Showing papers on "Breast cancer published in 1998"
TL;DR: The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in bRCA2 carriers <50 years of age.
Abstract: The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.
2,892 citations
TL;DR: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology.
Abstract: PURPOSETo determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies.PATIENTS AND METHODSWomen (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship b...
2,057 citations
TL;DR: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer, however, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient.
Abstract: Background Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. Methods We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. “Hot spots” representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. Results The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status o...
1,923 citations
TL;DR: There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented in this paper.
1,842 citations
TL;DR: A positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women, and may be useful in the identification of women at high risk of Breast cancer and in the development of risk reduction strategies.
1,820 citations
TL;DR: Tamoxifen was approved by the Food and Drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.
Abstract: Breast cancer is the most common cancer in women in the Western world. Because breast cancer is estrogen-dependent, reducing estrogen secretion by oophorectomy, hypophysectomy, or adrenalectomy can cause the cancer to regress. The need for these surgical procedures was reduced by the introduction of tamoxifen, which acts as an antiestrogen by inhibiting the binding of estrogen to estrogen receptors. Tamoxifen was approved by the Food and Drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.1 Pharmacology and Endocrinology Pharmacologic and Pharmacokinetic Properties The compound administered . . .
1,150 citations
TL;DR: Over 10 years, one third of women screened had an abnormal test result that required additional evaluation, even though no breast cancer was present, and Physicians should educate women about the risk of a false positive result from a screening test for breast cancer.
Abstract: Background The cumulative risk of a false positive result of a breast-cancer screening test is unknown. Methods We performed a 10-year retrospective cohort study of breast-cancer screening and diagnostic evaluations among 2400 women who were 40 to 69 years old at study entry. Mammograms or clinical breast examinations that were interpreted as indeterminate, aroused a suspicion of cancer, or prompted recommendations for additional workup in women in whom breast cancer was not diagnosed within the next year were considered to be false positive tests. Results A total of 9762 screening mammograms and 10,905 screening clinical breast examinations were performed, for a median of 4 mammograms and 5 clinical breast examinations per woman over the 10-year period. Of the women who were screened, 23.8 percent had at least one false positive mammogram, 13.4 percent had at least one false positive breast examination, and 31.7 percent had at least one false positive result for either test. The estimated cumulative risk...
1,056 citations
TL;DR: The review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment.
Abstract: The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin®), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.
1,027 citations
TL;DR: BCS report more frequent physical and menopausal symptoms than healthy women, yet report HRQL and sexual functioning comparable to that of healthy, age-matched women.
Abstract: PURPOSETo describe the health-related quality of life (HRQL), partner relationships, sexual functioning, and body image concerns of breast cancer survivors (BCS) in relation to age, menopausal status, and type of cancer treatment.PATIENTS AND METHODSA cross-sectional sample of BCS in two large metropolitan areas was invited to participate in a survey study that included the following standardized measures: the RAND 36-Item Health Survey; the Centers for Epidemiologic Studies-Depression Scale (CES-D); the Dyadic Adjustment Scale (DAS); the Breast Cancer Prevention Trial (BCPT) Symptom Checklist; the Watts Sexual Functioning Questionnaire (WSFQ); and subscales from the Cancer Rehabilitation Evaluation System (CARES).RESULTSEight hundred sixty-four BCS completed the survey. RAND Health Survey scores were as good or better than those of healthy, age-matched women, and the frequency of depression was similar to general population samples. Marital/partner adjustment was similar to normal healthy samples, and se...
933 citations
TL;DR: Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women, and reducing alcohol consumption is a potential means to reduce breast cancer risk.
Abstract: Objective. - To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. Data Sources. - We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322 647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. Data Extraction. - Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. Data Synthesis. - For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate- adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. Conclusions. - Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.
892 citations
TL;DR: The authors have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women, contrary to the report from the NSABP-P1 study showing a 45% reduction inhealthy women given tamoxIFen versus placebo.
TL;DR: The combination of TGZ and ATRA synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 breast cancer cells and the combination may provide a novel, nontoxic and selective therapy for human breast cancers.
Abstract: Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor γ (PPARγ) is expressed in breast cancer cells. Activation of PPARγ through a synthetic ligand, troglitazone (TGZ), and other PPARγ-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10−5 M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10−5 M) and ATRA (10−6 M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.
TL;DR: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.
Abstract: Background Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. Methods Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received...
Journal Article•
TL;DR: The mammographic parenchymal patterns are related to risk of breast cancer as discussed by the authors, and women with dense tissue in more than 60-75% of the breast are at four to six times higher risk of developing breast cancer than those with no densities.
Abstract: The radiological appearance of the female breast varies among individuals because of differences in the relative amounts and X-ray attenuation characteristics of fat and epithelial and stromal tissues Fat is radiolucent and appears dark on a mammogram, and epithelium and stroma are radiodense and appear light We review here the evidence that these variations, known as mammographic parenchymal patterns, are related to risk of breast cancer Studies that used quantitative measurement to classify mammographic patterns have consistently found that women with dense tissue in more than 60-75% of the breast are at four to six times greater risk of breast cancer than those with no densities These risk estimates are independent of the effects of other risk factors and have been shown to persist over at least 10 years of follow up Estimates of attributable risk suggest that this risk factor may account for as many as 30% of breast cancer cases Mammographically dense breast tissue is associated both with epithelial proliferation and with stromal fibrosis The relationship between these histological features and risk of breast cancer may by explained by the known actions of growth factors that are thought to play important roles in breast development and carcinogenesis Mammographically dense tissue differs from most other breast cancer risk factors in the strength of the associated relative and attributable risks for breast cancer, and because it can be changed by hormonal and dietary interventions This risk factor may be most useful as a means of investigating the etiology of breast cancer and of testing hypotheses about potential preventive strategies
TL;DR: Management of breast cancer was last reviewed in the Journal in 1992 and the accumulation of new biologic information, the results of recent clinical trials, and the availability of new diagnostic and therapeutic tools make it appropriate to review the subject again.
Abstract: Breast cancer is a major public health problem worldwide. Management of breast cancer was last reviewed in the Journal in 1992.1 The accumulation of new biologic information, the results of recent clinical trials, and the availability of new diagnostic and therapeutic tools make it appropriate to review the subject again. Epidemiology The incidence of breast cancer in the United States has been increasing gradually for the past three decades.2,3 It was estimated that 181,600 new cases of breast cancer were diagnosed in the United States in 1997 and that 44,190 people would die of breast cancer during the same . . .
TL;DR: High-dose chemotherapy appears to impair cognitive functioning more than standard- dose chemotherapy, and central nervous system toxicity may be a dose-limiting factor in high-dose cancer treatment regimens.
Abstract: Background Although high-dose chemotherapy is rapidly gaining acceptance as a treatment option for a number of cancers, the long-term toxic effects of such therapy are a concern. Cognitive deficits (e.g., problems with memory and concentration) are not uncommon after chemotherapy, but they have not been documented systematically. In this study, we assessed the prevalence of cognitive deficits in a group of patients with high-risk breast cancer who were randomly assigned to receive either high-dose or standard-dose adjuvant chemotherapy plus tamoxifen, and we investigated whether high-dose chemotherapy impaired cognitive functioning more than standard-dose chemotherapy. Methods Cognitive functioning was evaluated by use of a battery of neuropsychologic tests. In addition, patients were interviewed with regard to cognitive problems, health-related quality of life, anxiety, and depression. Results from patients who received adjuvant systemic therapy were compared with results from patients who had early stage breast cancer not treated with such therapy (control patients). Results The study population consisted of 34 patients treated with high-dose chemotherapy plus tamoxifen, 36 patients treated with standard-dose chemotherapy plus tamoxifen, and 34 control patients. For all patients, the average time since the completion of last nonhormonal therapy was 2 years. Cognitive impairment was found in 32% of the patients treated with high-dose chemotherapy, in 17% of the patients treated with standard-dose chemotherapy, and in 9% of the control patients. In comparison with the control patients, patients treated with high-dose chemotherapy appeared to have an 8.2-times higher risk of cognitive impairment (odds ratio; 95% confidence interval [CI] = 1.8-37.7); in comparison with the patients who received standard-dose chemotherapy, this risk of impairment was 3.5-times higher (95% CI = 1.0-12.8). Conclusion High-dose chemotherapy appears to impair cognitive functioning more than standard-dose chemotherapy. Central nervous system toxicity may be a dose-limiting factor in high-dose chemotherapy regimens.
TL;DR: A model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCa2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives is developed.
Abstract: Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.
TL;DR: In this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent and it is essential to continue follow-up to quantify the long-term risks and benefits of tamxifen therapy.
TL;DR: There was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status, and the present assay may be helpful in early detection, in monitoring disease, and in prognostication.
Abstract: A highly sensitive assay combining immunomagnetic enrichment with multiparameter flow cytometric and immunocytochemical analysis has been developed to detect, enumerate, and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood. Peripheral blood (10–20 ml) from 30 patients with carcinoma of the breast, from 3 patients with prostate cancer, and from 13 controls was examined by flow cytometry for the presence of circulating epithelial cells defined as nucleic acid+, CD45−, and cytokeratin+. Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with cancer including 17 with organ-confined disease. To determine whether the circulating epithelial cells in the cancer patients were neoplastic cells, cytospin preparations were made after immunomagnetic enrichment and were analyzed. Epithelial cells from patients with breast cancer generally stained with mAbs against cytokeratin and 3 of 5 for mucin-1. In contrast, no cells that stained for these antigens were observed in the blood from normal controls. The morphology of the stained cells was consistent with that of neoplastic cells. Of 8 patients with breast cancer followed for 1–10 months, there was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status. The present assay may be helpful in early detection, in monitoring disease, and in prognostication.
TL;DR: Biopsy of the Sentinel node (SN) is a highly accurate, minimally invasive method of staging patients with breast cancer and can substantially reduce the morbidity and costs of surgical treatment by avoiding unnecessary ALND in the majority of patients.
Abstract: Background: Sentinel node (SN) biopsy appears to offer an alternative to routine axillary lymph node dissection (ALND) for staging patients with breast cancer Various techniques have been studied for identifying the SN, using vital blue dye or radioactive colloid, and initial reports are promising The inherent limitations and pitfalls must be clearly understood before SN biopsy can be implemented in clinical practice Study Design: In a prospective trial, the feasibility of using lymphoscintigraphy and gamma probe detection for performing SN biopsy was studied In 130 consecutive patients with T1–T2, N0 breast cancer, preoperative lymphoscintigraphy was performed with technetium 99m-colloidal albumin During ALND, the radioactive axillary SNs were localized by the gamma probe Histopathologic examination of the harvested SNs was compared with the status of the axillary lymph nodes Results: Axillary focal accumulations were clearly identified on lymphoscintigraphy in 116 patients (89%) The failure rate was significantly higher in patients who had a previous excision biopsy (36%) than in those with a palpable tumor in situ (4%) Using the gamma probe, radiolabeled axillary SNs were successfully biopsied in 122 patients (94%) Because 18 of these patients did not undergo formal lymphadenectomy, the predictive accuracy of SN biopsy was analyzed in 104 patients Radioactive nodes revealed metastases in 44 of 104 patients (42%); in 26 of them (59%), these were the only involved axillary nodes The SN was negative in 60 patients (58%); in one patient the ALND was found to contain metastatic disease (17% false negatives) Biopsy of the SN was 98% accurate in predicting the absence of nodal metastases Conclusions: There are certain guidelines for performing SN biopsy by lymphoscintigraphy and gamma probe detection Success depends primarily on an adequate functional capacity of the SN, necessary for sufficient nodal uptake to ensure accurate identification Lymphoscintigraphy defines the pattern of lymph flow and may prevent failure or false-negative biopsies Biopsy of the SN is a highly accurate, minimally invasive method of staging patients with breast cancer and can substantially reduce the morbidity and costs of surgical treatment by avoiding unnecessary ALND in the majority of patients
TL;DR: The data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.
Abstract: ate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06‐3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05‐3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23‐ 4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11‐4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. Conclusion: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer. [J Natl Cancer Inst 1998;90: 1292‐9]
University College London1, French Institute of Health and Medical Research2, University of Liverpool3, University of Edinburgh4, Netherlands Cancer Institute5, University of Pennsylvania6, University of Melbourne7, University of Cambridge8, Western General Hospital9, University of St Andrews10, University of Aberdeen11, International Agency for Research on Cancer12, University of Utah13, Trinity College, Dublin14, Curie Institute15, St James's University Hospital16, Leiden University17
TL;DR: Key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCa2 genes are identified and this information may improve the classification of breast cancer in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Abstract: BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
TL;DR: The results suggest that overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial tumors.
Abstract: Background: Numerous studies have demonstrated that the levels of prostaglandins are greater in various cancers, including breast cancer and colon cancer, than in normal tissues. In particular, the inducible form of cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin biosynthesis, is overexpressed in colon tumors. Epidemiologic studies have demonstrated that the use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) can reduce the risk of colon cancer and, to a lesser extent, the risk of breast cancer. NSAIDs are known to inhibit COX, suggesting that the beneficial effect of NSAIDs in colon cancer may be related to COX overexpression in this disease. This possibility led us to ask whether COX is also overexpressed in breast cancers. Methods: Surgical specimens from 44 patients with breast cancer who had undergone lumpectomy or mastectomy were analyzed by immunoblot analysis and immunohistochemical analysis to determine the expression profile of the constitutively expressed form of cyclooxygenase (COX-1) and the inducible form (COX-2); the specimens from 14 patients included normal breast tissue. Results: Expression of COX-1 protein was substantially higher in 30 of 44 tumor samples than in any of the 14 normal tissue specimens. Immunoblot analysis revealed extremely high levels of COX-2 protein in two tumor samples. Immunohistochemical staining of specimens that expressed COX-1 and/or COX-2 revealed that COX-1 was localized in stromal cells adjacent to the tumor but not in tumor cells. In contrast, COX-2 was localized primarily in tumor cells but also appeared in stromal cells. Conclusion : Our results suggest that overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial tumors.
TL;DR: Socioeconomic factors alone were not sufficient to explain the dramatic effect of race on breast cancer stage; however, socioeconomic variables in conjunction with cultural beliefs and attitudes could largely account for the observed effect.
Abstract: Context.—Breast cancer mortality is higher among African American women than
among white women in the United States, but the reasons for the racial difference
are not known.Objective.—To evaluate the influence of socioeconomic and cultural factors on the
racial difference in breast cancer stage at diagnosis.Design.—Case-control study of patients diagnosed as having breast cancer at
the University Medical Center of Eastern Carolina from 1985 through 1992.Setting.—The major health care facility for 2 rural counties in eastern North
Carolina.Subjects.—Five hundred forty of 743 patients with newly diagnosed breast cancer
and 414 control women from the community matched by age, race, and area of
residence.Main Outcome Measures.—Breast cancer stage at diagnosis.Results.—Of the 540 patients, 94 (17.4%) presented with TNM stage III or IV disease.
The following demographic and socioeconomic factors were significant predictors
of advanced stage: being African American (odds ratio [OR], 3.0; 95% confidence
interval [CI], 1.9-4.7); having low income (OR, 3.7; 95% CI, 2.1-6.5); never
having been married (OR, 2.9; 95% CI, 1.4-5.9); having no private health insurance
(OR, 2.5; 95% CI, 1.6-4.0); delaying seeing a physician because of money (OR,
1.6; 95% CI, 1.1-2.5); or lacking transportation (OR, 2.0; 95% CI, 1.2-3.6).
Univariate analysis also revealed a large number of cultural beliefs to be
significant predictors. Examples include the following beliefs: air causes
a cancer to spread (OR, 2.8; 95% CI, 1.8-4.3); the devil can cause a person
to get cancer (OR, 2.1; 95% CI, 1.2-3.5); women who have breast surgery are
no longer attractive to men (OR, 1.9; 95% CI, 1.1-3.5); and chiropractic is
an effective treatment for breast cancer (OR, 2.4; 95% CI, 1.4-4.4). When
the demographic and socioeconomic variables were included in a multivariate
logistic regression model, the OR for late stage among African Americans decreased
to 1.8 (95% CI, 1.1-3.2) compared with 3.0 (95% CI, 1.9-4.7) for race alone.
However, when the belief measures were included with the demographic and socioeconomic
variables, the OR for late stage among African Americans decreased further
to 1.2 (95% CI, 0.6-2.5).Conclusions.—Socioeconomic factors alone were not sufficient to explain the dramatic
effect of race on breast cancer stage; however, socioeconomic variables in
conjunction with cultural beliefs and attitudes could largely account for
the observed effect.
TL;DR: The hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer is supported, with data supporting this hypothesis after a mean time of 13.5 years.
Abstract: Background: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis. Methods: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided. Results: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P = .02), lack of estrogen receptors (P = .008), and the number of positive lymph nodes (P = .0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors-DFS: relative risk of failure (RR) = 0.60 (95% confidence interval [CI] = 0.44-0.83), P = .001; survival: RR = 0.66 (95% CI = 0.47-0.92), P =.01 ; RFS: RR = 0.58 (95% CI = 0.42-0.82), P = .002; DDFS: RR = 0.61 (95% CI = 0.44-0.85), P = .003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR = 0.96 (95% CI = 0.75-1.23), P = .74; survival: RR = 0.90 (95% CI = 0.69-1.19), P = .47; RFS: RR = 0.88 (95% CI = 0.67-1.16), P = .37; DDFS: RR = 1.03 (95% CI = 0.79-1.35), P = .84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P = .02) and DDFS (P = .02) but not for survival (P = .15) or RFS (P = .06). Conclusions: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.
TL;DR: The risk for osteolytic bone lesion complications in metastatic breast cancer was significantly decreased with monthly infusions of 90 mg of pamidronate, and this effect was maintained for at least 2 years.
Abstract: PURPOSEPamidronate, an aminobisphosphonate, has been shown to lower the risk of skeletal complications associated with lytic bone lesions for up to 1 year in women with stage IV breast cancer who received chemotherapy. We studied the long-term effectiveness and safety of continued treatment with intravenous pamidronate infusions for up to 2 years.PATIENTS AND METHODSThree hundred eighty-two women with metastatic breast cancer and lytic bone lesions who received chemotherapy were randomly assigned to receive either 90 mg of pamidronate or placebo intravenously every 3 to 4 weeks in this double-blind, multicenter, parallel-group trial. Patients were evaluated monthly for 2 years for skeletal complications, which included pathologic fractures, need for radiation or surgery to treat bone complications, spinal cord compression, and hypercalcemia. Bone pain, analgesic use, bone biochemical markers, performance status, quality of life, radiologic response in bone, and survival were also evaluated.RESULTSAs in th...
Northwestern University1, NorthShore University HealthSystem2, Durham University3, North Shore-LIJ Health System4, University of Vermont5, Wake Forest University6, University of California, San Francisco7, Roswell Park Cancer Institute8, University of Texas at San Antonio9, Memorial Sloan Kettering Cancer Center10, University of North Carolina at Chapel Hill11, National Institutes of Health12
TL;DR: The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further validated before clinical implementation.
Abstract: Background We have previously reported that high expression of the erbB-2 gene (also known as HER-2/neu and ERBB2) in breast cancer is associated with patient response to dose-intensive treatment with cyclophosphamide, doxorubicin (Adriamycin), and 5-flurouracil (CAF) on the basis of short-term follow-up of 397 patients (set A) with axillary lymph node-positive tumors who were enrolled in Cancer and Leukemia Group B (CALGB) protocol 8541. Methods To validate those findings, we conducted immunohistochemical analyses of erbB-2 and p53 protein expression in an additional cohort of 595 patients (set B) from CALGB 8541, as well as a molecular analysis of erbB-2 gene amplification in tumors from all patients (sets A and B). Marker data were compared with clinical, histologic, treatment, and outcome data. Results Updated analyses of data from set A (median follow-up, 10.4 years) showed an even stronger interaction between erbB-2 expression and CAF dose, by use of either immunohistochemical or molecular data. A similar interaction between erbB-2 expression and CAF dose was observed in all 992 patients, analyzed as a single group. However, for set B alone (median follow-up, 8.2 years), results varied with the method of statistical analysis. By use of a proportional hazards model, the erbB-2 expression-CAF dose interaction was not significant for all patients. However, in the subgroups of patients randomly assigned to the high- or the moderate-dose arms, significance was achieved. When patient data were adjusted for differences by use of a prognostic index (to balance an apparent failure of randomization in the low-dose arm), the erbB-2 expression-CAF dose interaction was significant in all patients from the validation set B as well. An interaction was also observed between p53 immunopositivity and CAF dose. Conclusions The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further validated before clinical implementation. Interactions between erbB-2 expression, p53 expression, and CAF dose underscore the complexities of predictive markers where multiple interactions may confound the outcome.
Journal Article•
TL;DR: The author gives a short review of the most important prognostic factors in breast cancer, with emphasis was laid on steroid receptors, c-erpB-2, p53 and bcl-2 alterations.
Abstract: Prognostic factors are clinical and pathological features that give information in estimating the likely clinical outcome of an individual suffering from cancer. The author gives a short review of the most important prognostic factors in breast cancer. 376 breast cancer cases of a ten year interval in a county hospital are summarized. Traditional clinico-pathological parameters i.e. TNM and steroid receptor status are discussed. The more common karyotipic, oncogene and tumor suppressor gene alterations are outlined in the study. Methods for their detection are presented and their value in prognostication is reviewed. Emphasis was laid on steroid receptors, c-erpB-2, p53 and bcl-2 alterations. Genes responsible for heritable forms of increased breast cancer risk are briefly reviewed.
TL;DR: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.
Abstract: PURPOSETo determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer.PATIENTS AND METHODSPremenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy.RESULTSThe median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relaps...
TL;DR: Until findings from randomized trials confirm and quantitate the benefit of estrogen therapy for prevention of CHD, it is believed it should not be recommended to all postmenopausal women.
Abstract: Multiple observational studies suggest a marked reduction in risk of coronary heart disease (CHD) associated with postmenopausal estrogen use. A new metaanalysis presented here extends these results to estrogen plus progestin regimens. Although the findings from observational studies are strong and consistent, and there are several plausible mechanisms by which estrogen might reduce risk for CHD, most of the known biases would tend to exaggerate estrogen’s benefit. Further, estrogen therapy clearly increases risk for endometrial hyperplasia and cancer, venous thromboembolic events and gallbladder disease, and long-term use probably also increases the risk of breast cancer. Therefore, until findings from randomized trials confirm and quantitate the benefit of estrogen therapy for prevention of CHD, we believe it should not be recommended to all postmenopausal women.