Breast cancer angio-histogenesis: through a narrow window.
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Breast Neoplasms↗
Biomedical subjects
W D Dupont
Publications and source records attributed to W D Dupont.
Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood.
The presence of estrogen receptor (ER) is a well-known predictor of clinical outcome in human breast cancer. We examined the ER gene in 26 primary breast cancers (14 ER-positive, 12 ER-negative) to determine if alterations of the gene are associated with the ER-negative status. In tumor biopsies and peripheral blood DNA obtained from the same patients we analyzed the ER exon structure using polymerase chain reaction amplification, restriction endonuclease digestion, and agarose gel electrophoresis. All blood and tumor samples, regardless of ER status, showed a complete set of eight exons of normal sizes, ruling out deletions or rearrangements of the ER gene in excess of +/- 20 nucleotides. Previous reports indicate that the two-allele ER PvuII polymorphism could be associated with ER expression in breast cancer (Hill et al., Cancer Res., 49: 145-148, 1989) as well as with patient age at time of tumor diagnosis (Parl et al., Breast Cancer Res. Treat., 14: 57-64, 1989). We localized the PvuII polymorphism in intron 1, 0.4 kilobase upstream of exon 2. Sequence analysis showed the polymorphism to result from a point mutation (T----C) at the fifth position of the restriction site (CATCTG). We determined the PvuII restriction fragment-length polymorphism genotype in 257 primary breast cancers and 140 peripheral blood DNA samples obtained from women without breast cancer. The results indicate that the PvuII polymorphism is not associated with ER content or patient age at tumor diagnosis.
Adult↗
Indicators of increased breast cancer risk in humans.
Specific atypical histological patterns of epithelial hyperplasia (AH) indicate a medically relevant risk of breast cancer development in 5-10% of women with otherwise benign biopsies. This risk is about four times that of similar women, i.e., of the same age and at risk for the same length of time. These relative risks are not stable with time and fall 10-15 years after detection. Absolute risk for invasive breast cancer after AH is about 10% in 10-15 years after biopsy and is most certain for perimenopausal women. Proliferative disease without atypia predicts only a slight elevation of risk with a relative risk (RR) of 1.5 to 2 times that of the general population. There is such a strong interaction between family history and AH that it is relevant to consider women with atypical hyperplasia who have a positive family history (FH) of breast cancer separately from those who do not. The absolute risk of breast cancer development in women with AH without a FH was 8% in 10 years (RR about 4), whereas those with a positive family history experienced a risk of about 20% at 15 years (RR of about 10). This interaction of AH and FH has also been observed in other recent studies. Low replacement doses of conjugated estrogen after menopause do not further elevate risk beyond that identified by histology.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopsy↗
Benign breast disease: indicators of increased breast cancer risk.
Assessment of cancer risk, particularly with a view toward targeting strategies for prevention, is a recent development. The future will see the garnering of more specific information about determinants of risk and their interaction with screening prevention and therapeutic modalities. We are not a full professional generation removed from a time when the question of malignancy in the breast was absolute, yes or no. Now special types of breast cancer are recognized that pose little threat to life, while some benign conditions indicate greatly increased risk of death from cancer. Comparisons of premalignant determinants in other organ systems indicate that cytologic, histologic, and metaplastic features may be more or less important in different organs. Their separate and combined analysis as predictors give a complex measure of tissue organization, which is often predictive of concurrent cancer and/or future cancer development. In proliferative breast disease, the markers of cancer risk may be classified into histologic categories of slightly, moderately, and markedly increased risk. In cases of slightly increased risk, the probability for cancer development is 1.5 to 2 times that of the general population; a moderately increased risk denotes that the likelihood of cancer development may be 4 to 5 times greater; a markedly increased risk has a predictive value of 9 to 10 times that of the general population.
Breast↗
Proliferative breast disease: diagnosis and implications.
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Biopsy, Needle↗
Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease.
We have stratified the cancer risk implications of lobular pattern in situ neoplasias of the breast by separating marked examples of this histologic spectrum (lobular carcinoma in situ [LCIS]) from lesser examples (atypical lobular hyperplasia). The lesser-developed examples have been shown previously to have a lower relative risk (RR) of later invasive carcinoma of the breast (IBC). Forty-eight examples of LCIS were found in 10,542 otherwise benign breast biopsies, representing an incidence of 0.5%. Nine patients were excluded from follow-up because of bilateral mastectomy within 6 months of entry biopsy, IBC within 6 months of entry biopsy, or prior IBC. Follow-up of the remaining 39 patients was complete, averaged 18 years, and revealed an RR of subsequent IBC of 6.9 (P less than .00001). Average overall follow-up for LCIS patients was 19 years; it was 25 years for those alive and free of IBC at the time of their follow-up interview. Neither family history of IBC nor postmenopausal estrogen therapy further affected risk. The absolute risk of IBC after LCIS was 17% at 15 years (adjusted for withdrawals), and the RR was 8.0 in the first 15 years of follow-up compared with the general population. An analysis based on a time-dependent hazards model found that during the first 15 years following biopsy women with LCIS had 10.8 times the risk of breast cancer compared with biopsied women of comparable age who lacked proliferative disease. Some previously published articles reporting lobular neoplasia (LN) suggest that those series with the greatest incidences of LN (whether termed LN or LCIS) have the lowest RR of subsequent breast cancer. Those series with higher incidences of LN include less well-developed histologic patterns of LN (atypical lobular hyperplasia). We conclude that our study of LN and studies performed by others support the higher risk of IBC after histologically flagrant examples (LCIS, about nine times higher) and a relatively lower but definable risk after more histologically subtle examples (atypical lobular hyperplasia, four to five times lower). This relative cancer risk is probably not constant over more than 15 years; thus, cancer risk 15 to 25 years after initial diagnosis of LCIS is uncertain.
Adult↗
Menopausal estrogen replacement therapy and breast cancer.
We conducted a meta-analysis of the literature concerning breast cancer and estrogen replacement therapy. The overall relative risk of breast cancer associated with this therapy was 1.07. However, the variation of the estimated risks among the studies was far greater than could plausibly be explained by chance alone. To explain this variation, we looked at the effects of type, duration, and dosage of treatment. Overall, women who took 0.625 mg/d or less of conjugated estrogens had a risk of breast cancer that was 1.08 times that of women who did not receive this therapy (95% confidence interval [CI], 0.96 to 1.2). The relative risks from these individual studies of low-dosage therapy did not differ significantly from each other. Women who took 1.25 mg/d or more of conjugated estrogens had a breast cancer relative risk of 2.0 or less in all studies. However, the variation in observed risks at this higher dosage was significant. This implies that other risk factors varied among these studies, making it difficult to estimate the overall risk associated with this dosage. The relative risk of breast cancer associated with estrogen replacement therapy among women with a history of benign breast disease was 1.16 (95% CI, 0.89 to 1.5). The combined results from multiple studies provide strong evidence that menopausal therapy consisting of 0.625 mg/d or less of conjugated estrogens does not increase breast cancer risk.
Breast Diseases↗
Anatomic markers of human premalignancy and risk of breast cancer.
Epithelial hyperplasia of the breast carries an increased likelihood of carcinoma development, with most lesions best understood as markers of higher risk. The indication of increased cancer risk for more worrisome or complex histologic patterns has been supported in many studies. About 25% of women who underwent biopsies in the premammographic era had well-developed hyperplastic changes associated with an elevated risk of 1.5 to 2.0 times that of the general population when age and length of time of follow-up were considered. Somewhat fewer than 5% of women had specific patterns of atypical hyperplasia (AH) that approached the criteria of carcinoma in situ (CIS). These women with AH had a risk of cancer four to five times that of the general population, or about one half the risk associated with microscopic CIS. Only ductal CIS should be considered without question to be an intrinsic precancerous lesion because of its regular association with recurrence at the site of its initial diagnosis. Further studies indicated an appreciable interaction between AH and other nonanatomic risk factors, particularly a family history of breast cancer. Also, lower dosage estrogen replacement after menopause does not affect risk in any histologically defined group. The atypical hyperplastic lesions are more common in women undergoing biopsies on the indication of mammographic calcifications than because of palpable masses. The primary therapeutic implications of these premalignant lesions are intensified breast cancer surveillance and screening for these patients.
Breast↗
Power and sample size calculations. A review and computer program.
Methods of sample size and power calculations are reviewed for the most common study designs. The sample size and power equations for these designs are shown to be special cases of two generic formulae for sample size and power calculations. A computer program is available that can be used for studies with dichotomous, continuous, or survival response measures. The alternative hypotheses of interest may be specified either in terms of differing response rates, means, or survival times, or in terms of relative risks or odds ratios. Studies with dichotomous or continuous outcomes may involve either a matched or independent study design. The program can determine the sample size needed to detect a specified alternative hypothesis with the required power, the power with which a specific alternative hypothesis can be detected with a given sample size, or the specific alternative hypotheses that can be detected with a given power and sample size. The program can generate help messages on request that facilitate the use of this software. It writes a log file of all calculated estimates and can produce an output file for plotting power curves. It is written in FORTRAN-77 and is in the public domain.
Case-Control Studies↗
Premalignant conditions and markers of elevated risk in the breast and their management.
Most epithelial hyperplasias of the human breast indicate an increased likelihood of carcinoma development, and the majority are best understood as markers or indicators of higher risk. Prospective studies of women with hyperplasia biopsied in the premammographic era indicate that about 70 per cent of women had mild or no hyperplastic epithelial alterations and experienced no increase in the risk of subsequent carcinoma. About 25 per cent of women had well-developed hyperplastic changes associated with a risk 1.5 to 2.0 times that of the general population controlled for age and length of follow-up. Somewhat fewer than 5 per cent of women had specific patterns of atypical hyperplasia that approached the patterns of carcinoma in situ. The women with atypical hyperplasia had a risk of cancer four to five times that of the general population, or about half the risk associated with microscopic carcinoma in situ. Only ductal carcinoma in situ should be considered without question to be an intrinsically precancerous lesion because of its regular association with recurrence at the site of its initial diagnosis. No follow-up studies of comparable type involving women with mammographically detected lesions are as yet available. However, it is clear that the incidence of atypical hyperplasia is higher in mammographically directed biopsies. The principal therapeutic implication of these premalignant lesions is a need for intensified breast cancer surveillance and screening for these patients.
Breast↗
Invasive breast cancer risk in women with sclerosing adenosis.
To assess sclerosing adenosis (SA) as an independent risk factor for subsequent invasive breast cancer (IBC), the authors reviewed 10,366 benign breast biopsy specimens (BB) obtained between 1950 and 1968 and identified 547 cases of SA meeting strict histologic criteria of expanded lobular units with whorled compressed acini. Of those women targeted for follow-up (3303, of whom 349 had SA), 84% were successfully followed for an average of 17 years. The relative risk for IBC among patients with SA regardless of the presence of atypical hyperplasia (AH) was 2.1. This risk decreased to 1.7 when patients with AH were excluded, and rose to 6.7 when only those patients with SA and AH were analyzed. The coexistence of a family history of IBC in a first-degree relative did not further elevate risk above that of SA alone when women with AH were excluded. Sclerosing adenosis was found to be positively associated with atypical lobular hyperplasia (ALH) as ALH was present in biopsy specimens with SA 2.7 times more frequently than in other biopsy specimens. Perimenopausal age, histologic calcification, and family history of IBC (FH) were also positively associated with SA. Sclerosing adenosis was most frequent in the perimenopausal period and had a weak association with family history of IBC. No association with atypical ductal hyperplasia (ADH) was identified. The authors conclude sclerosing adenosis represents an independent risk factor for subsequent invasive breast cancer apart from its association with ALH, and the risk (excluding patients with coexistent atypical hyperplasia) is in the range of 1.7, times thereby justifying inclusion of sclerosing adenosis as a component of a group of histopathologically defined lesions termed "proliferative breast disease without atypia" which implies a relative cancer risk of 1.5 to 2.0.
Breast Neoplasms↗
Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk.
The authors reevaluated 10,366 consecutive breast biopsy specimens of benign lesions performed between 1950 and 1968. Follow-up information was obtained on 3303 women with a median duration of follow-up of 17 years. This sample contained 84% of the patients originally selected for follow-up. The relative risk (RR) of developing breast cancer was 0.98 for women who took exogenous estrogens as compared to 1.8 for women who did not. Exogenous estrogens lowered the observed breast cancer risk in women with atypical hyperplasia (RR = 3.0 versus 4.5), proliferative disease without atypia (RR = 0.92 versus 1.9), and in women without proliferative disease (RR = 0.69 versus 0.91). Women who took estrogens before 1956 were at 2.3 times the risk of other estrogen users, presumably due to a dose effect. There was no significant association between breast cancer risk and birth control pills, cigarette smoking, or alcohol consumption. Exogenous estrogens are not associated with increased breast cancer risk in women with benign breast disease. A previous history of benign breast disease does not contraindicate replacement estrogen therapy.
Adult↗
Converting relative risks to absolute risks: a graphical approach.
This paper presents a graphical method for converting relative risks to absolute risks. These absolute risk estimates are a function of the patient's current age, the patient's risk of developing cancer relative to some baseline population, the age specific cancer hazard in the baseline population, and the patient's competing mortal risk from all other causes. Graphs for breast cancer morbidity in women, cardiovascular mortality in men, and lung cancer morbidity in men illustrate the method. These graphs provide the probability of developing cancer in the next twenty years given the patient's current age and relative risk. They are derived under the proportional hazards model. A graph for lung cancer in men that uses a plausible exponential hazards model is also provided. The paper illustrates the importance of competing mortal hazard from other causes on absolute cancer risk. The strengths and weaknesses of this method are discussed. The graphs presented in this paper may be used as an aid in clinical decision making and in patient counselling.
Adult↗
Genomic DNA analysis of the estrogen receptor gene in breast cancer.
A human estrogen receptor (ER) cDNA probe was used to examine genomic DNA extracted from 59 primary invasive breast cancers. The tumors were also studied histopathologically, and their ER status was assessed by hormone-binding assay and immunohistochemical analysis. Southern blots of genomic DNA samples digested with restriction endonucleases (BamHI, EcoRI, HindIII, PvuII, XbaI) revealed identical restriction fragments for each tumor, indicating preservation of gross ER gene integrity regardless of ER status, clinical stage, or histopathologic appearance. Digestion with PvuII identified a single, two-allele polymorphism with band(s) at 1.6 and/or 0.7 kb. The homozygous 1.6 kb pattern was present in 14 (24%) patients, the heterozygous 1.6/0.7 kb pattern in 29 (49%) patients and the homozygous 0.7 kb pattern in 16 (27%) patients. The PvuII restriction fragment length polymorphism (RFLP) within the ER gene showed no correlation with the results of the ER binding assay, the immunohistochemical analysis, clinical stage, or histopathologic appearance. A significant correlation was found between the genotypes and patient age at the time of tumor diagnosis. Tumors with the homozygous 1.6 kb and the heterozygous 1.6/0.7 kb patterns were observed in older women with mean ages of 64.6 and 64.4 years, respectively. In contrast, patients with tumors containing the homozygous 0.7 kb pattern were significantly younger, with a mean age of 50.4 years (p-value = 0.0024). The mechanism by which the homozygous 0.7 kb genotype is associated with breast cancer in the premenopausal age group is unknown.
Adult↗
Relative risk of breast cancer varies with time since diagnosis of atypical hyperplasia.
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Adult↗
Early treatment with intravenous metoprolol for suspected acute myocardial infarction: a phase IV United States trial. Phase IV Metoprolol in Myocardial Infarction Study Group.
Recent randomized clinical trials have shown that total mortality and cardiovascular mortality are reduced by the early intravenous administration of beta-blockers to patients suspected of suffering from acute myocardial infarction. These trials were conducted on patients meeting strict entry criteria. In order to assess this therapy when applied to a broader range of myocardial infarction patients, we performed a Phase IV study of metoprolol in acute myocardial infarction. The study was designed to test whether early (less than 8 hours from onset of chest pain) intervention by practicing physicians with open label intravenous metoprolol for cases of suspected acute myocardial infarction achieved mortality results similar to those obtained in large randomized clinical trials. We studied 3824 patients treated by 741 physicians representing a broad spectrum of clinical practice in the United States. Seventy-two percent of the patients entered into the study had confirmed myocardial infarction (39% anterior, 39% inferior, 22% other locations) and 85% of all individuals treated tolerated the full intravenous dose of 15 mg of metoprolol. The 15 day total mortality and cardiovascular mortality rates were 4.9% and 4.5%; 90 day mortality rates were 6.9 and 5.9%. Patients with anterior infarctions had a significantly greater cumulative mortality rate than patients with other types of infarctions. Marked bradycardia (heart rate less than 45 beats per minute) in the first 8 hours post treatment occurred in 4.7% cases and hypotension (systolic blood pressure less than 90 mm Hg) occurred in 9.8% of cases. When compared with the results of the Göteborg and MIAMI trials of metoprolol, it appears that there is no appreciable increase in mortality or morbidity when metoprolol is used in the community practice of acute coronary care.
Adult↗
Evaluation of a new highly purified pertussis vaccine in infants and children.
Purified acellular pertussis vaccine (12.5 micrograms of lymphocytosis promoting factor [LPF] and 12.5 micrograms of filamentous hemagglutinin [FHA]) was compared with conventional pertussis vaccine in a randomized double-blind study involving 40 children aged 4-6 y, 40 children aged 18-24 mo, and 50 infants. Increases in antibody were significantly greater among recipients of acellular vaccine than among recipients of conventional vaccine for antibodies to LPF in all age groups and for antibodies to FHA in infants and children aged 4-6 y; the increase in FHA antibody was also greater with acellular vaccine among children aged 18-24 mo but not significantly so. Compared with conventional vaccine, acellular vaccine was significantly associated with reduced frequency of leg pain and fretfulness at all ages and less frequent fever and anorexia at some ages. The reduced reaction rates and comparable or enhanced immunogenicity of the acellular vaccine make it an attractive candidate for larger field trials, particularly among infants.
Antibodies, Bacterial↗
Intrinsic left ventricular contractility in normal subjects.
The influence of autonomic tone on left ventricular (LV) contractility, along with the range of normal values and the effects of exercise on contractile state, were studied in 12 normal volunteers. Serial reproducibility was examined in a subgroup of 6. LV contractility was estimated by the LV peak-systolic pressure to end-systolic volume relation (pressure-volume relation), and the ratio of peak-systolic pressure to end-systolic volume (pressure/volume ratio). The cuff blood pressure and radionuclide ventriculogram were recorded at rest, during exercise and during pharmacologic pressure-afterloading with phenylephrine, before and after vagal and beta-adrenergic "blockade." Both the pressure/volume ratio and ejection fraction increased during the stimulus of exercise (both p less than or equal to 0.008). After blockade, the pressure-volume relations were highly linear (r = 0.95 +/- 0.05 [standard deviation], n = 12), and there was no systematic difference in their slopes induced by blockade. The serial studies of pressure-volume relations showed no significant differences. The results demonstrated that vagal and sympathetic tone were not important in the support of LV contractility in normal subjects at rest, and that the pressure-volume relation and pressure/volume ratio are reproducible between studies. Also, the findings confirmed that both the pressure/volume ratio and the ejection fraction were sensitive to exercise-induced changes in contractility. This demonstration of intrinsic LV contractility in normal subjects, plus the reproducibility of the measurements, supports the feasibility of serial study of LV contractility.
Adult↗