Case-control Study Of Endometrial Cancer Research Articles

Long-term use of continuous-combined estrogen-progestin hormone therapy and risk of endometrial cancer

The daily administered dose of progestin in continuous-combined estrogen-progestin therapy is provided to counteract the proliferative effect of estrogen on the postmenopausal endometrium. However, there remains some uncertainty as to whether use of such a combined regimen, over the long term, is associated with an altered risk of endometrial cancer. We pooled data from four population-based case-control studies of endometrial cancer in western Washington State. Cases, ages 45-74, were diagnosed between 1985 and 2005. Using logistic regression with the adjustment for confounding factors, women who had exclusively used continuous-combined estrogen-progestin therapy (90 endometrial cancer cases, 227 controls) were compared with women who had never used any type of hormone therapy (774 cases, 1,116 controls). Associations with duration and recency of use were evaluated overall and within strata defined by body mass index. Long-term use of continuous-combined estrogen-progestin therapy (≥10years) was associated with a reduced risk of endometrial cancer (OR=0.37, 95% CI: 0.21-0.66). This association was most pronounced in women with a body mass index ≥30kg/m(2) (OR=0.19, 95% CI: 0.05-0.68). Associations did not differ according to recency of use. These results suggest that long duration of use of continuous-combined estrogen-progestin therapy is associated with a reduced risk of endometrial cancer.

Multivariate saddlepoint approximations in tail probability and conditional inference

We extend known saddlepoint tail probability approximations to multivariate cases, including multivariate conditional cases. Our approximation applies to both continuous and lattice variables, and requires the existence of a cumulant generating function. The method is applied to some examples, including a real data set from a case-control study of endometrial cancer. The method contains less terms and is easier to implement than existing methods, while showing an accuracy comparable to those methods.

Lifetime physical activity and risk of endometrial cancer.

The role of moderate physical activity and life patterns of activity in reducing endometrial cancer risk remains uncertain. We assessed lifetime histories of activity from recreation, transportation, chores, and occupation and other risk factors in a population-based case-control study of endometrial cancer conducted in the San Francisco Bay area. The analysis was based on 472 newly diagnosed cases ascertained by the regional cancer registry and 443 controls identified by random-digit dialing who completed an in-person interview. Reduced risks associated with greater lifetime physical activity (highest versus lowest tertile) were found for both total activity [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.43-0.87; Ptrend=0.01] and activity of moderate intensity (OR, 0.44; 95% CI, 0.30-0.64; Ptrend<0.0001). Compared with women with low lifetime physical activity (below median), those with greater activity throughout life had a higher reduction in risk (OR, 0.62; 95% CI, 0.44-0.88). Inverse associations were stronger in obese and overweight women, but differences were not statistically significantly different from those in normal-weight women. These findings suggest that physical activity in adulthood, even of moderate intensity, may be effective in lowering the risk of endometrial cancer, particularly among those at highest risk for this disease. The results emphasize the importance of evaluating lifetime histories of physical activity from multiple sources, including both recreational and nonrecreational activities of various intensities, to fully understand the relation between physical activity and disease risk.

The HER2/neu (erbB2) polymorphism, body mass index, and the risk of endometrial cancer

22199 Background: Obesity has been identified as a risk factor for endometrial cancer in epidemiologic studies. The transmembrane receptor with a tyrosine kinase encoded by the HER-2 proto-oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2 genes could be disease susceptibility candidate for endometrial cancer. We evaluated the association between HER-2 genotypes and body mass index (BMI) in a case-control study of endometrial cancer. Methods: Cases and controls for this study were recruited between 2001 and 2005. DNA sample and medical histories were obtained from incident cases of endometrial cancer (n= 126) and population controls (n=302). Genotypes evaluated included HER-2 gene single nucleotide polymorphisms (SNP) in coding region at position -423, -655, -776, -857, -1170, -1177, -1253; and two SNP in intron by SNP-IT assay using SNPstream UHT system. Four of 9 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Statistical adjustment was made for age. Results: We observed a statistically significant association between women who were overweight (BMI >25 kg/m2) and carried at least one variant allele with endometrial cancer risk. Compared with wild-type lean women, the odds ratio (OR) for overweight women variant carriers was about 2–4 fold stronger than that for overweight women who did not carry the variants in each SNPs. Conclusions: In summary, although there is no potential association between HER-2 polymorphisms and endometrial cancer risk, our finding suggest that the HER-2 minor variant alleles is reinforced the risk of endometrial cancer among women with higher BMI than low BMI. Future large studies of the HER-2 polymorphism might clarify this putative gene-epidemiologic interaction. No significant financial relationships to disclose.

Dietary patterns, Mediterranean diet, and endometrial cancer risk

This study examines the association between dietary patterns and endometrial cancer risk. A case-control study of endometrial cancer was conducted from 1996 to 1999 in the San Francisco Bay Area in white, African-American, and Latina women age 35-79. Dietary patterns were defined using a principal components analysis; scoring dietary intake based on correspondence to a Mediterranean-style diet; and by jointly categorizing intake of fruits/vegetables and dietary fat. Four dietary patterns were identified and labeled "plant-based," "western," "ethnic," and "phytoestrogen-rich." None of these dietary patterns nor adherence to a Mediterranean diet (to the extent consumed by this population) was associated with endometrial cancer risk. However, among non-users of supplements, greater consumption of the "western" dietary pattern was associated with a 60% increase in risk (95% CI: 0.95-2.7 per unit change; P-interaction = 0.10). A diet characterized by high fat consumption increased risk, regardless of fruit and vegetable consumption (OR = 1.4, 95% CI: 0.97-2.1 for high fat, low fruit/vegetable intake and OR = 1.4, 95% CI: 0.95-2.1 for high fat, high fruit/vegetable intake compared to low fat, high fruit/vegetable intake). Thus, while like others we found that dietary fat increases endometrial cancer risk, the evaluation of dietary patterns did not provide any additional information regarding risk.

Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk

Objective. Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. Methods. Subjects included 434 endometrial cancer cases and 2557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. Results. With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR) = 0.21, 95% confidence interval (CI) = 0.10 to 0.43] or with low potency progestin (OR = 0.39, 95% CI = 0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR = 0.52, 95% CI = 0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m 2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR = 0.31, 95% CI = 0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR = 1.36, 95% CI = 0.39 to 4.70). Conclusion. The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

Weight history and risk of endometrial cancer among Chinese women

Adult obesity is a well-established risk factor for endometrial cancer. However, little is known about the association of endometrial cancer risk with body size early in life and weight change during adulthood. We investigated whether women with greater early-age body size or with greater weight change during adulthood have an increased risk of endometrial cancer. We analysed data from a population-based case-control study of endometrial cancer conducted between 1997 and 2001 in Shanghai, China. Included in this analysis were 832 endometrial cancer cases aged 30-69 years and 846 population controls. Information on weight and height history from adolescence through adulthood was obtained via structured in-person interviews. A logistic regression model was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) for endometrial cancer in association with adolescent and adult adiposity, as well as adult body weight change. All ORs were adjusted for age, education, menstrual status, duration of menstruation, number of pregnancies, oral contraceptive use, and family history of cancer. Perceived weights and heights during puberty that were greater than average were associated with a modestly increased risk of cancer. The association for perceived weight was substantially weakened after adjustment for current body mass index (BMI). High BMI at all adult ages significantly predicted endometrial cancer risk, with recent BMI being the strongest predictor. Further analyses disclosed that weight gain during adulthood, particularly during the peri-menopausal period (age 40-50 years), was associated with a significantly elevated risk of endometrial cancer, even among currently non-obese women. Gaining >5 kg between age 40 and 50 was related to ORs of 2.3 (95% CI 1.4-3.9) for women with a BMI<25 kg/m2 and 2.0 (95% CI 1.3-3.0) for women with BMI>or=25 kg/m2. Adult weight gain, particularly during the peri-menopausal period, plays a significant role in the development of endometrial cancer risk.

Estrogen receptor beta (ESR2 ) polymorphisms and endometrial cancer (United States).

We hypothesized that variations in the ESR2 gene may influence estrogen exposure in the uterus and thus influence endometrial cancer risk. We validated and screened for variants in the ESR2 gene and examined whether they are associated with endometrial cancer risk. We resequenced the promoter and coding regions of the ESR2 gene in 24 endometrial cancer cases, and genotyped the validated/discovered SNPs and intronic dinucleotide CA repeat in a nested case-control study of endometrial cancer (cases = 222, controls = 666) in the Nurses' Health Study (NHS). We also explored statistical interaction between ESR2 genotypes and body mass index (BMI) or hormone replacement therapy (HRT) use among postmenopausal women and cancer risk. Two SNPs were validated [rs1256049 in exon 5 (allelic frequencies = 98% G, 2% A) and rs1271572 in the promoter region (allelic frequencies = 60% G, 40% T)]. After adjusting for potential confounders, we observed no association between ESR2 gene polymorphisms and endometrial cancer risk [rs1256049 (OR = 1.2; 95%CI: 0.7-2.3), rs1271572 (OR = 0.8; 95%CI: 0.5-1.1) and CA repeat (22 repeat allele versus > or = 22 repeat allele, OR = 1.1; 95%CI: 0.7-1.7)]. We also did not observe any significant effect modification of the ESR2 polymorphisms by BMI or HRT use among postmenopausal women. Our results indicate that ESR2 polymorphisms may not be associated with endometrial cancer risk.

No Association between MTHFR 677 C→T or 1298 A→C Polymorphisms and Endometrial Cancer Risk

No Association between <i>MTHFR</i> 677 C→T or 1298 A→C Polymorphisms and Endometrial Cancer Risk

HSD17B1 gene polymorphisms and risk of endometrial and breast cancer.

Estrogen exposure influences breast and endometrial cancer risk. The HSD17B1 gene produces an enzyme that catalyzes the conversion of estrone to estradiol. We hypothesized that genetic variations in HSD17B1 gene may alter endogenous estrogen levels and, thus, influence endometrial and breast cancer risk. We validated and genotyped polymorphisms in the HSD17B1 gene and assessed whether these single nucleotide polymorphisms (SNPs), or the imputed haplotypes, were associated with endometrial and breast cancer risk. We also assessed whether a priori risk factors modified the associations between HSD17B1 genotype and cancer risk, and whether HSD17B1 genotypes were associated with plasma estrogen levels among postmenopausal women not using hormone replacement therapy. Ten SNPs of HSD17B1 gene were validated in 30 women from the Nurses' Health Study. Using the expectation maximization algorithm, three common (>5% frequency) haplotypes accounted for 97% of the chromosomes at this locus, and seven SNPs were in complete linkage disequilibrium. We identified and genotyped two haplotype-tagging SNPs (+1004C/T and +1322C/A), and genotyped an additional SNP [+1954A/G (Ser312Gly)] in nested case-control studies of endometrial cancer (cases = 222, controls = 666) and breast cancer (cases = 1007, controls = 1441) in the prospective Nurses' Health Study. Although no overall association by SNP or haplotype analysis was observed with endometrial or breast cancer risk, the +1954A/A genotype was associated with higher estradiol levels in lean women (P = 0.01) and interaction between the +1954 genotype with body mass index in postmenopausal breast cancer (P = 0.05) was suggested. These findings suggest that the HSD17B1 may be associated with circulating estradiol levels and interact with body mass index in postmenopausal breast cancer.

Multivariate saddlepoint tail probability approximations

This paper presents a saddlepoint approximation to the cumulative distribution function of a random vector. The proposed approximation has accuracy comparable to that of existing expansions valid in two dimensions, and may be applied to random vectors of arbitrary length, subject only to the requirement that the distribution approximated either have a density or be confined to a lattice, and have a cumulant generating function. The result is derived by directly inverting the multivariate moment generating function. The result is applied to sufficient statistics from a regression model with exponential errors, and compared to an existing method in two dimensions. The result is also applied to multivariate inference from a data set arising from a case-control study of endometrial cancer.

A Case-Control Study of Endometrial Cancer after Antipsychotics Exposure in Premenopausal Women

Objective: Most endometrial cancers are related to hormonal imbalance, and antipsychotics are a common cause of hyperprolactinemia. We investigated the possible relation between the use of antipsychotics and the risk of endometrial cancer. Methods: A case-control study was conducted on premenopausal women at the Chiba University Hospital between 1989 and 2000. The cases were 41 patients with histologically confirmed endometrial cancer. For each case, there were 3 controls matched by age and date of visit. Subsequently 123 women without endometrial cancer were enrolled as controls. Detailed information including obesity, parity, hypertension, diabetes mellitus, use of exogenous estrogen and use of antipsychotics was analyzed. Odds ratios, two-sided p values and 95% confidence intervals were estimated by a conditional logistic regression analysis. Radioimmunoassays of serum luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol and progesterone were performed in 4 of 5 patients with endometrial cancer who were using antipsychotics. Results: Use of antipsychotics, diabetes mellitus and obesity were identified as independent variables with risk estimates of 5.4, 9.3 and 4.9, respectively. Serum progesterone, estradiol and prolactin levels ranged from 0.4 to 0.7 ng/ml, 32 to 110 pg/ml and 34 to 258 ng/ml, respectively. Conclusions: Use of antipsychotics is a risk factor for endometrial cancer, and hyperprolactinemia associated with antipsychotics may impart the risk of endometrial cancer in premenopausal women.

The Additional Risk of Endometrial Cancer Associated with Unopposed Estrogen Use in Women with Other Risk Factors

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.

Tamoxifen therapy for breast cancer and endometrial cancer risk.

Tamoxifen is effective in treating breast cancer, reduces breast cancer incidence among high-risk women, and is associated with increased endometrial cancer risk. This study was designed to examine the possible modifying effects of endometrial cancer risk factors on the tamoxifen-endometrial cancer association. We conducted a case-control study of endometrial cancer (324 case patients and 671 individually matched control subjects) nested within a population-based cohort of patients with breast cancer diagnosed from 1978 through 1992 within four regions of the United States. We obtained information on breast cancer treatment and endometrial cancer risk factors through interviews and reviews of medical records. All P values reported are two-sided. Endometrial cancer risk was associated with tamoxifen therapy for breast cancer (odds ratio = 1.52; 95% confidence interval [CI] = 1. 07-2.17). Risk increased with duration of tamoxifen use (P for trend =.0002). Women with more than 5 years of exposure to tamoxifen had 4. 06-fold greater odds of developing endometrial cancer than nonusers (95% CI = 1.74-9.47). Prior use of estrogen replacement therapy (ERT) increased risk associated with tamoxifen use (P for homogeneity of trends <.0001). Risk associated with tamoxifen use was stronger among heavier women than among thinner women, although trends did not differ statistically (P =.10). Tamoxifen dose-response effects were more pronounced among women with both previous ERT exposure and higher body mass index than among women in other risk groups. ERT use and obesity, both established endometrial cancer risk factors and markers of estrogen exposure, substantially modify the association between tamoxifen use and endometrial cancer risk among patients with breast cancer. Women with positive ERT histories and those who are obese, when prescribed tamoxifen, may warrant closer surveillance for endometrial cancer than women without such histories.

Dietary factors and the risk of endometrial cancer: a case--control study in Greece.

In a hospital-based case-control study of endometrial cancer undertaken in Athens (1992-94), 145 women residents of Greater Athens with confirmed cancer of the endometrium were compared with 298 control patients with orthopaedic diseases. Personal interviews were conducted in the hospital setting, and diet was assessed using a validated semiquantitative food frequency questionnaire. Nutrient intakes for individuals were calculated by multiplying the nutrient intake of a typical portion size for each specified food item by the frequency at which the food was consumed per month and summing these estimates for all food items. Data were modelled through logistic regression, controlling for demographic, reproductive and somatometric risk factors for endometrial cancer as well as for total energy intake. No macronutrient was significantly associated with endometrial cancer risk, but increasing intake of monounsaturated fat, mostly olive oil, by about one standard deviation was associated with a 26% risk reduction (odds ratio = 0.74; 95% confidence interval 0.54-1.3). Among micronutrients, only calcium intake was significantly inversely associated with endometrial cancer risk, whereas there was evidence against retinol and zinc imparting protection against the disease. With respect to food groups, there was weak and non-significant evidence that vegetables are protective, whereas consumption of pulses was positively associated with disease possibly because they contribute substantially in Greece to energy intake in excess of physical activity-dependent requirements.

Tubal sterilization and the risk of endometrial cancer

Several animal and human studies suggest that tubal occlusion may curtail ovarian function, altering the production and balance of endogenous estrogens and progesterone, 2 hormones closely related to endometrial carcinogenesis. Despite this, and the increasing world-wide popularity of this method of contraception, little is known about its relationship with the risk of developing endometrial cancer. To assess whether tubal sterilization influences a woman's risk of developing epithelial endometrial carcinoma, data from a large multicenter population-based case-control study of endometrial cancer were analyzed. Cases were 437 women aged 20 to 54 years with histologically confirmed epithelial endometrial cancer ascertained through 6 population-based cancer registries in the United States. Controls were 3200 women selected at random from the populations of the areas from which the cases were detected. As compared with women who had never had tubal sterilization, women who had had this surgery had a crude odds ratio of 0.58 [95% confidence interval (CI), 0.43-0.78]. However, after adjusting for the combined confounding effects of age and parity, the magnitude of the protective association decreased to 0.87 (95% CI, 0.63-1.20). The magnitude of the protective effect did not significantly change with years since surgery or age at surgery. Although a modest, non-significant protective effect is suggested, these findings indicate that tubal sterilization does not substantially alter the risk of developing epithelial endometrial cancer in women 20 to 54 years of age. If there is an increase in risk, these data indicate that it is unlikely to be any greater than 20%.

A critical look at methods for handling missing covariates in epidemiologic regression analyses.

Epidemiologic studies often encounter missing covariate values. While simple methods such as stratification on missing-data status, conditional-mean imputation, and complete-subject analysis are commonly employed for handling this problem, several studies have shown that these methods can be biased under reasonable circumstances. The authors review these results in the context of logistic regression and present simulation experiments showing the limitations of the methods. The method based on missing-data indicators can exhibit severe bias even when the data are missing completely at random, and regression (conditional-mean) imputation can be inordinately sensitive to model misspecification. Even complete-subject analysis can outperform these methods. More sophisticated methods, such as maximum likelihood, multiple imputation, and weighted estimating equations, have been given extensive attention in the statistics literature. While these methods are superior to simple methods, they are not commonly used in epidemiology, no doubt due to their complexity and the lack of packaged software to apply these methods. The authors contrast the results of multiple imputation to simple methods in the analysis of a case-control study of endometrial cancer, and they find a meaningful difference in results for age at menarche. In general, the authors recommend that epidemiologists avoid using the missing-indicator method and use more sophisticated methods whenever a large proportion of data are missing.

Recency, duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer (Washington, USA).

Women who have used combined oral contraceptives (COC) have a reduced risk of endometrial cancer relative to that of women who have never used oral contraceptives, but it is unclear whether the size of the reduction is influenced by the progestin content of the preparation. We analyzed data from two population-based case-control studies of endometrial cancer to investigate this question. Among women aged 40 to 59 years who were residents of King or Pierce Counties, Washington (United States), incident cases who were diagnosed during 1975-77 or 1985-87 were identified. Personal interviews were conducted with 316 such women and their responses compared with those of 501 controls who were selected by household surveys or random-digit dialing. A reduced risk of endometrial cancer associated with COC use was present only among users of five or more years' duration, and even then only in women who were not long-term users of unopposed postmenopausal estrogens. Among these women, the relative risk (RR) of endometrial cancer did not differ according to the progestin potency of the COC used: it was equally low for women who had used a COC with low progestin content (RR = 0.2, 95 percent confidence interval [CI] = 0.1-0.8) as for women who had used a COC with high progestin content (RR = 0.3, CI = 0.1-0.9). Our results argue that, if the reduced risk of endometrial cancer in long-term users of COCs is due to the progestins contained in these preparations, that amount of progestin in most COCs exceeds the threshold amount needed to produce this beneficial effect.

A case-control study of endometrial cancer in relation to cigarette smoking, serum estrogen levels, and alcohol use

The purpose of this study was to evaluate the effect of cigarette smoking and alcohol use on the risk of endometrial cancer. The impact of smoking on serum estrone, estradiol, and androstenedione levels also was examined. This hospital-based case-control study included 168 women with endometrial carcinoma and 334 control women. Women who were current smokers had a lower risk of endometrial cancer than did women who did not smoke (relative rate 0.69; 95% confidence interval 0.40-1.19), whereas women who were exsmokers and women who had never smoked had similar rates (relative rate 0.83; 95% confidence interval 0.46-1.48). There was little overall association between serum estrogen levels and cigarette smoking, although estradiol levels in overweight control subjects were lower among women who were current smokers than among women who had never smoked. Androstenedione levels were slightly higher among women in the control group who smoked than among women in the control group who did not smoke, but the difference was not statistically significant (p = 0.28, two-tailed). Alcohol use was unrelated to endometrial cancer in this study. The study provides additional support for the hypothesis that smoking is inversely related to endometrial cancer. The inverse smoking association with endometrial cancer may be more directly related to higher serum androstenedione levels than to lower serum estrogen levels except, perhaps, among overweight women.

Physical Activity and Risk of Endometrial Cancer

In a population-based case-control study of endometrial cancer, we interviewed 268 cases and an equal number of matched controls regarding physical activity at work and outside of work. We also obtained self-ratings of overall physical activity levels. The results showed that nonretired women holding sedentary jobs or those reporting sedentary life-styles were at somewhat increased risk of endometrial cancer. The associations remained unchanged after adjustment for caloric intake and body mass index. Although an effect of physical inactivity on endometrial cancer risk is biologically plausible, our results show some inconsistencies, such as a lack of elevation in risk among women who were physically inactive outside of work.