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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.

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

Background Ovarian carcinoma is not a single disease, but rather a collection of subtypes with differing molecular properties and risk profiles. The most common of these, and the subject of this work, is high-grade serous ovarian carcinoma (HGSC). Methods In this population-based study we identified a cohort of 441,382 women resident in Western Australia who had ever been admitted to hospital in the State. Of these, 454 were diagnosed with HGSC. We used Cox regression to derive hazard ratios (HRs) comparing the risk of disease in women who had each of a range of medical diagnoses and surgical procedures with women who did not. Results We found an increased risk of HGSC associated with a diagnosis of pelvic inflammatory disease (PID) (HR 1.47, 95% CI 1.04–2.07) but not with a diagnosis of infertility or endometriosis with HRs of 1.12 (95% CI 0.73–1.71) and 0.82 (95% CI 0.55–1.22) respectively. A personal history of breast cancer was associated with a three-fold increase in the rate of HGSC. Increased parity was associated with a reduced risk of HGSC in women without a personal history of breast cancer (HR 0.57; 95% CI 0.44-0.73), but not in women with a personal history of breast cancer (HR 1.48; 95% CI 0.74–2.95). Conclusions Our finding of an increased risk of HGSC associated with PID lends support to the hypothesis that inflammatory processes may be involved in the etiology of HGSC.

Purpose The incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC. Methods A population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use. Results The analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13–1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23–2.39) but not men (OR 0.83, 95% CI 0.58–1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054). Conclusion This study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.

Background Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear. Methods We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. We used causal mediation analysis to investigate potential mediation of the association by healthcare service use. Results Having had a hysterectomy was associated with an increased risk of thyroid cancer (odds ratio [OR] = 1.45, 95 % confidence interval [CI] 1.07–1.96). When stratified by indication for hysterectomy, the risk appeared stronger for those who had a hysterectomy for menstrual disorders (OR = 1.67, 95 % CI 1.17–2.37) but did not differ by tumour BRAF status. Approximately 20 % of the association between hysterectomy and thyroid cancer may be mediated by more frequent use of healthcare services. Conclusions The observed increased risk of thyroid cancer among those with hysterectomy may be driven, at least partly, by an altered sex steroid hormone milieu. More frequent healthcare service use by women with hysterectomy accounts for only a small proportion of the association.

Globally, ovarian cancer is the seventh most common cancer in women and the eighth most common cause of cancer death, with five-year survival rates below 45%. Although age-standardised rates are stable or falling in most high-income countries, they are rising in many low and middle income countries. Furthermore, with increasing life-expectancy, the number of cases diagnosed each year is increasing. To control ovarian cancer we need to understand the causes. This will allow better prediction of those at greatest risk for whom screening might be appropriate, while identification of potentially modifable causes provides an opportunity for intervention to reduce rates. In this paper we will summarise the current state of knowledge regarding the known and possible causes of epithelial ovarian cancer and discuss some of the main theories of ovarian carcinogenesis. We will also briefly review the relationship between lifestyle and survival after a diagnosis of ovarian cancer.

Background Hysterectomy is one of the most commonly performed gynecological surgeries, with an estimated 30% of women in Australia undergoing the procedure by age 70. In the USA, about 45% of women have a hysterectomy in their lifetime. Some studies have suggested this procedure increases the risk of premature mortality. With many women making the decision to have a hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy. Objective Our aim was 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. We used Cox regression models 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 had a hysterectomy with unilateral salpingo-oophorectomy. In our main analysis, women who had hysterectomy and/or oophorectomy undertaken as part of treatment for cancer were retained in the analysis and considered unexposed to that surgery. As a sensitivity analysis, we censored procedures undertaken for cancer. Results Compared to no surgery, having a hysterectomy without oophorectomy before age 35 was associated with an increase in all-cause mortality (HR=1.29, 95% CI:1.19-1.40); for surgery after age 35, there was an inverse association (35-44 years: HR=0.93, 95%CI:0.89,0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy was associated with increased all-cause mortality when undertaken before age 45 (35-44 years: HR=1.15, 95%CI:1.04-1.27), but decreased mortality rates when surgery was undertaken after age 45. In our sensitivity analysis, censoring gynecological 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 prior to 35 years and hysterectomy with bilateral salpingo-oophorectomy performed prior to 45 years were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p

There are strong associations between a number of reproductive factors and hormone-related cancers such as breast, ovarian and endometrial cancer, but most of these factors (e.g. numbers of pregnancies, age at first birth) cannot pragmatically be modified for the purposes of cancer prevention. Breastfeeding has marked effects on maternal reproductive hormones, has been inversely linked to breast and ovarian cancer and, unlike many other reproductive exposures, can be promoted to women for its public health and individual benefits. In the Second Expert Report on Food, Nutrition, Physical Activity and the Prevention of Cancer1 and subsequent Continuous Update Project (CUP),2 the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) concluded that there was convincing evidence that breastfeeding decreases risk of maternal pre- and post-menopausal breast cancer, but also concluded that the evidence for a causal association between breastfeeding and ovarian cancer1,3 was only “limited-suggestive”. This latter conclusion was based on their meta-analysis of three cohort studies4–6 which showed a non-significant 10% reduction in risk for ever versus never breastfeeding (relative risk [RR] 0.90; 95% confidence interval [CI] 0.75–1.08).3 However, results of another recently published meta-analysis of three cohort studies5,7,8 (only one of which5 was included in the WCRF review) suggested that each additional month of breastfeeding was associated with a significant 1.02% reduction in risk of ovarian cancer.9 There are several biologically plausible mechanisms by which breastfeeding might reduce risk of breast and ovarian cancers. Lactation causes differentiation of breast epithelial cells so they may be less susceptible to neoplastic transformation;2 ductal epithelial cells also exfoliate during lactation potentially eliminating those with DNA-damage.2 Furthermore, breastfeeding suppresses gonadotrophins, thereby lowering endogenous oestrogen and progesterone, and these hormones are thought to play an important role in the development of breast neoplasia.2 For ovarian cancer, most data suggest that repeated exposure of the ovarian/fallopian tube epithelium (many ovarian cancers may actually arise from the fallopian tube) to the effects of recurrent ovulation and/or reproductive hormones have an important role in carcinogenesis. In suppressing gonadotrophins and ovulation, lactation should decrease exposure of the ovary/fallopian tube to most factors postulated to have a strong causative role in cancer development.10 Our aim was to estimate the proportion of cancers attributable to little or no breastfeeding by parous women. Based on our a priori decision to limit our primary analyses to exposure-cancer relationships that either the WCRF or International Agency for Research on Cancer (IARC) had concluded were causal, in our primary analysis we estimated only the proportion of breast cancers diagnosed in 2010 that were attributable to little or no breastfeeding by women who had children. On the assumption that further studies will likely strengthen the evidence for a protective causal association between breastfeeding and ovarian cancer, we have undertaken a supplementary analysis to calculate PAF estimates for ovarian cancer.

An increasing body of observational1,2 and trial3 evidence suggests that frequent use of aspirin reduces the risk of cancer in several organs, particularly of the gastrointestinal tract. Currently, the evidence is strongest for colorectal cancer, with effect sizes from well-conducted prospective studies converging on about 20% lower incidence of cancer among daily users compared to non-users of aspirin. Frequent aspirin use is also associated with significantly lower risks of adenocarcinomas and squamous cell carcinomas of the oesophagus.1 The mechanisms through which aspirin may inhibit tumour development remain unclear, although there is widespread consensus that aspirin's inhibition of cyclo-oxygenase (COX) enzymes is likely to mediate some of the observed effects. COX enzymes (notably the inducible form of COX-2) are over-expressed in colorectal adenomatous polyps and in precursor lesions in other organs, and are known to play a role in carcinogenesis, apoptosis and angiogenesis.4,5 Thus, although regular aspirin use is not formally advocated by any agencies for the primary prevention of cancer, it remains of interest to determine the magnitude of potential benefit of daily aspirin consumption in terms of cancer incidence. We therefore estimated the number and fraction of colorectal cancers that may have been prevented from occurring in Australia in 2010 through prior daily aspirin use. Given the suggestive – but weaker – evidence that frequent aspirin use reduces the risks of oesophageal cancer, we also estimated the number and fraction of those cancers that may have been prevented.

Objectives: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to menopausal hormone therapy (MHT) use. Methods: We estimated the population attributable fraction for cancers causally associated with MHT (breast, endometrium, ovary), and the proportion of colorectal cancers prevented by MHT. We used standard formulae incorporating Australian prevalence data, relative risks of cancer associated with MHT and cancer incidence. We also estimated potential change in cancer incidence under two hypothetical scenarios whereby 25% fewer Australian women used MHT, or women exclusively used oestrogen-only MHT. Results: An estimated 539 cancers in Australia in 2010 were attributable to MHT: 453 breast, 67 endometrial and 19 ovarian cancers equating to 3.4%, 3.1% and 1.6% of each cancer type, respectively. In contrast, MHT may have prevented 52 colorectal cancers. If 25% fewer women used MHT, then 141 cancers may have been avoided. If women exclusively used oestrogen-only MHT then 240 cancers may have been avoided. Conclusions: MHT use caused more than 500 cancers in Australian women in 2010 and prevented ∼50 colorectal cancers. Implications: MHT use continues to cause an excess of cancers. The risks, benefits, regimen and treatment duration should be carefully considered for each woman before MHT is commenced.

Endometrioid and clear cell subtypes of ovarian cancer are both known to be closely associated with endometriosis and endometrial pathology, and so have often been combined in studies of causation. We have examined these ovarian cancers separately for potentially distinct risk factors in our population-based, Australia-wide case control study of 142 women with incident invasive endometrioid, 90 with clear cell ovarian cancers and 1508 population controls. Multivariate logistic regression was used to calculated odds ratios (ORs) and 95% confidence intervals (CIs). Increasing parity, and hormonal contraceptive use for > or = 5 years, strongly decreased the risks of both subtypes. Breast feeding and tubal ligation were also inversely associated, but significantly so only for the endometrioid subtype. As expected endometriosis increased the risk of both subtypes (OR 2.2, 95% CI 1.2-3.9 for endometrioid and OR 3.0, 95% CI 1.5-5.9 for clear cell). Obesity was associated only with clear cell cancers, where we observed a two-fold increased risk (OR 2.2, 95% CI 1.2-4.1). Also a significant trend of decreasing risk with increasing intensity of smoking (p trend 0.02) and education beyond high school was associated with decreased development of clear cell cancers only. Endometrioid and clear cell ovarian cancers have some shared as well as some distinct risk factors, and therefore should be considered separately in studies of ovarian cancer.

OBJECTIVE: Some molecular and histological evidence suggests that mucinous epithelial ovarian cancers develop via a sequence from benign tumor through borderline tumor to invasive cancer. Such a sequence would predict some shared risk factors between the different tumor types. To investigate this, we examined risk factors for benign, borderline and invasive mucinous ovarian tumors. METHODS: A population-based case-control study was conducted in Australia between 2002 and 2005. Women with benign (n=133), borderline (n=147) and invasive (n=43) mucinous tumors of the ovary and women from the general population (n=1487) completed comprehensive health and lifestyle questionnaires. RESULTS: Although parity was inversely related to risk of benign, borderline and invasive tumors, increasing numbers of births did not further decrease risk of any of the tumor types. Hormonal contraceptives and breast-feeding were unrelated to risk. However, 20 or more pack-years of smoking was associated with a more than twofold increase in risk of all three tumor types (OR=2.7, 95% CI 1.6-4.4 for benign tumors; OR=2.7, 95% CI 1.7-4.4 for borderline tumors; and OR=2.1, 95% CI 0.9-5.0 for invasive cancers) compared to never smoking. CONCLUSIONS: Overall, the risk factors for mucinous cancers appear to differ from other subtypes of ovarian cancer. Furthermore, patterns of risk factors across benign, borderline and invasive mucinous ovarian tumors are generally consistent with an adenoma-to-carcinoma sequence as the developmental pathway for this subtype of ovarian cancer. Our findings also suggest the potential preventability of borderline and invasive mucinous ovarian cancer by smoking cessation and by surgical excision of identifiable precursor lesions.

Objectives. Although early reports suggested that smoking was not associated with ovarian cancer risk, recent studies have reported positive associations for cancers of the mucinous subtype. We sought to clarify the relationship between smoking and ovarian cancer by histological subtype. Methods. We conducted a systematic literature review and meta-analysis of studies investigating the association between smoking and risk of the different histological subtypes of epithelial ovarian cancer. Eight population-based case–control studies, one pooled analysis of case–control studies, and one cohort study met the inclusion criteria. Summary relative risks (RR), 95% confidence intervals (CI), and tests for heterogeneity were generated from random effects models. Results. Combined, these studies included a total of 910 women with mucinous and 5564 with non-mucinous ovarian cancers. There was a significant doubling of risk of mucinous ovarian cancer in current smokers compared to never smokers (summary RR 2.1, 95%CI 1.7–2.7), but no increased risk of serous (1.0, 95%CI 0.8–1.2) or endometrioid (0.8, 95%CI 0.6–1.1) cancers and a significant risk reduction for clear cell cancers (0.6, 95%CI 0.3–0.9). The risk of mucinous cancer increased with increasing amount smoked but returned to that of never smokers within 20–30 years of stopping smoking. Conclusions. Meta-analysis suggests that current smoking doubles a woman's risk of developing mucinous ovarian cancer. Stopping smoking returns the risk to normal in the long term. Smoking may thus be one of the few modifiable factors offering potential for primary prevention of mucinous ovarian cancer.

s / Pancreatology 15 (2015) S1eS141 S85 Patients & methods: Data were collected manually from patient records in two states of Australia for all patients diagnosed with pancreatic cancer between July 2009 and June 2011. Determinants of attempted resectionwere estimated using multivariable logistic regression analyses. Results: Of the cohort 740 patients had stage I-III disease. Of these 38 (5%) declined surgery and 320 (43%) had an attempted resection. Patient factors associated with likelihood of surgery were being male (adjusted odds ratio (AOR) 1.48; 95% confidence interval (CI) 1.00 e 2.18), decreasing performance status (AOR 0.38, 95% CI 0.29 to 0.50), age (AOR 0.93, 95% CI 0.91 to 0.95 per year of age) and increasing Charlson co-morbidity index (AOR 0.79, 95% CI 0.64 to 0.97). Patients seen initially in the private system were more likely to undergo surgery (AOR 1.48, 95% CI 1.00 to 2.19). Being first seen in a facility that admittedmore pancreatic cancer cases increased the likelihood of receiving an attempted resection (AOR 1.47, 95% CI 1.08 to 2.01). Conclusion: Health service and patient factors are determinants of attempted resection for patients with non-metastatic pancreatic cancer.