MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216.

PURPOSE: Aim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction. METHODS: Data were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO-216, ranging 5-40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216. RESULTS: No inflammatory reaction was observed in HV and sCAD patients following MDCO-216 treatment, judging by body temperature, white cell counts, neutrophil counts, C-reactive protein, circulating cytokines (IL-6, TNF-α), and adverse events. In the ex vivo experiment, the geometric means (SD) of the ratio of MDCO-216 stimulated IL-6 over background levels were 0.8 (1.9), 0.7 (1.5), 1.0 (2.0) for respectively HV, sCAD, aCAD. The corresponding ETC-216 stimulated values were 15.8 (2.9), 9.5 (3.6), 3.8 (4.0). TNF-α results were comparable. Because many ETC-216 stimulated samples had cytokine concentrations >ULOQ, ratios were categorised and marginal homogeneity of the contingency table (MDCO-216 versus ETC-216) was assessed with the Stuart-Maxwell test. P-values were ≤0.0005 for all populations. CONCLUSIONS: MDCO-216 did not induce adverse immunostimulation in HV and sCAD patients, in contrast to ETC-216. Results from the ex vivo stimulation suggests the same holds true for aCAD patients.

Gene expression array testing of FFPE archival breast tumor samples: an optimized protocol for WG-DASL sample preparation.

Archived formalin-fixed, paraffin embedded (FFPE) tissues constitute a vast, well-annotated, but underexploited resource for the molecular study of cancer progression, largely because degradation, chemical modification, and cross-linking, render FFPE RNA a suboptimal substrate for conventional analytical methods. We report here a modified protocol for RNA extraction from FFPE tissues which maximized the success rate (with 100% of samples) in the expression profiling of a set of 60 breast cancer samples on the WG-DASL platform; yielding data of sufficient quality such that in hierarchical clustering (a) 12/12 (100%) replicates correctly identified their respective counterparts, with a high self-correlation (r = 0.979), and (b) the overall sample set grouped with high specificity into ER+ (38/40; 95%) and ER- (18/20; 90%) subtypes. These results indicate that a large fraction of decade-old FFPE samples, of diverse institutional origins and processing histories, can yield RNA suitable for gene expression profiling experiments.

Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients.

Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.

Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.

Medical and drug risk factors associated with neuroblastoma: a case-control study.

A matched case-control study of prenatal risk factors for neuroblastoma was conducted, including 104 cases diagnosed over the period 1970-79 in the Greater Delaware Valley. Significantly elevated odds ratios (ORs) were associated with maternal use of a neurally active drug during pregnancy (OR = 2.83), sex hormone exposure 3 months prior to or during pregnancy (OR = 2.25), frequent alcohol consumption during pregnancy (OR = 9.0), and maternal use of diuretic drugs during pregnancy (OR = 5.75). Significantly more case mothers than control mothers reported use of hair coloring products during pregnancy (OR = 3.0). No association was found between cigarette smoking, coffee consumption, or medical irradiation and case-control status.

Breast cancer among young U.S. women in relation to oral contraceptive use.

BACKGROUND: While most studies have found no association between oral contraceptive use and breast cancer, several studies of younger women have reported an association with long-term oral contraceptive use. PURPOSE. We studied the relationship of patterns of oral contraceptive use to breast cancer risk among younger women. These women have had oral contraceptives available their entire reproductive lives and are now entering the breast cancer-prone years. METHODS: A population-based, case-control study of breast cancer was conducted in three counties in western Washington State among women born in 1945 or later, ages 21-45. Case patients were 747 women with breast cancer diagnosed in 1983-1990 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. Control subjects were 961 women identified by random-digit telephone dialing. Subjects were interviewed in person, using pictures of brands of oral contraceptives and calendars of life events as recall aids. RESULTS: There was no increased incidence of breast cancer associated with ever having used oral contraceptives. Because only 8% of this cohort had never used oral contraceptives, short-term users (< 1 year) were combined with never users as the reference group for further analyses. A small increased risk of breast cancer was associated with long duration of oral contraceptive use (odds ratio for > or = 10 years = 1.3; 95% confidence interval [CI] = 0.9-1.9; P for trend = .03), particularly among women aged 35 years or younger (odds ratio for > or = 10 years = 1.7; 95% CI = 0.9-3.1). Breast cancer was also modestly related to oral contraceptive use early in reproductive life (odds ratio for use within 5 years of menarche = 1.3; 95% CI = 1.0-1.8; P for trend = .04) and to use of high-progestin-potency oral contraceptives for at least 1 year (odds ratio = 1.5; 95% CI = 1.1-2.1). These associations were adjusted for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. The associations were not further confounded by case-control differences in education, religion, breast feeding of offspring, or infertility; in oral contraceptive contraindications, indications, or complications; or in measures of breast cancer detection such as mammography or breast biopsy. CONCLUSIONS: Long-term oral contraceptive use among young women or use beginning near menarche may be associated with a small excess breast cancer risk, possibly due to susceptibility to genetic damage in breast epithelial cells at ages of high breast cell proliferative activity. IMPLICATIONS: Future studies should investigate whether the patterns of risk we reported are present as this cohort ages.

PIP: A case control study was conducted in Washington among 21-45 year old white women from King, Pierce, and Snohomish counties (i.e., Seattle metropolitan area) to examine the relationship between oral contraceptive (OC) use and breast cancer. The 747 cases were diagnosed with invasive breast cancer between January 1983 and April 1990. The researchers combined short term OC users with never users since just 8% of all subjects had never used OCs. They controlled for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. Longterm use (i.e., =or 10 years) of OCs was associated with a small increased risk of breast cancer (odds ratio [OR] = 1.3; p for trend = 0.03), especially among women not older than 35 years (OR = 1.7). This finding was consistent with results of other studies. OC use early in reproductive life (i.e., within 5 years of menarche) was also associated with a moderate increase in breast cancer (OR = 1.3; p for trend = 0.04). Breast cancer risk was also elevated among women who used high progestin potency OCs (as defined by the Dickey method for classifying OC potency) for at least 1 year (OR = 1.5). Case control differences in education, religion, breast feeding of children, or infertility; in OC contraindications, indications, complications; or in measures of breast cancer detection (e.g., mammography or breast biopsy) did not confound the associations. An association between breast cancer and long term OC use among young women and OC use beginning close to menarche suggest that puberty, a time when breast epithelial cells are undergoing considerable proliferative activity, are susceptible to genetic damage. Further research is needed to determine whether the aforementioned patterns of breast cancer risk continues as the cohort becomes older.

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.

Risk of breast cancer among young women: relationship to induced abortion.

BACKGROUND: Certain events of reproductive life, especially completed pregnancies, have been found to influence a woman's risk of breast cancer. Prior studies of the relationship between breast cancer and a history of incomplete pregnancies have provided inconsistent results. Most of these studies included women beyond the early part of their reproductive years at the time induced abortion became legal in the United States. PURPOSE: We conducted a case-control study of breast cancer in young women born recently enough so that some or most of their reproductive years were after the legalization of induced abortion to determine if certain aspects of a woman's experience with abortion might be associated with risk of breast cancer. METHODS: Female residents of three counties in western Washington State, who were diagnosed with breast cancer (n = 845) from January 1983 through April 1990, and who were born after 1944, were interviewed in detail about their reproductive histories, including the occurrence of induced abortion. Case patients were obtained through our population-based tumor registry (part of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute). Similar information was obtained from 961 control women identified through random digit dialing within these same counties. Logistic regression analysis was used to estimate odds ratios and confidence intervals (CIs). RESULTS: Among women who had been pregnant at least once, the risk of breast cancer in those who had experienced an induced abortion was 50% higher than among other women (95% CI = 1.2-1.9). While this increased risk did not vary by the number of induced abortions or by the history of a completed pregnancy, it did vary according to the age at which the abortion occurred and the duration of that pregnancy. Highest risks were observed when the abortion was done at ages younger than 18 years--particularly if it took place after 8 weeks' gestation--or at 30 years of age or older. No increased risk of breast cancer was associated with a spontaneous abortion (RR = 0.9; 95% CI = 0.7-1.2). CONCLUSION: Our data support the hypothesis that an induced abortion can adversely influence a woman's subsequent risk of breast cancer. However, the results across all epidemiologic studies of this premise are inconsistent--both overall and within specific subgroups. The risk of breast cancer should be reexamined in future studies of women who have had legal abortion available to them throughout the majority of their reproductive years, with particular attention to the potential influence of induced abortion early in life.

PIP: Epidemiologists compared data on 845 white women who were diagnosed with breast cancer between January 1983 and April 1990, were born after 1944, and lived in King, Pierce, or Snohomish counties in Washington State with data on 961 white women with no breast cancer from the same counties. They wanted to determine whether induced abortion increases the risk of breast cancer. Restricting cases to women born after 1944 allowed the researchers to focus only on legal induced abortions. When the researchers limited the analysis only to women who had been pregnant at least once, the risk of developing breast cancer in women who had had at least 1 induced abortion was 50% greater than those who had not had an induced abortion. This risk differed depending on the age at which the women underwent the induced abortion and the duration of that pregnancy. A gestational age (at the time of the first aborted pregnancy) of 9-12 weeks carried the highest risk of breast cancer (RR = 1.9 vs. 1.4 for =or 8 weeks and =or 13 weeks). Further, the breast cancer risk was greatest among women who underwent the induced abortion when they were less than 18 years old (relative risk [RR] = 2.5). It was especially high for women who were less than 18 years old and who had the abortion between 9 and 24 weeks of gestation (RR = 9). It was also high for those who were at least 30 years old at the time of the abortion (RR = 2.1). Spontaneous abortion was not associated with an increased risk (RR = 0.9). Neither the number of induced abortions nor the history of a completed pregnancy were associated with an increased risk of breast cancer. These findings suggest that an induced abortion during the last month of the first trimester increases the risk of breast cancer and that women who were at a very young age at the time of the first induced abortion face an increased risk of breast cancer.

Oral contraceptives and breast cancer risk among younger women.

BACKGROUND: Several studies have suggested a link between oral contraceptive use and breast cancer in younger women, but it is possible that chance or bias, including selective screening of contraceptive users, contributed to the putative association. PURPOSE: Given that oral contraceptives were first marketed in the United States in the early 1960s, we conducted a population-based case-control study to examine the relationship between use of oral contraceptives and breast cancer among women in a recently assembled cohort, focusing on women younger than 45 years of age who had the opportunity for exposure throughout their entire reproductive years. METHODS: Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Ga., Seattle/Puget Sound, Wash., and central New Jersey. In Seattle and New Jersey, the study was confined to women 20 through 44 years of age; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years of age (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs) and their 95% confidence intervals (CIs). RESULTS: Among women younger than 45 years, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3 (95% CI = 1.1-1.5). Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7; 95% CI = 1.2-2.6), with the RR rising to 2.2 (95% CI = 1.2-4.1) for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began early (before age 18 years) and continued long-term (> 10 years) was even higher (RR = 3.1; 95% CI = 1.4-6.7). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than age 35 years (RR = 2.0; 95% CI = 1.3-3.1). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. Evaluation of screening histories and methods of diagnosis failed to support the speculation that associations could be due to selective screening. Among women 45 years of age and older, no associations of risk with use of oral contraceptives were noted. CONCLUSIONS: The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

PIP: A population-based case control study examined the relationship between use of oral contraceptives and breast cancer among women in a cohort, focusing on women younger than 45 years old who had the opportunity for exposure throughout their entire reproductive years. Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Georgia, Seattle/Puget Sound, Washington, and central New Jersey. In Seattle and New Jersey, the study was confined to women 20-44 years old; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years old (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs). Among women under 45, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3. Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7) with the RR rising to 2.2 for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began before age 18 years and continued long-term ( 10 years) was even higher (RR = 3.1). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than 35 years (RR = 2.0). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

Diet during adolescence and risk of breast cancer among young women.

BACKGROUND: A variety of breast cancer risk factors pertain to a woman's adolescence and may be related to nutritional influences. We assessed risk of early-onset breast cancer related to diet during adolescence in a case-control study. METHODS: Study participants were accrued from the following three geographical regions covered by cancer registries: Atlanta, GA; Seattle/Puget Sound, WA; and central New Jersey. Case patients (n = 1647) were newly diagnosed with breast cancer, and control subjects (n = 1501) were identified by random-digit-dialing techniques. In an interview, each subject was asked to recall the frequency of consumption and portion size of 29 key food items at ages 12-13 years. Mothers of a subset of respondents completed questionnaires, and food groups were recalculated after removal of foods with poor agreement between mother and daughter. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals. RESULTS: When high versus low quartiles of consumption were compared, there was a suggestion of a reduced risk associated with high consumption of fruits and vegetables, although this finding was not statistically significant. Slight increases (of borderline statistical significance) in risk of breast cancer were found for intake of chicken or high-fat meat. Intake of animal fat, high-fat foods, high-fat snacks and desserts, or dairy products during adolescence had no apparent influence on breast cancer risk. Removal of foods suspected to be poorly recalled by the daughters did not change any of the risk estimates. CONCLUSION: These data do not provide evidence for a strong influence of dietary intakes during adolescence on risk of early-onset breast cancer.

Body mass index and asthma in the military population of the northwestern United States.

BACKGROUND: Patients with asthma commonly have other medical problems such as obesity, but it is unclear if obesity independently relates to asthma occurrence. OBJECTIVE: To examine the association between asthma and obesity. METHODS: We studied enrollees aged 17 to 96 years in region 11 of TRICARE, a military managed health care program encompassing Washington, Oregon, and northern Idaho, using an enrollment questionnaire from January 1997 to December 1998. We performed case-control analyses on 2788 asthma cases and 39 637 controls. From these cases and controls, we selected a random sample of 1000 asthma cases and 1000 controls, linking them to a computerized military health record system to verify if medications indicated for asthma therapy were prescribed. After excluding cases not prescribed bronchodilator medications and excluding controls prescribed bronchodilator medications or steroids, we used logistic regression to estimate associations among asthma, body mass index, and demographic, lifestyle, and comorbid risk factors in 386 verified cases and 744 verified controls. RESULTS: Increasing body mass index, younger age, female sex, non-active duty beneficiary status, and arthritis were significant independent predictors of asthma prevalence in both our larger analysis and our verified substudy, whereas stomach ulcer, depression, hypertension, and white race are also independent predictors of asthma prevalence in our larger analysis. CONCLUSIONS: Increasing body mass index is a key factor predicting prevalence of asthma and, if determined to be etiologically related to asthma incidence, is a potentially modifiable risk factor for asthma.

Integrated designs for gene discovery and characterization.

Recent advances, including near completion of the human genome map, ever improving high-throughput technologies, and successes in discovering chronic disease-related genes, have stimulated the further development of genetic epidemiology. The primary mission of genetic epidemiology is to discover and characterize genes, whether independent of or interactive with environmental factors, that cause human diseases. To accomplish such a mission, genetic epidemiology needs to integrate both genetic and epidemiologic approaches. One of the challenges facing such an integrated approach is the identification of study designs that are efficient for both gene discovery and characterization. Because designs for gene discovery alone and designs for gene characterization alone have been elaborated in the other two panels, the focus of this paper is to describe those designs that may be useful for discovery and characterization jointly, including case-family and case-control-family designs. Examples of integrated designs are described, and studies of breast cancer conducted at the Fred Hutchinson Cancer Research Center are used for illustration. Finally, related analytic issues are also discussed.

Measurement of urinary estrogen metabolites using a monoclonal enzyme-linked immunoassay kit: assay performance and feasibility for epidemiological studies.

We evaluated an enzyme-linked immunoassay kit (Estramet 2/16) for the measurement of 2-hydroxyestrone (2-OH E1) and 16-alpha hydroxyestrone (16 alpha-OH E1), major metabolites of estradiol. Urine samples from 14 healthy premenopausal women on days 1, 8, 15, and 22 of their menstrual cycle were assayed along with standards, kit controls, and in-house controls. The intra-assay percentage CVs of 2-OH E1, 16 alpha-OH E1, and the 2-OH E1: 16 alpha-OH E1 ratio were 6.8, 7.4, and 1.8, respectively; the interassay percentage CVs were 15.3, 30.7, and 23.3, respectively. The assay linearity was between 0 and 40 ng/ml. The mean 2-OH E1:16 alpha-OH E1 ratio was relatively constant throughout the day, but it increased by around 50% between the follicular and luteal portions of the menstrual cycle. Individual reagent kits within each lot for 16 alpha-OH E1 were stable for 2 weeks. There was considerable lot-to-lot variation over a 5-month period. In lots used during the last 2 months of the study, values of 2-OH E1 from in-house controls increased by 30-50%, and those of 16 alpha-OH E1 by 50-100%, relative to values obtained initially on the same samples. Depending on the lot, the ratio of the two metabolites ranged from 2 to 5.5. These data suggest that the assay is useful for studies where samples can be assayed with the same kit lot over a period of not more than 2 weeks, but that it is not now suitable for studies that extend over a long enough period of time so that multiple kit lots are required.

Childhood brain tumor risk in relation to birth characteristics.

A population-based case-control study was conducted utilizing linked cancer registry and birth certificate data to examine potential associations between selected birth characteristics and the occurrence of brain tumors in children. Cases (n = 157) were those children ages 10 and under who were born in Washington state and who were diagnosed with a primary brain tumor between 1974 and 1986. Controls were randomly selected from the Washington State birth files and were matched 5:1 to cases on year and county of birth. A limited number of positive findings emerged from the study. Results suggested that high birthweight may be related to an increased risk of childhood brain tumor (odds ratio (OR) = 1.4, 95% CI 1.0-2.0 for all histologies combined; OR = 1.9, 95% CI 1.1-3.1 for astrocytomas). The risk of astrocytoma was also observed to be associated with older maternal age (OR = 2.2, 95% CI 1.2-4.0) and a history of prior fetal death(s) (OR = 1.9, 95% CI 1.0-3.8).

Characteristics of respondents and non-respondents from a case-control study of breast cancer in younger women.

BACKGROUND: This study assessed the nature of potential biases by comparing respondents with non-respondents from a case-control study of breast cancer in younger women. METHODS: The case-control study was conducted in three regions in the US: Atlanta GA, Seattle/Puget Sound WA, and central New Jersey. An abbreviated interview or mailed questionnaire was completed by willing non-respondents, most of whom had refused participation in the main study. RESULTS: Respondents and non-respondents appeared similar with respect to age, race, relative weight, smoking, family history of breast cancer, number of births, age at first birth, and several dietary items. Compared to non-respondents, case and control respondents were of shorter stature, and reported less frequent consumption of doughnuts/pastries. Respondent cases, compared with non-respondent cases, were more highly educated and more likely to have consumed alcohol regularly; similar but not statistically significant tendencies were observed for controls. Respondent cases experienced menarche earlier than non-respondents. Respondent controls were more likely to have used oral contraceptives than non-respondents; a similar but not statistically significant tendency was observed in cases. Comparisons of crude and simulated relative risks using available non-respondents' data generally showed a low impact of non-response on relative risks in this study. CONCLUSIONS: Our results suggest that non-response would not greatly affect relative risk estimates in this study, except possibly regarding height. However, we were limited by the numbers of informative non-respondents and the amount of data collected. Collecting similar information in future studies would be useful, especially since varying methods used to encourage participation may lead to differences in respondents' characteristics.

Breast cancer risk in young women and history of selected medical conditions.

BACKGROUND: Several common medical conditions are associated with altered hormone levels, and may thus plausibly influence breast cancer risk. Few studies have examined such relationships, and we utilized a population-based case-control study of young women in the US to examine breast cancer risk following a history of various medical conditions. Relationships between breast cancer and each medical condition examined are biologically plausible, and relevant in terms of public health. METHODS: The study included 2173 breast cancer cases and 1990 population-based controls from three areas of the US, under 55 years, who were administered a questionnaire including details of physician-diagnosed medical conditions. RESULTS: No significantly increased or decreased breast cancer risk was associated with a history of thyroid disease, gallbladder disease, colorectal polyps, diabetes, high blood pressure, high cholesterol or surgery for endometriosis. There was some evidence of an increased breast cancer risk associated with ovarian cysts among women who did not receive an oophorectomy (relative risk [RR] = 1.94, 95% CI: 1.0-3.9). Non-significant increases in breast cancer risk were observed following diagnoses of several other cancers, including thyroid cancer, basal cell carcinoma, Hodgkin's disease and malignant melanoma. CONCLUSIONS: To conclude, our generally null results from this large, population-based study support results from previous studies in providing reassurance that women with a history of several common medical conditions do not appear to be at an increased risk of breast cancer at a young age.

Modification of oral contraceptive relationships on breast cancer risk by selected factors among younger women.

In a case-control study of 1647 breast cancer cases and 1501 population controls under 45 years of age, potential modifying effects of other risk factors on the relationship of oral contraceptives to breast cancer were examined. Among the total series of study subjects, the relationship of extended pill usage was greater in non-white than white women. Oral contraceptive associations, however, did not appear to be substantially modified by other risk factors, including parity, body size, or family history of breast cancer (apart from a somewhat enhanced relationship among subjects who reported a sister with breast cancer. Further, oral contraceptive relationships did not vary by a history of benign breast disease, although the majority of subjects began pill usage prior to the development of benign breast disease. Among the women under the age of 35, in whom oral contraceptive relationships were heightened (over a twofold excess risk for use of 5 years or longer), pill relationships were less modified by race than in the total series. Although among these younger subjects there was no effect of pill usage in heavy women, and an enhanced relationship among heavier consumers of alcoholic beverages, these interactive effects were not statistically significant. The findings of this study generally support no substantial variation in oral contraceptive relationships by other breast cancer risk factors, although some further attention might be warranted regarding possible modifying effects of race, body size, type of relative with breast cancer, and alcohol consumption.

PIP: To assess the possible interactive effects of oral contraceptives (OCs) with selected breast cancer risk factors, a case-control study involving US women diagnosed with breast cancer before 45 years of age was conducted. All incident cases of breast cancer diagnosed among younger women during 1990-92 in Atlanta, Georgia, Seattle/Puget Sound, Washington, and five counties of central New Jersey were eligible. Controls were identified through random-digit dialing. The final sample consisted of 1647 cases and 1501 controls. Ever-use of OCs for 6 months or more was associated with a slightly elevated breast cancer risk (relative risk (RR), 1.3; 95% confidence interval (CI), 1.1-1.5), with a stronger association for women whose breast cancer was diagnosed prior to age 35 years (RR, 1.8; 95% CI, 1.2-2.7). Among women under age 35 years, the risk was highest among women who had used OCs for 5 or more years and for those who used them within the past 5 years. In general, study findings did not support extensive variations in the risk associated with OC use across most risk factors. However, there were some noteworthy variations. At ages 35-44 years, long-term OC use exerted stronger effects in African-American women (RR, 1.5; 95% CI, 0.9-2.6) and other non-White women (RR, 2.8; 95% CI, 1.2-6.6) than among White women (RR, 1.0; 95% CI, 0.8-1.3). Although there was no interaction between OC use and a family history of breast cancer, OC use by a woman with a sister with breast cancer elevated the cancer risk. Body size was inversely associated with breast cancer risk in OC users, while weekly consumption of 7 or more alcoholic drinks slightly raised this risk.

Breast enlargement and reduction: results from a breast cancer case-control study.

In a population-based case-control study of breast cancer that included 2174 cases and 2009 population controls under 55 years of age, prior breast implants were reported by 36 cases versus 44 controls. After adjustment for the matching factors as well as variables associated with both breast cancer risk and breast enlargement (race, family history of breast cancer, body size, screening history), the relative risk of breast cancer associated with a prior implant was 0.6 (95% CI 0.4-1.0). The reduced risk persisted with increasing interval since surgery, arguing against selection bias as an explanation. Further, although a deficit of in situ tumors was seen among women with implants (RR = 0.2), the risk associated with implants remained reduced for both localized and distant tumors (RR = 0.8 for both stages). In a smaller group of women who had prior breast reduction surgery (10 cases, 13 controls), a reduced risk of breast cancer also was observed (RR = 0.7, 95% CI 0.3-1.6). The results of this study must be interpreted cautiously because of the small number of women involved and reliance on patient reports of prior operations. In not showing any elevation in breast cancer risk following a breast implant, our results confirm several record linkage studies but contradict some clinical studies that suggest an adverse effect. Additional investigations are needed in relation to specific types of breast implants, including the polyurethane-coated implants, which have been linked to high cancer rates in laboratory animals.