Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?

Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk; however, the moderating effects of usage patterns or patient characteristics, including body mass index (BMI), are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n = 885) in 68,419 postmenopausal women with intact uteri enrolled in the National Institutes of Health‐American Association of Retired Persons Diet and Health study. Participants completed a risk factor questionnaire in 1996–1997 and were followed up through 2006. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer (RR = 0.88; 95% CI = 0.74–1.06). Long‐duration (≥10 years) sequential (<15 days progestin per month) estrogen plus progestin use was positively associated with risk (RR = 1.88; 95% CI = 1.36–2.60], whereas continuous (>25 days progestin per month) estrogen plus progestin use was associated with a decreased risk (RR = 0.64; 95% CI = 0.49–0.83). Increased risk for sequential estrogen plus progestin was seen only among thin‐to‐normal weight women (BMI < 25 kg/m²; RR = 2.53). Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins, whereas decreased endometrial cancer risk was observed for users of short‐duration continuous progestins. Risks were highest among thin‐to‐normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.     

Endometrial cancer risk in estrogen users after switching to estrogen–progestin therapy

Objective It is unknown whether postmenopausal unopposed estrogen users are better off, in terms of endometrial cancer risk, switching to a combined estrogen–progestin regimen or stopping hormone use altogether. Methods We analyzed data from a series of three population-based case–control studies in western Washington state during 1985–1999, comparing proportions of “switchers” and “stoppers” in cases and controls. We also assessed whether the risk of endometrial cancer in either group of former unopposed estrogen users returned to that of never users. Results After multivariate adjustment using unconditional logistic regression, women who switched to a combined regimen with a progestin added for at least ten days/month (37 cases, 47 controls) had half the risk of endometrial cancer of women who stopped hormone use altogether (86 cases, 78 controls) (adjusted odds ratio = 0.5, 95% confidence interval: 0.3–1.1). Most subgroups of former users, whether they switched or stopped, had some increased risk of endometrial cancer compared to never users. Conclusions Results from this study suggest that unopposed estrogen users may reduce their risk of endometrial cancer more by switching to a combined regimen with progestin added for at least ten days/month than by stopping hormone use altogether.     

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.     

A large cohort study of nonsteroidal anti-inflammatory drugs and renal cell carcinoma incidence in the National Institutes of Health–AARP Diet and Health Study

Aim

Existing epidemiologic evidence for the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and renal cell carcinoma (RCC) risk is inconsistent.

Methods

We investigated the association between the use of aspirin and nonaspirin NSAIDs and RCC risk in the National Institutes of Health–American Association of Retired Persons (AARP) Diet and Health Study, for which 298,468 AARP members free of cancer, aged 50–71 years, completed a survey on use of NSAIDs (1996–1997). Multivariate Cox proportional hazards models were used to estimate the hazard ratio (HR).

Results

The state cancer registry and mortality index linkage identified 1,084 incident RCC cases through 31 December 2006. No statistically significant associations between the use of aspirin or nonaspirin NSAIDs and RCC risk were found. Compared to nonuse of any NSAIDs, the multivariate-adjusted HRs were 0.95 (95 % CI 0.75–1.21) and 0.93 (95 % CI 0.68–1.26) for monthly use of aspirin and nonaspirin NSAIDs, respectively, 0.92 (95 % CI: 0.69-1.23) and 1.11 (95 % CI: 0.76-1.62) for weekly use, 0.87 (95 % CI: 0.69-1.11) and 1.06 (95 % CI: 0.75-1.48) for daily use; and 0.95 (95 % CI 0.78–1.14) for the use of both aspirin and nonaspirin NSAIDs. We found some suggestions of an increased risk of RCC associated with frequent NSAID use among participants who were <63 years and a reduced risk associated with aspirin use among those ≥63 years. No significant associations were found in other stratified analyses by gender, BMI, smoking, history of diabetes, or history of hypertension.

Conclusion

RCC risk was not significantly associated with NSAID use overall. The difference in association by age needs to be explored further.     

Intake of meat and fish and risk of head–neck cancer subtypes in the Netherlands Cohort Study

Purpose

To date, the role of meat and fish intake in head–neck cancer (HNC) etiology is not well understood and prospective evidence is limited. This prompted us to study the association between meat, fish, and HNC subtypes, i.e., oral cavity cancer (OCC), oro- and hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), within the Netherlands Cohort Study (NLCS).

Methods

In 1986, 120,852 participants (aged 55–69 years) completed a baseline 150-item food frequency questionnaire (FFQ), from which daily meat and fish intake were calculated. After 20.3 years of follow-up, 430 HNC overall (134 OCC, 90 OHPC and 203 LC) cases and 4,111 subcohort members were found to be eligible for case–cohort analysis. Multivariate hazard ratios were calculated using Cox’s proportional hazards model within quartiles of energy-adjusted meat and fish intake.

Results

Processed meat intake, but not red meat intake, was positively associated with HNC overall [HR(Q4 vs. Q1)?=?1.46, 95% CI 1.06–2.00; ptrend?=?0.03]. Among HNC subtypes, processed meat was positively associated with OCC, while no associations were found with OHPC and LC. Fish intake was not associated with HNC risk. Tests for interaction did not reveal statistically significant interaction between meat, fish, and alcohol or smoking on HNC overall risk.

Conclusions

In this large cohort study, processed meat intake was positively associated with HNC overall and HNC subtype OCC, but not with OHPC and LC.

     

Plasma enterolactone and breast cancer risk in the Nurses’ Health Study II

Lignans are plant-based phytoestrogens with both estrogenic and anti-estrogenic properties that may be important for breast carcinogenesis. Retrospective studies have observed decreased breast cancer risk associated with high circulating enterolactone concentrations, a biomarker of lignan intake, but results from prospective studies are conflicting. To prospectively examine this association, we measured plasma enterolactone levels in 802 breast cancer cases and 802 matched controls nested among predominantly premenopausal women in the Nurses’ Health Study II cohort. We used conditional logistic regression and polytomous logistic regression models, adjusting for known breast cancer risk factors, to calculate relative risks (RR) and 95 % confidence intervals (CI). Compared to women with enterolactone concentrations ≤4 nmol/L, the multivariate-adjusted RRs for breast cancer were 1.18 (95 % CI 0.86–1.62), 0.91 (95 % CI 0.66–1.25), and 0.96 (95 % CI 0.70–1.33) for women with enterolactone levels in the second to the fourth quartiles, respectively; P _trend = 0.60. Results were similar across tumors defined by estrogen and progesterone receptor status. Among premenopausal women with follicular estradiol levels below the median (<47 pg/mL), women in the highest category of enterolactone levels had a 51 % lower breast cancer risk compared to those in the lowest category (95 % CI 0.27–0.91); P _trend = 0.02. No association was observed among women with high-follicular estradiol levels (≥47 pg/mL), (comparable RR = 1.39, 95 % CI 0.73–2.65; P _interaction = 0.02). We did not observe an overall association between plasma enterolactone and breast cancer risk in a large nested case–control study of US women. However, a significant inverse association was observed among premenopausal women with low-follicular estradiol levels, suggesting that enterolactone may be important in a low-estrogen environment. This should be confirmed in future studies.     

Long-term alcohol intake and risk of endometrial cancer in the Nurses' Health Study, 1980–2010

Background:

Previous epidemiologic studies have shown inconsistent results for the association between alcohol intake and endometrial cancer risk. Most of the studies, however, assessed alcohol intake after cancer diagnosis, or measured alcohol intake at baseline only.

Methods:

We prospectively examined the association between alcohol intake and endometrial cancer risk in the Nurses'' Health Study with 68 067 female participants aged 34–59 years in 1980. Alcohol intake was measured several times with validated dietary questionnaires. We calculated cumulative average alcohol intake to represent long-term intakes of individual subjects. Using Cox proportional hazards models, we estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for endometrial cancer risk after controlling for several risk factors simultaneously.

Results:

We identified a total of 794 invasive endometrial adenocarcinoma from 1980 to 2010. We found an inverse association among alcohol drinkers (multivariable RR=0.81; 95% CI: 0.68–0.96) compared with nondrinkers. Women with light alcohol intake of <5 g per day (∼half drink per day) had a 22% lower risk of endometrial cancer (multivariable RR=0.78; 95% CI: 0.66–0.94). Higher intake of alcohol, however, did not provide additional benefits against endometrial cancer: multivariable RRs for 5–14.9 g (∼1 drink), 15–29.9 g (∼2 drinks), or ⩾30 g (⩾2 drinks) versus 0 g per day were 0.88, 0.83, and 0.78 (95% CI: 0.49–1.25), respectively. The lower risk among drinkers (∼half drink per day) appeared to be stronger for obese women, but no significant interaction by body mass index was found.

Conclusions:

This study provides prospective evidence for an inverse association between light alcohol intake (∼half drink per day) in the long term and endometrial cancer risk, but above that level no significant association was found.     

Family history of cancer and risk of breast cancer in the Black Women’s Health Study

Introduction  

Relatively little research has been conducted on familial breast cancer in African American women.     

Abuse victimization and risk of breast cancer in the Black Women’s Health Study

Few studies have examined the relation between abuse victimization and breast cancer, and results have been inconclusive. Using data from 35,728 participants in the Black Women’s Health Study, we conducted multivariable Cox regression to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CI) for the association of abuse across the life span (childhood, adolescence, and adulthood) with breast cancer. Incident breast cancer diagnoses were reported during 1995–2009, and abuse histories were reported in 2005. No associations were found between abuse victimization in either childhood or adolescence and breast cancer. We found a weak positive association between abuse in adulthood and breast cancer (IRR = 1.18, 95% CI = 1.03–1.34). IRRs for physical abuse only, sexual abuse only, and both physical and sexual abuse in adulthood, relative to no abuse, were 1.28 (95% CI = 1.09–1.49), 0.96 (95% CI = 0.76–1.20), and 1.22 (95% CI = 1.00–1.49), respectively. IRRs for low, intermediate, and high frequencies of physical abuse in adulthood, relative to no abuse, were 1.28 (95% CI = 1.07–1.52), 1.37 (95% CI = 1.04–1.79), and 1.24 (95% CI = 0.95–1.62), respectively. Our data suggest an increased risk of breast cancer among African-American women who reported physical abuse in adulthood, but there was little evidence of a dose–response relation. These results require confirmation in other studies.     

Endocrinology and hormone therapy in breast cancer: New insight into estrogen receptor-α function and its implication for endocrine therapy resistance in breast cancer

Estrogen and its receptor (ER) are critical for development and progression of breast cancer. This pathway is targeted by endocrine therapies that either block ER functions or deplete ER's estrogen ligand. While endocrine therapies are very effective, de novo and acquired resistance are still common. Laboratory and clinical data now indicate that bidirectional molecular crosstalk between nuclear or membrane ER and growth factor receptor pathways such as HER2/neu is involved in endocrine resistance. Preclinical data suggest that blockade of selected growth factor receptor signaling can overcome this type of resistance, and this strategy is already being tested in clinical trials     

Breast cancer incidence and use of hormone therapy in Denmark 1978–2007

Objective  

Internationally, there have recently been reports of declining incidence rates for breast cancer. Decreased use of hormone therapy and decreased use of mammography has been put forward as possible reasons for this decline. The aim of this study was to analyse breast cancer incidence trends in Denmark, and to evaluate if these trends could be explained by changes in use of hormone therapy and screening with mammography.     

Non-steroidal anti-inflammatory drugs, acetaminophen, and risk of skin cancer in the Nurses’ Health Study

Purpose

Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with lower risk of certain cancers, but data on the effect on skin cancer risk have been limited and contradictory. We prospectively examined whether use of NSAIDS or acetaminophen was associated with a lower risk of skin cancer in women.

Methods

The 92,125 Caucasian women in the Nurses’ Health Study provided information on aspirin use in 1980. Other NSAIDs and acetaminophen were added in 1990. Medication use, frequency, and quantity were reassessed on biennial questionnaires. Through 2008, we confirmed 658 melanoma cases, 1,337 squamous cell carcinoma (SCC) cases, and had 15,079 self-reports of basal cell carcinoma (BCC). We used COX proportional hazards models to compute relative risks (RR) adjusted for known skin cancer risk factors.

Results

Neither aspirin nor non-aspirin NSAID use was associated with a lower risk of melanoma, SCC, or BCC, even for women with high quantity, frequency, or duration of use. Instead, we observed an increased risk of melanoma among current aspirin users (RR?=?1.32, 95?% CI 1.03–1.70), though an increase of similar magnitude among past users and lack of a dose–response effect did not support a pharmacologic mechanism. We observed a mild reduction in SCC risk in current acetaminophen users (RR?=?0.88, 95?% CI 0.75–1.02), with a linear decrease in risk with greater frequency of use (p?=?0.04).

Conclusions

Aspirin and other NSAIDs were not associated with a lower risk of melanoma, SCC, or BCC in women. Our large, prospective study does not support a chemoprotective effect of NSAIDs against skin cancers.     

Plasma florescent oxidation products and breast cancer risk: repeated measures in the Nurses’ Health Study

The coactivator-associated arginine methyltransferase-1 (CARM1) is implicated in regulation of oestrogen receptor (ER) α-mediated gene pathways in response to ER activation. It plays an important role in breast cancer growth by regulating the E2F1 expression suggesting that CARM1 could be a target in the subclassification of oestrogen-dependent breast cancer. This study aims to investigate the clinical and biological importance of CARM1 protein expression in a large (1,130 patients), well-characterised and annotated series of invasive breast cancers using tissue microarrays and immunohistochemistry. In the whole series, increased CARM1 expression is correlated with features associated with aggressive behaviour such as young age, premenopausal status, large tumour size and high tumour grade. There is a positive correlation between CARM1 expression and biomarkers associated with non-luminal phenotype and poor prognosis such as HER2, basal cytokeratins, EGFR, p53 and the proliferation markers Ki67, TK1, CD71 and Cyclin E. Negative associations with the luminal-associated markers including steroid receptors and luminal cytokeratins are found. Similar associations are identified in the ER-positive/luminal subgroup (n = 767). Outcome analyses indicate that CARM1 expression is an independent predictor of shorter breast cancer-specific survival and disease-free interval in the whole series and in the ER-positive subgroup. CARM1 shows an oncogenic effect in breast cancer and its expression is associated with poor prognosis. CARM1 could be a potential marker of luminal class subclassification and for target therapy, particularly in the ER-positive luminal-like subgroup.     

Assessing environmental and occupational risk factors for lung cancer in Mexican–Americans

Background

We investigated environmental and occupational exposures and smoking history (while controlling for demographics) in a population of Mexican–American lung cancer cases and controls from the Houston metropolitan area.

Methods

Data were collected between 1991 and 2005 as part of an on-going multi-racial/ethnic, lung cancer case–control study. Cases included 212 Mexican–American lung cancer cases from UT MD Anderson Cancer Center. Controls (n = 328) were recruited from Houston’s largest multispecialty group practice and frequency matched to the cases by age (±5 years), sex, and ethnicity. Environmental and occupational factors were analyzed and odds ratios and 95% confidence intervals were calculated using logistic regression.

Results

We detected elevated risks of lung cancer associated with pesticide exposure and found conventional and antimicrobial (e.g., sterilizers, disinfectants, antiseptics) pesticides were associated with an increased risk of lung cancer in Mexican–Americans (conventional pesticides and antimicrobial pesticides combined: OR = 1.80, 95% CI 1.13–2.86; conventional pesticides: OR = 2.05, 95% CI 1.23–2.39; antimicrobial pesticides: OR = 2.48, 95% CI 1.46–4.21).

Conclusions

Although we found over a two-fold increased risk of lung cancer among Mexican–Americans for pesticides, we could not identify individual pesticides. Our findings are an important preliminary step in identifying factors that are specifically associated with lung cancer risk among Mexican Americans.     

History of periodontal disease diagnosis and lung cancer incidence in the Women’s Health Initiative Observational Study

Purpose

While some evidence suggests that periodontal disease (PD) might be positively associated with lung cancer, prospective studies in women are limited. Previous findings may reflect residual confounding by smoking. The study aims to determine whether history of PD diagnosis is associated with incident lung cancer in a large cohort of postmenopausal women.

Methods

Prospective analyses were conducted in a cohort of 77,485 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. History of PD (prevalence of 26.1 %) was self-reported, and 754 incident lung cancer cases occurred during an average 6.8 (SD ± 2.6) years of follow-up. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs).

Results

Overall, PD was positively associated with lung cancer risk after adjusting for detailed smoking history including smoking status and pack-years of smoking (HR 1.24, 95 % CI 1.07–1.45). There was a positive additive interaction between PD with pack-years of smoking (p = 0.02), suggesting a potential synergistic effect between PD and smoking intensity on lung cancer. The association between PD and lung cancer was stronger in former smokers. When restricted to never-smokers, PD was not associated with lung cancer (HR 1.02, 95 % CI 0.68–1.53).

Conclusions

Periodontal disease was not independently associated with lung cancer in non-smoking postmenopausal women. However, smoking and PD jointly increased lung cancer risk beyond that expected from the sum of the each effect separately. The potential synergism between PD and smoking on lung cancer warrants further examination.     

Menopausal vasomotor symptoms and incident breast cancer risk in the Study of Women’s Health Across the Nation

Purpose

Two case–control studies reported a 50 % decreased breast cancer risk among women who experienced menopausal vasomotor symptoms (VMS), but one cohort study found no association. VMS may be triggered by declining estrogen levels during menopause, whereas elevated estrogen levels have been associated with increased breast cancer risk. VMS may thus be indicative of lower susceptibility to breast cancer.

Methods

We evaluated this relationship in the longitudinal Study of Women’s Health Across the Nation (SWAN), using discrete survival analysis of approximately annual data on VMS and self-reported breast cancer occurrences for up to 13 years of follow-up in 3,098 women who were pre- or early perimenopausal at enrollment.

Results

Over an average 11.4 years of follow-up, 129 incident breast cancer cases were self-reported, and approximately 50 % of participants experienced VMS. Symptomatic women had a reduced risk of breast cancer compared to non-symptomatic women (adjusted HR 0.63, 95 % CI 0.39, 1.00). The association was stronger in the subgroup of women who fully transitioned to postmenopause during follow-up (n = 67 cases, adjusted HR 0.45, 95 % CI 0.26, 0.77).

Conclusion

VMS appeared to be a marker of reduced breast cancer risk. Future research is needed to understand the biology underlying this relationship.

     

Consumption of dairy and meat in relation to breast cancer risk in the Black Women’s Health Study

Purpose

Dairy and meat consumption may impact breast cancer risk through modification of hormones (e.g., estrogen), through specific nutrients (e.g., vitamin D), or through products formed in processing/cooking (e.g., heterocyclic amines). Results relating meat and dairy intake to breast cancer risk have been conflicting. Thus, we examined the risk of breast cancer in relation to intake of dairy and meat in a large prospective cohort study.

Methods

In the Black Women’s Health Study, 1,268 incident breast cancer cases were identified among 52,062 women during 12 years of follow-up. Multivariable (MV) relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results

Null associations were observed for total milk (MV RR = 1.05, 95 % CI 0.74–1.46 comparing ≥1,000–0 g/week) and total meat (MV RR = 1.04, 95 % CI 0.85–1.28 comparing ≥1,000 < 400 g/week) intake and risk of breast cancer. Associations with intakes of specific types of dairy, specific types of meat, and dietary calcium and vitamin D were also null. The associations were not modified by reproductive (e.g., parity) or lifestyle factors (e.g., smoking). Associations with estrogen receptor (ER) positive (+), ER negative (?), progesterone receptor (PR) +, PR?, ER+/PR+, and ER?/PR? breast cancer were generally null.

Conclusions

This analysis of African-American women provides little support for associations of dairy and meat intake with breast cancer risk.     

Tea and coffee intake in relation to risk of breast cancer in the Black Women’s Health Study

Objective

Prospective studies of tea and coffee intake and breast cancer risk have yielded inconsistent results. None of these studies has reported separately on African-American women. We prospectively examined the relation of tea and coffee consumption to risk of breast cancer among 52,062 women aged 21–69 at enrollment in 1995 in the Black Women’s Health Study.

Methods

Dietary intake was assessed in 1995 and 2001 using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI), adjusted for breast cancer risk factors.

Results

During 12 years of follow-up through 2007, there were 1,268 incident cases of breast cancer. Intakes of tea, coffee, and caffeine were not significantly associated with the risk of breast cancer overall. The IRRs for consumption of ≥4 cups/day compared with none were 1.13 (95% CI 0.78–1.63) for tea and 1.03 (95% CI 0.77–1.39) for caffeinated coffee, and the IRR for the top quintile relative to the bottom quintile of caffeine intake was 1.04 (95% CI 0.87–1.24). Consumption of tea, coffee, and caffeine was not significantly associated with breast cancer risk according to menopausal status or hormone receptor status.

Conclusion

Our findings suggest that intakes of tea, coffee, and caffeine are not associated with the risk of breast cancer among African-American women.