. RESULTS: The concentration of LASA-P was elevated in women with both benign and malignant tumors and no family history of breast cancer (p = 0.046, one-way ANOVA). Because LASA-P levels rise with age and number of pregnancies, we analyzed our data using multiple linear regression. Benign versus malignant character of the tumor, family history of breast cancer, number of pregnancies, and age were the independent variables. Family history of breast cancer had a significant effect on LASA-P levels (p = 0.0146) independent of the effects of age (p = 0.011), number of pregnancies (0.012), and whether the tumor was benign or malignant (p = 0.31). CONCLUSIONS: We hypothesize that elevated LASA-P in women with breast tumors and no family history of breast cancer is a result of the genetic changes occurring in nonfamilial breast cancer. These genetic changes, possibly related to environmental estrogens or other environmental factors, are distinct from the changes due to mutations of BRCA1 or other familial breast cancer genes. Moreover, the elevation of LASA-P suggests that the surface membranes of breast cancer may differ in composition. Further study may lead to exact characterization of the genetic and cell membrane changes associated with familial and nonfamilial breast tumors, and perhaps to better methods of breast cancer prevention and treatment.

Adolescent↗

Elevated luteinizing hormone in serum, breast cancer tissue, and normal breast tissue from breast cancer patients.

PURPOSE: Hormones are known to be important in breast cancer, but studies have focused on steroid hormones and their cognate receptors. We report here an analysis of luteinizing hormone (LH) concentration in serum and breast tissue samples. MATERIALS AND METHODS: We studied serum and breast tissue samples from 353 women, 231 with breast cancer and 122 controls. Four breast tissue sites were sampled in every case. Tumor samples were also available from 48 patients and serum from 101 subjects. LH was measured by enzyme-linked immunosorbent assay. RESULTS: LH concentration in breast tissue was significantly higher in samples from patients with breast cancer than in samples from control subjects. In breast cancer patients, there was a decreasing gradiant from the cancer to the normal breast tissue, near and far from the tumor. Serum LH levels could not distinguish between breast cancer and control cases in most cases; but tissue LH could. CONCLUSIONS: LH concentrations were higher in breast tumors than in normal tissue near to or far from the tumor in women with breast cancer, and these concentrations were higher in women with breast cancer than in control cases. The different LH concentrations in breast tissue might be used to detect small or hidden carcinomas. In addition, the identification of luteinizing hormone in breast tissue offers a different explanation for the mechanism of action of LHRH agonists and might identify patients that respond to this treatment.

Adult↗

Mammography and subsequent whole-breast sonography of nonpalpable breast cancers: the importance of radiologic breast density.

OBJECTIVE: Our purpose was to determine the contribution of mammography followed by sonography for the detection of nonpalpable breast cancers in Breast Imaging Reporting and Data System (BI-RADS) density grades 1-4 breasts, in grades 1 and 2 breasts, and in grades 3 and 4 breasts. MATERIALS AND METHODS: The results of physical, mammographic, and sonographic examinations performed in 4236 patients were reviewed to determine the sensitivities of mammography and sonography for the detection of nonpalpable breast cancers and to calculate the relative risk for detecting nonpalpable breast cancers using sonography in comparison with mammography in density grades 1-4, grades 1 and 2, and grades 3 and 4 breasts. Sonography was performed after mammographic interpretation. RESULTS: Sensitivities of mammography and subsequent sonography for the detection of nonpalpable breast cancers were 69% and 88% in grades 1-4, 80% and 88% in grades 1 and 2, and 56% and 88% in grades 3 and 4 breasts, respectively. The relative risk for detecting nonpalpable breast cancers using sonography was statistically significantly greater than that for detecting nonpalpable breast cancers using mammography in grades 1-4 (relative risk, 1.29; p = 0.024) and in grades 3 and 4 (relative risk, 1.57; p = 0.013) but not in grades 1 and 2 (relative risk, 1.1; p = 0.445) breasts. CONCLUSION: Sonography is a useful adjunct after mammography for the detection of nonpalpable breast cancer, particularly in the dense breast.

Adult↗

Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue.

Prostate specific antigen (PSA) is a tumor marker used widely for the diagnosis and monitoring of prostatic adenocarcinoma. Recently, we provided evidence that PSA may also be produced by breast tumors. In this report we examined quantitatively the PSA levels in 199 breast tumors, 48 tissues with benign breast disease (BBD, 34 fibroadenomas), and 36 normal breast tissues. Significant amounts of PSA (> or = 0.030 ng of PSA per mg of total protein) were found in 28% of breast tumors, 65% of BBD tissues, and 33% of normal breast tissues. PSA positivity in breast tumors was highest in stage I disease (34%) and decreased with disease stage (24% in stage II and 18% in stage III-IV). Using polymerase chain reaction amplification we have shown PSA mRNA presence in patients with PSA protein-positive tissues (benign and malignant) but not in patients with PSA protein-negative tissues. Our data suggest that PSA is expressed frequently by normal breast tissue, by tissue of benign breast diseases, and by breast cancer tissue. Highest expression is seen in benign breast disease and lowest expression in advanced stage cancerous tissue. As PSA production is mediated by steroid hormones and their receptors, we propose that PSA may be a new marker of steroid hormone action in the normal or diseased female breast. The role of this enzyme in the development of breast diseases including breast cancer is currently unknown.

Adolescent↗

Chemoprevention of breast cancer. A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.

OBJECTIVE: To assist women and their physicians in making decisions regarding the prevention of breast cancer with tamoxifen and raloxifene. EVIDENCE: Systematic review of English-language literature published from 1966 to August 2000 retrieved from MEDLINE, HealthSTAR, Current Contents and Cochrane Library. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. RECOMMENDATIONS: Women at low or normal risk of breast cancer (Gail risk assessment index < 1.66% at 5 years): There is fair evidence to recommend against the use of tamoxifen to reduce the risk of breast cancer in women at low or normal risk of the disease (grade D recommendation). Women at higher risk of breast cancer (Gail index > or = 1.66% at 5 years): Evidence supports counselling women at high risk on the potential benefits and harms of breast cancer prevention with tamoxifen (grade B recommendation). The cutoff for defining high risk is arbitrary, but the National Surgical Adjuvant Breast and Bowel Project P-1 Study included women with a 5-year projected risk of at least 1.66% according to the Gail index, and the average risk of patients entered in the trial was 3.2%. Examples of high-risk clinical situations are 2 first-degree relatives with breast cancer, a history of lobular carcinoma in situ or a history of atypical hyperplasia. As the risk of breast cancer increases above 5% and the benefits outweigh the harms, a woman may choose to take tamoxifen. The duration of tamoxifen use in such situations is 5 years based on the results from trials of tamoxifen involving women with early breast cancer. If a woman raises concerns or has already been evaluated and is calculated to be at high risk, then individuals experienced and skilled in counselling may discuss the potential benefits and harms of tamoxifen use. Important additional issues: Prevention of breast cancer with raloxifene: Current evidence does not support recommending chemoprevention of breast cancer with raloxifene outside of a clinical trial setting. Screening using the Gail risk assessment index: This index was the main eligibility criterion for enrolling women in the one study that showed potential benefit from chemoprevention. However, it has not been evaluated for use as a routine screening or case-finding instrument; validation of the index is required. Overall, current evidence does not support a shift to its routine use in physicians' offices for screening or case finding. However, when a woman or her physician is concerned about the woman's increased risk of breast cancer, the index can be a useful tool in deciding whether to pursue an in-depth discussion of the potential benefits and harms of chemoprevention. Hence, the approach to identifying women at higher risk who warrant counselling and shared decision-making will vary across practices. (The risk assessment index is available online at http://bcra.nci.nih.gov/brc/). [A patient version of these guidelines appears in Appendix 2.] VALIDATION: The authors' original text was revised by both the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The final document reflects a consensus of these contributors. SPONSOR: Health Canada. COMPLETION DATE: February 2001.

Adult↗

Breast cancer mortality in relation to clinical breast examination and breast self-examination.

Mammography is the most sensitive available means for early detection of breast cancer, but both clinical breast examination (CBE) and breast self-examination (BSE) have the potential to advance the diagnosis of breast cancer without the expense of a mammography facility. CBE detects about 60% of cancers detected by mammography, as well as some cancers not detected by mammography. There have been no randomized trials comparing breast cancer mortality between women offered and not offered CBE. However, indirect evidence comes from a Canadian study in which women were randomly assigned to CBE alone or CBE plus mammography. Women in the two groups had similar rates of nodal involvement at diagnosis and of breast cancer mortality. Thus if receipt of mammography averts some deaths from breast cancer, the results of this study suggest that CBE has the potential to do so as well. Most studies have found that breast cancers detected by BSE are smaller than those detected without screening and are more likely to be confined to the breast; furthermore, survival after a diagnosis of breast cancer tends to be longer among women who practice BSE than among women who do not. However, neither observational nor randomized studies of BSE provide evidence that this screening modality reduces breast cancer mortality. A recent randomized study in Shanghai, China, found that women assigned to extensive BSE instruction and women assigned to another health intervention had similar distributions of cancer size and stage at diagnosis and similar breast cancer mortality rates. In summary, CBE appears to be a promising means of averting some deaths from breast cancer, whereas BSE appears to have little or no impact on breast cancer mortality.

Breast Neoplasms↗

Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status.

PURPOSE: This study was performed to determine the long-term outcome for women with mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 422 mammographically detected intraductal breast carcinomas in 418 women from 11 institutions in North America and Europe. All patients were treated with breast-conserving surgery followed by definitive breast irradiation. The median follow-up time was 9.4 years (mean, 9.4 years; range, 0.1-19.8 years). RESULTS: The 15-year overall survival rate was 92%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 94%. There were 48 local failures in the treated breast, and the 15-year rate of any local failure was 16%. The median time to local failure was 5.0 years (mean, 5.7 years; range, 1.0-15.2 years). Patient age at the time of treatment and final pathology margin status from the primary tumor excision were both significantly associated with local failure. The 10-year rate of local failure was 31% for patient age < or = 39 years, 13% for age 40-49 years, 8% for age 50-59 years, and 6% for age > or = 60 years (p = 0.0001). The 10-year rate of local failure was 24% when the margins of resection were positive, 9% when the margins of resection were negative, 7% when the margins of resection were close, and 12% when the margins of resection were unknown (p = 0.030). Patient age < or = 39 years and positive margins of resection were both independently associated with an increased risk of local failure (p = 0.0006 and p = 0.023, respectively) in the multivariable Cox regression model. CONCLUSIONS: The 15-year results from the present study demonstrated high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of mammographically detected ductal carcinoma in situ of the breast using breast-conserving surgery and definitive breast irradiation. Younger age and positive margins of resection were both independently associated with an increased risk of local failure. The 15-year results in the present study serve as an important benchmark for comparison with other treatment modalities. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of appropriately selected patients with mammographically detected ductal carcinoma in situ of the breast.

Adult↗

Correlation between carotenoid concentrations in serum and normal breast adipose tissue of women with benign breast tumor or breast cancer.

To evaluate the relationship between carotenoid concentrations in serum and breast tissue, we measured serum carotenoid concentrations and endogenous carotenoid levels in breast adipose tissue of women with benign breast tumor (n = 46) or breast cancer (n = 44). Before extraction, serum was digested with lipase and cholesterol esterase, and breast adipose tissue was saponified. Serum and tissue carotenoids were extracted with ether/hexane and measured by using HPLC with a C30 column. Serum retinoic acid was extracted with chloroform/methanol and measured using HPLC with a C18 column. There were no significant differences in serum carotenoids [lutein, zeaxanthin, cryptoxanthin (both alpha- and beta-), alpha-carotene, all-trans beta-carotene, 13-cis beta-carotene and lycopene], retinoids (retinol, all-trans and 13-cis retinoic acids), and alpha- and gamma- tocopherol concentrations between benign breast tumor patients and breast cancer patients. A substantial amount of 9-cis beta-carotene was present in adipose tissue and was the only carotenoid that had a significantly lower level in benign breast tumor patients than in breast cancer patients. Correlations between carotenoid concentrations in serum and in breast adipose tissue were determined by combining the data of the two groups. Concentrations of the major serum carotenoids except cryptoxanthin showed significant correlations with breast adipose tissue carotenoid levels. When the concentrations of serum carotenoids were adjusted for serum triglycerides or LDL, correlations between serum carotenoid concentrations and breast adipose tissue carotenoid levels markedly increased, including that of cryptoxanthin (P <0. 001). The strong correlation between serum carotenoid concentrations and endogenous breast adipose tissue carotenoid levels indicate that dietary intake influences adipose tissue carotenoid levels as well as serum concentrations, and that adipose tissue is a dynamic reservoir of fat-soluble nutrients.

Adipose Tissue↗