Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. METHODS: Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. RESULTS: Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. CONCLUSIONS: Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Global epidemiology of epithelial ovarian cancer.

Globally, ovarian cancer is the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020. Until the early 2000s, age-standardized incidence was highest in northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of eastern Europe and Asia. Ovarian cancer is a very heterogeneous disease and, even among the most common type, namely epithelial ovarian cancer, five major clinically and genetically distinct histotypes exist. Most high-grade serous ovarian carcinomas are now recognized to originate in the fimbrial ends of the fallopian tube. This knowledge has led to more cancers being coded as fallopian tube in origin, which probably explains some of the apparent declines in ovarian cancer incidence, particularly in high-income countries; however, it also suggests that opportunistic salpingectomy offers an important opportunity for prevention. The five histotypes share several reproductive and hormonal risk factors, although differences also exist. In this Review, we summarize the epidemiology of this complex disease, comparing the different histotypes, and consider the potential for prevention. We also discuss how changes in the prevalence of risk and protective factors might have contributed to the observed changes in incidence and what this might mean for incidence in the future.

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.

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.

Association between antihypertensive medicine use and risk of ovarian cancer in women aged 50 years and older.

BACKGROUND: Epithelial ovarian cancer (EOC) has few modifiable risk factors. There is evidence that some antihypertensive medicines may have cancer preventive and/or therapeutic actions; therefore, we assessed the associations between use of different antihypertensive medicines and risk of specific EOC histotypes. METHODS: Our nested case-control study of linked administrative health data included 6070 Australian women aged over 50 years diagnosed with EOC from 2004 to 2013, and 30,337 matched controls. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between ever use of each antihypertensive medicine group, including beta-adrenergic blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, and alpha blockers, and the risk of EOC overall and separately for the serous, endometrioid, mucinous, clear cell and other histotypes. RESULTS: We found that most antihypertensive medicines were not associated with risk of EOC. However, women who used calcium channel blockers had a reduced risk of serous EOC (OR= 0.89, 95 % CI:0.81,0.98) and use of combination thiazide and potassium-sparing diuretics was associated with an increased risk of endometroid EOC (OR= 2.09, 95 % CI:1.15,3.82). CONCLUSION: Our results provide little support for a chemo-preventive role for most antihypertensives, however, the histotype-specific associations we found warrant further investigation.

International Phase IV Field Study for the Reliability and Validity of the European Organisation for Research and Treatment of Cancer Thyroid Cancer Module EORTC QLQ-THY34.

Purpose: The aim of this study was to validate the new European Organisation for Research and Treatment of Cancer Quality of Life Thyroid Cancer Module (EORTC QLQ-THY34). Methods: We enrolled 437 thyroid cancer patients from 17 countries. One group (n = 303), undergoing treatment or best supportive care, completed the questionnaires at three time points (before therapy [t1], 6 weeks later [t2], and 6 months after t2 [t3]). A second group (survivors ≥2 years after diagnosis, n = 134) completed it at a random baseline time point and a second time 1 week later. We determined internal consistency (using Cronbach's alpha), the scale structure (with confirmatory factor analysis), and discriminant validity (using known-group comparisons). Group 1 data were used to assess responsiveness and group 2 data to determine test-retest reliability using intra-class correlations (ICC). Results: All 34 items fulfilled the criteria to be kept in the questionnaire. Cronbach's alpha was >0.70 in 8 of the 9 multi-item scales. All standardized factor loadings exceeded 0.40, confirming the proposed scale structure. The ICC was >0.70 in all scales expressing good test-retest reliability. Differences in scale scores between patients with different histology were >5 points in all scales. In all but one of the pre-specified scales (Dry Mouth), changes over time were ≥|4| points between at least two time points. Conclusion: The EORTC QLQ-THY34 with its 9 multi-item and 8 single-item scales is a reliable and valid tool to measure quality of life in thyroid cancer patients and can be used in future trials and studies.

Obesity and thyroid cancer risk.

PURPOSE OF REVIEW: This review explores recent evidence assessing the relationship between obesity and thyroid cancer. RECENT FINDINGS: Consistent evidence from observational studies suggests that obesity increases the risk of thyroid cancer. The relationship persists when alternative measures of adiposity are used, but the strength of association may vary according to the timing and duration of obesity and how obesity or other metabolic parameters are defined as exposures. Recent studies have reported an association between obesity and thyroid cancers that are larger or have adverse clinicopathologic features, including those with BRAF mutations, thus providing evidence that the association is relevant for clinically significant thyroid cancers. The underlying mechanism for the association remains uncertain but may be driven by disruption in adipokines and growth-signaling pathways. SUMMARY: Obesity is associated with an increased risk of thyroid cancer, although further research is required to understand the biological mechanisms underpinning this relationship. Reducing the prevalence of obesity is predicted to lessen the future burden of thyroid cancer. However, the presence of obesity does not impact current recommendations for screening or management of thyroid cancer.

Common analgesics and ovarian cancer survival: the Ovarian cancer Prognosis And Lifestyle (OPAL) Study.

BACKGROUND: Most women with ovarian cancer (OC) are diagnosed with advanced disease. They often experience recurrence after primary treatment, and their subsequent prognosis is poor. Our goal was to evaluate the association between use of nonsteroidal antiinflammatory drugs (NSAIDs), including regular and low-dose aspirin, and 5-year cancer-specific survival after an OC diagnosis. METHODS: The Ovarian cancer Prognosis And Lifestyle study is a prospective population-based cohort of 958 Australian women with OC. Information was gathered through self-completed questionnaires. We classified NSAID use during the year prediagnosis and postdiagnosis as none or occasional (<1 d/wk), infrequent (1-3 d/wk), and frequent (≥4 d/wk) use. We measured survival from the start of primary treatment: surgery or neoadjuvant chemotherapy for analyses of prediagnosis use, or 12 months after starting treatment (postdiagnosis use) until the earliest of date of death from OC (other deaths were censored) or last follow-up to 5 years. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and applied inverse-probability of treatment weighting to minimize confounding. We also calculated restricted mean survival times. RESULTS: Compared with nonusers and infrequent users, we observed better survival associated with frequent NSAID use prediagnosis (HR = 0.73, 95% CI = 0.55 to 0.97) or postdiagnosis (HR = 0.65, 95% CI = 0.45 to 0.94). Estimates were similar for aspirin and nonaspirin NSAIDs, new and continuous users and in weighted models. These differences would translate to a 2.5-month increase in mean survival by 5 years postdiagnosis. There was no association with acetaminophen. CONCLUSIONS: Our findings confirm a previous study suggesting NSAID use might improve OC survival.

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility.

Importance: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. Objective: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. Design, Setting, and Participants: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. Exposures: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. Main Outcomes and Measures: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. Results: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. Conclusions and Relevance: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

Perioperative Beta-Blocker Supply and Survival in Women With Epithelial Ovarian Cancer and a History of Cardiovascular Conditions.

PURPOSE: Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study. MATERIALS AND METHODS: Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects. RESULTS: Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery. CONCLUSION: Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.

Colorectal cancer treatment in people with severe mental illness: a systematic review and meta-analysis.

AIMS: People with severe mental illness (SMI) have a greater risk of dying from colorectal cancer (CRC), even though the incidence is lower or similar to that of the general population This pattern is unlikely to be solely explained by lifestyle factors, while the role of differences in cancer healthcare access or treatment is uncertain. METHODS: We undertook a systematic review and meta-analysis on access to guideline-appropriate care following CRC diagnosis in people with SMI including the receipt of surgery, chemo- or radiotherapy. We searched for full-text articles indexed by PubMed, EMBASE, PsychInfo and CINAHL that compared CRC treatment in those with and without pre-existing SMI (schizophrenia, schizoaffective, bipolar and major affective disorders). Designs included cohort or population-based case-control designs. RESULTS: There were ten studies (sample size = 3501-591 561). People with SMI had a reduced likelihood of surgery (RR = 0.90, 95% CI 0.92-0.97; p = 0.005; k = 4). Meta-analyses were not possible for the other outcomes but in results from individual studies, people with SMI were less likely to receive radiotherapy, chemotherapy or sphincter-sparing procedures. The disparity in care was greatest for those who had been psychiatric inpatients. CONCLUSIONS: People with SMI, including both psychotic and affective disorders, receive less CRC care than the general population. This might contribute to higher case-fatality rates for an illness where the incidence is no higher than that of the general population. The reasons for this require further investigation, as does the extent to which differences in treatment access or quality contribute to excess CRC mortality in people with SMI.

The association between diabetes mellitus of different durations and risk of pancreatic cancer: an Australian national data-linkage study in women.

AIMS: The bidirectional association between diabetes mellitus (DM) and pancreatic cancer (PC) is established; however, the strength of association between duration of DM and risk of PC needs further investigation. METHODS: We conducted a case-control study nested within a population-based cohort of Australian women established using record linkage. Women diagnosed with PC from July 2007 to December 2013, were matched to five controls based on age and state of residence. DM was defined according to prescription of anti-diabetic medication from administrative prescription data. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI), adjusted for area-level socioeconomic status, rurality of residence, weighted comorbidity score, and predicted probability of obesity. RESULTS: The analyses included 7,267 cases and 35,978 controls. The mean age at the time of DM diagnosis was 71 years whereas the mean age at the time of diagnosis of PC was 76 years. A history of DM of any duration was associated with a 2-fold increase in risk of PC (OR=2.12; 95%CI:1.96-2.29) compared to having no history of DM. The risk decreased with increasing duration of DM. The highest risk was in those who had recent-onset DM (OR=8.08; 95%CI:6.88-9.50 for <12 months of DM), but the risk remained elevated with ≥5 years of DM (OR=1.40; 95%CI:1.27-1.55). CONCLUSION: The markedly increased risk of PC in those with recent-onset DM emphasises the need for further research to distinguish patients for whom new-onset DM is a manifestation of PC from those with type-2 DM. The elevated risk associated with long-standing DM suggests that preventing DM may contribute to a reduction in the incidence of PC.

Effects of risk factors for ovarian cancer in women with and without endometriosis.

OBJECTIVE: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. DESIGN: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. SETTING: Population-based. PATIENT(S): We included 8,500 women with ovarian cancer, 13,592 control women. INTERVENTION(S): Ten well-established ovarian cancer risk factors. MAIN OUTCOME MEASURE(S): Risk of ovarian cancer for women with and without endometriosis. RESULT(S): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). CONCLUSION(S): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia.

PURPOSE: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS: Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS: Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION: This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

Pre-existing Thyroid Autoimmunity and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study of US Active-Duty Personnel.

PURPOSE: Thyroid autoimmunity has been associated with differentiated thyroid cancer although multiple potential biases might have influenced the results of previous studies. METHODS: We conducted a case-control study nested within the cohort of US active-duty personnel 1996-2014 to assess the association between thyroid autoimmunity, defined by serology, and thyroid cancer diagnosis. The primary exposure was thyroid peroxidase (TPO) antibody status 7-10 years before the thyroid cancer index date. We also assessed whether diagnosis of thyroid autoimmunity mediated any associations identified and if thyroid cancer features differed by autoimmunity status. RESULTS: Among 451 incident cases of papillary thyroid cancer and matched controls (median age 36 years, 61.4% men), TPO antibody positivity (v negative) 7-10 years prediagnosis was associated with thyroid cancer (odds ratio [OR] 1.90 [95% CI, 1.33 to 2.70]). Exploratory analyses suggested an increasing risk of thyroid cancer with higher TPO antibody titer (TPO antibody 550-1,399 IU/mL: OR 2.95 [95% CI, 1.37 to 6.36]; and ≥ 1,400 IU/mL: OR 3.91 [95% CI, 1.66 to 9.24]). Positive TPO antibody status remained associated with thyroid cancer after those with diagnosed autoimmunity were excluded, and the association was not mediated by diagnosis of thyroid autoimmunity. Among the cases with diagnosed autoimmunity, 58% thyroid cancers were ≤ 10 mm diameter. CONCLUSION: Longstanding prior thyroid autoimmunity up to 10 years before thyroid cancer diagnosis was associated with papillary thyroid cancer risk. The results could not be fully explained by diagnosis of thyroid autoimmunity although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage.

Nitrogen-based Bisphosphonate Use and Ovarian Cancer Risk in Women Aged 50 Years and Older.

BACKGROUND: There are few readily modifiable risk factors for epithelial ovarian cancer; preclinical studies suggest bisphosphonates could have chemopreventive actions. Our study aimed to assess the association between use of nitrogen-based bisphosphonate medicine and risk of epithelial ovarian cancer, overall and by histotype. METHODS: We conducted a case-control study nested within a large, linked administrative dataset including all Australian women enrolled for Medicare, Australia's universal health insurance scheme, between July 2002 and December 2013. We included all women with epithelial ovarian cancer diagnosed at age 50 years and older between July 1, 2004, and December 31, 2013 (n = 9367) and randomly selected up to 5 controls per case, individually matched to cases by age, state of residence, area-level socioeconomic status, and remoteness of residence category (n = 46 830). We used prescription records to ascertain use of nitrogen-based bisphosphonates (ever use and duration of use), raloxifene, and other osteoporosis medicines (no nitrogen-based bisphosphonates, strontium and denosumab). We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Ever use of nitrogen-based bisphosphonates was associated with a reduced risk of epithelial ovarian cancer compared with no use (OR = 0.81, 95% CI = 0.75 to 0.88). There was a reduced risk of endometrioid (OR = 0.51, 95% CI = 0.33 to 0.79) and serous histotypes (OR = 0.84, 95% CI = 0.75 to 0.93) but no association with the mucinous or clear cell histotypes. CONCLUSION: Use of nitrogen-based bisphosphonates was associated with a reduced risk of endometrioid and serous ovarian cancer. This suggests the potential for use for prevention, although validation of our findings is required.

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.