Objective

To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels thereby modifying risks of cardiovascular disease and breast cancer.

Design

The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995–1996 through a mailed, self-administered questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.

Subjects

CTS participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n=9,785), were compared to participants with natural menopause (n=32,219).

Main outcome measures

We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy (HT) use status.

Results

Among participants younger than 45 years of age at menopause, multivariable relative risks were 0.86 (95% CI, 0.74–1.00), 0.85 (95% CI, 0.66–1.11) and 0.91 (95% CI, 0.67–1.23) for all-cause mortality, cardiovascular mortality and cancer mortality, respectively. Among participants with an age at menopause of 45 years or later, multivariable relative risks were 0.87 (95% CI, 0.80–0.94), 0.83 (95% CI, 0.71–0.96) and 0.84 (95% CI, 0.72–0.98) for all-cause, cardiovascular and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of HT use.

Conclusions

Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.

Convincing epidemiologic evidence links excess body mass to increased risks of endometrial and postmenopausal breast cancers but the relation of body mass index (BMI) to ovarian cancer risk remains inconclusive. Potential similarities regarding a hormonal mechanism in the etiology of female cancers highlight the importance of investigating associations according to menopausal hormone therapy (MHT) use. However, data addressing whether the relation of BMI to ovarian cancer differs by MHT use are very sparse. We prospectively investigated the association between BMI and ovarian cancer among 94,525 U.S. women, followed from 1996–1997 to December 31, 2003. During 7 years of follow-up, we documented 303 epithelial ovarian cancer cases. As compared with normal weight women (BMI 18.5–24.9 kg/m2), the multivariate relative risk (MVRR) of ovarian cancer for obese women (BMI ≥30 kg/m2) in the cohort as a whole was 1.25 (95%-CI=0.93–1.68). Among women who never used MHT, the MVRR for obese versus normal weight women was 1.80 (95%-CI=1.16–2.80). In contrast, no relation between BMI and ovarian cancer was apparent among women who ever used MHT (MVRR=0.96; 95%-CI=0.64–1.43; P-interaction=0.02). Exploratory analyses also suggested a positive association between BMI and ovarian cancer among women without a family history of ovarian cancer (MVRR comparing obese versus normal weight women=1.36; 95%-CI=0.99–1.85), but no relation with BMI was apparent among women with a positive family history of ovarian cancer (MVRR=0.73; 95%-CI=0.34–1.60; P-interaction=0.02). We suspect that obesity is associated with enhanced ovarian cancer risk through a hormonal mechanism.

We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and stratified Cox proportional hazards models were fit to estimate relative risks (RR) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95%CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95%CI=0.83-1.33) overall, or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95%CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.

Purpose

Contralateral breast cancer (CBC) is the most frequent new malignancy among women diagnosed with a first breast cancer. Although temporal trends for first breast cancers have been well studied, trends for CBC are not so well established.

Patients and Methods

We examined temporal trends in CBC incidence using US Surveillance, Epidemiology, and End Results database (1975 to 2006). Data were stratified by estrogen receptor (ER) status of the first breast cancer for the available time period (1990+). We estimated the annual percent change (EAPC) in CBC rates using Poisson regression models adjusted for the age at and time since first breast cancer diagnosis.

Results

Before 1985, CBC incidence rates were stable (EAPC, 0.27% per year; 95% CI, −0.4 to 0.9), after which they declined with an EAPC of −3.07% per year (95% CI, −3.5 to −2.7). From 1990 forward, the declines were restricted to CBC after an ER-positive cancer (EAPC, −3.18%; 95% CI, −4.2 to −2.2) with no clear decreases after an ER-negative cancer. Estimated current age-specific CBC rates (per 100/year) after an ER-positive first cancer were: 0.45 for first cancers diagnosed before age 30 years and 0.25 to 0.37 for age 30 years or older. Rates after an ER-negative cancer were higher: 1.26 before age 30 years, 0.85 for age 30 to 35 years, and 0.45 to 0.65 for age 40 or older.

Conclusion

Results show a favorable decrease of 3% per year for CBC incidence in the United States since 1985. This overall trend was driven by declining CBC rates after an ER-positive cancer, possibly because of the widespread usage of adjuvant hormone therapies, after the results of the Nolvadex Adjuvant Trial Organisation were published in 1983, and/or other adjuvant treatments.

Although exposure to estrogen may directly influence or modify the association between cigarette smoking and lung cancer risk, results from epidemiologic studies examining the association between reproductive and hormonal factors and risk of lung cancer among women have been inconsistent. Between 1998 and 2008, 430 women diagnosed with non-small cell lung cancer, 316 hospital controls, and 295 population controls were recruited into the multi-center Maryland Lung Cancer Study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) according to reproductive and hormonal exposures adjusting for age, smoking, passive smoking, education, and household income. Results were similar for hospital and population based controls, so the control groups were combined. Reduced risks of lung cancer were observed among women with greater parity (≥5 vs. 1-2 births: OR=0.50, 95% CI 0.32, 0.78, P-trend=0.002) and later ages at last birth (≥30 vs <25 years old: OR=0.68, 95% CI 0.48, 0.98, P-trend=0.04). After mutual adjustment parity, but not age at last birth, remained significantly inversely associated with risk (P-trend=0.01). No associations were found for non-small cell lung cancer risk with age at menarche, age at first birth, menopausal status, oral contraceptive use, or menopausal hormone use, including use of oral estrogens. Compatible with findings from recent epidemiologic studies, we observed a reduction in the risk of non-small cell lung cancer with increasing number of births. Other reproductive and hormonal exposures, including menopausal hormone therapy use, were not associated with risk.

Nulliparity is an established breast cancer risk factor, particularly when compared with parity at young ages. The authors aggregated data from 4 US prospective studies (1979–2006) including 32,641 nulliparous (1,612 breast cancers) and 204,270 parous (8,180 breast cancers) women to examine the hypothesis that nulliparity may increase susceptibility to established postmenopausal breast cancer risk factors. The aggregated hazard ratio for nulliparous versus all parous women = 1.27 (95% confidence interval: 1.21, 1.34), and that for nulliparous versus women <25 years of age at first birth = 1.38 (95% confidence interval: 1.30, 1.46). Among nulliparous women, the hazard ratios for current menopausal hormone therapy use (vs. never use), body mass index ≥30 kg/m2 (vs. <25 kg/m2), and weekly consumption of ≥7 alcoholic drinks (vs. none) ranged from 1.3 to 1.6. The hazard ratios did not differ by parity. In a model including all women, the joint association for each of these factors and nulliparity combined compared with first birth before age 25 years was an approximately 2-fold increased breast cancer risk. Although the baseline risk is higher for nulliparous women compared with parous women, these results suggest that the associations between hormone-related factors and breast cancer do not differ by parity.

Background

Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.

Methods

We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.

Results

No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.

Conclusions

Our findings do not support an association between HT and lung cancer.

Impact

This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.

Objective

We assessed whether common genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2—genes that reportedly are frequently altered in endometrial cancer—was associated with risk of endometrial cancer.

Methods

Using data from a population-based case-control study in Poland (PECS) of 417 cases and 407 matched controls, we genotyped 76 tagging single nucleotide polymorphisms (tagSNPs; located in or within 10kb upstream or 5kb downstream of the gene of interest, minor allele frequency>=5% among various ethnic groups, and not already represented by another tagSNP at a LD of r2>=0.80) on an Illumina Custom Infinium iSelect assay that included over 29,000 SNPs in 1316 genes. For individual SNPs, we used unconditional logistic regression models, adjusted for age and site, to generate odds ratios (ORs) and 95% confidence intervals (CIs). To replicate the one statistically significant association in PECS, we independently genotyped that tagSNP among 1141 endometrial cancer cases and 2275 controls from the SEARCH study in the UK. We assessed haplotypes via extended haplotype blocks and the sequential haplotype scan method.

Results

The rs2677764 tagSNP in PIK3CA was statistically significantly associated with endometrial cancer in PECS (OR=1.42, 95% CI, 1.03–1.95; P=0.03) but not SEARCH (OR=0.98, 95% CI=0.82–1.17). Of the 25 haplotypes observed in at least 5% of cases and controls in PECS, only 1, in PIK3CA, was statistically significantly associated with endometrial cancer (OR=1.39, 95% CI, 1.00–1.93). All haplotype global p-values were null.

Conclusion

Common genetic variation in PTEN, PIK3CA, AKT1, MLH1, or MSH2 was not statistically significantly associated with endometrial cancer.

Obesity is a well-established risk factor for postmenopausal breast cancer, but mechanisms underlying the association are unclear. Adipocyte-derived, cytokine-like adipokines have been suggested as contributory factors. To evaluate their association with breast cancer risk factors and breast cancer risk, we conducted a nested case-control study of 234 postmenopausal breast cancer cases and 234 controls in a cohort of U.S. women with prospectively-collected serum samples obtained in the mid 1970’s and followed for up to 25 years. Adiponectin, absolute plasminogen activator inhibitor-1 (aPAI-1), and resistin were measured by a multiplex immunoassay. Sex hormones were available for 67 cases and 67 controls. Among controls, we found that lower levels of adiponectin and higher levels of aPAI-1 were correlated with increasing levels of estradiol (Spearman r=−0.26, p-value=0.033; r=0.42, p=0.0003), decreasing levels of sex hormone binding globulin (r=0.38, p=0.0013; r=−0.32, p=0.0076), and increasing body mass index (BMI) (r=−0.31, p=<0.0001; r=0.39, p=<0.0001). Hormones were not associated with resistin. Among the relatively small percentage of women using postmenopausal hormones at the time of blood collection (13.7%), aPAI-1 levels were higher than in nonusers (p=0.0054). Breast cancer risk was not associated with circulating levels of adiponectin (age-adjusted p for linear trend=0.43), aPAI-1 (p=0.78), or resistin (p=0.91). The association was not confounded by BMI, parity, age at first full-term birth, age at menopause, current postmenopausal hormone use, and circulating sex steroid hormones. Furthermore, adipokine associations were not modified by BMI (p>0.05). The lack of association with risk may be due to measurement error of the laboratory assays. In conclusion, lower levels of adiponectin and higher levels of aPAI-1 measured in prospectively-collected serum from postmenopausal women were associated with increasing BMI but not breast cancer risk.

Purpose

The Gail model combines relative risks (RRs) for five breast cancer risk factors with age-specific breast cancer incidence rates and competing mortality rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1983 to 1987 to predict risk of invasive breast cancer over a given time period. Motivated by changes in breast cancer incidence during the 1990s, we evaluated the model's calibration in two recent cohorts.

Methods

We included white, postmenopausal women from the National Institutes of Health (NIH) –AARP Diet and Health Study (NIH-AARP, 1995 to 2003), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, 1993 to 2006). Calibration was assessed by comparing the number of breast cancers expected from the Gail model with that observed. We then evaluated calibration by using an updated model that combined Gail model RRs with 1995 to 2003 SEER invasive breast cancer incidence rates.

Results

Overall, the Gail model significantly underpredicted the number of invasive breast cancers in NIH-AARP, with an expected-to-observed ratio of 0.87 (95% CI, 0.85 to 0.89), and in PLCO, with an expected-to-observed ratio of 0.86 (95% CI, 0.82 to 0.90). The updated model was well-calibrated overall, with an expected-to-observed ratio of 1.03 (95% CI, 1.00 to 1.05) in NIH-AARP and an expected-to-observed ratio of 1.01 (95% CI: 0.97 to 1.06) in PLCO. Of women age 50 to 55 years at baseline, 13% to 14% had a projected Gail model 5-year risk lower than the recommended threshold of 1.66% for use of tamoxifen or raloxifene but ≥ 1.66% when using the updated model. The Gail model was well calibrated in PLCO when the prediction period was restricted to 2003 to 2006.

Conclusion

This study highlights that model calibration is important to ensure the usefulness of risk prediction models for clinical decision making.

Background. Estrogen plays a major role in endometrial carcinogenesis, suggesting that common variants of genes in the sex hormone metabolic pathway may be related to endometrial cancer risk. In support of this view, variants in CYP19A1 [cytochrome P450 (CYP), family 19, subfamily A, polypeptide 1] have been associated with both circulating estrogen levels and endometrial cancer risk. Associations with variants in other genes have been suggested, but findings have been inconsistent. Methods. We examined 36 sex hormone-related genes using a tagging approach in a population-based case–control study of 417 endometrial cancer cases and 407 controls conducted in Poland. We evaluated common variation in these genes in relation to endometrial cancer risk using sequential haplotype scan, variable-sized sliding window and adaptive rank-truncated product (ARTP) methods. Results. In our case–control study, the strongest association with endometrial cancer risk was for AR (androgen receptor; ARTP P = 0.006). Multilocus analyses also identified boundaries for a region of interest in AR and in CYP19A1 around a previously identified susceptibility loci. We did not find evidence for consistent associations between previously reported candidate single-nucleotide polymorphisms in this pathway and endometrial cancer risk. Discussion. In summary, we identified regions in AR and CYP19A1 that are of interest for further evaluation in relation to endometrial cancer risk in future haplotype and subsequent fine mapping studies in larger study populations.

Background

In most populations, incidence rates of upper gastrointestinal tract cancers (UGI: head and neck, esophagus, and stomach) are higher among men than among women. Established risk factors do not appear to explain these differences, suggesting a possible role for sex hormones.

Methods

201,506 women of the NIH-AARP Diet and Health cohort completed a questionnaire in 1995-1996. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models.

Results

During follow-up through 2003, 162 incident adenocarcinomas (ACs; esophagus (N=25) and stomach (N=137)) and 353 incident squamous cell carcinomas (SCCs; head and neck (n=297), and esophagus (N=56)) occurred. Among examined exposures, older age at menopause was associated inversely with SCC (p-trend across categories=0.013) but not AC (p-trend=0.501). Use of menopausal hormone therapy (MHT) was significantly associated with lower risk of SCC (HR=0.77, 0.62-0.96) and non-significantly associated with lower risk of AC (HR=0.81, 0.59-1.12). A subset (N=127,386) of the cohort completed a more detailed MHT questionnaire a year after baseline. In 74,372 women with intact uteri, ever use of estrogen-plus-progestin MHT conferred 0.47 (0.30-0.75) times the risk for SCC and 0.52 (0.26-1.07) times the risk for ACC. In 51,515 women with a hysterectomy before baseline, we found no associations between use of estrogen MHT and AC or SCC.

Conclusions

Higher estrogen and progesterone levels may be related inversely to UGI cancers and in this way help explain lower incidence rates in women compared to men.

Background

Epidemiological studies have consistently reported that active cigarette smoking is inversely associated with endometrial cancer risk. However, dose-response relationships with quantitative measures of active smoking or passive smoking remain less clear.

Methods

Data on lifetime active and passive smoking were collected for 551 endometrial cancer cases and 1925 controls in a population-based case-control study conducted during 2001–2003 in Poland (Warsaw and Łódz).

Results

Compared with never active smokers, active current (Odds Ratio (OR)=0.51, 95% Confidence Interval (CI): 0.39, 0.68) and former smokers (OR=0.60, 95% CI: 0.45, 0.80) were at a statistically significantly decreased risk. We did not observe statistically significant inverse dose-response relationships with increasing exposure with duration and cumulative measures. However, there was some indication that the highest category of number of years (OR=0.35, 95% CI: 0.23–0.55), intensity (OR=0.41, 95% CI: 0.24–0.69), and dose (OR=0.38, 95% CI: 0.24–0.60) of smoking among current smokers had the greatest inverse association compared to never smokers. Our data did not support the presence of an inverse association with passive smoking among never active smokers (OR=0.92; 95% CI: 0.65, 1.29).

Conclusion

Our results support that long-term and heavy smoking among current smokers strongly influence endometrial cancer risk.

Purpose

The severity of endometrial hyperplasia (EH)—simple (SH), complex (CH), or atypical (AH)—influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking.

Materials and Methods

We conducted a case-control study nested in a cohort of 7,947 women diagnosed with EH (1970-2002) at one prepaid health plan who remained at risk for at least 1 year. Patient cases (N = 138) were diagnosed with carcinoma, on average, 6 years later (range, 1 to 24 years). Patient controls (N = 241) were matched to patient cases on age at EH, date of EH, and duration of follow-up, and they were counter-matched to patient cases on EH severity. After we independently reviewed original slides and medical records of patient controls and patient cases, we combined progression relative risks (AH v SH, CH, or disordered proliferative endometrium [ie, equivocal EH]) from the case-control analysis with clinical censoring information (ie, hysterectomy, death, or left the health plan) on all cohort members to estimate interval-specific (ie, 1 to 4, 5 to 9, and 10 to 19 years) and cumulative (ie, through 4, 9, and 19 years) progression risks.

Results

For nonatypical EH, cumulative progression risk increased from 1.2% (95% CI, 0.6% to 1.9%) through 4 years to 1.9% (95% CI, 1.2% to 2.6%) through 9 years to 4.6% (95% CI, 3.3% to 5.8%) through 19 years after EH diagnosis. For AH, cumulative risk increased from 8.2% (95% CI, 1.3% to 14.6%) through 4 years to 12.4% (95% CI, 3.0% to 20.8%) through 9 years to 27.5% (95% CI, 8.6% to 42.5%) through 19 years after AH.

Conclusion

Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for nonatypical EH but is 28% for AH.

Introduction

Obesity and diabetes are known risk factors for endometrial cancer; thus genetic risk factors of these phenotypes may also be associated with endometrial cancer risk. To evaluate this hypothesis, we genotyped tagSNPs and candidate SNPs in FTO and HHEX in a primary set of 417 endometrial cancer cases and 406 population-based controls, and validated significant findings in a replication set of approximately 2,347 cases and 3,140 controls from three additional studies.

Methods

We genotyped 189 tagSNPs in FTO (including rs8050136) and five tagSNPs in HHEX (including rs1111875) in the primary set and one SNP in each of FTO (rs12927155) and HHEX (rs1111875) in the validation set. Per allele odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the genotypes of each SNPs(as an ordinal variable)and endometrial cancer risk using unconditional logistic regression models, controlling for age and site.

Results

In the primary study, the most significant findings in FTO was rs12927155 (OR=1.56, 95% CI 1.21–2.01, p=5.8×10−4) and HHEX was rs1111875 (OR=0.80, 95% CI 0.66–0.97; p=0.026). In the validation studies, the pooled per allele ORs, adjusted for age and study, were for FTO rs12927155: OR=0.94, 95% CI 0.83–1.06, p=0.29 and for HHEX rs1111875: OR=1.00, 95%CI 0.92–1.10, p=0.96.

Conclusion

Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans are not associatedwith endometrial cancer risk.

Impact

Polymorphisms in FTO and HHEX are unlikely to have large effects on endometrial cancer risk but may have weaker effects.

Chronic inflammation may play an etiologic role in endometrial cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammatory activity by inhibiting the pro-inflammatory cyclooxygenase enzymes and therefore may decrease cancer risk. However, few studies have examined the association between NSAID use and endometrial cancer. We conducted a prospective study among 72,524 women in the NIH-AARP Diet and Health Study. Women completed a questionnaire in 1996–97 on lifestyle and health-related factors, including type and frequency of NSAID use within the past year, and were followed through 2003 by linkages to cancer registries and vital status databases. During 488,261 person-years of follow-up, there were 732 incident endometrial cancers. NSAID use, compared with non-use of NSAIDs, was not significantly associated with endometrial cancer risk (relative risk (RR) = 0.90, 95% CI: 0.74–1.09). Null associations also were observed by type of NSAID use (aspirin only, RR = 0.88, 95% CI: 0.70–1.11; non-aspirin NSAID [NA-NSAID] only, RR= 1.01, 95% CI: 0.79–1.29; both aspirin and NA-NSAIDs, RR=0.85, 95% CI: 0.68–1.06). Generally, results were not statistically significant by frequency of use for aspirin or non-aspirin NSAIDs. Results did not change when women with a history of heart disease, hypertension, or diabetes were excluded to minimize the potential for confounding by indication. Overall, our data do not support an association between aspirin or NA-NSAID use and endometrial cancer risk.

Abstract

Objective

Osteoporosis and osteoporotic fractures are hypothesized to reflect circulating hormone levels in older women and have been inversely associated with breast and endometrial cancers. However, associations between fractures and ovarian cancer, another hormonal cancer, have not been examined. Therefore, we conducted a prospective study among women in the Breast Cancer Detection Demonstration Project Follow-up Study.

Methods

Fractures after age 45 were assessed using two questionnaires from 1987 to 1995. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards models, adjusting for potential confounders. Fracture location was used to further evaluate the fractures most likely to be osteoporotic.

Results

Among 36,115 women with up to 11 years of follow-up (average follow-up was 8.3 years), there were 151 cases of incident ovarian cancer. Fractures were reported by 19% (n = 6,919) of women. Ovarian cancer risk was not associated with any (RR = 1.13, 95% CI 0.74-1.71) or likely osteoporotic (RR = 1.05, 95% CI 0.65-1.69) fractures. Among never users of postmenopausal hormones, the association between any fracture and ovarian cancer (RR = 1.21, 95% CI 0.55-2.65, n = 50 cases) also was statistically nonsignificant.

Conclusions

Data from this large, prospective study do not support an association between fractures and ovarian cancer risk.

Reasons for higher incidence of lymphoid neoplasms among men than women are unknown. Because female sex hormones have immunomodulatory effects, reproductive factors and exogenous hormone use may affect risk for lymphoid malignancies. Previous epidemiologic studies on this topic have yielded conflicting results. Within the National Institutes of Health-AARP Diet and Health Study cohort, we prospectively analyzed detailed, questionnaire-derived information on menstrual and reproductive factors and use of oral contraceptives and menopausal hormone therapy among 134,074 US women. Using multivariable proportional hazards regression models, we estimated relative risks (RRs) for 85 plasma cell neoplasms and 417 non-Hodgkin lymphomas (NHLs) identified during follow-up from 1996-2002. We observed no statistically significant associations between plasma cell neoplasms, NHL, or the three most common NHL subtypes and age at menarche, parity, age at first birth, oral contraceptive use, or menopausal status at baseline. For menopausal hormone therapy use, overall associations between NHL and unopposed estrogen and estrogen plus progestin were null, with the potential exception of an inverse association (RR=0.49, 95% CI, 0.25-0.96) between use of unopposed estrogen and diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, among women with a hysterectomy. These data do not support an important role for reproductive factors or exogenous hormones in modulating lymphomagenesis.

Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. While obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH-AARP Diet and Health Study cohort, which included 109,621 women, ages 50–71, without cancer history, who in 1995–1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of ≥ 20 minutes of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996–1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose-response manner (p for trend=0.02) (relative risk (RR) for ≥ 5 times/week vs. never/rarely=0.77, 95% confidence interval (CI): 0.63, 0.95); this association was more pronounced among overweight and obese women (body mass index ≥ 25; RR=0.61, 95% CI: 0.47, 0.79) than among lean women (body mass index <25; RR=0.76, 95% CI: 0.52, 1.10; p for interaction=0.12). While we observed no associations with light/moderate, daily routine or occupational physical activities, risk did increase with number of hours of daily sitting (p for trend=0.02). Associations with vigorous activities, which may interact with body mass index, suggest directions for future research to clarify underlying biologic mechanisms, including those relating to hormonal alterations.

Objectives

Data suggest that post-menopausal women with larger ovaries are at increased risk for endometrial carcinoma; however, analyses comparing ovarian volume to serum hormone levels are limited. Accordingly, we assessed ovarian volumes in relation to serum sex hormone levels among post-menopausal women with endometrial carcinoma who participated in a multi-center case control study.

Methods

Data for established risk and protective factors for endometrial carcinoma were collected via in-person interviews. Ovarian volumes were estimated from pathology reports. Associations between exposures and age-adjusted ovarian volumes were analyzed for 175 cases with available data. For a subset of 135 cases, we analyzed relationships between ovarian volume, adjusted for age and body mass index (BMI), and serum hormone levels by analysis of variance.

Results

Ovarian volume declined progressively from 1.83 cm3 among women ages 55–59 years to 1.23 cm3 among women age 70 years or older (p-trend = 0.02). Larger ovarian volume was associated with early menarche (p-trend = 0.03), having given birth (p = 0.01), and weakly with elevated BMI (p- trend = 0.06). After adjustment, increased ovarian volume, was associated with higher estradiol (p - trend = 0.007); albumin-bound estradiol (p - trend = 0.01); and free estradiol (p - trend = 0.006) levels; androstenedione, estrone and estrone sulfate showed similar, though non-significant associations.

Conclusions

Among women with endometrial carcinoma, larger ovaries were associated with higher serum levels of estrogens. Further studies examining the role of the ovaries in post-menopausal hormonal carcinogenesis are warranted.

Genetic variation in the androgen receptor gene (AR) may be associated with endometrial cancer risk based on the androgen receptor’s role in regulating androgen levels. However, endometrial cancer studies reported inconsistent associations for a CAG repeat polymorphism in exon 1. Only one of these studies measured haplotype-tagging single nucleotide polymorphisms (htSNPs) in AR, and found statistically non-significant, decreased associations with endometrial cancer risk. In a population-based case-control study of 497 cases and 1024 controls, we examined the CAG repeat polymorphism and six htSNPs (rs962458, rs6152, rs1204038, rs2361634, rs1337080, and rs1337082), which cover an estimated 80% of the known common variation in AR among Caucasian populations. CAG repeat length was not significantly associated with endometrial cancer (OR (95%CI) per unit increase in the average number of repeats =1.02 (0.97 – 1.08); P-trend=0.29). Minor alleles in three correlated htSNPs (rs6152, rs1204038, and rs1337082; r2≥0.6) were associated with increased risk for endometrial cancer. The strongest association was observed for rs6152: the ORs (95% CIs) were 1.13 (0.89–1.44) for heterozygous and 2.40 (1.28–4.51) for homozygous minor genotypes (P-trend=0.02), compared to homozygous major allele genotype. However, these associations were not statistically significant after permutation adjustment for multiple comparisons (P-trend ≥ 0.09). Haplotype analyses did not reveal any additional associations with endometrial cancer. Results from our study taken together with previously published studies provide little evidence of a consistent association between common genetic variation in AR and endometrial cancer risk.

Background

Although physical activity has been associated with reduced breast cancer risk, whether this association varies across breast cancer subtypes or is modified by reproductive and lifestyle factors is unclear.

Methods

We examined physical activity in relation to postmenopausal breast cancer risk in 182,862 U.S. women in the NIH-AARP Diet and Health Study. Physical activity was assessed by self-report at baseline (1995–1996), and 6,609 incident breast cancers were identified through December 31, 2003. Cox regression was used to estimate the relative risk (RR) and 95% confidence interval (95% CI) of postmenopausal breast cancer overall and by tumor characteristics. Effect modification by select reproductive and lifestyle factors was also explored.

Results

In multivariate models, the most active women experienced a 13% lower breast cancer risk versus inactive women (RR, 0.87; 95% CI, 0.81–0.95). This inverse relation was not modified by tumor stage or histology but was suggestively stronger for estrogen receptor (ER)-negative (RR, 0.75; 95% CI, 0.54–1.04) than ER-positive (RR, 0.97; 95% CI, 0.84–1.12) breast tumors and was suggestively stronger for overweight/obese (RR, 0.86; 95% CI, 0.77–0.96) than lean (RR, 0.95; 95% CI, 0.87–1.05) women. The inverse relation with physical activity was also more pronounced among women who had never used menopausal hormone therapy and those with a positive family history of breast cancer than their respective counterparts.

Conclusions

Physical activity was associated with reduced postmenopausal breast cancer risk, particular to ER-negative tumors. These results, along with heterogeneity in the physical activity-breast cancer relation for subgroups of menopausal hormone therapy use and adiposity, indicate that physical activity likely influences breast cancer risk via both estrogenic and estrogen-independent mechanisms.

We evaluated colorectal cancer risk associated with duration and recency of specific menopausal hormone therapy formulations (i.e., unopposed estrogen versus estrogen plus progestin) and regimens (i.e., sequential versus continuous estrogen plus progestin use) among 56,733 postmenopausal women participating in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998. The final cancer group included 960 women who were identified from self report, medical records, state registry data, and the National Death Index. Poisson regression was used to generate multivariable rate ratios (RRs) and 95% confidence intervals (95% CI). We observed a decreased risk of colorectal cancer among ever-users of unopposed estrogen therapy (RR, 0.83; 95% CI, 0.70-0.99). Among estrogen users, the largest reduced risk was observed for current users (RR, 0.75; 95% CI, 0.54-1.05) and users of ten or more years duration (RR, 0.74; 95% CI, 0.56-0.96). We found a reduced risk among users of estrogen plus progestin therapy (RR, 0.78; 95% CI, 0.60-1.02), with sequential regimen users (progestin <15 days per cycle) having the largest risk reduction (RR 0.64; 95% CI, 0.43-0.95). Past users of five or more years ago (RR, 0.55; 95% CI, 0.32-0.98) had the largest risk reduction. In this study, estrogen plus progestin use, especially sequential regimen use, was associated with the largest overall reduction of colorectal cancer risk.

BACKGROUND

Results from the Women’s Health Initiative (WHI) trial raise new questions regarding the effects of estrogen therapy (ET) and estrogen plus progestin therapy (EPT) on breast cancer risk.

METHODS

We analyzed data from 126,638 females, 50–71 years of age at baseline, who completed two questionnaires (1995–1996, 1996–1997) as part of the NIH-AARP Diet and Health Cohort Study and in whom 3,657 incident breast cancers were identified through June 30, 2002. Hormone-associated relative risks (RR) and 95% confidence intervals (CI) of breast cancer were estimated via multivariable regression models.

RESULTS

Among thin women (body mass index <25 kg/m2), ET use was associated with a significant 60% excess risk after 10 years of use. EPT was associated with a significantly increased risk among women with intact uteri, with the highest risk among current, long-term (≥10 years) users (RR=2.44, 95% CI 2.13–2.79). These risks were slightly higher when progestins were prescribed continuously than sequentially (<15 days/month) (respective RRs of 2.76 vs. 2.01). EPT associations were strongest in thin women, but elevated risks persisted among heavy women. EPT use was strongly related to estrogen receptor positive (ER+) tumors, requiring consideration of this parameter when assessing relationships according to other clinical features. For instance, ER− ductal tumors were unaffected by EPT use, but all histologic subgroups of ER+ tumors were increased, especially low-grade and mixed ductal-lobular tumors.

CONCLUSIONS

Both ET and EPT were associated with breast cancer risks with the magnitude of increase varying according to body mass and clinical characteristics of the tumors.