Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

Objective: Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery. Methods: Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC). Results: Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62). Conclusions: Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.

Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients with Metastatic Castration-resistant Prostate Cancer in the CARD Study.

BACKGROUND: In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide). OBJECTIVE: To assess cabazitaxel versus abiraterone/enzalutamide in older (≥70 yr) and younger (<70 yr) patients in CARD. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were randomized 1:1 to cabazitaxel (25 mg/m2 plus prednisone and granulocyte colony-stimulating factor) versus abiraterone (1000 mg plus prednisone) or enzalutamide (160 mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analyses of rPFS (primary endpoint) and safety by age were prespecified; others were post hoc. Treatment groups were compared using stratified log-rank or Cochran-Mantel-Haenszel tests. RESULTS AND LIMITATIONS: Of the 255 patients randomized, 135 were aged ≥70 yr (median 76 yr). Cabazitaxel, compared with abiraterone/enzalutamide, significantly improved median rPFS in older (8.2 vs 4.5 mo; hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.38-0.89; p = 0.012) and younger (7.4 vs 3.2 mo; HR = 0.47; 95% CI = 0.30-0.74; p < 0.001) patients. The median OS of cabazitaxel versus abiraterone/enzalutamide was 13.9 versus 9.4 mo in older patients (HR = 0.66; 95% CI = 0.41-1.06; p = 0.084), and it was 13.6 versus 11.8 mo in younger patients (HR = 0.66; 95% CI = 0.41-1.08; p = 0.093). Progression-free survival, prostate-specific antigen, and tumor and pain responses favored cabazitaxel, regardless of age. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 58% versus 49% of older patients receiving cabazitaxel versus abiraterone/enzalutamide and 48% versus 42% of younger patients. In older patients, cardiac adverse events were more frequent with abiraterone/enzalutamide; asthenia and diarrhea were more frequent with cabazitaxel. CONCLUSIONS: Cabazitaxel improved efficacy outcomes versus abiraterone/enzalutamide in patients with mCRPC after prior docetaxel and abiraterone/enzalutamide, regardless of age. TEAEs were more frequent among older patients. The cabazitaxel safety profile was manageable across age groups. PATIENT SUMMARY: Clinical trial data showed that cabazitaxel improved survival versus abiraterone/enzalutamide with manageable side effects in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative agent (abiraterone/enzalutamide), irrespective of age.

Post Hoc Health-Related Quality of Life Analysis According to Response Among Patients with Prostate Cancer in the PROSELICA and FIRSTANA Studies.

BACKGROUND: The phase III PROSELICA (NCT01308580) and FIRSTANA (NCT01308567) trials investigated taxane chemotherapy among men with postdocetaxel metastatic, castration-resistant prostate cancer (mCRPC) or chemotherapy-naïve mCRPC, respectively. We present a post hoc analysis of patient-reported health-related quality of life (HRQL) among patients with or without a clinical (pain, tumor, or prostate-specific antigen [PSA]) response. MATERIALS AND METHODS: PROSELICA and FIRSTANA HRQL and pain data were collected and analyzed using protocol-defined Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack (Present Pain Intensity scale) questionnaires. Outcomes included definitive FACT-P Total Score (TS) improvements and longitudinal assessment of FACT-P TS. RESULTS: In PROSELICA and FIRSTANA, the proportion of patients receiving taxane chemotherapy with a definitive FACT-P TS improvement was significantly higher among patients with versus without a pain or PSA response (pain: PROSELICA: 67% vs. 33.5%; p < .001; FIRSTANA: 75.2% vs. 45.8%; p < .001; PSA: PROSELICA: 50.3% vs. 34.2%; p < .001; FIRSTANA: 49.8% vs. 38.9%; p = .001). In PROSELICA, the proportion of patients receiving taxane chemotherapy with a definitive FACT-P TS improvement was significantly higher among patients with versus without a tumor response; the proportion was numerically higher in FIRSTANA (PROSELICA: 54.4% vs. 36.7%; p = .001; FIRSTANA: 50.6% vs. 45.3%). FACT-P TS was significantly improved or maintained for the majority of treatment cycles analyzed. CONCLUSION: In PROSELICA and FIRSTANA, HRQL improvements were significantly higher among patients with a pain, tumor, or PSA response versus those without, with the exception of patients with a tumor response in FIRSTANA. IMPLICATIONS FOR PRACTICE: Using data from the FIRSTANA and PROSELICA phase III clinical trials, this study demonstrated that patients with metastatic, castration-resistant prostate cancer (mCRPC) receiving docetaxel or cabazitaxel who exhibited a response (pain, tumor, prostate-specific antigen), often experienced significantly greater improvements in health-related quality of life (HRQL) compared with patients without a response. For patients with a pain response, significant HRQL improvements occurred early and were maintained. This study provides further insight into the impact of taxane chemotherapy on the HRQL of patients with mCRPC and allows for a better understanding of the relationship between treatment, response, and HRQL, supporting therapeutic decision making.

Postdiagnostic Dietary Glycemic Index, Glycemic Load, Dietary Insulin Index, and Insulin Load and Breast Cancer Survival.

BACKGROUND: We investigated the associations of postdiagnostic dietary glycemic index (GI), glycemic load (GL), insulin index (II), and insulin load (IL) with breast cancer-specific and all-cause mortality. METHODS: Among 8,932 women with stage I-III breast cancer identified in the Nurses' Health Study (NHS; 1980-2010) and NHSII (1991-2011), we prospectively evaluated the associations between postdiagnostic GI, GL, II, and IL, and breast cancer-specific and all-cause mortality. Participants completed a validated food frequency questionnaire every 4 years after diagnosis. RESULTS: During follow-up by 2014 in the NHS and 2015 in the NHSII, 2,523 deaths, including 1,071 from breast cancer, were documented. Higher postdiagnostic GL was associated with higher risk of both breast cancer-specific mortality [HRQ5vsQ1 = 1.33; 95% confidence interval (CI) = 1.09-1.63; P trend = 0.008] and all-cause mortality (HRQ5vsQ1 = 1.26; 95% CI = 1.10-1.45; P trend = 0.0006). Higher all-cause mortality was also observed with higher postdiagnostic GI (HRQ5vsQ1 = 1.23; 95% CI = 1.08-1.40; P trend = 0.001), II (HRQ5vsQ1 = 1.20; 95% CI = 1.04-1.38; P trend = 0.005), and IL (HRQ5vsQ1 = 1.23; 95% CI = 1.07-1.42; P trend = 0.0003). The associations were not modified by insulin receptor or estrogen receptor status of the tumor, or body mass index. CONCLUSIONS: We found that higher dietary GL, reflecting postprandial glucose response, after a breast cancer diagnosis was associated with higher risk of breast cancer-specific mortality. Higher dietary GI, GL, II, and IL after a breast cancer diagnosis were associated with higher risk of death from any cause. IMPACT: These results suggest that carbohydrate quantity and quality may be important in breast cancer prognosis.See related commentary by McTiernan, p. 252.

Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS: CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS: Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION: Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING: Sanofi.

A Prospective Analysis of Circulating Plasma Metabolites Associated with Ovarian Cancer Risk.

Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of prediagnostic plasma metabolites (N = 420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. A total of 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI), comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene coexpression network analysis (WGCNA; n = 10 metabolite modules) and metabolite set enrichment analysis (n = 23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR = 2.56; 95% CI, 1.48-4.45; P = 0.001/adjusted P = 0.15); a similar risk estimate was observed for serous/poorly differentiated tumors (n = 176 cases; comparable OR = 2.38; 95% CI, 1.33-4.32; P = 0.004/adjusted P = 0.55). For nonserous tumors (n = 34 cases), pseudouridine and C36:2 phosphatidylcholine plasmalogen had the strongest statistical associations (OR = 9.84; 95% CI, 2.89-37.82; P < 0.001/adjusted P = 0.07; and OR = 0.11; 95% CI, 0.03-0.35; P < 0.001/adjusted P = 0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR ≤ 0.20. Triacylglycerols (TAG) showed heterogeneity by tumor aggressiveness (case-only heterogeneity P < 0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. SIGNIFICANCE: Pseudouridine represents a potential novel risk factor for ovarian cancer and triglycerides may be important particularly in rapidly fatal ovarian tumors.

Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience.

BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Adult dietary fat intake and ovarian cancer risk.

The association of dietary fat intake with ovarian cancer risk has been inconsistent across populations. We examined dietary fat intake, overall and by type and ovarian cancer risk in two prospective cohort studies. We assessed long-term dietary fat intake among Nurses' Health Study (NHS) and NHSII participants using food frequency questionnaires administered every 2-4 years beginning in 1984 and 1991, respectively. We examined cumulative energy-adjusted intake of total fat, specific types of fat (animal, vegetable, saturated, monounsaturated, polyunsaturated and trans fat) and cholesterol. We identified 700 ovarian cancer cases in NHS and 196 in NHSII with dietary information. Cox proportional hazards regression was used to estimate associations between intake and ovarian cancer risk. Dietary fat intake changed over time in both cohorts and was lower in NHS than NHSII. Higher cumulative average intakes of animal fat and cholesterol were significantly positively associated with risk of ovarian cancer in NHS (relative risk [RR] comparing extreme quartiles = 1.57, 95% CI: 1.20, 2.06 and 1.35, 95% CI: 1.08, 1.69, respectively), but not in NHSII. Other dietary fat sources were not clearly associated with risk in either population. We did not observe clear associations between dietary fat and ovarian cancer risk in two large prospective cohort studies.

Social Integration, Marital Status, and Ovarian Cancer Risk: A 20-Year Prospective Cohort Study.

OBJECTIVE: Low social integration and divorce/widowhood are chronic psychosocial stressors that may affect health. When assessed after cancer diagnosis, they have been associated with poorer survival, but their role in cancer development, particularly ovarian cancer (OvCA), is less understood. We investigated whether social integration and marital status were related to OvCA risk in a large population-based study. METHODS: Women from the Nurses' Health Study completed the Berkman-Syme Social Network Index and reported their marital status every 4 years starting in 1992 (N = 72,206), and were followed up until 2012 (20-year follow-up period). Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of OvCA risk, considering relevant potential confounders, in lagged analyses whereby psychosocial indicators were assessed 4 to 8 years (n = 436 cases) and 8 to 12 years (n = 306 cases) before diagnosis to account for the effects of prediagnostic symptoms on social measures. Secondary analyses evaluated the stability of and cumulative exposure to these social factors on OvCA risk. RESULTS: Being socially isolated versus integrated was related to an increased OvCA risk 8 to 12 years later (HR = 1.51, 95% CI = 1.07-2.13), but not 4 to 8 years later. Compared with married women, OvCA risk was significantly higher in widowed but not in separated/divorced individuals, with both time periods (e.g., 8-12 years later: HRwidowed = 1.57 [95% CI = 1.15-2.14] versus HRseparated/divorced = 1.13 [95% CI = 0.74-1.72]). Estimates were comparable or stronger when investigating stability in and cumulative effects of social indicators. CONCLUSIONS: Results suggest higher OvCA risk among socially isolated and widowed women, particularly when such psychosocial stressors were experienced a decade before diagnosis or were sustained over time.

High Levels of C-Reactive Protein Are Associated with an Increased Risk of Ovarian Cancer: Results from the Ovarian Cancer Cohort Consortium.

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case-control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with <1 mg/L (OR = 1.67; 95% CI = 1.12-2.48). A CRP concentration >10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10-84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07-10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82-2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36-11.57; P heterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (P interaction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62-6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma. SIGNIFICANCE: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.

The Mind-Body Study: study design and reproducibility and interrelationships of psychosocial factors in the Nurses' Health Study II.

PURPOSE: Associations between psychosocial factors and biomarkers are increasingly investigated in studies of cancer incidence and mortality. Documenting optimal data/biospecimen collection protocols and scale properties are fundamental for elucidating the impact of psychosocial factors on biologic systems and ultimately cancer development/progression. METHODS: Between 2013 and 2014, 233 Nurses' Health Study II women (mean age: 60.6) participated in the Mind-Body Study. Participants completed a detailed online psychosocial assessment and provided hair, toenail, timed saliva over 1 day, urine and fasting blood twice, 1 year apart. Additionally, two separate microbiome collections for stool and saliva were conducted between the psychosocial assessments. We assessed correlations between various psychosocial measures and evaluated their 1-year reproducibility using intraclass correlations (ICC). RESULTS: Compliance with the protocols was high among participants. Psychosocial measures showed moderate-to-high reproducibility over 1 year (ICCs = 0.51-0.81). There was clear clustering of psychosocial factors according to whether they were querying positive (e.g., optimism, mastery, mindfulness) or negative (e.g., anxiety, depression, discrimination) emotion-related or social constructs. CONCLUSION: Results suggest feasibility for self-administered collection of various biospecimens and moderate-to-high reproducibility of psychosocial factors. The Mind-Body Study provides a unique resource for assessing inter-relationships between psychosocial factors and biological processes linked with long-term health outcomes, including carcinogenesis.

Particulate Matter and Traffic-Related Exposures in Relation to Breast Cancer Survival.

BACKGROUND: Although particulate matter (PM) has not been consistently associated with breast cancer risk, two studies have reported harmful associations for breast cancer survival. We examined PM exposures and breast cancer survival in two U.S.-based prospective cohort studies. METHODS: The Nurses' Health Study (NHS) and NHSII are cohorts with detailed data on medical history, lifestyle factors, and causes of death. Women with Stage I-III breast cancer (n = 8,936) were followed through June 2014. Residential PM was estimated using spatio-temporal models. We performed Cox regression to estimate hazard ratios (HR) of breast cancer-specific mortality and all-cause mortality for 10 µg/m3 increases in post-diagnosis PM. RESULTS: There were 1,211 breast cancer-specific deaths. Overall, PM was not associated with breast cancer-specific mortality [PM2.5: HR, 1.09; 95% confidence interval (CI), 0.87-1.36; PM2.5-10: HR, 1.03; 95% CI, 0.85-1.24; PM10: HR, 1.05; 95% CI, 0.89-1.24], but was associated with modest increases in all-cause mortality (PM2.5: HR, 1.12; 95% CI, 0.96-1.30; PM2.5-10: HR, 1.12; 95% CI, 1.00-1.24; PM10: HR, 1.09; 95% CI, 1.01-1.18). However, among participants with Stage I disease, PM2.5 was associated with higher breast cancer-specific mortality (HR, 1.64; 95% CI, 1.11-2.43). CONCLUSIONS: PM was not associated with breast cancer-specific death overall; however, higher PM was associated with all-cause mortality. Higher PM2.5 was associated with higher breast cancer-specific mortality among patients with Stage I breast cancer even after adjustment. IMPACT: Studies on ambient PM and breast cancer survival demonstrate that PM2.5 may have broader health effects than previously recognized and warrants further research on breast tumor progression.

Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium.

BACKGROUND: Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case-control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3). METHODS: The current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided. RESULTS: Women who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so. CONCLUSIONS: This large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)-similar to the risk reduction observed in case-control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing.

Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses' Health Studies.

BACKGROUND: Hormone receptor signaling is critical in the progression of breast cancers, although the role of the androgen receptor (AR) remains unclear, particularly for estrogen receptor (ER)-negative tumors. This study assessed AR protein expression as a prognostic marker for breast cancer mortality. METHODS: This study included 4147 pre- and postmenopausal women with invasive breast cancer from the Nurses' Health Study (diagnosed 1976-2008) and Nurses' Health Study II (1989-2008) cohorts. AR protein expression was evaluated by immunohistochemistry and scored through pathologist review and as a digitally quantified continuous measure. Hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer mortality were estimated from Cox proportional hazards models, adjusting for patient, tumor, and treatment covariates. RESULTS: Over a median 16.5 years of follow-up, there were 806 deaths due to breast cancer. In the 7 years following diagnosis, AR expression was associated with a 27% reduction in breast cancer mortality overall (multivariable HR = 0.73, 95% CI = 0.58 to 0.91) a 47% reduction for ER+ cancers (HR = 0.53, 95% CI = 0.41 to 0.69), and a 62% increase for ER- cancers (HR = 1.62, 95% CI = 1.18 to 2.22) (P heterogeneity < .001). A log-linear association was observed between AR expression and breast cancer mortality among ER- cancers (HR = 1.14, 95% CI = 1.02 to 1.26 per each 10% increase in AR), although no log-linear association was observed among ER+ cancers. CONCLUSIONS: AR expression was associated with improved prognosis in ER+ tumors and worse prognosis in ER- tumors in the first 5-10 years postdiagnosis. These findings support the continued evaluation of AR-targeted therapies for AR+/ER- breast cancers.

Habitual sleep quality, plasma metabolites and risk of coronary heart disease in post-menopausal women.

BACKGROUND: Epidemiologic studies suggest a strong link between poor habitual sleep quality and increased cardiovascular disease risk. However, the underlying mechanisms are not entirely clear. Metabolomic profiling may elucidate systemic differences associated with sleep quality that influence cardiometabolic health. METHODS: We explored cross-sectional associations between sleep quality and plasma metabolites in a nested case-control study of coronary heart disease (CHD) in the Women's Health Initiative (WHI; n = 1956) and attempted to replicate the results in an independent sample from the Nurses' Health Study II (NHSII; n = 209). A sleep-quality score (SQS) was derived from self-reported sleep problems asked in both populations. Plasma metabolomics were assayed using LC-MS with 347 known metabolites. General linear regression was used to identify individual metabolites associated with continuous SQS (false-discovery rate <0.05). Using least absolute shrinkage and selection operator (LASSO) algorithms, a metabolite score was created from replicated metabolites and evaluated with CHD risk in the WHI. RESULTS: After adjusting for age, race/ethnicity, body mass index (BMI) and smoking, we identified 69 metabolites associated with SQS in the WHI (59 were lipids). Of these, 16 were replicated in NHSII (15 were lipids), including 6 triglycerides (TAGs), 4 phosphatidylethanolamines (PEs), 3 phosphatidylcholines (PCs), 1 diglyceride (DAG), 1 lysophosphatidylcholine and N6-acetyl-L-lysine (a product of histone acetylation). These metabolites were consistently higher among women with poorer sleep quality. The LASSO selection resulted in a nine-metabolite score (TAGs 45: 1, 48: 1, 50: 4; DAG 32: 1; PEs 36: 4, 38: 5; PCs 30: 1, 40: 6; N6-acetyl-L-lysine), which was positively associated with CHD risk (odds ratio per SD increase in the score: 1.16; 95% confidence interval: 1.05, 1.28; p = 0.0003) in the WHI after adjustment for matching factors and conventional CHD risk factors. CONCLUSIONS: Differences in lipid metabolites may be an important pathogenic pathway linking poor habitual sleep quality and CHD risk.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses' Health Studies.

Importance: Ovarian cancer is a highly fatal malignant neoplasm with few modifiable risk factors. Case-control studies have reported a modest reduced risk of ovarian cancer among women who frequently use aspirin or regularly use low-dose aspirin. Objective: To evaluate whether regular aspirin or nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use and patterns of use are associated with lower ovarian cancer risk. Design, Setting, and Participants: This cohort study analyzed NSAID use and ovarian cancer diagnosis data from 2 prospective cohorts, 93 664 women in the Nurses' Health Study (NHS), who were followed up from 1980 to 2014, and 111 834 in the Nurses' Health Study II (NHSII), who were followed up from 1989 to 2015. Follow-up was completed on June 30, 2014, for the NHS and June 30, 2015, for NHSII. Data were analyzed from June 13, 2016, to September 18, 2017. Exposures: For each analgesic type (aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen), timing, duration, frequency, and number of tablets used were evaluated; exposure information was updated every 2 to 4 years. Main Outcomes and Measures: Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for associations of aspirin, nonaspirin NSAIDs, and acetaminophen with risk of epithelial ovarian cancer. All statistical tests were 2-sided, with a significance level of .05. Results: In the NHS, the mean (SD) age at baseline (1980) was 45.9 (7.2) years, and 93% of participants identified as non-Hispanic white. In the NHSII, the mean age at baseline (1989) was 34.2 (4.7) years, and 92% identified as non-Hispanic white. Among the 205 498 women in both cohorts, there were 1054 cases of incident epithelial ovarian cancer. Significant associations between aspirin and ovarian cancer risk were not observed when current vs nonuse of any aspirin was evaluated regardless of dose (HR, 0.99; 95% CI, 0.83-1.19). However, when low-dose (≤100-mg) and standard-dose (325-mg) aspirin were evaluated separately, an inverse association for low-dose aspirin (HR, 0.77; 95% CI, 0.61-0.96), but no association for standard-dose aspirin (HR, 1.17; 95% CI, 0.92-1.49) was observed. Current use of nonaspirin NSAIDs was positively associated with risk of ovarian cancer compared with nonuse (HR, 1.19; 95% CI, 1.00-1.41), and significant positive trends for duration of use (P = .02 for trend) and cumulative average tablets per week (P = .03 for trend) were observed. There were no clear associations for the use of acetaminophen. Conclusions and Relevance: These results appear to be consistent with case-control studies that show a reduced risk of ovarian cancer among regular users of low-dose aspirin. An increased risk of ovarian cancer with long-term high-quantity use of other analgesics, particularly nonaspirin NSAIDs, was observed, although this finding requires confirmation.

Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS/NHSII): a cohort study.

BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death among women in the USA. In this study, our objective was to determine whether modifiable exposures to common analgesics outside of standard treatment influence prognosis in patients with ovarian cancer. METHODS: The Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) are ongoing prospective studies of 121 700 and 116 429 US nurses who have completed biennial questionnaires since 1976 and 1989, respectively. We retrieved information from medical records, death certificates, or linkage to a state or Surveillance, Epidemiology, and End Results (SEER) cancer registry on ovarian cancer cases. Eligible participants had confirmed invasive, stage I-III epithelial ovarian cancer, and had data available on analgesic use. The primary objective was to determine whether self-reported regular use (≥2 days per week) of aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), or paracetamol before and after ovarian cancer diagnosis, was associated with ovarian cancer-specific survival. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for these associations, adjusting for age and year of diagnosis, disease stage, and histology. FINDINGS: Between June 1, 1976, and May 31, 2012, for the NHS and between June 1, 1989, and May 31, 2013, for NHSII, 1789 participants of the NHS and NHSII studies were diagnosed with epithelial ovarian cancer and 1143 (64%) were eligible to be included in this study; 1031 (90%) of 1143 cases were included in the pre-diagnosis exposure analysis and 964 cases (84%) in the post-diagnosis exposure analysis. Compared with never-users, participants who reported recent (current use in the past 2 years) post-diagnosis use of aspirin (HR 0·68 [95% CI 0·52-0·89]) and non-aspirin NSAIDs (HR 0·67 [95% CI 0·51-0·87]) had an improved ovarian cancer-specific survival. Any type of analgesic use pre-diagnosis, and post-diagnosis use of paracetamol, were not positively associated with ovarian cancer-specific survival. In analyses of change in analgesic use from pre-diagnosis to post-diagnosis, those participants who became recent users of aspirin (HR 0·44 [95% CI 0·26-0·74]) or became recent users of non-aspirin NSAIDs (HR 0·46 [95% CI 0·29-0·73]) post-diagnosis had a lower risk of ovarian cancer-specific death than never-users. INTERPRETATION: Recent use of aspirin or non-aspirin NSAIDs, defined as current use in the past 2 years, after diagnosis appears to improve ovarian cancer-specific survival. If these results are confirmed in further studies, further research should explore potential synergistic effects of anti-inflammatory medications used in combination with standard ovarian cancer therapies to improve the prognosis for patients diagnosed with ovarian cancer. FUNDING: National Institutes of Health, National Cancer Institute, The Marsha Rivkin Center for Ovarian Cancer Research.