Relative Risk Of Endometrial Cancer Research Articles

Risk of endometrial cancer and endometrial hyperplasia with atypia in asymptomatic postmenopausal women with endometrial thickness ≥11 mm: A systematic review and meta‐analysis

To evaluate the risk of endometrial cancer and/or endometrial hyperplasia with atypia in asymptomatic postmenopausal women with endometrial thickness ≥ 11 mm. Systematic review of literature using database search (PubMed and Web of Science) of articles published between January 1990 and December 2016 evaluating the correlation between endometrial thickness as measured by transvaginal ultrasound (double layer) and histopathological findings in asymptomatic postmenopausal women, using the following terms: "endometrial thickness," "postmenopausal," "postmenopause," and "asymptomatic." Inclusion criteria were prospective or retrospective studies of more than 150 cases that provided information on endometrial thickness and its correlation with histopathological data. Studies that included patients with hormone replacement therapy, tamoxifen, or aromatase inhibitors were excluded. The overall relative risk (RR) for EC/EHA was calculated, stratifying the patients into two groups according to endometrial thickness (<11 mm and ≥11 mm). Heterogeneity was assessed by calculating I2 . The search identified 289 studies. After exclusions, nine articles that met all the inclusion criteria were included, comprising data from 4751 women. The prevalence of endometrial cancer and/or endometrial hyperplasia with atypia was 2.4%. The relative risk of endometrial cancer and/or endometrial hyperplasia with atypia in the ≥11 mm group was 2.59 (95% CI: 1.66-4.05). High heterogeneity was observed between studies (I2 : 57.3%, P = .016). Overall the risk for EC/EHA was 2.6 times greater in women with ET ≥11 mm vs women with ET 5-10 mm, although there was significant heterogeneity in estimates across studies.

Diabetes and Risk of Endometrial Cancer: A Population-Based Prospective Cohort Study

Although there is accumulating evidence that hyperinsulinemia in the context of insulin resistance is associated with carcinogenesis, only one prospective study of endometrial cancer incidence, in relation to diabetes, addressed this issue and showed no significant positive association. No previous study has investigated whether physical activity can modify the association between diabetes and endometrial cancer. We examined the association between diabetes and incidence of endometrial cancer and the potential effect modification by obesity and physical activity in the Swedish Mammography Cohort, a prospective cohort of 36,773 women, including 225 incident endometrial adenocarcinoma cases. After adjustments, the relative risk (RR) for endometrial cancer among women with diabetes comparing with nondiabetic women was 1.94 [95% confidence interval (95% CI), 1.23-3.08]. Among obese diabetics, the RR was 6.39 (95% CI, 3.28-12.06) compared with nonobese nondiabetic women. Among diabetics with low physical activity, the RR for endometrial cancer was 2.80 (95% CI, 1.62-4.85) compared with physically active nondiabetic women. Obese diabetics with low physical activity had a RR of 9.61 (95% CI, 4.66-19.83) compared with normal weight nondiabetic women with high physical activity. Diabetes was associated with a 2-fold increased risk, and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer. Interventions to reduce body weight and increase physical activity may have important implications in terms of prevention of endometrial cancer and future management of diabetic subjects.

The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study

To evaluate the risk of endometrial cancer in women who carry a deleterious mutation in the BRCA1 or BRCA2 genes. Women known to carry a BRCA1 or BRCA2 mutation, aged 45 to 70, were identified from an international registry and were followed prospectively. A total of 857 women completed a baseline questionnaire and one or more follow-up questionnaires. Study subjects were followed until diagnosis of endometrial cancer, ovarian cancer, death or the date of completion of the last questionnaire. The expected number of endometrial cancers was calculated using age and country-specific incidence rates. After an average follow-up period of 3.3 years, six women were diagnosed with endometrial cancer, compared to 1.13 cancers expected (SIR=5.3, p=0.0011). Four of these six patients used tamoxifen in the past. The risk among women who were never exposed to tamoxifen treatment was not significantly elevated (SIR=2.7, p=0.17), but among the 226 participants who had used tamoxifen (220 as treatment and six for the primary prevention of breast cancer) the relative risk for endometrial cancer was 11.6 (p=0.0004). The main contributor to the increased risk of endometrial cancer among BRCA carriers is tamoxifen treatment for a previous breast cancer. The risk and benefits of prophylactic hysterectomy should be discussed with women with a BRCA mutation considering tamoxifen therapy.

Effect of raloxifene on endometrial cancer risk in a population-based, case-control study

5001 Background: Raloxifene, a selective estrogen receptor modulator, has been shown to reduce breast cancer risk in women with osteoporosis, and is currently being compared to tamoxifen for breast cancer chemoprevention in the “STAR” trial. In contrast to tamoxifen, raloxifene does not stimulate endometrial estrogen receptors, and may therefore be associated with a lower risk of endometrial cancer compared with tamoxifen. However, there are few data available on the absolute risk of endometrial cancer in users of raloxifene, or the relative risks of endometrial cancer among raloxifene and tamoxifen users in the general population. Methods: We performed a population-based, case-control study of breast and endometrial cancer. Cases had pathologically-confirmed endometrial cancer, and resided in a 9-county area surrounding Philadelphia. Controls with no history of endometrial cancer were obtained through random-digit dialing and matched to cases by age and race. Only African-American and Caucasian women were included in the study. Results: A total of 547 cases and 1412 controls were included in the current analysis. Among cases, 18 (3.3%) ever used raloxifene and 34 (6.2%) ever used tamoxifen. Among controls, 93 (6.6%) ever used raloxifene and 34 (2.2%) ever used tamoxifen. Compared to non-users, the odds ratio for development of endometrial cancer was 0.43 (95% CI 0.26 - 0.73) for raloxifene users, and 2.35 (95% CI 1.43 - 3.86) for tamoxifen users. After adjustment for other confounders, including BMI and previous history of breast cancer, the odds ratio associated with developing endometrial cancer among raloxifene users was 0.50 (95% CI 0.29 - 0.85), while the odds ratio among tamoxifen users was 1.50 (95% CI 0.77 - 2.92). The benefit of raloxifene on endometrial cancer risk remained even among those with short-term use (<3 years). Conclusions: Raloxifene use was associated with a 50% reduction in the odds of developing endometrial cancer in this population-based case-control study. These data suggest a possible protective effect of raloxifene on the endometrium, providing a further benefit to this drug in cancer chemoprevention. No significant financial relationships to disclose.

Polycystic ovary syndrome and gynecological cancers: Is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.

The risks and benefits of hormonal replacement therapy in healthy women and in breast cancer survivors

For many years hormonal replacement therapy (HRT) has been considered to offer not only effective relief of climacteric symptoms but also a reduction in the risk of osteoporosis and cardiovascular disease, plus a possible prevention of cognitive decline. Randomised trials of HRT in women with preexisting coronary heart disease have not confirmed, however, cardiovascular benefits of HRT and have even suggested increased cardiac risk associated with this management. Numerous retrospective studies demonstrated that the risk of breast cancer is higher in HRT-users and is related to therapy duration. More recent studies suggested that breast cancer risk increases further if oestrogen is coupled with progestogen. On the other hand, some data show that breast cancers diagnosed in women during HRT administration may be less aggressive. Typically, tumours in these patients are smaller and better differentiated. HRT also increases the relative risk of endometrial cancer, particularly if oestrogen alone is administered. Currently, the indications for HRT in healthy subjects should include only reduction of menopausal symptoms and prevention of osteoporosis. The use of HRT in breast cancer survivors is controversial, and until the results from prospective randomised trials are available, cannot be recommended in this group as a standard care.

Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer

Objective: The purpose of this study was to evaluate postmenopausal bleeding and transvaginal sonographic measurement of endometrial thickness as predictors of endometrial cancer and atypical hyperplasia in women whose cases were followed for ≥10 years after referral for postmenopausal bleeding. Study design: Women (n = 394) who had postmenopausal bleeding from November 1987 to October 1990 underwent transvaginal sonographic measurement of endometrial thickness and curettage. It was possible to assess the medical records (regarding recurrence of a postmenopausal bleeding, development of endometrial cancer, and death) in 339 of the 394 women (86%) ≥10 years after referral for postmenopausal bleeding. Results: Thirty-nine of the 339 women (11.5%) had endometrial cancer, and 5 women (1.5%) had atypical hyperplasia. The relative risk of endometrial cancer in women who were referred for postmenopausal bleeding was 63.9 (95% CI, 46.0-88.8); the corresponding relative risk for endometrial cancer and atypical hyperplasia together was 72.1 (95% CI, 52.8-98.5) compared with women of the same age from the general population of the same region of Sweden. No woman with an endometrial thickness of ≤4 mm was diagnosed as having endometrial cancer. The relative risk of the development of endometrial cancer in women with an endometrial thickness of >4 mm was 44.5 (95% CI, 6.5-320.1) compared with women with an endometrial thickness of ≤4 mm. The reliability of endometrial thickness (cutoff value, ≤4 mm) as a diagnostic test for endometrial cancer was assessed: Sensitivity, 100%; specificity, 60%; positive predictive value, 25%; and negative predictive value, 100%. The incidence of endometrial cancer or atypical hyperplasia in women with an intact uterus whose cases had been followed for ≥10 years was 5.8% (15/257 women) compared with 22.7% (15/66 women) in women who had ≤1 episode of recurrent bleeding. No endometrial cancer was diagnosed in women with a recurrent postmenopausal bleeding who had an endometrial thickness of ≤4 mm at the initial scan. Conclusion: Postmenopausal bleeding incurs a 64-fold increase risk for endometrial cancer. There was no increased risk of endometrial cancer or atypia in women who did not have recurrent bleeding, whereas women with recurrent bleeding were a high-risk group. No endometrial cancer was missed when endometrial thickness measurement (cutoff value, ≤4 mm) was used, even if the women were followed up for ≤10 years. We conclude that transvaginal sonographic scanning is an excellent tool for the determination of whether further investigation with curettage or some form of endometrial biopsy is necessary (Am J Obstet Gynecol 2003;188:401-8.)

A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer

Objective: To evaluate postmenopausal bleeding (PMB) and transvaginal sonographic (TVS) measurement of endometrial thickness (ET) as predictors of endometrial cancer (EC) and atypical hyperplasia (AH) in women during a &gt;10‐year period following a PMB.Study design: Women presented with a PMB from November 1987 to October 1990 were included in this study (n = 394). The women underwent TVS with measurement of ET and a dilation and curettage (D &amp; C). It was possible to assess the medical records of 339 of the 394 women (86%) &gt;10 years after referral for PMB. During the follow up period the recurrence of a PMB, the development of EC and mortality were assessed.Results: After the primary investigation, 39 of the 339 women were diagnosed as having EC (11.5%) and 5 women had AH (1.5%). The relative risk (RR) of diagnosing an EC in women referred for a PMB was 63.9 (CI 46.0 Ð 88.8) and the corresponding RR for EC and AH together was 72.1 (CI 52.8 Ð 98.5) compared to women of the same age from the same region of Sweden. The reliability of PMB as a diagnostic test for EC was assessed: sensitivity 18%; specificity 100%; positive predictive value 12%; and negative predictive value 100%. None of the women with an ET of 2 × 4 mm were diagnosed as having EC. The reliability of ET (cut‐off 2 × 4 mm) as a diagnostic test for EC was assessed: sensitivity 100%; specificity 60%; positive predictive value 25% and negative predictive value 100%. The incidence of EC or AH in women with an intact uterus followed 3 × 10 years was 5.8%. The corresponding figure for women who had 3 × 1 recurrent bleeding during follow up was 22.7%. No EC was diagnosed in women with a recurrent PMB who had an ET of 2 × 4 mm at the initial scan. No EC was diagnosed in the absence of a recurrent bleeding.Conclusion: PMB incurs a 64‐fold increase risk for EC. No EC was missed when ET measurement (cut‐off 2 × 4 mm) was used even if the women were followed 3 × 10 years. About 5.8% of the women referred for a PMB later developed EC or atypia during the 10‐year observation period. There was no increased risk of EC or AH in women who did not have recurrent bleedings whereas women with a recurrent bleeding were a high risk group. A thick endometrium, with histopathological diagnosis of atrophy or insufficient for diagnosis, should be taken seriously and a guided biopsy should be taken or saline instillation sonography performed with ultrasound‐guided biopsy.

Endometrial and other primary cancers after tamoxifen treatment of breast cancer — results of retrospective cohort study

Objectives: The aim of the retrospective cohort study was to evaluate the relationship between the influence of tamoxifen on the development of endometrial and other second primary cancers in the patients with invasive breast cancer. Study Design: A cohort of 630 women diagnosed with breast cancer from 1987 to 1994 was selected from a population-based registry; 440 patients were treated with tamoxifen and 190 patients without it. The observation period was 8.5 years (range 5–12 years). The data were analysed by the relative risk (RR) calculation at a confidence interval (CI) of 95%, using a Mantel–Haenszel χ 2-test and Fisher’s p-test to evaluate statistical significance. Results: There were no statistically significant differences between the group of breast cancer patients treated with tamoxifen and without it as regards the age at the breast cancer diagnosis, family medical histories, body mass, age at menopause, fertility, diabetes, hormone replacement therapy and oestrogen-hormone replacement therapy. In 41/440 (9.3%) tamoxifen-treated patients and in 8/190 (4.2%) non-users of tamoxifen, diagnostic curettage was performed due to benign endometrial changes and endometrial cancer (EC). The difference in the proportions of patients with diagnostic curettage in both group was statistically significant ( χ 2=4.45, p=0.03). In the group of patients treated with tamoxifen, with the median treatment duration of 40 months (range 1–97 months) and in the group of patients without tamoxifen, EC was diagnosed in 11 and in two patients, respectively. The evaluated RR was 2.38 (0.53–10.61, 95% CI). The second primary cancer, excluding contralateral breast cancer and EC, was diagnosed in the group of breast cancer patients treated with tamoxifen and without it in almost the same percentage, i.e. in 12 patients (3%) in the group of patients who were treated with tamoxifen and in 10 patients (5%) in the group of patients without tamoxifen treatment. Conclusion: Despite the fact that the calculated RR of EC in our study (2.4) was not statistically significant, due to a small number of patients, our results support the IARC evaluation that tamoxifen is carcinogenic to humans. Our data also suggest that tamoxifen does not increase the risk of other second primary cancers. However, the risk of individual second primary cancers cannot be reliably assessed due to a limited number of patients.

Hormonal risk factors for endometrial cancer: modification by cigarette smoking (United States).

To evaluate whether smoking modifies the risk of endometrial cancer associated with body mass index (BMI), postmenopausal hormone use, and other hormonal factors. Using multivariate adjusted models we examined interview data from a population-based case-control study of Wisconsin women (n = 740 cases, n = 2,372 controls). The relative risk for endometrial cancer associated with current smoking was 0.8 (95% CI: 0.6-1.0) compared to never smokers. No clear dose-response relationship was evident for pack-years smoked. When examined according to smoking status the risk associated with the highest quartile of BMI seemed to be greater among non-smokers (OR = 3.6, 95% CI: 2.4-5.3) than among current smokers (OR = 2.8, 95% CI: 1.4-5.6). Among postmenopausal women the risk associated with current use of postmenopausal hormones appeared to be greater among non-smokers (OR = 3.3, 95% CI: 2.3-4.9) than among current smokers (OR = 2.7. 95% CI: 1.3-5.5). Risk for long-term use (10 or more years) compared with never users was 8.3 (95% CI: 4.6-15.1) among never smokers and 2.5 (95% CI: 0.8-7.9) among current smokers. The risk associated with non-insulin-dependent diabetes was greater among non-smokers (OR = 2.5, 95% CI: 1.7-3.6) than current smokers (OR = 1.1, 95% CI: 0.4-3.1). There was no modifying effect of smoking on the risk associated with parity. These results suggest that smoking moderates the risk associated with endometrial cancer among women at greatest risk, specifically women who are obese or who use postmenopausal hormones.

Risk of endometrial cancer following estrogen replacement with and without progestins.

Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.

Low-potency oestrogen and risk of endometrial cancer: a case-control study

Urogenital symptoms are common among postmenopausal women. Such symptoms may be alleviated by low-potency oestrogen formulations administered orally or vaginally. Although low-potency oestrogen formulations are assumed to have few, if any, adverse effects on the endometrium, risk of endometrial neoplasia has not been quantified. In a nationwide population-based case-control study in Sweden of endometrial cancer among postmenopausal women, we obtained detailed information on hormone replacement from 789 cases of endometrial cancer and 3368 population controls. In a histopathological review, 80 cases were reclassified as having endometrial atypical hyperplasia. Odds ratios and 95% CI were calculated with unconditional logistic regression. After multivariate adjustment, oral use of oestriol 1-2 mg daily increased the relative risk of endometrial cancer and endometrial atypical hyperplasia: the odds ratios for at least 5 years of use compared with never use were 3.0 (95% CI 2.0-4.4) and 8.3 (4.0-17.4), respectively. The association was stronger for well-differentiated cancers and those with limited invasion. The excess relative risk was lost rapidly after cessation of treatment. Only weak associations were observed between vaginal application of low-potency oestrogen formulations and relative risk of endometrial neoplasia. Oral, but not vaginal, treatment with low-potency oestrogen formulations increases the relative risk of endometrial neoplasia. Thus close surveillance of patients is needed, and addition of a progestagen should be considered.

IV.6 Tamoxifen and endometrial cancer: most cancers are early stage and highly curable

Abstract A large randomised trial comparing tamoxifen with placebo for breast cancer treatment has demonstrated an average annual hazard rate for endometrial cancer in the placebo group of 0.2 1000 compared to 1.6 1000 for the tamoxifen-treated group, with tamoxifen causing a 7.5-fold increase in the relative risk of endometrial cancer. If the effect of tamoxifen on the endometrium is that of a weak oestrogen agonist, one could expect associated endometrial cancers to have clinical characteristics comparable to those associated with unopposed oestrogen i.e. low stage, well differentiated tumours that are highly curable.

Risk of endometrial cancer in breast cancer patients under long-term adjuvant treatment with tamoxifen.

To evaluate the relative risk of endometrial cancer with respect to the expected underlying incidence in breast cancer patients undergoing long-term adjuvant tamoxifen therapy. A total of 1010 postmenopausal breast cancer patients receiving adjuvant tamoxifen and with a first negative endometrial ultrasonography (cutoff for abnormal endometrial thickness >5 mm) were followed by annual transvaginal ultrasonography. Abnormal endometrial thickness prompted an outpatient endometrial biopsy or curettage under anesthesia in the case of cervical stenosis and increasing endometrial thickness. The standardized incidence ratio (SIR) with respect to underlying incidence was determined. A total of 1,010 eligible subjects who had been receiving tamoxifen for an average of 51 months were enrolled and followed for a total of 2,361 patient-years between January 1993 and December 1996. Five cases of endometrial cancer were observed in the study period: 1 was detected at screening, and 4 were diagnosed for vaginal bleeding in the interval between screening examinations. SIR was 4.0 (95% confidence interval, 1.3-9.4) and increased to 4.8 (CI, 1.6-10.5) when the single cancer detected at first screening was considered as incident. This study adds evidence to the hypothesis that long-term tamoxifen treatment may be responsible for a relevant increase in the risk of developing endometrial cancer. Surveillance based on endometrial ultrasonography was poorly sensitive, but the favorable stage at diagnosis of screen-detected or interval endometrial cancers does not support a more aggressive screening approach.

Oestrogen-related cancer risk in mothers of testicular-cancer patients.

The belief that oestrogens are involved in the pathogenesis both of testicular cancer in young men and of cancers of the endometrium and female breast has become widespread. In a search for possible hormonal links between these cancers, we investigated the cancer pattern in a cohort of women who had given birth to sons who developed testicular cancer. Particular focus, was given to oestrogen-related cancers. The present retrospective population-based cohort study is based on data from the Danish Cancer Registry. Mothers of 2,204 testicular-cancer patients were followed for the occurrence of cancer over a total of 70,063 person years. The ratio of observed cancers in the cohort over the expected numbers based on cancer incidence in the underlying female population served as measure of the relative risk (RR). The RR of developing breast cancer among mothers of testicular-cancer patients was 0.8 (95% confidence interval 0.6-1.1), the relative risk of endometrial cancer 0.6 (0.3-1.0) and of ovarian cancer 1.0 (0.6-1.6). Mothers of testicular-cancer patients are not at increased risk of developing oestrogen-related cancers.

Endometrial cancer following breast cancer: Effect of tamoxifen and castration by radiotherapy.

Tamoxifen, a synthetic antiestrogen, has been shown to be effective in reducing mortality from breast cancer and the occurrence of contralateral breast cancer. Tamoxifen is now being studied as a preventive of breast cancer among healthy women considered to be at high risk; preventive trials are now under way both in the USA and in Europe. We undertook a case-control study in Lyon and Dijon, France, to assess the effect of tamoxifen and other treatments for breast cancer on subsequent endometrial cancer. Through the use of clinicians' surveys in Lyon and a population-based cancer registry in Dijon, we identified 43 cases of endometrial cancer diagnosed at least 1 year after the diagnosis of breast cancer. We matched 177 controls to the cases for age, region, year of diagnosis of breast cancer, and survival from breast cancer. Tamoxifen had been used in 67% of cases and 60% of controls [odds ratio (OR) = 1.4; 95% confidence interval (CI) = 0.60-3.5]. Relative risk of endometrial cancer increased with duration of tamoxifen use: less than 2 years, 1.5; 95% CI = 0.44-4.9; 2-5 years, 1.5; 95% CI = 0.42-5.6; more than 5 years, 3.5; 95% CI = 0.94-12.7. Radiotherapeutic castration increased the risk for endometrial cancer more than tamoxifen (OR = 7.7; 95% CI = 1.8-32.8).

A longitudinal study of screening for endometrial cancer by endometrial biopsy in diabetic females.

Diabetics are at high risk of developing endometrial cancer; the relative risk of endometrial cancer in diabetics is fourfold in comparison to non-diabetic controls. The purpose of this longitudinal study was to evaluate the effectiveness of screening asymptomatic diabetic females in terms of the premalignant and malignant endometrial findings, and to try to determine the optimal screening interval. In 1980-1981, a group of 462 diabetic females was identified and registered. One half of them (237) was invited to be screened. Endometrial samples were taken by using Vabra aspiration. The results of this first randomized screening in 1980-1981 have been published elsewhere. At that time 124 females participated. The remaining 225 females acted as an unscreened control group. Eight years later (1988-1989), both groups were invited to be screened. The Pistolet aspiration method was used. At this stage, group 1 (screened in 1980-1981) consisted of 78 females, and group 2 (not screened in 1980-1981) consisted of 148 females. In 85% (193/226) of the females, the uterine cavity was reached with the Pistolet instrument; 96% of the females found the pain acceptable. In the group screened twice (group 1), no pathologic lesions of the endometrium were found in the second screening. In the group screened for the first time (group 2), one female had endometrial adenocarcinoma (0.8%), one had complex hyperplasia without atypia (0.8%) and four had endometrial polyps (3.3%). In 165 cases of 193, both a cytologic and a histologic specimen were available. In 130 cases (79%) the cytology was of class I, including the one endometrial adenocarcinoma. In three cases (2%) it was of class II and in one case (1%) of class III. Endometrial biopsy by Pistolet aspiration was a method highly acceptable by the patients for examining the endometrium. However, cytologic examination was not able to show the existing endometrial adenocarcinoma. One endometrial sampling of asymptomatic diabetic females during early menopause could detect the bulk of the occult, slowly progressing lesions of the endometrium. Such screeening might be most efficient in terms of cost-benefit ratio.

Hormone replacement therapy: II. A pharmacoeconomic appraisal of its role in the prevention of postmenopausal osteoporosis and ischaemic heart disease.

The reduction in estrogen production that occurs at menopause is associated with several long term sequelae. There is an accelerated decrease in bone mineral density leading to an increased risk of osteoporotic fracture. Furthermore, changes in plasma lipid profiles and other cardiovascular parameters increase the risk of cardiovascular and cerebrovascular pathology. These effects are additional to the menopausal symptoms experienced by many women. The effectiveness of estrogen-based hormone replacement therapy (HRT) is well established in preventing bone mineral loss and also in ameliorating menopausal symptoms, with the addition of progestogen maintaining or possibly enhancing the bone-conserving effects. However, prolonged therapy appears to be necessary to conserve bone mineral density and prevent osteoporotic fracture, particularly in women aged greater than or equal to 75 years, and compliance with long term therapy is likely to be poor. Estrogen favourably alters plasma lipid profiles, improves coronary blood flow and inhibits the central distribution of body fat. Effects on haemostatic mechanisms and coronary vasomotor response to acetylcholine have also been suggested as mechanisms for the beneficial effects of estrogen on ischaemic heart disease. The effects of concomitant progestogens on plasma lipids are variable, and may depend on the type, dosage regimen and duration of therapy. Pharmacoeconomic analyses of HRT have used a variety of risk assumptions. Relative risk rates of osteoporotic fracture and mortality from myocardial infarction are assumed to reduce to 0.5 after greater than 5 years' therapy. Long term HRT is associated with a relative risk of approximately 1.3 for breast cancer, whereas the relative risk of endometrial cancer is 4.0 to 8.0 in women with intact uteri receiving prolonged unopposed estrogen therapy. HRT that includes progestogens is assumed to incur no added risk of endometrial cancer, and this treatment is generally recommended for women with intact uteri. Data concerning the effect of HRT on quality of life are limited and utility values for hip fracture of 0.95 to 0.36 have been assigned, depending on assumptions of disability. Cost-benefit, cost-effectiveness and cost-utility studies evaluating HRT in the prevention of osteoporotic fracture have differed widely in methodology, making comparison of results difficult. HRT appears to be most economically useful in the prevention of fracture if used in women who have undergone hysterectomy, in women with high risk of osteoporotic fracture or ischaemic heart disease, and/or in women with menopausal symptoms.(ABSTRACT TRUNCATED AT 400 WORDS)

Endometrial Cancer in Tamoxifen-Treated Breast Cancer Patients: Findings From the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 *

Tamoxifen is advantageous in treating all stages of breast cancer. However, studies have suggested that incidence and severity of endometrial cancer increase in women treated with tamoxifen. We compared rates of endometrial and other cancers in tamoxifen- and non-tamoxifen-treated patients and described the pathologic characteristics of the endometrial cancers. Data were analyzed on 2843 patients with node-negative, estrogen receptor-positive, invasive breast cancer randomly assigned to placebo or tamoxifen (20 mg/d) and on 1220 tamoxifen-treated patients registered in NSABP B-14 subsequent to randomization. Average time on study is 8 years for randomly assigned patients and 5 years for registered patients. The incidence rates of liver, gastrointestinal, urinary tract, and nonuterine genital tumors were not increased by tamoxifen treatment. Twenty-five endometrial cancers were originally reported, one of which was reclassified after subsequent review. Two cases occurred in the placebo group in patients whose medical status subsequent to random assignment had required tamoxifen treatment. Twenty-three occurred in the tamoxifen groups. Twenty-one of the 24 originally reported endometrial cancers were FIGO stage 1; 18 of 23 gradable cases were of good to moderate histologic grade. Four tamoxifen-treated women died of uterine cancer. The average annual hazard rate of endometrial cancer as a first event within the first 5 years of follow-up in the randomized, tamoxifen-treated group was 1.2/1000 patient-years; the cumulative hazard rate was 6.3/1000. Findings for the registered, tamoxifen-treated group were similar. Including all originally reported endometrial cancers, the annual hazard rate through all follow-up was 0.2/1000 in the placebo group and 1.6/1000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. Again for the latter group, using population-based rates of endometrial cancer from SEER data and information from another NSABP (B-06) trial, relative risks were 2.2 and 2.3, respectively. The 5-year cumulative hazard rate for disease-free survival in the randomized tamoxifen group was 38% less than that in the placebo group. Some data in this paper were provided by an investigator who submitted fraudulent data to the NSABP [see the "News" section]; therefore, the reader must read the entire text including Table 10 and the Editor's notes. In brief, data on 182 of the 2843 randomly assigned patients and 37 of the 1220 registered patients were provided by the investigator in question. After review, 24 of the 182 records showed falsification, all involving characteristics of patients prior to random assignment. Of the 37 registered-patient records, 8 showed falsification. Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk. Endometrial cancers occurring after tamoxifen therapy do not appear to be of a different type with a worse prognosis than are such tumors in non-tamoxifen-treated patients. Tamoxifen treatment for breast cancer should continue. In addition, the relative risk of endometrial cancer observed in B-14 tamoxifen-treated patients is consistent with the twofold relative risk used in the initial risk-benefit computation for the NSABP breast cancer prevention trial.

Moderate Alcohol Consumption and the Risk of Endometrial Cancer

In a multicenter case-control study that included 400 cases and 297 controls, we examined the relation of moderate alcohol consumption to risk of endometrial cancer. We estimated average weekly intake of alcohol during adulthood from the reported frequency of intake of beer, wine, and liquor. The relative risk of endometrial cancer was 0.82 (95% confidence interval = 0.6-1.2) among women who drank, compared with lifelong abstainers. The weak protective effect of alcohol was due to a stronger inverse association among young women (< 55 years). In young women, the age-adjusted relative risks for three levels of drinking ( < 1, 1-4, > 4 drinks per week), from lowest to highest, were 0.78, 0.64, and 0.41 compared with nondrinkers. The risk estimates were not materially altered after adjustment for a variety of factors related to alcohol intake and to low risk of the disease (for example, smoking, oral contraceptive use, low body mass index, increased physical activity). The protective effect of alcohol could not be attributed to one particular type of alcohol-containing beverage, but beer appeared to have the most pronounced effect. These results suggest an inverse association between moderate alcohol consumption and endometrial cancer risk among young women, but support for a causal association is qualified and requires confirmation.