Showing papers on "Breast cancer published in 1995"

Identification of the breast cancer susceptibility gene BRCA2

Abstract: IN Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.

Abstract: Dominant predisposition to early-onset breast cancer and/or ovarian cancer in many families is known to be the result of germ-line mutations in a gene on chromosome 17q, known as BRCA1. In this paper we use data from families with evidence of linkage to BRCA1 to estimate the age-specific risks of breast and ovarian cancer in BRCA1-mutation carriers and to examine the variation in risk between and within families. Under the assumption of no heterogeneity of risk between families, BRCA1 is estimated to confer a breast cancer risk of 54% by age 60 years (95% confidence interval [CI] 27%-71%) and an ovarian cancer risk of 30% by age 60 years (95% CI 8%-47%). Similar lifetime-risk estimates are obtained by examining the risks of contralateral breast cancer and of ovarian cancer, in breast cancer cases in linked families. However, there is significant evidence of heterogeneity of risk between families; a much better fit to the data is obtained by assuming two BRCA1 alleles, one conferring a breast cancer risk of 62% and an ovarian cancer risk of 11% by age 60 years, the other conferring a breast cancer risk of 39% and an ovarian cancer risk of 42%, with the first allele representing 71% of all mutations (95% CI 55%-87%). There is no evidence of clustering of breast and ovarian cancer cases within families.

The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.

Abstract: Background The effect of adding progestins to estrogen therapy on the risk of breast cancer in postmenopausal women is controversial. Methods To quantify the relation between the use of hormones and the risk of breast cancer in postmenopausal women, we extended our follow-up of the participants in the Nurses' Health Study to 1992. The women were asked to complete questionnaires every two years to update information on their menopausal status, use of estrogen and progestin preparations, and any diagnosis of breast cancer. During 725,550 person-years of follow-up, we documented 1935 cases of newly diagnosed invasive breast cancer. Results The risk of breast cancer was significantly increased among women who were currently using estrogen alone (relative risk, 1.32; 95 percent confidence interval, 1.14 to 1.54) or estrogen plus progestin (relative risk, 1.41; 95 percent confidence interval, 1.15 to 1.74), as compared with postmenopausal women who had never used hormones. Women currently taking hormones who ha...

Inactivation of the CDKN2/p16/MTS1 Gene Is Frequently Associated with Aberrant DNA Methylation in All Common Human Cancers

Abstract: The tumor suppressor gene CDKN2/p16/MTS1, located on chromosome 9p21, is frequently inactivated in many human cancers through homozygous deletion. Recently, we have reported another pathway of inactivation that involves loss of transcription associated with de novo methylation of a 5' CpG island of CDKN2/p16 in lung cancers, gliomas, and head and neck squamous cell carcinomas. We now show that this aberrant CpG island methylation also occurs frequently in cell lines of breast cancer (33%), prostate cancer (60%), renal cancer (23%), and colon cancer (92%) and is associated with loss of transcription. Primary tumors of the breast (31%) and colon (40%) also displayed de novo methylation of this CpG island. This alteration of p16 in colon cancer was particularly striking, since inactivation does not occur through homozygous deletion in this tumor type. Our data show that in tumors, de novo methylation of the 5' CpG island is a frequent mode of inactivation of CDKN2/p16 and also firmly demonstrate that CDKN2/p16 is one of the most frequently altered genes in human neoplasia.

Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer.

Abstract: Background Previous findings from a clinical trial (Protocol B-06) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) indicated the worth of lumpectomy and breast irradiation for treating breast cancer. After the discovery by NSABP staff members of falsified information on patients enrolled in the study by St. Luc Hospital in Montreal, separate audits were conducted at St. Luc Hospital and other participating institutions. We report the results of both audits and update the study findings through an average of 12 years of follow-up. Methods Patients with either negative or positive axillary nodes and tumors 4 cm or less in diameter were randomly assigned to one of three treatments: total mastectomy, lumpectomy followed by breast irradiation, or lumpectomy without irradiation. Three cohorts of patients were analyzed. The first cohort included all 2105 randomized patients, who were analyzed according to the intention-to-treat principle. The second cohort consisted of 1851 eligible ...

Quantitative Classification of Mammographic Densities and Breast Cancer Risk: Results From the Canadian National Breast Screening Study

Abstract: BACKGROUND The radiographic appearance of the female breast varies from woman to woman depending on the relative amounts of fat and connective and epithelial tissues present. Variations in the mammographic density of breast tissue are referred to as the parenchymal pattern of the breast. Fat is radiologically translucent or clear (darker appearance), and both connective and epithelial tissues are radiologically dense (lighter appearance). Previous studies have generally supported an association between parenchymal patterns and breast cancer risk (greater risk with increasing densities), but there has been considerable heterogeneity in risk estimates reported. PURPOSE Our objective was to determine the level of breast cancer risk associated with varying mammographic densities by quantitatively classifying breast density with conventional radiological methods and novel computer-assisted methods. METHODS From the medical records of a cohort of 45,000 women assigned to mammography in the Canadian National Breast Cancer Screening Study (NBSS), a multicenter, randomized trial, mammograms from 354 case subjects and 354 control subjects were identified. Case subjects were selected from those women in whom histologically verified invasive breast cancer had developed 12 months or more after entering the trial. Control subjects were selected from those of similar age who, after a similar period of observation, had not developed breast cancer. The mammogram taken at the beginning of the NBSS was the image used for measurements. Mammograms were classified into six categories of density, either by radiologists or by computer-assisted measurements. All radiological classification and computer-assisted measurements were made using one craniocaudal view from the breast contralateral to the cancer site in case subjects and the corresponding breast of control subjects. All P values represent two-sided tests of statistical significance. RESULTS For all subjects, there was a 43% increase in the relative risk (RR) between the lower and the next higher category of density, as determined by radiologists, and there was a 32% increase as determined by the computer-assisted method. For all subjects, the RR in the most extensive category relative to the least was 6.05 (95% confidence interval [CI] = 2.82-12.97) for radiologists and 4.04 (95% CI = 2.12-7.69) for computer-assisted methods. Statistically significant increases in breast cancer risk associated with increasing mammographic density were found by both radiologists and computer-assisted methods for women in the age category 40-49 years (P = .005 for radiologists and P = .003 for computer-assisted measurements) and the age category 50-59 years (P = .002 for radiologists and P = .001 for computer-assisted measurements). CONCLUSION These results show that increases in the level of breast tissue density as assessed by mammography are associated with increases in risk for breast cancer.

Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in Node-Positive Breast Cancer — The Results of 20 Years of Follow-up

Abstract: Background Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil was administered after radical mastectomy for primary breast cancer with histologically positive axillary lymph nodes to assess whether it would improve treatment outcome as compared with surgery alone. Here we report a 20-year follow-up of this investigation. Methods In 1973 we began a trial involving 386 women who were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant combination chemotherapy (207 women). All patients were admitted to the Istituto Nazionale Tumori in Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. Results After a median follow-up of 19.4 years, the patients given adjuvant combination chemotherapy had significantly better rates of relapse-free survival (unadjusted relative risk of relapse, 0.71; 95 percent confidence interval, 0.56 to 0.90; P = 0.004; ...

Improved axillary staging of breast cancer with sentinel lymphadenectomy.

Abstract: Objective The authors evaluated the effect of intraoperative lymphatic mapping and sentinel lymphadenectomy (SLND) on the axillary staging of patients with carcinoma of the breast. Background Data The accurate staging of patients with breast cancer is essential to guide management and determine prognosis. The authors previously reported the feasibility and accuracy of SLND in breast carcinoma. Sentinel lymphadenectomy identifies the first (sentinel) axillary lymph node draining the site of a primary tumor ; because this node is the most likely site of axillary metastasis, histopathologic examination of the sentinel node correlates well with examination of the entire axillary contents. The current study compares SLND with standard axillary lymphadenectomy (ALND) for the staging of breast carcinoma. Methods The incidence of axillary node metastasis and micrometastasis in SLND and ALND specimens from patients undergoing operative treatment of a primary breast carcinoma was compared prospectively. Multiple sections of each sentinel lymph node in SLND specimens were examined by hematoxylin and eosin (H&E) staining and by immunohistochemical techniques using antibodies to cytokeratin. One or two sections of each nonsentinel lymph node in ALND specimens were examined by routine H&E staining. Results One hundred thirty-four patients underwent ALND (ALND group), and 162 underwent successful SLND followed by completion ALND (SLND group). Both groups were similar with respect to age (median, 55 and 54 years, respectively), palpable primary tumors (54.5% and 59.3%, respectively), palpable axillary nodes (5.2% and 7.4%, respectively), size of primary tumor (median, 1.5 cm in each group), and total number of axillary lymph nodes examined (median, 19 and 21, respectively). The number of patients with axillary metastasis was 39 (29.1%) in the ALND group and 68 (42.0%) in the SLND group (p < 0.03). Of these, 4 of 39 (10.3%) ALND patients (3.0% of all ALND patients) and 26 of 68 (38.2%) SLND patients (16.0% of all SLND patients) had micrometastasis (≤2 mm), a highly significant difference (p < 0.0005) Conclusions Sentinel lymphadenectomy with multiple sectioning and immunohistochemical staining of sentinel nodes increases the accuracy of axillary staging in breast cancer and can identify significantly more patients with lymph nodes metastases, especially micrometastases, than can ALND with routine histopathologic processing of lymph nodes.

Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas.

Abstract: The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto-oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness.

Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.

Abstract: Angiogenesis plays a fundamental role in human breast tumor progression. In fact, recent findings indicate that vascular density is a prognostic indicator of breast cancer disease status. Evidence is presented that the integrin alpha v beta 3 is not only a marker of human breast tumor-associated blood vessels, but that it plays a significant role in human angiogenesis and breast tumor growth. To assess the role of alpha v beta 3-dependent angiogenesis in the progression of human breast cancer, we examined a SCID mouse/human chimeric model with transplanted full thickness human skin containing alpha v beta 3-negative human breast tumor cells. This tumor induced a human angiogenic response as measured by vascular cell immunoreactivity with monoclonal antibodies LM609 and P2B1 directed to human alpha v beta 3 and CD31, respectively. Intravenous administration of LM609 either prevented tumor growth or markedly reduced tumor cell proliferation within the microenvironment of the human skin. These LM609-treated tumors not only contained significantly fewer human blood vessels but also appeared considerably less invasive than tumors in control animals. These findings demonstrate that alpha v beta 3 antagonists may provide an effective antiangiogenic approach for the treatment of human breast cancer.

Mammographic Features and Breast Cancer Risk: Effects With Time, Age, and Menopause Status

Abstract: Background : Mammographic images from women with a high proportion of epithelial and stromal breast tissues are described as showing high-density parenchymal patterns. Most past studies that noted an increase in breast cancer risk associated with mammographic parenchymal patterns showing high density either 1) lacked information on other breast cancer risk factors, 2) were too small, or 3) included insufficient follow-up time to adequately resolve persisting doubts whether mammographic features are independent measures of breast cancer risk and not a detection artifact. Purpose : The purpose of this study was twofold : 1) to evaluate the associations between mammographic features and other breast cancer risk factors and 2) to assess effects of mammographic features on breast cancer risk by time, age, and menopause status. Methods : To address these questions, we analyzed detailed information from a large, nested case-control study with 16 years of follow-up. This study used information from both screening and follow-up phases of the Breast Cancer Detection Demonstration Project, a nationwide program that offered annual breast cancer screening for more than 280 000 women from 1973 to 1980. Mammographic features were assessed from the base-line screening mammographic examination for 1880 incident case subjects and 2152 control subjects. Control subjects were randomly selected from women of the same age and race as each case subject. Control subjects attended the same screening center as the case subject and were free of breast cancer at the case subject's date of diagnosis. Odds ratios (ORs) with 95% confidence intervals (CIs) provided estimates of the relative risk of breast cancer. Results : Mammographic features were associated with known breast cancer risk factors. However, the high-density parenchymal pattern effects were independent of family history, age at first birth, alcohol consumption, and benign breast disease. The increased risk for women with Wolfe's two high-density parenchymal patterns, P2 (OR = 3.2 ; 95% CI = 2.5-4.0) and Dy (OR = 2.9 ; 95% CI = 2.2-3.9), was explained primarily by measured percent of the breast with dense mammographic appearance. Compared with women with no visible breast density, women who had a breast density of 75% or greater had an almost fivefold increased risk of breast cancer (95% CI = 3.6-7.1). These effects persisted for 10 or more years and were noted for both premenopausal and postmenopausal women of all ages. Conclusions : Of the breast cancer risk factors assessed in the participants, high-density mammographic parenchymal patterns, as measured by the proportion of breast area composed of epithelial and stromal tissue, had the greatest impact on breast cancer risk. Of the breast cancers in this study, 28% were attributable to having 50% or greater breast density.

Ten-Year Results of a Comparison of Conservation with Mastectomy in the Treatment of Stage I and II Breast Cancer

Abstract: Background Breast-conservation therapy for early-stage breast cancer is now an accepted treatment, but there is still controversy about its comparability with mastectomy. Between 1979 and 1987, the National Cancer Institute conducted a randomized, single-institution trial comparing lumpectomy, axillary dissection, and radiation with mastectomy and axillary dissection for stage I and II breast cancer. We update the results of that trial after a median potential follow-up of 10.1 years. Methods Two hundred forty-seven patients with clinical stage I and II breast cancer were randomly assigned to undergo either modified radical mastectomy or lumpectomy, axillary dissection, and radiation therapy. The 237 patients who actually underwent randomization have been followed for a median of 10.1 years. The primary end points were overall survival and disease-free survival. Results At 10 years overall survival was 75 percent for the patients assigned to mastectomy and 77 percent for those assigned to lumpectomy plus ...

Breast Cancer Diagnosis and Prognosis Via Linear Programming

Abstract: Two medical applications of linear programming are described in this paper. Specifically, linear programming-based machine learning techniques are used to increase the accuracy and objectivity of breast cancer diagnosis and prognosis. The first application to breast cancer diagnosis utilizes characteristics of individual cells, obtained from a minimally invasive fine needle aspirate, to discriminate benign from malignant breast lumps. This allows an accurate diagnosis without the need for a surgical biopsy. The diagnostic system in current operation at University of Wisconsin Hospitals was trained on samples from 569 patients and has had 100% chronological correctness in diagnosing 131 subsequent patients. The second application, recently put into clinical practice, is a method that constructs a surface that predicts when breast cancer is likely to recur in patients that have had their cancers excised. This gives the physician and the patient better information with which to plan treatment, and may elimin...

E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers.

Abstract: Compelling experimental evidence exists for a potent invasion suppressor role of the cell-cell adhesion molecule E-cadherin. In addition, a tumour suppressor effect has been suggested for E-cadherin. In human cancers, partial or complete loss of E-cadherin expression correlates with malignancy. To investigate the molecular basis for this altered expression we developed a comprehensive PCR/SSCP mutation screen for the human E-cadherin gene. For 49 breast cancer patients the occurrence of tumour-specific mutations in the E-cadherin gene was examined. No relevant DNA changes were encountered in any of 42 infiltrative ductal or medullary breast carcinoma samples. In contrast, four out of seven infiltrative lobular breast carcinomas harboured protein truncation mutations (three nonsense and one frameshift) in the extracellular part of the E-cadherin protein. Each of the four lobular carcinomas with E-cadherin mutations showed tumour-specific loss of heterozygosity of chromosomal region 16q22.1 containing the E-cadherin locus. In compliance with this, no E-cadherin expression was detectable by immunohistochemistry in these four tumours. These findings offer a molecular explanation for the typical scattered tumour cell growth in infiltrative lobular breast cancer.

Factors that influence collection and engraftment of autologous peripheral-blood stem cells.

Abstract: PURPOSETo analyze factors that affect the collection of peripheral-blood stem cells (PBSC) before transplant and the tempo of engraftment after transplant.PATIENTS AND METHODSA consecutive series of 243 patients with breast cancer (n = 87), malignant lymphoma (n = 90), multiple myeloma (n = 32), or other malignancies (n = 34) had PBSC collected following stimulation with colony-stimulating factors (CSFs) or after chemotherapy followed by CSF. Infusion of PBSC was performed following myeloablative chemotherapy with chemotherapy with or without total-body irradiation (TBI). Postinfusion CSFs were administered to 72 patients. An analysis of factors that influence CD34+ cell yield was performed by linear regression. Cox regression analysis was used to determine factors that affect the kinetics of granulocyte and platelet recovery following infusion of PBSC.RESULTSMobilization with chemotherapy followed by CSF, a diagnosis of breast cancer, absence of marrow disease, no prior history of radiation therapy, and ...

Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists' Collaborative Group.

Abstract: BACKGROUND Randomized trials of radiotherapy and surgery for early breast cancer may have been too small to detect differences in long-term survival and recurrence reliably. We therefore performed a systematic overview (meta-analysis) of the results of such trials. METHODS Information was sought on each subject from investigators who conducted trials that began before 1985 and that compared local therapies for early breast cancer. Data on mortality were available from 36 trials comparing radiotherapy plus surgery with the same type of surgery alone, 10 comparing more extensive surgery with less extensive surgery, and 18 comparing more extensive surgery with less extensive surgery plus radiotherapy. Information on mortality was available for 28,405 women (97.4 percent of the 29,175 women in the trials). RESULTS The addition of radiotherapy to surgery resulted in a rate of local recurrence that was three times lower than the rate with surgery alone, but there was no significant difference in 10-year survival; among a total of 17,273 women enrolled in such trials, mortality was 40.3 percent with radiotherapy and 41.4 percent without radiotherapy (P = 0.3). Radiotherapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94; 95 percent confidence interval, 0.88 to 1.00; P = 0.03), which indicates that, after 10 years, there would be about 0 to 5 fewer deaths due to breast cancer per 100 women. However, there was an increased risk of death from other causes (odds ratio, 1.24; 95 percent confidence interval, 1.09 to 1.42; P = 0.002). This, together with the age-specific death rates, implies, after 10 years, a few extra deaths not due to breast cancer per 100 older women or per 1000 younger women. During the first decade or two after diagnosis, the excess in the rate of such deaths that was associated with radiotherapy was much greater women who were over 60 years of age at randomization (15.3 percent vs. 11.1 percent [339 vs. 249 deaths]) than among those under 50 (2.5 percent vs. 2.0 percent [62 vs. 49 deaths]). Breast-conserving surgery involved some risk of recurrence in the remaining tissue, but no significant differences in overall survival at 10 years were found in the studies of mastectomy versus breast-conserving surgery plus radiotherapy (4891 women), more extensive surgery versus less extensive surgery (4818 women), or axillary clearance versus radiotherapy as adjuncts to mastectomy (4370 women). CONCLUSIONS Some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence--such as the reduced recurrence with the addition of radiotherapy to surgery--but there were no definite differences in overall survival at 10 years.

Proportion of Breast Cancer Cases in the United States Explained by Well-Established Risk Factors

Abstract: Background : Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain. Purpose : Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population. Methods : From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey. Results : Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population. Conclusions : The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors. Implications : Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.

A Prospective Study of Endogenous Estrogens and Breast Cancer in Postmenopausal Women

Abstract: BACKGROUND Circumstantial evidence links endogenous estrogens to increased risk of breast cancer in women, but direct epidemiologic support is limited. In particular, only a few small prospective studies have addressed this issue. PURPOSE Our purpose was to assess breast cancer risk in relation to circulating levels of the two major endogenous estrogens, estrone and estradiol, measured before the clinical onset of the disease. METHODS The association between serum levels of estrogens and the risk of breast cancer was examined in a prospective cohort study of 14,291 New York City women, 35-65 years of age, who received screening for breast cancer at the time of blood sampling and who had not been diagnosed with breast cancer. During the first 5 1/2 years of study, we identified 130 breast cancers among the postmenopausal group (7063 women, 35,509 person-years). The case subjects and twice as many postmenopausal control subjects were included in a case-control study nested within the cohort. Biochemical analyses for percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), total estradiol, estrone, and follicle-stimulating hormone were performed on sera that had been kept at -80 degrees C since sampling. RESULTS For increasing quartiles of total estradiol, the odds ratio (ORs) of breast cancer, as adjusted for Quetelet index (weight in kilograms divided by the square of the height in meters), were 1.0, 0.9, 1.8, and 1.8 (P value for trend = .06); the ORs for increasing quartiles of estrone were 1.0, 2.2, 3.7, and 2.5 (P value for trend = .06). For increasing quartiles of free estradiol, defined as the fraction of estradiol that is not bound to proteins, the Quetelet index-adjusted ORs of breast cancer were 1.0, 1.4, 3.0, and 2.9 (P value for trend < .01). When we considered the percent of estradiol bound to SHBG, the Quetelet index-adjusted ORs were 1.0, 0.70, 0.40, and 0.32 (P value for trend < .01), thus suggesting a strong protective effect. These associations persisted or became even stronger when analyses were restricted to women whose samples had been drawn 2 or more years before breast cancer diagnosis. CONCLUSIONS These data represent the first confirmation in a large prospective epidemiologic study of a link between circulating estrogens and breast cancer risk. Although estrogen levels appeared to fall within the conventional limits of normality in all women under study, those who subsequently developed breast cancer tended to show higher levels of estrone, total estradiol, and free estradiol, and a lower percent of estradiol bound to SHBG than women who remained free of cancer. IMPLICATIONS Factors that increase endogenous estrogen production or reduce the binding of estradiol to SHBG may increase a woman's risk of developing breast cancer later in life.

The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

Abstract: Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned1, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer1‐10. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80–90% lifetime risk of breast cancer11, and a 40–50% risk of ovarian cancer12. However, the mutation status of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families8,9,13, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4%–1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.

Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression

Abstract: We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.

Efficacy of breast cancer screening by age. New results swedish two-county trial

Abstract: Background. Several studies have found a smaller effect of breast cancer screening on breast cancer mortality in women aged younger than 50 years compared with older women. Various possible reasons have been suggested for this, but none firmly is established. Methods. The Swedish Two-County Study is a randomized trial of breast cancer screening of women aged 40-74 years, comprising with 133,065 women with a 13-year follow-up of 2467 cancers. The Breast Cancer Detection Demonstration Project (BCDDP) is a nonrandomized screening program in the United States, with a 14-year follow-up of 3778 cancers in women aged 40-74 years. The Swedish results by age were updated. The lesser effect of screening at ages 40-49 years was investigated in terms of sojourn time (the duration of the preclinical but detectable phase) size, lymph node status, and histologic type of the tumors diagnosed in the Swedish Study and their subsequent effect on survival using survival data from both studies. Results. In the Swedish Trial, a 30% reduction in mortality associated with the invitation to screening of women aged 40-74 years was maintained after 13-years of follow-up. The reduction was 34% for women aged 50-74 years and 13% for women aged 40-49 years. Results indicated that the reduced effect on mortality for women aged 40-49 years was due to a differential effect of screening on the prognostic factors of tumor size, lymph node status, and histologic type. The mean sojourn times in the age groups 40-49 years, 50-59 years, 60-69 years, and 70-74 years were 1.7, 3.3, 3.8, and 2.6 years, respectively. Conclusions. These results suggest that much, although not all, of the smaller effect of screening on mortality in women aged 40-49 years is due to faster progression of a substantial proportion of tumors in this age group and the rapid increase in incidence during this decade of life. It is concluded that the interval between screenings should be shortened to achieve a greater benefit in this age group. It is estimated that a 19% reduction in mortality would result from an annual screening regime. Cancer 1995 ;75 :2507-17.

Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence.

Abstract: The majority of multiple-case families that segregate both breast and ovarian cancer in a dominant fashion are due to mutations in the BRCA1 gene on chromosome 17q. In this paper, we have combined penetrance estimates for BRCA1 with the results of two population-based genetic epidemiological studies to estimate the gene frequency of BRCA1. On the assumption that the excess risk of ovarian cancer in first degree relatives of breast cancer patients and the breast cancer excess in relatives of ovarian cancer patients are both entirely accounted for by BRCA1, we estimate that the BRCA1 gene frequency is 0.0006 (95% confidence interval [0.0002-0.001]) and that the proportion of breast cancer cases in the general population due to BRCA1 is 5.3% below age 40 years, 2.2% between ages 40 and 49 years, and 1.1% between ages 50 and 70 years. The corresponding estimates for ovarian cancer are 5.7%, 4.6%, and 2.1%, respectively. Our results suggest that the majority of breast cancer families with less than four cases and no ovarian cancer are not due to rare highly penetrant genes such as BRCA1 but are more likely to be due either to chance or to more common genes of lower penetrance. 22 refs.,more » 3 tabs.« less

Adjuvant Tamoxifen Therapy for Early Stage Breast Cancer and Second Primary Malignancies

Abstract: BACKGROUND Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers. PURPOSE Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer. METHODS The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance. RESULTS In the Stockholm Trial, there was a statistically significant (P = .008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P < .001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1-3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9-11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients. CONCLUSION The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans. IMPLICATIONS The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials.

Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events.

Abstract: Background : Local disease recurrences are a concern in conservative breast cancer surgery, and many studies have attempted to identify risk factors for these events. It is important to distinguish local recurrences linked to increased risk of distant spread from those due to inadequate local treatment. Purpose : We evaluated the incidence of local and distant recurrences according to demographic, biological, and pathologic variables in a large series of women who were conservatively and uniformly treated for breast cancer, with the aim of identifying women in whom local failure is predictive for distant metastases and who are therefore candidates for aggressive systemic treatment. Methods : Medical records of 2233 women who had been hospitalized at the Milan Cancer Institute from 1970 to 1987 were analyzed. All women received quadrantectomy and axillary lymph node dissection followed by radiotherapy for the breast. Quadrantectomy is breast-conserving removal of most of the affected quadrant by a radial incision that includes part of the skin. The end points considered were local failures (including local recurrences and new ipsilateral carcinomas) and distant metastases. Statistical analysis employed the competing risks and multiple failures approaches. Results : There were 119 local recurrences, 32 new ipsilateral carcinomas, and 414 distant metastases as first events. The timing of local failures and distant metastases differed : The yearly probability for local failures was approximately 1% up to the 10th year and for distant metastases was 5% in the 2nd year and decreased progressively until the 8th year. Young age was an important risk factor, with peritumoral lymphatic invasion also predictive for local and distant recurrences. Tumor size and axillary lymph node involvement were not related to local recurrence but were important predictors of distant metastases. Extensive intraductal component was only a risk factor for local recurrence. Early (<2 years) local failure predicted for distant metastases compared with later failure. In local failure patients, the 5-year survival rate was 69% from failure. Conclusions : Local recurrences and distant metastases are partially independent events that occur at different times ; several predicting factors also differ. However, women with local recurrences have increased risk of distant metastases. In particular, women 35 years old or younger at first diagnosis who had initial peritumoral lymphatic invasion and local recurrence within 2 years are at high risk for distant spread. For recurrence in cases with an extensive intraductal component or where initial local surgery was possibly inadequate, women are at lower risk. [J Natl Cancer Inst

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Abstract: Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

Frequency and correlates of posttraumatic-stress-disorder-like symptoms after treatment for breast cancer.

Abstract: Diagnosis of life-threatening illness now meets Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria for traumatic stressor exposure for posttraumatic stress disorder (PTSD). Quality of life (QOL) and PTSD-like symptoms were assessed in 55 women posttreatment for breast cancer. PTSD symptom measures included the PTSD Checklist--Civilian Version (PCL-C) and the Impact of Events Scale. QOL was assessed using the 20-item Medical Outcomes Study Questionnaire. PTSD symptomatology was negatively related to QOL, income, and age. Time since treatment, type of cytotoxic treatment, and stage of disease were unrelated to PTSD symptoms. With suggested criteria for the PCL-C, 5% to 10% of the sample would likely meet DSM-IV PTSD criteria. Findings suggest that in survivors of breast cancer, these symptoms might be fairly common, may exceed the base rate of these symptoms in the general population, are associated with reports of poorer QOL, and, therefore, warrant further research and clinical attention.

Cutaneous metastatic disease.

Abstract: The relative frequencies of cutaneous metastases are similar to those of the primary cancers; breast, colon, and melanoma are the most frequent in women and lung, colon, and melanoma are the most common in men. Cutaneous metastases represent an opportunity to detect a potentially treatable cancer before other evidence of it is present, to modify therapy as appropriate to the tumor stage, or possibly to use the cutaneous lesion as a source of easily accessible tumor cells for specific therapy. Cutaneous metastatic disease as the first sign of internal cancer is most commonly seen with cancer of the lung, kidney, and ovary.

Bisphosphonate Risedronate Reduces Metastatic Human Breast Cancer Burden in Bone in Nude Mice

Abstract: Human breast cancer frequently metastasizes to the skeleton to cause osteolysis and subsequent pain, pathological fracture, and hypercalcemia. Because bone continuously releases growth factors stored in bone matrix by bone resorption during physiological remodeling and, thus, possibly provides a favorable microenvironment for metastatic breast cancer cells to proliferate, inhibitors of bone resorption used either prophylactically or in patients with established disease, therefore, would seem likely to be useful adjuvant therapy in patients with breast cancer. However, the parameters for monitoring progressive osteolytic bone disease in humans are imprecise. We examined the effects of the third generation bisphosphonate, risedronate, which is a specific inhibitor of osteoclastic bone resorption, in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-231 leads to osteolytic bone metastases. Risedronate (4 µg/animal/day) was given s.c. to animals ( a ) after radiologically small but defined osteolytic metastases were observed; ( b ) simultaneously with MDA-231 cell inoculation through the entire experimental period; or ( c ) by short-term prophylactic administration before inoculation of MDA-231 cells. In all experiments, risedronate either slowed progression or inhibited the development of bone metastases assessed radiographically. Furthermore, mice treated continuously with risedronate showed significantly longer survival than did control mice. Histomorphometrical analysis revealed that osteoclast numbers were diminished at metastatic tumor sites. Unexpectedly, there was also a marked decrease in tumor burden in bone in risedronate-treated animals. In contrast, the growth of metastatic breast cancer in soft tissues surrounding bones was not affected by risedronate. Moreover, risedronate had no effects on the local growth of s.c. implanted MDA-231 breast cancers in nude mice or on MDA-231 cell proliferation in culture. These data demonstrate that risedronate decreases metastatic MDA-231 breast cancer burden selectively in bone, as well as suppresses progression of established osteolytic lesions and prevents the development of new osteolytic lesions; thus, the data suggest that inhibition of osteoclastic bone resorption may be a useful adjunctive therapy for the treatment of cancers that have colonized in bone.