Causal association between aspirin use and risk of endometrioid carcinoma: a Mendelian randomization study.

OBJECTIVE: The aim of the study was to investigate the causal relationship between aspirin use and the risk of endometrial endometrioid cancer (EEC) using two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) study. MATERIALS AND METHODS: A TSMR analysis was conducted to estimate the potential causal relationship between aspirin use and the risk of EEC using genome-wide data from Genome-wide association study (GWAS). The causal association between aspirin use and EEC was further analyzed by MVMR analysis after adjusting for various factors such as obesity, hypertension, diabetes, and infertility. The single nucleotide polymorphism (SNP) data associated with aspirin use and EEC was obtained from the GWAS catalog database. RESULTS: A total of six SNPs were included as instrumental variables in TSMR, which showed that taking aspirin reduced the risk of EEC [OR = 0.02, 95% CI = 0-0.28, p = 0.005, inverse variance weighted (IVW) method]. Besides, the results of the weighted median (WME) method, weighted mode, and simple mode were consistent with the results shown by the IVW method. After further using the MVMR method, the causal association of aspirin use and prevention of EEC onset remained significant after adjusting for the effects of obesity, hypertension, and diabetes (OR = 0.076, 95% CI = 0.007-0.793, p = 0.031). Sensitivity analyses, including heterogeneity, horizontal multiplicity, and leave-one-out tests, showed the reliability of the instrumental variables, proving that the results were reliable and not significantly biased. CONCLUSIONS: Taking aspirin can reduce the risk of EEC morbidity, and it is expected to be of great significance for the early prevention and treatment of endometrial cancer by exploring the biological mechanism of aspirin on endometrioid cancer at a deeper level.

Perimenopausal management of ovarian endometriosis and associated cancer risk: When is medical or surgical treatment indicated?

In women with endometriosis, the lifetime risk of ovarian cancer is increased from 1.4% to about 1.9%. The risk of clear cell and endometrioid ovarian cancer is, respectively, tripled and doubled. Atypical endometriosis, observed in 1-3% of endometriomas excised in premenopausal women, is the intermediate precursor lesion linking typical endometriosis and clear cell/endometrioid tumors. Prolonged oral contraceptive use is associated with a major reduction in ovarian cancer risk among women with endometriosis. Surveillance ± progestogen treatment or surgery should be discussed in perimenopausal women with small, typical endometriomas. In most perimenopausal women with a history of endometriosis but without endometriomas, surveillance instead of risk-reducing bilateral salpingo-oophorectomy seems advisable. Risk-reducing salpingo-oophorectomy might benefit patients at particularly increased risk, but the evidence is inconclusive. Risk profiling models and decision aids may assist patients in their choice. Screening of the general perimenopausal population to detect asymptomatic endometriomas is unlikely to reduce disease-specific mortality.

Development of endometrioid adenocarcinoma despite Levonorgestrel-releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia.

Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG-IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG-IUS following a negative hysteroscopy in a 56-year-old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity.

Pathologic Findings in Prophylactic and Nonprophylactic Hysterectomy Specimens of Patients With Lynch Syndrome.

Women with Lynch syndrome (LS) have a high risk of developing endometrial carcinoma (EC) and, less frequently, ovarian carcinoma. As EC not uncommonly is the first malignancy, prophylactic hysterectomy (PH) has been increasingly implemented. In this study, we report the clinicopathologic features of a series of 70 LS patients who underwent either PH (n=39) or nonprophylactic hysterectomy (NPH) (n=31) at 3 tertiary referral centers. Among the 39 patients with PH, 2 had endometrial tumors seen grossly, whereas 37 showed no macroscopic lesions. Total inclusion of the endometrium was performed in 24/39 (61.5%). Abnormal histologic findings were identified in 9/39 (23.1%) PHs: 3 endometrial endometrioid carcinomas (EECs), including the 2 macroscopic and 1 microscopic (0.6 cm), and 4 atypical and 6 nonatypical hyperplasias. NPH included those performed for endometrial and ovarian cancer treatment. Tumor sampling followed standard protocols. ECs comprised 26 EECs and 1 clear cell carcinoma, with a median size of 3.7 cm. Hyperplasia was observed in 10 (33.3%) as background in EC, in 4 showing atypia. Eight (29.6%) tumors were centered in the lower uterine segment (all EECs). EECs were predominantly well differentiated (53.8%) and FIGO stage I (77.8%). A papillary architecture was common (51.9%) and associated with microcystic elongated and fragmented foci in 4. Mucinous differentiation was observed in 25.9% of endometrial tumors, typically representing <10%. Most endometrial tumors (81.5%) showed tumor-infiltrating lymphocyte counts ≥42/10 high-power fields. Four tumors showed extensive necrosis. Eight patients had ovarian tumors (4 synchronous), including 2 endometrioid carcinomas, 2 clear cell carcinomas, 1 borderline clear cell adenofibroma, 1 Müllerian carcinoma of mixed cell types, 1 primitive neuroectodermal tumor, and 1 metastatic melanoma. Total inclusion of the endometrium should be done in all LS patients' surgical specimens without macroscopic lesions as some of these patients harbor preneoplastic or neoplastic conditions treatable at an early stage. The phenotype of LS-associated endometrial and ovarian tumors is variable and frequently includes features not commonly observed in sporadic cancers, but in our experience carcinomas were in general low grade and low stage.

Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells.

Polymorphonuclear neutrophils (PMNs) are largely considered to foster cancer development despite wielding an arsenal of cytotoxic agents. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for PMNs in epithelial carcinogenesis. By inducing tumor cell detachment from the basement membrane, PMNs impeded early-stage tumor growth and retarded malignant progression. Unexpectedly, PMN recruitment and tumor growth control occurred independently of lymphocytes and cellular senescence and instead ensued as part of the tumor's intrinsic inflammatory response to hypoxia. In humans, a PMN gene signature correlated with improved survival in several cancer subtypes, including PTEN-deficient uterine cancer. These findings provide insight into tumor-associated PMNs and reveal a context-specific capacity for PMNs to directly combat tumorigenesis.

[Levonorgestrel-releasing intrauterine system Mirena® (Bayer) for the prevention and treatment of endometrial adenocarcinoma and the incidence of other malignancies in women]. / Wplyw systemu wewnatrzmacicznego uwalniajacego lewonorgestrel Mirena® (Bayer) na prewencje i leczenie raka gruczlowego blony sluzowej macicy oraz na inne nowotwory zlosliwe u kobiet.

The use of hormone-releasing intrauterine devices has been on the increase for the last three decades. To date, evidence of their long-term efficiency is available. The aim of the present paper was to briefly review beneficial prophylactic effects of the levonorgestrel-releasing intrauterine system on the incidence of a variety of malignancies in women. Such an influence is of a particular importance in the light of the currently observed increased prevalence of endometrial and cervical adenocarcinomas. Low-dose releasing intrauterine systems are also available, but the hard evidence-based medical data have been derived primarily for Mirena® (Bayer) device, which topically releases from 20 to 14 pg of levonorgestrel daily. Consequently the risk of developing endometrial carcinoma in Mirena® users is lowered by as much as 50% compared with the general population risk To a lesser extent, the intrauterine system decreases the risk for cervical adenocarcinoma and squamous cell carcinoma, as well as ovarian, pancreas, and lung carcinomas. In one population-based study Mirena® increased the risk for breast carcinoma by approximately 20%, whereas a number of other studies failed to demonstrate such a hazard. In the recent decades of the increased predominance of insulin resistance and obesity and an occurrence of hormone-dependent carcinomas at earlier age, a broad application of levonorgestrel-releasing intrauterine systems may become a particularly important component of primary prevention of malignancies in women. Both obese and overweight patients seem perfect candidates for such a hormonal intervention.

New insights in the pathophysiology of ovarian cancer and implications for screening and prevention.

Despite advances in medicine, ovarian cancer remains the deadliest of the gynecological malignancies. Herein we present the latest information on the pathophysiology of ovarian cancer and its significance for ovarian cancer screening and prevention. A new paradigm for ovarian cancer pathogenesis presupposes 2 distinct types of ovarian epithelial carcinoma with distinct molecular profiles: type I and type II carcinomas. Type I tumors include endometrioid, clear-cell carcinoma, and low-grade serous carcinoma and mostly arise via defined sequence either from endometriosis or from borderline serous tumors, mostly presenting in an early stage. More frequent type II carcinomas are usually high-grade serous tumors, and recent evidence suggests that the majority arise from the fimbriated end of the fallopian tube. Subsequently, high-grade serous carcinomas usually present at advanced stages, likely as a consequence of the rapid peritoneal seeding from the open ends of the fallopian tubes. On the other hand, careful clinical evaluation should be performed along with risk stratification and targeted treatment of women with premalignant conditions leading to type I cancers, most notably endometriosis and endometriomas. Although the chance of malignant transformation is low, an understanding of this link offers a possibility of prevention and early intervention. This new evidence explains difficulties in ovarian cancer screening and helps in forming new recommendations for ovarian cancer risk evaluation and prophylactic treatments.

[Prophylactic salpingectomy or salpingo-oophorectomy as an ovarian cancer prevention?]. / Salpingectomie prophylactique ou annexectomie prophylactique dans la prévention du cancer de l'ovaire ?

A recent hypothesis has stated that many ovarian cancers (especially high-grade serous histotype) could arise from the distal part of the fallopian tube. On one hand we know that risk-reducing salpingo-oophorectomy is the most effective prevention for ovarian cancer among BRCA mutation carriers. On the other, oophorectomy increases the relative risk for cardiovascular, osteoporotic psychosexual and cognitive dysfunctions in premenopausal women. This raises the question whether bilateral salpingectomy could be an effective strategy in the prevention of ovarian cancer in case of hereditary predisposition and in the general population. Here we discuss origin of ovarian cancer in the light of the latest molecular studies and the relative risks and benefits of a strategy of exclusive salpingectomy in comparison with the classical adnexectomy.

Food intake and the risk of endometrial endometrioid adenocarcinoma in Japanese women.

The present study examined the association between food intake and endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case-control study in Japanese women. One hundred sixty-one cases and 380 controls who completed a questionnaire regarding demographic, lifestyle, and food frequency questionnaire were analyzed. Odds ratio (OR) between selected food intakes and EEA were calculated by logistic regression analysis. After adjustment putative confounding factors, the higher intakes of vegetables [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.26-0.83], peanuts (OR = 0.48, CI = 0.27-0.86), fish (OR = 0.52, CI = 0.29-0.93), boiled egg (OR = 0.24, CI = 0.33-0.92), instant noodles (OR = 1.94, CI = 1.12-3.34), instant food items (OR = 2.21, CI = 1.31-3.74), and deep-fried foods (OR = 2.87, CI = 1.58-5.21) were associated with a risk for EEA. The inverse association with a risk of EEA was also seen in higher intakes (g/1000 kcal) for vegetables (0.45, CI = 0.25-0.81) and fish (0.53, CI = 0.30-0.94) as compare to lower intake. Higher intake of vegetables, peanuts, fish, and boiled egg was associated with a reduced risk for EEA, whereas instant noodles, instant food items, and deep-fried foods was associated with an increased risk for EAA as compared to lower levels of intake.

MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1.

MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3' untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC.

Beneficio extraóseo de los moduladores selectivos del receptor estrogénico de tercera generación: II, acción en el endometrio / Third generation selective estrogen receptor modulators: benefits beyond bone. II, endometrial action

Los selective estrogen receptor modulators (SERM, «moduladores selectivos del receptor estrogénico») son moléculas que se vinculan a los receptores de estrógenos ejerciendo un efecto estrogénico o antiestrogénico, según su estructura y el tipo de tejido. Desde el descubrimiento del efecto preventivo en cáncer de mama del tamoxifeno y el raloxifeno (RLX), el SERM ideal sería el que indujera efectos estrogénicos a nivel óseo o en el sistema nervioso central y antiestrogénicos en la mama y el endometrio. Sin embargo, uno de los inconvenientes más importantes para la consolidación de tamoxifeno ha sido su relación con la aparición de cáncer de endometrio. Por ello, se inicia la búsqueda de una molécula con efectos neutros o protectores a este nivel. Así aparecieron ospemifeno, arzoxifeno, lasofoxifeno (LFX) y bazedoxifeno (BZA) como SERM de tercera generación. De todos ellos, tan solo BZA ha alcanzado la etapa de utilización clínica. Los datos experimentales y clínicos tanto para RLX como para los SERM de tercera generación de los que se dispone de información (BZA y LFX) muestran neutralidad o incluso antagonismo frente a los estrógenos a nivel endometrial. El BZA ha demostrado un comportamiento equivalente al vehículo en distintas condiciones experimentales y actúa como un antagonista de los estrógenos en diseños en los que se coadministran estradiol o estrógenos equinos conjugados (EEC). En los estudios de referencia a 7 años se detectaron diferencias significativas en la incidencia de adenocarcinoma de endometrio a favor de BZA comparado con placebo. En un ensayo clínico para valorar en mujeres posmenopaúsicas el efecto de la combinación de EEC y BZA sobre la sintomatología, se comprobó la capacidad de dosis de BZA de 20 mg o superiores para evitar la presentación de hiperplasia inducida por 0,625 o 0,450 de EEC (AU)

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or thirdgeneration SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20 mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450 mg of CEE (AU)

Life-style and metformin for the prevention of endometrial pathology in postmenopausal women.

In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation.

A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families.

OBJECTIVE/DESIGN: We performed a systematic review of studies that evaluate the role of gynecological cancer surveillance in women who carry a hereditary nonpolyposis colorectal cancer (HNPCC) mutation or belong to a family that fulfills the criteria for HNPCC. METHODS: The PubMed database and a clinical trials database were used to identify relevant studies. We included studies that reported results of gynecological cancer surveillance in women who carry a HNPCC mutation, belong to a family in which a HNPCC mutation was detected or belong to a family fulfilling the Amsterdam II criteria. MAIN OUTCOME MEASURES: Number and stage of cancers, interval cancers and cancer precursor states detected at screening. RESULTS: Five studies fulfilled our review criteria. Surveillance modalities for endometrial cancer included transvaginal ultrasound combined with endometrial sampling when indicated, or transvaginal ultrasound with a routine endometrial biopsy, and, in certain studies, the tumor marker CA-125. The highest yield of pathological findings in surveillance visits, from 5 to 6.5%, occurred in studies that included routine endometrial biopsies. Without a routine sampling, 7/14 cancers and 11/18 hyperplasias would have been missed. One case of advanced ovarian cancer was detected at surveillance. CONCLUSIONS: Currently available published studies on gynecological cancer surveillance in women with HNPCC do not adequately allow for evidence-based clinical decisions. Detection of endometrial cancer or hyperplasia in nonsymptomatic women belonging to an HNPCC family is improved by adding routine endometrial sampling along with transvaginal ultrasound for surveillance visits. No benefit was shown for ovarian cancer surveillance.

Adjuvant pelvic radiation therapy in endometrial cancer: The pro argument.

Adjuvant external beam pelvic radiation therapy for stage I endometrial cancer has become increasingly confusing and controversial. Despite repeated studies showing a disease-free survival benefit to the therapy, its role is being questioned because overall survival has not been demonstrated. By using evidence from the literature, including the most recent randomized data, an argument is made for the use of external beam pelvic radiotherapy for a 63-year-old woman who has undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a grade 2 endometrioid adenocarcinoma of the uterus with 9 of 12 mm of invasion and the presence of lymphovascular space involvement. Her risk of relapse is approximately 25%, and adjuvant external beam radiation can improve her disease-free survival and even possibly improve her chances of cure.

A role for adjuvant radiation in clinically early carcinoma of the endometrium?

Whereas radiation is recognized as a highly effective treatment modality in endometrial cancer, its role as adjuvant treatment after surgery in clinically early disease is declining. Randomized trials of both pelvic external beam radiation and vaginal vault brachytherapy have been conducted to evaluate their respective contribution. These trials have demonstrated that external beam radiation may decrease pelvic relapse rates compared with observation alone in high intermediate-risk groups, but this does not improve survival. Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) Study 2 confirmed that vaginal vault brachytherapy was equivalent to external beam radiation in preventing vaginal relapse. However, given the high rate of salvage of patients who develop vaginal recurrence and the significant risk of death from comorbidities, questions arise as to the relative merit of administering adjuvant radiation for all compared with a strategy of observation after surgery with treatment only for the 10% who have a relapse.The contribution of adjuvant radiation for high-risk disease, including those with grade III tumors with deep myometrial penetration, however, remains to be determined in ongoing trials.

Novel fluoroimmunoassay for ovarian cancer biomarker CA-125.

Cancer antigen 125 (CA-125) is a glycoprotein biomarker that denotes the presence of ovarian and reproductive cancers in women, with serum concentrations of CA-125 greater than 35 U/ml considered indicative of potential malignancies. A fluorescent immunoassay recently developed in our laboratory employing the ALYGNSA antibody-orientation system has been used to measure CA-125 levels. This system displayed significantly increased sensitivity with a detection limit of 1.5 U/ml compared to that of a commercial CA-125 enzyme-linked immunosorbent assay (15 U/ml) This tenfold lower level of detection of the ALYGNSA CA-125 assay should permit better identification and monitoring of ovarian cancer.

Case-control study of green tea consumption and the risk of endometrial endometrioid adenocarcinoma.

OBJECTIVE: To investigate the association between green tea consumption and the risk of endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case-control design in Japan. METHODS: The cases were 152 patients with histopathologically diagnosed EEA, and the controls were 285 healthy women who were matched for age and area of residence with individual cases. The subjects completed a questionnaire regarding health-related lifestyle and reproductive history, and a food frequency questionnaire. Odds ratios (ORs) of EEA for frequency of green tea consumption were calculated by conditional logistic regression analysis. RESULTS: We observed a significant inverse association between green tea consumption and the risk of EEA with a dose-response relationship. The multivariate-adjusted OR of EEA was 0.77 (95% CI: 0.37-1.58) for those in the second quartile of green tea consumption (5-6 cups/week-1 cup/day), 0.61 (0.30-1.23) in the third quartile (2-3 cups/day), and 0.33 (0.15-0.75) in the highest quartile (> or = 4 cups/day), as referenced with those in the lowest quartile (< or = 4 cups/week; p for trend = 0.007). This inverse association was consistently observed regardless of the presence or absence of factors such as obesity and menopause. CONCLUSION: Green tea consumption may be associated with a lower risk of EEA.

Case-control study of coffee consumption and the risk of endometrial endometrioid adenocarcinoma.

This study examined the association between coffee consumption and the risk of endometrial endometrioid adenocarcinoma (EEA) in Japan by a case-control design. The cases consisted of 107 women less than 80 years of age from two medical centers who had been histopathologically diagnosed to have EEA. The controls, selected from the participants of a cancer-screening program, were 214 women, with two controls selected for each case (matched for age and for area of residence). A self-administered questionnaire containing questions to determine dietary and beverage consumption, as well as reproductive history, was distributed to the cases and controls. Conditional logistic regression analysis was used to estimate the odds ratio (OR) of EEA for three levels of coffee consumption with adjustment for potential confounding factors. The multivariate-adjusted OR of EEA for individuals in the highest tertile of coffee consumption (2 to 3 cups or more/day) was 0.4 [95% confidence interval (CI), 0.2-0.9], and that of cases in the intermediate tertile (5 to 6 times/week-1 cup/day) was 0.6 (95% CI, 0.3-1.2), relative to the individuals in the lowest tertile of coffee consumption (3 to 4 times or less/week) (P for trend=0.014). The above association was observed in postmenopausal women (P for trend=0.016), but not in premenopausal women (P for trend=0.90). This study thus revealed an inverse dose-response relationship between coffee consumption and the risk of EEA, and its strong association in postmenopausal women but not in premenopausal women.

Low-fat dietary pattern and cancer incidence in the Women's Health Initiative Dietary Modification Randomized Controlled Trial.

BACKGROUND: The Women's Health Initiative Dietary Modification (DM) Randomized Controlled Trial evaluated the effects of a low-fat dietary pattern on chronic disease incidence, with breast cancer and colorectal cancer as primary outcomes. The trial protocol also listed ovarian cancer and endometrial cancer as outcomes that may be favorably affected by the intervention. METHODS: A total of 48,835 postmenopausal women were randomly assigned during 1993-1998 to a DM intervention (n = 19,541) or comparison (usual diet; n = 29,294) group and followed up for an average of 8.1 years. The intervention goal was to reduce total fat intake to 20% of energy and to increase consumption of vegetables, fruits, and grains. Cancer outcomes were verified by pathology report review. We used weighted log-rank tests to compare incidence of invasive cancers of the ovary and endometrium, total invasive cancer, and invasive cancers at other sites between the groups. All statistical tests were two-sided. RESULTS: Ovarian cancer risk was lower in the intervention than in the comparison group (P = .03). Although the overall ovarian cancer hazard ratio (HR) was not statistically significantly less than 1.0, the hazard ratio decreased with increasing intervention duration (P(trend) = .01). For the first 4 years, the risk for ovarian cancer was similar in the intervention and control groups (0.52 cases per 1000 person-years in the intervention group versus 0.45 per 1000 person-years in the comparison group; HR = 1.16, 95% confidence interval [CI] = 0.73 to 1.84); over the next 4.1 years, the risk was lower in the intervention group (0.38 cases per 1000 person-years in the intervention group versus 0.64 per 1000 person-years in the comparison group; HR = 0.60, 95% CI = 0.38 to 0.96). Risk of cancer of the endometrium did not differ between the groups (P = .18). The estimated risk of total invasive cancer was slightly lower in the intervention group than in the control group (HR = 0.95, 95% CI = 0.89 to 1.01; P = .10). CONCLUSIONS: A low-fat dietary pattern may reduce the incidence of ovarian cancer among postmenopausal women.