Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Association between unstable diabetes mellitus and risk of pancreatic cancer.

BACKGROUND: Deterioration of glycaemic control in people with long-standing diabetes mellitus (diabetes) may be a possible indicator of pancreatic cancer. However, the magnitude of the association between diabetes deterioration and pancreatic cancer has received little attention. METHODS: We conducted a matched cohort study, nested within a population-based cohort of Australian women with diabetes. Women with unstable diabetes, defined as a change in medication after a 2-year period of stable medication use, were matched by birth year to those with stable diabetes, in a 1:4 ratio. We used flexible parametric survival models to estimate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: We included 134,954 and 539,789 women in the unstable and stable diabetes cohorts, respectively (mean age 68 years). In total, 1,315 pancreatic cancers were diagnosed. Deterioration of stable diabetes was associated with a 2.5-fold increased risk of pancreatic cancer (HR 2.55; 95% CI 2.29-2.85). The risk was particularly high within the first year after diabetes deteriorated. HRs at 3 months, 6 months and 1 year were: 5.76 (95% CI 4.72-7.04); 4.56 (95% CI 3.81-5.46); and 3.33 (95% CI 2.86-3.89), respectively. The risk was no longer significantly different after 7 years. CONCLUSIONS: Deterioration in glycaemic control in people with previously stable diabetes may be an indicator of pancreatic cancer, suggesting investigations of the pancreas may be appropriate. The weaker longer-term (3-7 years) association between diabetes deterioration and pancreatic cancer may indicate that poor glycaemic control can be a risk factor for pancreatic cancer.

Predicting the risk of pancreatic cancer in women with new-onset diabetes mellitus.

BACKGROUND AND AIM: People with new-onset diabetes mellitus (diabetes) could be a possible target population for pancreatic cancer surveillance. However, distinguishing diabetes caused by pancreatic cancer from type 2 diabetes remains challenging. We aimed to develop and validate a model to predict pancreatic cancer among women with new-onset diabetes. METHODS: We conducted a retrospective cohort study among Australian women newly diagnosed with diabetes, using first prescription of anti-diabetic medications, sourced from administrative data, as a surrogate for the diagnosis of diabetes. The outcome was a diagnosis of pancreatic cancer within 3 years of diabetes diagnosis. We used prescription medications, severity of diabetes (i.e., change/addition of medication within 2 months after first medication), and age at diabetes diagnosis as potential predictors of pancreatic cancer. RESULTS: Among 99 687 women aged ≥ 50 years with new-onset diabetes, 602 (0.6%) were diagnosed with pancreatic cancer within 3 years. The area under the receiver operating curve for the risk prediction model was 0.73. Age and diabetes severity were the two most influential predictors followed by beta-blockers, acid disorder drugs, and lipid-modifying agents. Using a risk threshold of 50%, sensitivity and specificity were 69% and the positive predictive value (PPV) was 1.3%. CONCLUSIONS: Our model doubled the PPV of pancreatic cancer in women with new-onset diabetes from 0.6% to 1.3%. Age and rapid progression of diabetes were important risk factors, and pancreatic cancer occurred more commonly in women without typical risk factors for type 2 diabetes. This model could prove valuable as an initial screening tool, especially as new biomarkers emerge.

Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization.

Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5-2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants.

Germline BRCA variants, lifestyle and ovarian cancer survival.

OBJECTIVE: Women with ovarian cancer who have a pathogenic germline variant in BRCA1 or BRCA2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA-wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. METHODS: We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20-3.27) than non-carriers (HR 1.18; 95% CI 0.96-1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28-2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90-1.29) for non-carriers. CONCLUSIONS: Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers.

Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.

OBJECTIVE: To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. METHODS: We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). CONCLUSIONS: The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

Predicting obesity and smoking using medication data: A machine-learning approach.

PURPOSE: Administrative health datasets are widely used in public health research but often lack information about common confounders. We aimed to develop and validate machine learning (ML)-based models using medication data from Australia's Pharmaceutical Benefits Scheme (PBS) database to predict obesity and smoking. METHODS: We used data from the D-Health Trial (N = 18 000) and the QSkin Study (N = 43 794). Smoking history, and height and weight were self-reported at study entry. Linkage to the PBS dataset captured 5 years of medication data after cohort entry. We used age, sex, and medication use, classified using anatomical therapeutic classification codes, as potential predictors of smoking (current or quit <10 years ago; never or quit ≥10 years ago) and obesity (obese; non-obese). We trained gradient-boosted machine learning models using data for the first 80% of participants enrolled; models were validated using the remaining 20%. We assessed model performance overall and by sex and age, and compared models generated using 3 and 5 years of PBS data. RESULTS: Based on the validation dataset using 3 years of PBS data, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI] 0.68-0.71) for predicting obesity and 0.71 (95% CI 0.70-0.72) for predicting smoking. Models performed better in women than in men. Using 5 years of PBS data resulted in marginal improvement. CONCLUSIONS: Medication data in combination with age and sex can be used to predict obesity and smoking. These models may be of value to researchers using data collected for administrative purposes.

Statin use and survival following a diagnosis of ovarian cancer: A prospective observational study.

Most women with ovarian cancer have a poor prognosis, but studies have reported an association between statin use and improved survival. We investigated the potential survival benefit of statins in women with ovarian cancer using data from the Ovarian cancer Prognosis and Lifestyle study, a prospective study of Australian women aged 18 to 79 years, diagnosed with ovarian cancer from 2012 to 2015 and followed for 5 to 8 years. We obtained information from patient-completed questionnaires and medical records. We defined exposure based on prediagnosis use, as most women used statins continuously (prediagnosis and postdiagnosis) and few started using statins postdiagnosis. We measured survival from date of first treatment (surgery or neoadjuvant chemotherapy) until date of death or last follow-up. We used Cox regression to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders. To reduce bias due to confounding by indication, we also applied inverse probability of treatment weighting (IPTW). Of 955 eligible women, 21% reported statin use before diagnosis. Statin users had a slightly better survival (HR = 0.90, 95% CI = 0.70-1.15) that was driven by lipophilic statin use (HR = 0.82, 95% CI = 0.61-1.11), with no association for hydrophilic statins (HR = 1.04, 95% CI = 0.72-1.49). The IPTW model weighted to all women with ovarian cancer also suggested a possible reduction in mortality associated with lipophilic statins (HR = 0.80, 95% CI = 0.54-1.21). In analyses restricted to women with hyperlipidaemia, the HRs were further from the null. Our findings are consistent with previous evidence, suggesting that lipophilic statins might improve ovarian cancer survival. Further investigation, in larger cohorts, or preferably in a randomised trial, is required.

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

Statin use and survival among women with ovarian cancer: an Australian national data-linkage study.

BACKGROUND: Five-year ovarian cancer survival rates are below 50%; there is considerable interest in whether common medications like statins may improve survival. METHODS: We identified women diagnosed with ovarian cancer in Australia from 2003 to 2013 through the Australian Cancer Database and linked these records to national medication and death databases. We used Cox proportional hazards regression to estimate hazard ratios (HR) and confidence intervals (CI) for associations between statins and survival. RESULTS: Pre-diagnosis statin use was not associated with survival overall but was associated with better survival among women with endometrioid cancers. Statin use after diagnosis was associated with better ovarian cancer-specific survival (OVS, HR = 0.87, 95%CI 0.81-0.94), but this association was largely restricted to women who started using statins after their cancer diagnosis (OVS HR = 0.68, 0.57-0.81 vs. HR = 0.94, 0.87-1.01 for continuing users). The association was strongest for endometrioid cancers (OVS HR = 0.48, 0.29-0.77). CONCLUSIONS: Use of statins may confer a survival benefit for women with ovarian cancer but it is impossible to rule out bias in observational studies. Particularly problematic are reverse causation where disease status affects statin use, confounding by indication and the absence of data for women with normal cholesterol levels. A randomised trial is required to provide definitive evidence.

Tobacco smoking and risk of thyroid cancer according to BRAFV600E mutational subtypes.

OBJECTIVE: Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer. DESIGN AND PATIENTS: We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex. METHODS: Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias. RESULTS: We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99). CONCLUSION: We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Is there sufficient evidence to recommend women diagnosed with endometrial cancer take a statin: Results from an Australian record-linkage study.

OBJECTIVE: A recent paper suggested all women with endometrial cancer should take statins but it is unclear whether there is sufficient evidence to justify this recommendation. METHODS: We identified all women diagnosed with uterine cancer in Australia between July 2003 and December 2013 (2012 in New South Wales) through the Australian Cancer Database (N = 16,501) and linked these to the national prescription database and National Death Index to identify statin use and survival outcomes to December 2015. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between statin use and survival. RESULTS: Among the 15,703 women with endometrial cancer, pre-diagnosis statin use was not associated with survival. Endometrial cancer-specific mortality was lower among women who used statins after diagnosis (time-varying models: HR = 0.92; 95%CI 0.82-1.03) but the association was only seen among women with type 1 cancers (0.87; 0.76-1.00), for hydrophilic statins (0.84; 0.68-1.03) and for new use of statins after diagnosis (0.75; 0.59-0.95). There was a weak dose-response with increasing number of statin prescriptions. Sensitivity analyses using inverse probability of treatment weights were similar. CONCLUSION: Women with endometrial cancer who take statins after diagnosis may have better survival than those who do not use statins. However, it is impossible to completely rule out bias, particularly reverse causation where disease status may affect statin use. We believe it is too early to recommend all women with endometrial cancer take statins, but there is sufficient evidence to justify a randomized trial.

A Simple Clinical Tool for Stratifying Risk of Clinically Significant CKD after Nephrectomy: Development and Multinational Validation.

BACKGROUND: Clinically significant CKD following surgery for kidney cancer is associated with increased morbidity and mortality, but identifying patients at increased CKD risk remains difficult. Simple methods to stratify risk of clinically significant CKD after nephrectomy are needed. METHODS: To develop a tool for stratifying patients' risk of CKD arising after surgery for kidney cancer, we tested models in a population-based cohort of 699 patients with kidney cancer in Queensland, Australia (2012-2013). We validated these models in a population-based cohort of 423 patients from Victoria, Australia, and in patient cohorts from single centers in Queensland, Scotland, and England. Eligible patients had two functioning kidneys and a preoperative eGFR ≥60 ml/min per 1.73 m2. The main outcome was incident eGFR <45 ml/min per 1.73 m2 at 12 months postnephrectomy. We used prespecified predictors-age ≥65 years old, diabetes mellitus, preoperative eGFR, and nephrectomy type (partial/radical)-to fit logistic regression models and grouped patients according to degree of risk of clinically significant CKD (negligible, low, moderate, or high risk). RESULTS: Absolute risks of stage 3b or higher CKD were <2%, 3% to 14%, 21% to 26%, and 46% to 69% across the four strata of negligible, low, moderate, and high risk, respectively. The negative predictive value of the negligible risk category was 98.9% for clinically significant CKD. The c statistic for this score ranged from 0.84 to 0.88 across derivation and validation cohorts. CONCLUSIONS: Our simple scoring system can reproducibly stratify postnephrectomy CKD risk on the basis of readily available parameters. This clinical tool's quantitative assessment of CKD risk may be weighed against other considerations when planning management of kidney tumors and help inform shared decision making between clinicians and patients.

Application of Combinatorial Methods for the Identifi cation of Synthetic Hair-Conditioning Polymers.

Cationic conditioning polymers have a role as deposition aids for depositing benefit agents such as silicone polymers and are used in shampoo formulations to provide improved combing properties, feel, and look. The objective of this work was to develop synthetic high-performance polymeric conditioning agents that exhibit conditioning performance as good as, or better than, the current commercially available polymers. We describe the application of high throughput methods to identify high-performance synthetic hair-conditioning polymers through using high throughput combinatorial methods for polymer synthesis and screening to prepare several hundred cationic polymer candidates. Shampoo formulations were then formulated with these polymers; hair tresses were treated with these formulations and tested via a parallel automated wet combing method. Three high-performing polymer candidates were selected for further evaluation, prepared on a larger scale and evaluated via a panel study. A (3-acrylamidopropyl)trimethylammonium chloride-vinyl monomer-based cationic copolymer is shown to exhibit hair conditioning efficiency equal to or greater than that of a high-performance cellulose ether-based polymer, SOFTCAT™ SL-5 (Polyquaternium-67) in a shampoo formulation.

Determining the CA19-9 concentration that best predicts the presence of CT-occult unresectable features in patients with pancreatic cancer: A population-based analysis.

BACKGROUND: Serum CA19-9 concentration may be useful in triaging patients with pancreatic cancer for more intensive staging investigations. Our aim was to identify the CA19-9 cut-point with the greatest accuracy for detecting unresectable features not identified by CT scan, and to examine the performance of this and other cut-points in predicting the outcome of staging laparoscopy (SL). METHODS: Patients with pancreatic cancer were drawn from two state-wide cancer registries between 2009 and 2011. We used classification and regression tree (CART) analysis to identify the CA19-9 cut-point which best predicted the presence of imaging-occult unresectable features, and compared its performance with that of a number of alternative cut-points. We then used logistic regression to test the association between CA19-9 concentration and detection of unresectable features in patients who underwent SL. RESULTS: From the CART analysis, the optimal CA19-9 cut-point was 440 U/mL. CA19-9 ≥ 150 U/mL had a similar Youden Index, but greater sensitivity (69% versus 47%). This remained true for those who had obstructive jaundice at the time of CA19-9 sampling. CA19-9 concentration greater than or equal to 110 U/mL, 150 U/mL and 200 U/mL was associated with significantly greater odds of unresectable features being detected during SL. CONCLUSION: Elevated serum CA19-9 concentration is a valid marker for CT-occult unresectable features; the most clinically appropriate cut-point appears to be ≥ 150 U/mL irrespective of the presence of jaundice. Clinical trials which evaluate the value of CA19-9 in the staging algorithm for pancreatic cancer are needed before it is routinely used in clinical practice.

Common medications and survival in women with ovarian cancer: A systematic review and meta-analysis.

OBJECTIVES: Ovarian cancer is usually diagnosed at an advanced stage when five-year relative survival is <50%. Therefore, strategies to improve survival are required. Studies suggest associations between common chronic disease medications such as metformin, statins, beta-blockers, aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) and improved cancer survival. We aimed to review the evidence for a possible relation between these medications and survival among women with ovarian cancer. METHODS: We conducted four systematic reviews and evaluated the risk of bias in the included studies. Where possible, we calculated pooled hazard ratios (pHR) and 95% confidence intervals (CI), excluding studies considered to have the potential for immortal time bias (ITB) which, in practice, was the major source of bias. RESULTS: We identified 36 studies evaluating one or more of the medications (metformin n = 8, statins n = 12, beta-blockers n = 11, aspirin and/or NA-NSAIDs n = 9). We rated 21 studies as ITB-free. The meta-analysis of the ITB-free studies suggested improved survival in statin users compared to non-users (pHR: 0.76, 95%CI: 0.68-0.85), but no overall survival benefit associated with use of metformin, beta-blockers, aspirin or NA-NSAIDs. The pooled result of two studies did, however, suggest a possible association between perioperative beta-blocker use and improved survival. Studies considered to have potential ITB were more likely to report survival benefits associated with these medications. CONCLUSION: Statin use is associated with better ovarian cancer survival but further study, preferably a clinical trial, is required. There are insufficient data to draw conclusions regarding metformin, beta-blockers, aspirin and NA-NSAIDs.

Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

Hysterectomy with and without oophorectomy and all-cause and cause-specific mortality.

BACKGROUND: Hysterectomy is one of the most commonly performed gynecologic surgeries, with an estimated 30% of women in Australia undergoing the procedure by age of 70 years. In the United States, about 45% of women undergo hysterectomy in their lifetime. Some studies have suggested that this procedure increases the risk of premature mortality. With many women making the decision to undergo hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy. OBJECTIVE: This study aimed to examine the association between hysterectomy for benign indications, with or without removal of the ovaries, and cause-specific and all-cause mortality. STUDY DESIGN: Our cohort of 666,588 women comprised the female population of Western Australia with linked hospital and health records from 1970 to 2015. Cox regression models were used to assess the association between hysterectomy and all-cause, cardiovascular disease, cancer, and other mortality by oophorectomy type (categorized as none, unilateral, and bilateral), with no hysterectomy or oophorectomy as the reference group. We repeated these analyses using hysterectomy without oophorectomy as the reference group. We also investigated whether associations varied by age at the time of surgery, although small sample size precluded this analysis in women who underwent hysterectomy with unilateral salpingo-oophorectomy. In our main analysis, women who underwent hysterectomy or oophorectomy as part of cancer treatment were retained in the analysis and considered unexposed to that surgery. For a sensitivity analysis, we censored procedures performed for cancer. RESULTS: Compared with no surgery, hysterectomy without oophorectomy before 35 years was associated with an increase in all-cause mortality (hazard ratio, 1.29; 95% confidence interval, 1.19-1.40); for surgery after 35 years of age, there was an inverse association (35-44 years: hazard ratio, 0.93; 95% confidence interval, 0.89-0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy before 45 years of age was associated with increased all-cause mortality (35-44 years: hazard ratio, 1.15; 95% confidence interval, 1.04-1.27), but decreased mortality rates after 45 years of age. In our sensitivity analysis, censoring gynecologic surgeries for cancer resulted in many cancer-related deaths being excluded for women who did not have surgery for benign indications and thus increased the hazard ratios for the associations between both hysterectomy without oophorectomy and hysterectomy with bilateral salpingo-oophorectomy and risk of all-cause and cancer-specific mortality. The sensitivity analysis therefore potentially biased the results in favor of no surgery. CONCLUSION: Among women having surgery for benign indications, hysterectomy without oophorectomy performed before 35 years of age and hysterectomy with bilateral salpingo-oophorectomy performed before 45 years of age were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.

Offspring sex and risk of epithelial ovarian cancer: a multinational pooled analysis of 12 case-control studies.

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.

The impact of changing the prevalence of overweight/obesity and physical inactivity in Australia: An estimate of the proportion of potentially avoidable cancers 2013-2037.

Globally, 39% of the world's adult population is overweight or obese and 23% is insufficiently active. These percentages are even larger in high-income countries with 58% overweight/obese and 33% insufficiently active. Fourteen cancer types have been declared by the World Cancer Research Fund to be causally associated with being overweight or obese: oesophageal adenocarcinoma, stomach cardia, colon, rectum, liver, gallbladder, pancreas, breast, endometrium, ovary, advanced/fatal prostate, kidney, thyroid and multiple myeloma. Colon, postmenopausal breast and endometrial cancers have also been judged causally associated with physical inactivity. We aimed to quantify the proportion of cancer cases that would be potentially avoidable in Australia if the prevalence of overweight/obesity and physical inactivity in the population could be reduced. We used the simulation modelling software PREVENT 3.01 to calculate the proportion of avoidable cancers over a 25-year period under different theoretical intervention scenarios that change the prevalence of overweight/obesity and physical inactivity in the population. Between 2013 and 2037, 10-13% of overweight/obesity-related cancers in men and 7-11% in women could be avoided if overweight and obesity were eliminated in the Australian population. If everyone in the population met the Australian physical activity guidelines for cancer prevention (i.e. engaged in at least 300 min of moderate-intensity physical activity per week), an estimated 2-3% of physical inactivity-related cancers could be prevented in men (colon cancer) and 1-2% in women (colon, breast and endometrial cancers). This would translate to the prevention of up to 190,500 overweight/obesity-related cancers and 19,200 inactivity-related cancers over 25 years.