The association between hysterectomy and ovarian cancer risk: A population-based record-linkage study

Background: Recent studies have called into question the long-held belief that hysterectomy without oophorectomy protects against ovarian cancer. This population-based longitudinal record-linkage study aimed to explore this relationship, overall and by age at hysterectomy, time period, surgery type, and indication for hysterectomy. Methods: We followed the female adult Western Australian population (837 942 women) across a 27-year period using linked electoral, hospital, births, deaths, and cancer records. Surgery dates were determined from hospital records, and ovarian cancer diagnoses (n¼1640) were ascertained from cancer registry records.We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer incidence. Results: Hysterectomy without oophorectomy (n¼78 594) was not associated with risk of invasive ovarian cancer overall (HR ¼ 0.98, 95% CI ¼ 0.85 to 1.11) or with the most common serous subtype (HR ¼ 1.05, 95% CI ¼ 0.89 to 1.23). Estimates did not vary statistically significantly by age at procedure, time period, or surgical approach. However, among women with endometriosis (5.8%) or with fibroids (5.7%), hysterectomy was associated with substantially decreased ovarian cancer risk overall (HR ¼ 0.17, 95% CI ¼ 0.12 to 0.24, and HR ¼ 0.27, 95% CI ¼ 0.20 to 0.36, respectively) and across all subtypes. Conclusions: Our results suggest that for most women, having a hysterectomy with ovarian conservation is not likely to substantially alter their risk of developing ovarian cancer. However, our results, if confirmed, suggest that ovarian cancer risk reduction could be considered as a possible benefit of hysterectomy when making decisions about surgical management of endometriosis or fibroids

Linking Physical Activity to Breast Cancer via Sex Steroid Hormones, Part 2:The Effect of Sex Steroid Hormones on Breast Cancer Risk

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone–binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose–response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for post-menopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. See related reviews by Lynch et al., p. 11 and Swain et al., p. 1

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

Using ‘Big Data’ to explore unanswered questions in ovarian cancer epidemiology

BackgroundEach year nearly 300,000 women are diagnosed with ovarian cancer worldwide, and more than half of these women die within five years of their diagnosis. Clear evidence from epidemiological studies about factors affecting risk or survival is critical for efforts to prevent this cancer and improve prognosis. However, interpretation of findings has often been hampered by low sample sizes, biases in observational studies, and the historic practice of considering all ovarian cancers as one disease, although aetiological distinctions between the major histotypes are now recognised. Due partly to these limitations, it was unclear whether adiposity, greater height, or hysterectomy without oophorectomy are associated with ovarian cancer risk, and whether the use of common analgesic medications (aspirin and nonaspirin nonsteroidal anti-inflammatory drugs [NSAIDs], and acetaminophen) is associated with ovarian cancer survival. Each of these exposures affects a large, and growing, number of women globally.AimThe overall aim of this thesis was to address knowledge gaps in ovarian cancer epidemiology relating to several potential risk factors (adiposity, height, and hysterectomy) and exposures that may influence survival after diagnosis (common analgesic medications), using large complex datasets and non-traditional approaches.MethodsThe four studies included in this thesis each examined one exposure or several closely-related exposures in relation to ovarian cancer risk or survival, using two datasets and a variety of analytical methods. Two studies (examining adiposity and height in relation to ovarian cancer risk) applied Mendelian randomization (MR), a method which uses genetic variants as proxies for epidemiological exposures to overcome some of the biases that can affect observational research. Data were pooled from approximately 37,000 women (for adiposity analyses) or approximately 39,400 women (for height analyses) participating in 39 studies in the international Ovarian Cancer Association Consortium (OCAC). The third study used linked administrative data to follow approximately 840,000 Western Australian women over a 27-year period, and applied Cox proportional hazards regression with time-varying exposures and covariates to examine the association between hysterectomy and ovarian cancer risk. The final study used Cox proportional hazards regression to investigate the relationships between pre-diagnosis use of common analgesic medications and survival among approximately 7,700 women with ovarian cancer from 12 OCAC studies.ResultsThe first study used MR to show that greater adiposity increases risk (about a 30% increase in risk per five units of body mass index) of ovarian cancers other than high-grade serous, but not the common and aggressive high-grade serous cancers. Abdominal adiposity (waist-hip ratio) was not associated with risk of either high-grade serous or non-high grade serous ovarian cancers. The second study indicated that greater height is associated with increased risk of invasive (a 6% increase in risk per five centimetres) and borderline (15% risk increase) ovarian cancers, and that risk is most elevated for clear cell cancers (20% risk increase). In the third study, hysterectomy was not associated with risk of invasive ovarian cancer overall or with the common serous cancers, although there was a suggestion of reduced risk of the rarer histotypes (mucinous, endometrioid, and clear cell cancers). For women with endometriosis or uterine fibroids, hysterectomy was associated with a markedly decreased risk of ovarian cancer (about 85% and 75% decreases in overall risk, respectively). Results of the fourth study indicated that use of aspirin, nonaspirin NSAIDs, or acetaminophen before diagnosis of ovarian cancer is unlikely to substantially affect survival.ConclusionsThis thesis contributed new evidence on the relevance of several factors to ovarian cancer risk and survival. The finding that adiposity increases risk of non-high grade serous ovarian cancers, but not high-grade serous cancers, adds to growing evidence on the health benefits of avoiding overweight, but suggests that obesity prevention will not reduce incidence of the histotype responsible for most ovarian cancer deaths. The finding that pathways determining stature are important for ovarian carcinogenesis suggests avenues for future prevention research, for instance continued investigation of growth hormones. The results of the third study suggested that most women should continue to be vigilant for ovarian cancer symptoms after hysterectomy with conservation of ovaries. Future research is needed to confirm the protective association for hysterectomy among women with endometriosis or fibroids before this evidence can be considered in treatment decisions. The finding that pre-diagnosis use of common analgesic medications has minimal effect, if any, on ovarian cancer survival is useful to reassure women at diagnosis about past use of these medications, but future studies with large samples and post-diagnosis exposure data should continue to investigate this relationship. Overall, the evidence from this thesis will contribute to helping public health practitioners, policymakers, clinicians, and researchers better understand the epidemiological relationships covered by this research, communicate these accurately to women at risk, and act on these exposures where possible to reduce population burden from this cancer