There is a wide range of aggressiveness of endometrial tumors, some being indolent and easily treated while others metastasize and prove fatal. The authors used data from three population-based, case-control studies to determine if etiologic factors differ for aggressive disease. Interview data were obtained from 1,304 female residents of western Washington State who were 45-74 years of age and diagnosed with endometrial cancer during 1985-1991, 1994-1995, and 1997-1999 and from 1,779 controls who were of similar ages and selected primarily by random digit dialing. As a means of gauging aggressiveness, tumor characteristics were abstracted from the population-based cancer registry that serves western Washington State. The risk of endometrial cancer among long-term users (> or = 8 years) of unopposed estrogens was particularly high for the least aggressive tumors (odds ratio = 18.6, 95% confidence interval: 12.2, 28.6) but was elevated for moderate and highly aggressive tumors as well (odds ratios = 6.6 and 7.1, respectively). Women who were obese, had a history of diabetes, and had fewer than two children were also at increased risk, regardless of tumor aggressiveness, while oral contraceptive users were at decreased risk of only relatively more aggressive disease. In general, a woman's risk of endometrial cancer appears to be influenced by similar risk factors regardless of disease severity.

Progestogens are given to diminish the risk of endometrial cancer (ECA) observed with postmenopausal estrogen therapy. The pattern of progestogen administration and number of days that the progestogen is given per month appear to affect ECA risk. We studied the impact of dose of progestogen, specifically medroxyprogesterone acetate (MPA), on ECA risk in a population-based case control study of 647 cases and 1,209 controls, ages 45-74 years. Among women who took a combined hormone regimen with MPA for less than 10 days/mo, the overall adjusted risk of ECA (relative to that of hormone non-users) was 4.2 [95%, Confidence Interval (CI) 2.0, 8.9] in those with an MPA dose less than 70 mg/mo,- and the adjusted risk of ECA was 2.8 (95%, CI 0.9, 8.6) in those with a higher monthly MPA dose. Among women who took MPA cyclically for 10-24 days/mo or as continuous combined therapy, the risk of ECA was similar to non-users, irrespective of the monthly dose. Our findings showed that among the combined hormone regimens most commonly used by postmenopausal women in the USA today, monthly dose of MPA bears little or no relation to risk of ECA.

2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a population-based case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile(462)Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr(461)Asn, CYP1A2 A734C, and CYP1B1 Leu(432)Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.

Exposure to estrogens is a likely cause of endometrial cancer, but the means by which estrogens exert this effect are not entirely clear. One hypothesis is that certain estrogen metabolites bind to the DNA, forming bulky adducts that damage the DNA and initiate carcinogenesis. A woman's reduced capacity to repair such damage may increase her risk of endometrial cancer. We conducted a population-based case-control study in western Washington State to address the role of variation in nucleotide excision repair genes on the risk of endometrial cancer. Case women (n = 371), ages 50 to 69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n = 420) were selected using random-digit dialing (ages 50-65 years) and by random selection from Health Care Financing Administration data files (ages 66-69 years). Genotyping assays were done for ERCC1, ERCC2 (XPD), ERCC4 (XPF), ERCC5 (XPG), XPA, and XPC. No appreciable differences between cases and controls were observed in the genotype distributions of ERCC1 (c8092a and c19007t), ERCC2 (D312N, K751Q, and c22541a), ERCC4 (R415Q and t30028c), or ERCC5 (D1104H). Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93]. Carriage of at least one XPC A499V variant allele was associated with a modest decrease in risk (OR, 0.79; 95% CI, 0.59-1.05). Women with variant alleles at both XPC A499V and K939Q had 58% of the risk of women with no XPC variant alleles (OR, 0.58; 95% CI, 0.35-0.96). Our data suggest that interindividual variation in XPA and XPC influences a woman's risk of endometrial cancer.

When conducting epidemiologic case-control studies, some investigators include only controls who can be interviewed within a certain time after contact and/or do not recontact potential participants who initially refuse, whereas others expend considerable effort to recruit reluctant respondents. This additional effort is only worthwhile if it results in a sample that is more representative of the target population. In this study, the authors used data collected from in-person interviews of 5,616 female controls to compare characteristics of willing, accessible respondents with those of their less accessible or less willing counterparts to determine whether or not the two groups differed with respect to lifestyle, socioeconomic status, health history, and demographic characteristics. Late responders were younger, were more likely to be non-White, were less likely to have attended college, and were more likely to be current smokers than early responders. Initial refusers were similar to late responders with respect to education and race. Initial refusers were also older, were less likely to be currently married, were less likely to have a managerial occupation, had fewer lifetime sexual partners, and were more likely to have a history of diabetes than early responders. These findings suggest that additional effort expended in recruiting reluctant respondents may often result in more accurate estimates of population characteristics that are of interest in epidemiologic research.

This study was conducted to assess the histopathological features of breast cancers in women diagnosed with breast cancer at 50-64 years of age who have and have not used hormone replacement therapy (HRT). A case-case analysis of the tumors from women aged 50-64 years who participated in a multicenter population-based case-control study of invasive breast cancer was conducted. In-person interviews collected a detailed history of all episodes of hormone use. Information was collected on selected tumor characteristics from 2346 women with breast cancer. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), contrasting the histopathological characteristics of the tumors of women who used various regimens of HRT with those of women who have never used HRT. The tumors of cases who used each regimen of HRT were smaller and of earlier stage than those of non-HRT users. Adjustment for screening diminished the magnitude of the effect, and only cases who used estrogen alone (estrogen replacement therapy) had reduced odds of being diagnosed with later-stage disease (regional or distant) than cases who never used HRT (OR, 0.7; 95% CI, 0.6-0.9). Higher proportions of estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors were seen in cases who used any regimen of HRT versus those who did not use HRT. However, after adjustment for age and race, only the tumors of cases who used continuous combined HRT remained more likely to be ER+ and PR+ [OR ER- = 0.6 (95% CI, 0.4-0.9) and OR PR- = 0.5 (95% CI, 0.4-0.7)]. The tumors of women with breast cancer who used HRT have some better prognostic factors than those of women who have not used HRT. However, with the exception of the results noted above, this advantage may be due to the racial and age differences in those who use the various regimens of HRT and the effect of more frequent screening among HRT users, leading to earlier diagnosis.

Although low participation in case-control studies may threaten their validity, it is difficult to evaluate the potential problem of nonresponse across studies because the level of participation among subjects is not reported in a consistent manner. This commentary presents a proposal for standard reporting of the process by which control subjects are recruited to a study and the outcomes of recruitment attempts. We encourage authors to provide a description of the sampling frame, the method of selecting units from the frame, and the number of units selected. For each unit selected, an outcome should be classified into four broad categories: ineligible sampling unit, unable to determine eligibility, respondent not eligible, and respondent screened and eligible. Details should be provided in each category; these details would differ according to the method used to contact potential respondents (by random-digit dialing, by telephone from a list, in person, or by mail). The proportion who participated can be reported as the investigator sees fit, as long as reporting of the components is complete. The sampling frame and outcomes should be reported separately for various parts of the study, such as controls from different sources or those who gave biological specimens. Standardized reporting will allow an evaluation of the success of various methods in recruiting potential participants, and will contribute important information for assessing the validity of individual studies.

Purpose: Racial differences in the incidence of squamous cell carcinoma of the bladder may provide insight into the pathogenesis of this disease. We determined the incidence of squamous cell carcinoma of the bladder according to race in the United States.Materials and Methods: Data obtained from the Surveillance, Epidemiology and End Results program from 1973 to 1997 were analyzed to determine the incidence of squamous cell carcinoma of the bladder in individuals 35 to 84 years old. Incidence rates by race and gender were then adjusted to the age distribution of the 1970 American population.Results: The average annual incidence of squamous cell carcinoma of the bladder was 1.20/100,000 in black and 0.60/100,000 in white Americans (relative risk 2.0, 95% CI 1.74 to 2.29). Black men were at increased risk compared with white men and black women were at increased risk compared with white women. The higher incidence in black versus white individuals existed in all age groups beyond 45 years and was present throughout the study period.Conclusions: Squamous cell carcinoma of the bladder appears to be twice as common in black as in white individuals in the United States.

BACKGROUND. The incidence of invasive lobular carcinoma, has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma.METHODS. A large, multicenter case-control study of Caucasian and African-American women who were diagnosed at age < 65 years with their first invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In-person interviews were conducted with 1749 postmenopausal patients, and their responses were compared with the responses of 1953 postmenopausal control women identified through random-digit dialing who met the study criteria of being postmenopausal at the time of diagnosis. Polytomous logistic regression was used to calculate the odds ratio (OR) as an estimate of the relative risk and to compute the 95% confidence interval (95%CI) associated with the use of various regimens of hormone replacement therapy (HRT) among women diagnosed with ductal breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a grouping of other histologic types of breast carcinoma.RESULTS. Ever use of unopposed estrogen therapy (ERT) was not associated with an increase in the risk of any histologic type of breast carcinoma. The risk of invasive lobular breast carcinoma and the risk of breast carcinoma of the grouping of other histologies increased among women currently using CHRT (OR, 2.2; 95%CI, 1.4-3.3; and OR, 1.9; 95%CI, 1.0-3.4, respectively). The risk increase was greater for the mixed lobular-ductal type than for the pure lobular type of breast carcinoma, although the difference was not statistically significant. There was some indication that 5 years of continuous CHRT (greater than or equal to 25 days per month of progestin) was associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, 1.4-4.3) compared with sequential CHRT (<25 days per month of progestin; OR, 1.5; 95%CI, 0.8-2.6). Current use of continuous CHRT was only moderately associated with risk of ductal breast carcinoma.CONCLUSIONS. Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age < 65 years. Cancer 2002;95:2455-64. Published 2002 by the American Cancer Society.*

Hormone replacement therapy (HRT) has increased in the United States over the past 2 decades in response to reports of long-term health benefits. A relationship between HRT and breast cancer risk has been observed in a number of epidemiological studies. In 2002, the Women's Health Initiative Randomized Controlled Trial reported an association between continuous combined HRT and breast cancer risk. The objective of this study was to examine the association between breast cancer risk and HRT according to regimen and duration and recency of use.A multicenter, population-based, case-control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35-64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two-sided P values for trend were computed from the likelihood ratio statistic. Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P =.01). There were no positive associations between breast cancer risk and other HRT regimens. Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued.

PURPOSE: The incidence of synchronous primary endometrial and ovarian cancer is 2- to W-fold higher than that expected based on the incidence of each cancer alone, We sought to evaluate reasons for this in a case-control study.METHODS: We combined data on a maternal history of cancer and reproductive and menstrual factors from 56 women with synchronous multiple primary disease who had participated in three population-based studies of gynecologic cancer. For comparison, we analyzed the same information from 280 women with endometrial cancer alone, 280 with ovarian cancer alone, and 280 without a history of either cancer.RESULTS: The reduced risk of multiple primary disease associated with high parity (2 or more births vs 0: OR = 0.37, 95% Cl, 0.19-76) and long-term use of oral contraceptives (12 or more months vs none: OR = 0,60, 95% Cl, 0.24-1.5) tended to be more pronounced than that associated with endometrial cancer alone or with ovarian cancer alone.CONCLUSIONS: Though limited by relatively small numbers, our results suggest that the presence of some common etiologies is a basis for the unusually high co-occurrence of endometrial and ovarian cancers. (C) 2001 Elsevier Science Inc. All rights reserved.

To investigate the association between recreational physical activity and endometrial cancer risk, a population-based case-control study was conducted in Washington State. The study included 822 incident cases of endometrial cancer diagnosed between 1985 and 1991 and 1,111 randomly selected population-based controls. Detailed information on recreational physical activities as well as other endometrial cancer risk factors was obtained in structured, in-person interviews. Unconditional logistic regression, adjusted for age, county, energy intake, unopposed estrogen use, income, and, in separate models, body mass index (kg/m(2)), was used to estimate the odds ratios and their 95% confidence intervals, relating endometrial cancer to each level of physical activity. A greater proportion of controls (49.3%) than cases (40.5%) reported doing regular exercise (compared with no exercise: adjusted odds ratio = 0.62, 95% confidence interval: 0.51, 0.76) in the 2-year period prior to diagnosis date. There was little evidence of a trend of decreasing risk with increasing duration or intensity of recreational physical activities. These results provide support for an association between the lack of recent recreational physical activity and endometrial cancer risk. However, the absence of a difference by duration or intensity levels and the inconsistent results from other studies suggest caution before interpreting this association as causal.

Both smoking and alcohol consumption may influence thyroid function, although the nature of these relations is not well understood. We examined the influence of tobacco and alcohol use on risk of papillary thyroid cancer in a population-based case-control study. Of 558 women with thyroid cancer diagnosed during 1988-1994 identified as eligible, 468 (83.9%) were interviewed; this analysis was restricted to women with papillary histology (N = 410). Controls (N = 574) were identified by random digit dialing, with a response proportion of 73.6%. We used logistic regression to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with cigarette smoking and alcohol consumption. A history of ever having smoked more than 100 cigarettes was associated with a reduced risk of disease (OR = 0.7, 95% CI = 0.5-0.9). This reduction in risk was most evident in current smokers (OR = 0.5, 95% CI = 0.4-0.7). Women who reported that they had ever consumed 12 or more alcohol-containing drinks within a year were also at reduced risk (OR 0.7, 95% CI = 0.5-1.0). Similar to the association noted with smoking, the reduction in risk was primarily present among current alcohol consumers. The associations we observed, if not due to chance, may be related to actions of cigarette smoking and alcohol consumption that reduce thyroid cell proliferation through effects on thyroid stimulating hormone, estrogen, or other mechanisms.

The authors conducted a population-based case-control study of 410 women residing in three counties in western Washington State who were aged 18-64 years when diagnosed with papillary thyroid cancer in 1988-1994 and 574 controls to assess the effects of pregnancy history and other aspects of reproductive life on risk of this disease. Among women aged 45-64, the authors observed no associations with number of live births, age at first live birth, or age at last live birth. Risk was somewhat increased in women <45 years who had given birth within the previous 5 years; this association was most evident among women who reported that cancer symptoms had led to diagnosis. Among women who had given birth within the last 5 years, risk was greatest among those with two or more births during that time period (relative risk (RR) = 4.2, 95% confidence interval (CI): 2.0, 8.9, relative to parous women whose last birth was >5 years before the reference date). Risk of thyroid cancer was also associated with lactation during the previous 5 years (e.g., RR = 2.9, 95% CI: 1.5, 5.5, among parous women who had breastfed > or =12 months, vs. 0-1 months, during that interval). Our results suggest that thyroid stimulation during both pregnancy and lactation may result in a transient increase in risk of papillary thyroid cancer.

Histamine (H2) receptor antagonists, such as cimetidine and ranitidine, became available in the late 1970s and presently number among the most commonly used drugs. Cimetidine has been hypothesized to exert a cancer preventive effect on the prostate due to its ability to inhibit the binding of dihydrotestosterone to androgen receptors. Other hormonal effects of this drug include increases in serum prolactin levels and inhibition of 2-hydroxylation of estradiol. We assessed risk of prostate and breast cancers in a cohort of 48,512 members of the Group Health Cooperative of Puget Sound prescribed cimetidine or another H2 blocker between 1977 and 1995. Standardized incidence ratios were calculated comparing the observed numbers of cancers to those expected based on population rates in western Washington State. Because cimetidine, but not other H2 blockers, influences hormonal activity and metabolism, we conducted nested case-control studies comparing cancer risk among individuals treated with cimetidine to individuals who used other H2 blockers. Risks of breast and prostate cancers were identical among users of cimetidine and users of other H2 blockers (relative risk, 1.0 for both cancers). We observed no trend in risk of breast cancer according to time since first or last cimetidine prescription or number of cimetidine prescriptions filled. For prostate cancer, our findings were similar save for a modest increase in risk among men who had filled > or =21 cimetidine prescriptions (relative risk, 1.4; 95% confidence interval, 1.0-1.9). Our results suggest that use of cimetidine does not influence risk of female breast cancer. Further, these data provide little evidence to support the previously hypothesized preventive effect of cimetidine on risk of prostate cancer.

We analyzed data from a population-based case-control study of endometrial cancer. Our goal was to identify a subgroup of women in whom the additional cancer risk associated with unopposed estrogen use was sufficiently small so as to not be a deterrent to taking a hormone preparation of this type. Researchers interviewed women with endometrial cancer (N = 553) and controls (N = 752) regarding hormone use. The additional risk of endometrial cancer associated with unopposed estrogen use did not vary substantially in the presence or absence of hypertension, parity, oral contraceptive use, or smoking. The results suggest that, although heavier women may experience a greater risk of endometrial cancer associated with unopposed estrogen use (8.2 per 1,000 per year) than lighter women (4.2 per 1,000 per year), long-term users in the latter group nonetheless face a substantial absolute increase in risk. We conclude that subdividing women on the basis of the presence or absence of other known risk factors for endometrial cancer fails to delineate a subgroup that is exempt from the increased risk of this cancer associated with use of unopposed estrogens. 83.6% of estrogen users reported taking conjugated estrogens.