Showing papers on "Breast cancer published in 1996"

Lymphatic mapping and sentinel node biopsy in the patient with breast cancer

Abstract: Objective. —To identify the sentinel lymph node(s) (SLN[s]) (the first node[s] draining the primary tumor in the regional lymphatic basin) in patients with invasive breast cancer and to test the hypothesis that the histologic characteristics of the SLN predict the histologic characteristics of the remaining lymph nodes in the axilla. Design. —A prospective trial. Participants. —Sixty-two patients with newly diagnosed invasive breast cancers. Intervention. —Patients underwent intraoperative lymphatic mapping using a combination of a vital blue dye and filtered technetium-labeled sulfur colloid. The SLN was identified and removed, followed by a definitive cancer operation, including a complete axillary node dissection. Main Outcome Measure. —The metastatic distribution in the axilla was determined in patients with occult nodal disease. Results. —The SLN was successfully identified in 57 (92%) of 62 patients using the 2 lymphatic mapping procedures. After localization, 18 patients (32%) were found to have metastatic disease, and the SLN tested positive in all 18 patients. There were no "skip" metastases, defined as an SLN that tested negative with higher nodes that tested positive. In 12 (67%) of 18 patients with metastatic disease, the SLN was the only site of disease. The metastatic distribution significantly favored SLN involvement. Among subjects with discordant nodal involvement, the probability of observing the distribution of SLN involvement by chance is very small (P Conclusions. —This study confirms that lymphatic mapping is technically possible in the patient with breast cancer and that the histologic characteristics of the SLN probably reflect the histologic characteristics of the rest of the axillary lymph nodes. The procedure also allows the pathologist to focus the histologic examination on 1 or 2 nodes, potentially increasing the yield of positive dissections and the accuracy of staging.

Association of Macrophage Infiltration with Angiogenesis and Prognosis in Invasive Breast Carcinoma

Abstract: Angiogenesis is a key process in tumor growth and metastasis and is a major independent prognostic factor in breast cancer A range of cytokines stimulate the tumor neovasculature, and tumor-associated macrophages have been shown recently to produce several important angiogenic factors We have quantified macrophage infiltration using Chalkley count morphometry in a series of invasive breast carcinomas to investigate the relationship between tumor-associated macrophage infiltration and tumor angiogenesis, and prognosis There was a significant positive correlation between high vascular grade and increased macrophage index (P = 003), and a strong relationship was observed between increased macrophage counts and reduced relapse-free survival (P = 0006) and reduced overall survival (P = 0004) as an independent prognostic variable These data indicate a role for macrophages in angiogenesis and prognosis in breast cancer and that this cell type may represent an important target for immunoinhibitory therapy in breast cancer

Efficacy of Pamidronate in Reducing Skeletal Complications in Patients with Breast Cancer and Lytic Bone Metastases

Abstract: Background Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone. Methods Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial. Results The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pa...

The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study.

Abstract: PURPOSETo construct a breast cancer-specific quality-of-life questionnaire (QLQ) module to be used in conjunction with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and to test its reliability and validity cross-culturally.PATIENTS AND METHODSModule construction took place after the EORTC guidelines for module development. The module--the QLQ-BR23--consists of 23 items covering symptoms and side effects related to different treatment modalities, body image, sexuality, and future perspective. This module was tested in 170 Dutch, 168 Spanish, and 158 American cancer patients at two points in time. The timing for the Dutch and Spanish patients was before and during treatment with radiotherapy or chemotherapy. For the American patients, the questionnaire was administered at admission at the breast clinic and 3 months after the first assessment.RESULTSMultitrait scaling analysis confirmed the hypothesized structure of four of the five scales. Cronbach's alpha coefficients were,...

Five Versus More Than Five Years of Tamoxifen Therapy for Breast Cancer Patients With Negative Lymph Nodes and Estrogen Receptor-Positive Tumors

Abstract: BACKGROUND In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

Breast Cancer and Other Second Neoplasms after Childhood Hodgkin's Disease

Abstract: Background Patients who survive Hodgkin's disease are at increased risk for second neoplasms. As survival times increase, solid tumors are emerging as a serious long-term complication. Methods The Late Effects Study Group followed a cohort of 1380 children with Hodgkin's disease to determine the incidence of second neoplasms and the risk factors associated with them. Results In this cohort, there were 88 second neoplasms as compared with 4.4 expected in the general population (standardized incidence ratio, 18.1; 95 percent confidence interval, 14.3 to 22.3). The estimated actuarial incidence of any second neoplasm 15 years after the diagnosis of Hodgkin's disease was 7.0 percent (95 percent confidence interval, 5.2 to 8.8 percent); the incidence of solid tumors was 3.9 percent (95 percent confidence interval, 2.3 to 5.5 percent). Breast cancer was the most common solid tumor (standardized incidence ratio, 75.3; 95 percent confidence interval, 44.9 to 118.4), with an estimated actuarial incidence in women ...

Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis.

Abstract: Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis. Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment. Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases. Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations. PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations. In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer. Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.

BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes.

Abstract: Objectives. —To identify predictors of utilization of breast-ovarian cancer susceptibility ( BRCA1 gene) testing and to evaluate outcomes of participation in a testing program. Design. —Prospective cohort study with baseline interview assessment of predictor variables (eg, sociodemographic factors, knowledge about hereditary cancer and genetic testing, perceptions of testing benefits, limitations, and risks). BRCA1 test results were offered after an education and counseling session in a research setting. Outcome variables (including depression, functional health status, and prophylactic surgery plans [follow-up only]) were assessed at baseline and 1-month follow-up interviews. Participants. —Adult male and female members (n=279) of families with BRCA 1 -linked hereditary breast-ovarian cancer (HBOC). Results. —Of subjects who completed a baseline interview (n=192), 60% requested BRCA 1 test results (43% of all study subjects requested results). Requests for results were more frequent for persons with health insurance (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.06-6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI, 1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals. Individuals identified as mutation carriers did not exhibit increases in depression and functional impairment. Among unaffected women with no prior prophylactic surgery, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) to have oophorectomies. Conclusions. —Only a subset of HBOC family members are likely to request BRCA 1 testing when available. Rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer. For some high-risk individuals who receive test results in a research setting that includes counseling, there may be psychological benefits. More research is needed to assess the generalizability of these results and evaluate the long-term consequences of BRCA1 testing. ( JAMA . 1996;275:1885-1892)

Annual hazard rates of recurrence for breast cancer after primary therapy.

Abstract: PURPOSETo determine if the long-term increase of recurrence for breast cancer is stable or slowly decreasing, or if it ever reaches zero; and to determine the effect of prognostic factors on the hazard of recurrence.METHODSAll patients entered onto the seven completed and unblinded Eastern Cooperative Oncology Group (ECOG) coordinated studies of postoperative adjuvant therapy for breast cancer were analyzed in terms of annual hazard of recurrence of breast cancer.RESULTSFor the entire group, the peak hazard of recurrence occurred in the interval of 1 to 2 years. The hazard decreased consistently in the interval of 2 to 5 years. Beyond 5 years, the hazard of recurrence decreased very, very slowly through year 12. The average hazard of recurrence between years 5 and 12 for the entire population was 4.3% per year. The pattern of a peak hazard of recurrence during the first 5 years with a slowly decreasing hazard of recurrence beyond 5 years was also observed to varying degrees in most subsets. Higher risk su...

Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients

Abstract: The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.

Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer.

Abstract: PURPOSEAdjuvant chemotherapy for breast cancer causes significant changes in ovarian function. More young women survive breast cancer than ever before and they are at risk of the sequelae of early menopause. We attempted to (1) define menopausal status in the setting of adjuvant chemotherapy; (2) define chemotherapy-related amenorrhea (CRA); (3) document rates of permanent amenorrhea, temporary amenorrhea, and oligomenorrhea among different regimens; and (4) analyze variables that influence ovarian function.DESIGNWe reviewed reports of the effects of adjuvant chemotherapy for breast cancer on ovarian function in premenopausal women. We searched Medline and Cancerlit from 1966 to 1995 on the following terms: breast neoplasms; chemotherapy, adjuvant; menstruation disorders; premature menopause, and amenorrhea. Further references were obtained from reports retrieved in the initial search.RESULTSA uniform definition of menopause and CRA is lacking. The wide range of CRA rates reported in adjuvant chemotherapy...

The genetic attributable risk of breast and ovarian cancer

Abstract: BACKGROUND The age-specific proportion of breast and ovarian cancer in the general population that is likely to be due to a breast/ovarian cancer susceptibility gene(s) is estimated. In addition, the age-specific penetrance of ovarian cancer for women predicted to be carriers of a susceptibility gene is calculated using population-based data. METHODS Data are from the Cancer and Steroid Hormone Study, a population-based, case–control study conducted by the Centers for Disease Control, which includes 4730 breast cancer cases aged 20 to 54 years. Information regarding the occurrence of breast and ovarian cancer was collected for mothers and sisters of the cases during an in-home interview. The probability of being a breast cancer susceptibility gene carrier was calculated for each of the breast cancer cases using information on the family history of breast cancer. The calculated risk of ovarian cancer in the first-degree relatives of breast cancer cases with a high probability of being a gene carrier is compared with that seen in first-degree relatives of breast cancer cases with a low probability of being a gene carrier and used to calculate the proportion of ovarian cancer cases that are likely to be due to a breast/ovarian susceptibility gene(s) as well as the age-specific risk of developing ovarian cancer for gene carriers. RESULTS Approximately 10% of ovarian cancer cases and 7% of breast cancer cases in the general population are estimated to be carriers of a breast/ovarian cancer susceptibility gene; these women are found primarily in families characterized by multiple cases of the early onset of breast cancer. The proportion of breast cancer cases predicted to be attributable to the gene decreases markedly with age; approximately 33% of cases age 20–29 years compared with approximately 2% of cases age 70–79 years. The proportion of ovarian cancer cases predicted to be due to the susceptibility gene ranges from 14% among patients diagnosed in their 30s to 7% among those diagnosed in their 50s. Carriers are predicted to have at least 15 times the age-specific risk of ovarian cancer of noncarriers. Among women predicted to carry the gene, the cumulative risk of developing ovarian cancer by the age of 59 years is approximately 10%. CONCLUSIONS The estimates provided may prove helpful to clinicians until such time as large scale population-based screening for breast and ovarian cancer susceptibility genes is possible. Cancer 1996;77:2318-24.

Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2

Abstract: BRCA1 and BRCA2 are the two major identified causes of inherited breast cancer, with mutations in either gene conferring up to 80-90% lifetime risk of breast cancer in carrier females. Mutations in BRCA1 account for approximately 45% of familial breast cancer and 90% of inherited breast/ovarian cancer, whereas mutations in BRCA2 account for a comparable percentage of inherited breast cancer cases. Over 85 distinct BRCA1 mutations and a growing list of BRCA2 mutations have been identified, with the majority resulting in protein truncation. A specific BRCA1 mutation, 185delAG, has a reported increased carrier frequency of approximately 0.9% in the Ashkenazi Jewish population, but is also found in rare non-Jewish patients with a different haplotype. The 6174delT mutation in BRCA2 was recently identified as a frequent mutation in 8 out of 107 Ashkenazi Jewish women diagnosed with breast cancer by age 50 (ref. 8), as well as in three Ashkenazi male breast cancer patients. We have conducted a large-scale population study to investigate the prevalence of specific BRCA1 and BRCA2 mutations in Ashkenazi Jewish individuals who were unselected for breast cancer. BRCA1 mutation screening on approximately 3,000 Ashkenazi Jewish samples determined a carrier frequency of 1.09% for the 185delAG mutation and 0.13% for the 5382insC mutation. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation. This expanded population-based study confirms that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constitute the two most frequent mutation alleles predisposing to hereditary breast cancer among the Ashkenazim, and suggests a relatively lower penetrance for the 6174delT mutation in BRCA2.

Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer.

Abstract: PURPOSETo determine the long-term clinical course of patients with metastatic breast cancer (MBC) who achieved a complete remission with doxorubicin-alkylating agent-containing combination chemotherapy programs.PATIENTS AND METHODSTo assess the long-term prognosis of MBC, we reviewed our experience with 1,581 patients treated on consecutive doxorubicin and alkylating agent-containing front-line treatment protocols between 1973 and 1982. Treatment was administered for a maximum duration of 2 years. Characteristics of long-term survivors were evaluated, and hazard rates for progression were calculated.RESULTSFrom this group, 263 (16.6%) achieved complete responses (CR) and 49 (3.1%) remained in CR for more than 5 years. After a median duration of 191 months, 26 patients remain in first CR, four patients died in CR at times ranging from 118 to 234 months, 18 patients died of breast cancer, and one is alive with metastatic disease. Compared with the overall CR and total patient populations, the long-term CR g...

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials

Abstract: *MRC Cyclotron Unit, Hammersmith Hospital, London, United Kingdom; +MRC Cancer Trials Office, Cambridge, United Kingdom; *Departments of Hyperthermia and Statistics, Daniel den Hoed Cancer Center, Rotterdam,The Netherlands; “Department of Radiotherapy, Academic Medical Center, Amsterdam,The Netherlands; apartments of Radiation Oncology, Biostatistics, and Clinical Physics, Princess Margaret Hospital/Ontario Cancer Institute, University of Toronto, Canada purpose: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of thii form of treatment, randomized phase III trials were needed. Methods and Materials: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced prhnary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of ail trials was local complete response. Slow recruitment led to a decision to collaborate and combii the trial rest&s in one analysis, and report them simuhaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically sign&ant difference in complete response rate was observed in the two larger trials. Results: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of tbe 306 patients randomized. The overali CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not alI trials demonstrated an advantage for the combined treatment, although tbe 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. Conclusion: The combined result of the five trials has demonstrated the efficacy of hyperthemia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hypertbermia are warranted. Breast cancer, Hyperthermia, Radiotherapy, Randomized trial. Reprint requests to: Jill B. Whaley, MRC Cancer Trials Office, 5 Shaftesbury Road, Cambridge CB2 2BW UK Accepted for publication 6 March 1996.

Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women.

Abstract: PURPOSETamoxifen is an effective treatment for metastatic and primary breast cancer and is now being evaluated as a chemoprevention agent in healthy women. Any long-term effects on estrogen-sensitive tissues such as bone may have important therapeutic implications.METHODSWe measured bone mineral density (BMD) in the lumbar spine and hip using dual-energy x-ray absorptiometry (DXA) in premenopausal and postmenopausal healthy women who participated in our placebo-controlled tamoxifen chemoprevention of breast cancer trial.RESULTSBMD data are now available from 179 women for this analysis. In premenopausal women, BMD decreased progressively in the lumbar spine (P < .001) and in the hip (P < .05) for women on tamoxifen, but not those on placebo. The mean annual loss in lumbar BMD per year over the 3-year study period in tamoxifen-treated compliant women who remained premenopausal throughout the study period was 1.44% (1.88% calculated on an intent-to-treat basis) compared with a small gain of 0.24% per annum ...

Incidence of and treatment for ductal carcinoma in situ of the breast.

Abstract: Objective. —To describe trends in incidence and treatment for ductal carcinoma in situ (DCIS) of the breast in the United States between 1973 and 1992 and to estimate total numbers of in situ cases diagnosed and numbers treated by mastectomy since 1983, when screening mammography for breast cancer began to become widespread. Design. —Analysis of population-based breast cancer incidence data collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program since 1973 and treatment data collected by the SEER program since 1983. Study Population. —All women in the geographic areas of the United States included in the SEER program. Main Outcome Measures. —Annual age-adjusted and age-specific incidence rates for DCIS; time trends in distribution of cases by type of treatment; percentage of cases treated by mastectomy by geographic area; and estimated numbers for the entire United States of DCIS cases, mastectomies for DCIS, and cases attributable to mammography. Results. —There was a marked increase in DCIS incidence beginning in the early 1980s. Average annual increases in rates between 1973 and 1983 and between 1983 and 1992 changed from 0.3% to 12.0% among women aged 30 to 39 years, from 0.4% to 17.4% among women aged 40 to 49 years, and from 5.2% to 18.1% among women aged 50 years or older. The total estimated number of DCIS cases in the United States in 1992 (23368) was 200% higher than expected based on 1983 rates and trends between 1973 and 1983. Between 1983 and 1992, there was a marked decline in the proportion of DCIS cases treated by mastectomy (from 71% to 43.8%) and an increase in those treated by lumpectomy (from 25.6% to 53.3%). In 1992, 23.3% of cases were treated by lumpectomy and radiation, 30.2% by lumpectomy alone, and 2.6% with no surgery. Treatment patterns varied substantially by geographic area, with 57.7% of cases in New Mexico treated by mastectomy in 1992 compared with 28.8% in Connecticut. Despite the decline in the proportion of cases treated by mastectomy, the increased DCIS incidence rates resulted in an increase in the absolute number of cases treated by mastectomy until 1990 (n=10657); in 1992, there were an estimated 10242 DCIS cases treated by mastectomy. Conclusions —Incidence rates of DCIS of the breast have increased dramatically since 1983. This increase correlates with the widespread adoption of modern mammographic screening. While early detection of invasive breast cancer is beneficial, the value of DCIS detection is currently unknown. There is cause for concern about the large number of DCIS cases that are being diagnosed as a consequence of screening mammography, most of which are treated by some form of surgery. In addition, the proportion of cases treated by mastectomy may be inappropriately high, particularly in some areas of the United States. ( JAMA . 1996;275:913-918)

Localization of the gene for Cowden disease to chromosome 10q22-23

Abstract: Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

Effect of Age, Breast Density, and Family History on the Sensitivity of First Screening Mammography

Abstract: Objective. —To determine factors that influence the sensitivity of modern first screening mammography. Design. —Cross-sectional. Setting. —Nine counties in northern California. Paticipants. —A total of 28 271 women aged 30 years and older referred for first screening mammography to the Mobile Mammography Screening Program of the University of California, San Francisco, from April 1985 to March 1992, of whom 238 were subsequently diagnosed as having breast cancer. Measurements. —Breast cancer risk profile, 2 standard mammographic views per breast, breast density, and follow-up of abnormal and normal mammography by contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results tumor registry to determine the occurrence of any invasive cancer or ductal carcinoma in situ. Results. —For women aged 50 years and older, the sensitivity of first screening mammography was relatively high and decreased slightly with increasing length of follow-up after mammography: 98.5% for 7 months of follow-up, 93.2% for 13 months, and 85.7% for 25 months. Sensitivity was higher among women aged 50 years and older when breast density was primarily fatty rather than primarily dense (98.4% vs 83.7%;P Conclusions. —The sensitivity of modern mammography is highest among women aged 50 years and older who have primarily fatty breast density. Sensitivity is lowest among women younger than 50 years and particularly low when the time between screenings is about 2 years or when women have a family history of breast cancer, possibly because of rapid tumor growth.

Cohort studies of fat intake and the risk of breast cancer--a pooled analysis.

Abstract: Background. Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogeneous fat intake, and measurement errors in estimates of fat intake. Methods. We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error. Results. Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings. Conclusions. We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women whose energy intake from tat was less than 20 percent of total energy intake. In the context of the Western lifestyle, lowering the total intake of fat in midlife is unlikely to reduce the risk of breast cancer substantially. Chemicals/CAS: Dietary Fats

Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group.

Abstract: PURPOSESA randomized trial was conducted to compare tumorectomy and breast irradiation with modified radical mastectomy. We have analyzed the patterns of failure in each arm of the trial and the prognostic factors that have an independent effect on treatment failures and overall survival.PATIENTS AND METHODSThe trial included 179 patients with breast cancer of up to 20 mm in diameter at macroscopic examination. Eighty-eight patients had conservative management and 91 a mastectomy. All patients had axillary dissection with frozen-section examination. For patients with positive axillary nodes (N+), a second randomization was performed: lymph node irradiation versus no further regional treatment. Patterns of failure were determined by a competing-risk approach and multivariate analysis. A prognostic-score was determined by multivariate analysis.RESULTSOverall survival, distant metastasis, contralateral breast cancer, new primary malignancy, and locoregional recurrence rates were not significantly different b...

Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization.

Abstract: Amplification and overexpression of the HER-2/neu gene occurs in 25-30% of human breast cancers. This genetic alteration is associated with a poor clinical prognosis in women with either node negative or node positive breast cancers. The initial studies testing this association were somewhat controversial and this controversy was due in large part to significant heterogeneity in both the methods and/or reagents used in testing archival material for the presence of the alteration. These methods included a number of solid matrix blotting techniques for DNA, RNA and protein as well as immunohistochemistry. Fluorescence in situ hybridization (FISH) represents the newest methodologic approach for testing for this genetic alteration. In this study, FISH is compared to Southern, Northern and Western blot analyses as well as immunohistochemistry in a large cohort of archival human breast cancer specimens. FISH was found to be superior to all other methodologies tested in assessing formalin fixed, paraffin embedded material for HER-2/neu amplification. The results from this study also confirm that overexpression of HER-2/neu rarely occurs in the absence of gene amplification in breast cancer (approximately 3% of cases). This method of analysis is rapid, reproducible and extremely reliable in detecting presence of HER-2/neu gene amplification and should have clinical utility.

Randomized Clinical Trial of Breast Irradiation Following Lumpectomy and Axillary Dissection for Node-Negative Breast Cancer: an Update

Abstract: Background: Breast-conservation surgery is now commonly used to treat breast cancer. Postoperative breast irradiation reduces cancer recurrence in the breast. There is still controversy concerning the necessity of irradiation of the breast in all patients. Purpose: We present an update of results from a randomized clinical trial designed to examine the efficacy of breast irradiation following conservation surgery in the treatment of women with axillary lymph node-negative breast cancer. The patients were enrolled from April 1984 through February 1989. Initial results were published in 1992 after a median follow-up time of 43 months. It was reported that recurrence of cancer in the breast occurred in 5.5% of the patients who received breast irradiation compared with 25.7% of those who did not. No difference in survival was detected between the two treatment groups. Now that the median patient follow-up has reached 7.6 years, the trial end points have been re-examined and an attempt has again been made to identify a group of patients at low risk for recurrence of cancer in the breast Methods: Eight hundred thirty-seven patients with node-negative breast cancer were randomly assigned to receive either radiation therapy (n = 416) or no radiation therapy (n = 421) following lumpectomy and axillary lymph node dissection. The cumulative local recurrence rate as a first event, distant recurrence (i.e., occurrence of metastasis) rate, and overall mortality rate for the treatment groups were described by the Kaplan—Meier method and compared with the use of the logrank test The Cox proportional hazards model was used to adjust the observed treatment effect for the influence of various prognostic factors (patient age, tumor size, estrogen receptor level, and tumor histology) at study entry on the outcomes of local breast recurrence, distant recurrence, and overall mortality. All P values resulted from the use of twotailed statistical tests. Results: One hundred forty eight (35%) of the nonirradiated patients and 47 (11%) of the irradiated patients developed recurrent cancer in the breast (relative risk for patients in the former versus the latter group = 4.0; 95% confidence interval = 2.83-5.65; P 2 cm), and tumor nuclear grade (poor) continued to be important predictors for local breast relapse. On the basis of these factors, we were unable to identify a subgroup of patients with a very low risk for local breast cancer recurrence. Tumor nuclear grade, as previously reported, and tumor size were important predictors for mortality. Conclusions: Breast irradiation was shown to reduce cancer recurrence in the breast, but there was no statistically significant reduction in mortality. A subgroup of patients with a very low risk for local breast recurrence who might not require radiation therapy was not identified. [J Natl Cancer List 1996;88:1659-64]

In situ detection of tissue factor in vascular endothelial cells: Correlation with the malignant phenotype of human breast disease

Abstract: Expression of tissue factor (TF) in the endothelium has been observed only rarely in human disease and has been thought to be elaborated on the surface of vascular endothelial cells (VECs) in vitro as an artifact of tissue culture. Using monoclonal antibodies and a novel probe for functional TF, we have localized TF to the VECs (and tumor cells) within the tumors of seven patients with invasive breast cancer but not in the VECs (or tumor cells) of benign tumors from ten patients with fibrocystic disease of the breast. The potent procoagulant TF was shown to be a marker of the initiation of angiogenesis in human breast cancer. Further evidence that the TF was the demonstration of a similar distribution of cross–linked fibrin only in the VECs of the malignant tumors. We interpret these data as further support for the concept that tumor cells can activate nearby VECs and regulate blood vessel growth in vivo. Large clinicalpathologic studies will be necessary to determine whether TF is a useful marker for the “switch to the angiogenic phenotype” in human breast disease and/or correlates with the thromboembolic complications of breast cancer.

Breast cancer survivors : psychosocial concerns and quality of life

Abstract: To describe the psychosocial concerns and quality of life of breast cancer survivors evaluated 2 and 3 years after primary treatment A sample of 139 breast cancer survivors who had been interviewed during the first year after primary treatment participated in a mailed survey at 2 years (N = 69) and 3 years (N = 70) after initial surgery A random sample of these survivors were also interviewed in person The mailed questionnaire included standardized instruments to assess quality of life (QL), rehabilitation needs, and psychological distress Additional survey questions were developed to examine post-surgical recovery, employment and insurance problems social support, and existential concerns The in-person interviews expanded on these questions and systematically compared these patients' rehabilitation needs to those which existed at the time of an interview 1 year after surgery The 2 and 3 year participants in this follow-up study did not differ from each other on their prior assessments with standardized QL instruments during the first year after surgery, nor did they differ from the full study sample of 227 women The scores on the Profile of Mood States and the Functional Living Index-Cancer were the same for the 2 and 3 year survivor groups and did not differ from the previous assessments at 1 year after initial treatment The scores on the Cancer Rehabilitation Evaluation System showed a significant decline in Global Quality of Life, Sexual Functioning and Marital Functioning between the 1 year and 3 year evaluations For the 2 year sample only Sexual Functioning showed a deterioration between the 1 and 2 year evaluations Using the RAND 36-Item Health Survey 10, the breast cancer survivors were compared with patients from the Medical Outcomes Study The breast cancer survivors demonstrated higher levels of functioning in many dimensions (role functioning, social functioning, pain, and general health) than the patients with chronic medical conditions In spite of relatively good physical and emotional functioning on this generic measure of health status and quality of life, these breast cancer survivors reported a number of important and severe rehabilitation problems that persisted beyond one year after primary treatment Especially frequent were problems associated with physical and recreational activities, body image, sexual interest, sexual function, and problems with dating for those who were single Breast cancer survivors appear to attain maximum recovery from the physical and psychological trauma of cancer treatment by one year after surgery A number of aspects of QL and rehabilitation problems worsen after that time Nevertheless, breast cancer survivors rate their QL more favorably than outpatients with other common medical conditions, and they identify many positive aspects from the cancer experience

A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.

Abstract: The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family1 and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family2. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.

Micrometastatic Breast Cancer Cells in Bone Marrow at Primary Surgery: Prognostic Value in Comparison With Nodal Status

Abstract: Background: Approximately 30% of the patients with primary breast cancer who have no axillary lymph node involvement (i.e., lymph node negative) at the time of surgery will relapse within 10 years; 10% -20% of the patients with distant metastases will be lymph node negative at surgery. Axillary lymph node dissection, as a surgical procedure, is associated with frequent complications. A possible alternative to nodal dissection in terms of prognosis may be the immunocytochemical detection of tumor cells in bone marrow. Purpose: In a prospective study, the value of tumor cell detection (TCD) in bone marrow was compared with axillary lymph node dissection in the prognosis of primary breast cancer after surgery. Methods: Data from 727 patients with primary, operable breast cancer were included in the analysis. All patients had surgery, including axillary lymph node dissection, from May 1985 through July 1994 at the Women's Hospital of the University of Heidelberg (Federal Republic of Germany). Bone marrow aspiration at two sites on each anterior iliac crest was performed immediately after surgery while the patients were under general anesthesia. Most patients received some type of systemic adjuvant therapy. The monoclonal antibody 2E11, directed against the polymorphic epithelial mucin TAG12, was used to detect tumor cells in bone marrow samples. The association of TCD with recognized prognostic indicators was evaluated by means of chi-squared tests. Survival without the development of distant metastases (i.e., distant diseasefree survival) and overall survival were estimated by use of the Kaplan-Meier method; the logrank test was used to compare survival curves. A multivariate Cox regression analysis with stratification according to adjuvant treatment type was used to assess the independent prognostic value of TCD in bone marrow in relation to other variables. Reported P values are two-sided. Results: Tumor cells were detected in the bone marrow of 203 (55%) of 367 lymph node-positive patients and in 112 (31%) of 360 lymph nodenegative patients. TCD was associated with larger tumors (P<.001), lymph node involvement (P = .001), and higher tumor grade (i.e., more undifferentiated) {P = .002). After a median follow-up of 36 months, patients with tumor cells in their bone marrow experienced reduced distant disease-free survival and overall survival (both P values <.001). TCD was an independent prognostic indicator for both distant disease-free survival and overall survival that was superior to axillary lymph node status, tumor stage, and tumor grade. Among patients with tumors less than 2 cm in diameter, TCD was the most powerful predictor of outcome. Conclusions and Implications: TCD in the bone marrow of patients with breast cancer is a valuable prognostic tool associated with negligible morbidity. Prospective randomized studies should be performed to determine whether TCD might replace axillary lymph node dissection in a defined subgroup of patients with small tumors. [J Natl Cancer Inst 1996;88:1652-64]