Tubal ligation,hysterectomy and epithelial ovarian cancer in the New England Case–Control Study

Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however, little is known about whether these associations vary by surgical characteristics, individual characteristics or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case–Control Study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.68–0.97], especially for endometrioid tumors (OR = 0.45, 95% CI: 0.29–0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR = 0.60, 95% CI: 0.42–0.84) rather than at a later time (OR = 0.93, 95% CI: 0.75–1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95% CI: 0.83–1.42), although it was associated with a nonsignificant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95% CI: 0.40–1.02) or within the last 10 years (OR = 0.65, 95% CI: 0.38–1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR = 0.65, 95% CI: 0.45–0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population‐based case–control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk.     

Tubal ligation and risk of breast cancer

Although it has been demonstrated in previous studies that tubal ligation can have widespread effects on ovarian function, including a decrease in the risk of subsequent ovarian cancer, few studies have evaluated effects on breast cancer risk. In a population-based case-control study of breast cancer among women 20-54 years of age conducted in three geographic areas, previous tubal ligations were reported by 25.3% of the 2173 cases and 25.8% of the 1990 controls. Initially it appeared that tubal ligations might impart a slight reduction in risk, particularly among women undergoing the procedure at young ages (<25 years). However, women were more likely to have had the procedure if they were black, less educated, young when they bore their first child, or multiparous. After accounting for these factors, tubal ligations were unrelated to breast cancer risk (relative risk (RR) = 1.09, 95% confidence interval (CI) 0.9-1.3), with no variation in risk by age at, interval since, or calendar year of the procedure. The relationship of tubal ligations to risk did not vary according to the presence of a number of other risk factors, including menopausal status or screening history. Furthermore, effects of tubal ligation were similar for all stages at breast cancer diagnosis. Further studies would be worthwhile given the biologic plausibility of an association. However, future investigations should include information on type of procedure performed (since this may relate to biologic effects) as well as other breast cancer risk factors.     

Tubal ligation in relation to menopausal symptoms and breast cancer risk

Background:

Local inflammation after tubal ligation may affect ovarian function and breast cancer risk.

Methods:

We analysed tubal ligation, menopausal characteristics, and breast cancer risk in the Sister Study cohort (N=50 884 women).

Results:

Tubal ligation was associated with hot flashes (hazard ratio (HR) 1.09; 95% confidence interval (CI): 1.06–1.12) but not menopausal age (HR 0.99; 95% CI: 0.96–1.02). Tubal ligation did not have an impact on breast cancer overall (HR 0.95; 95% CI: 0.85–1.06), but had a suggested inverse relation with oestrogen receptor+/progesterone receptor+ invasive tumours (HR 0.84; 95% CI: 0.70–1.01), possibly because of subsequent hysterectomy/bilateral oophorectomy.

Conclusion:

Tubal ligation does not influence overall breast cancer risk.     

Tubal sterilization in relation to breast cancer risk

Tubal sterilization methods may damage surrounding tissue, potentially disrupting the ovarian blood supply and hormonal functioning, and may decrease breast cancer risk. We examined this hypothesis, within the Nurses' Health Study, among 77,511 women, aged 30-55 years and free of cancer at the start of follow-up in 1976. We documented 4,176 cases of invasive breast cancer from 1976 to 2000. Cox proportional hazards models, adjusting for multiple breast cancer risk factors, provided rate ratios (RR) and 95% confidence intervals (CI). Overall, tubal sterilization was not associated with breast cancer risk (RR=0.95, 95% CI=0.88-1.03). However, tubal sterilizations performed from 1970 to 1974 were inversely associated with risk (RR=0.84, 95% CI=0.73-0.97), while procedures performed in other years were not associated with risk. Among women with procedures performed in 1970-1974, those who were >or=35 years old at the time of sterilization were at the lowest risk (RR=0.81, 95% CI=0.66-0.98), while younger women had a suggested decreased risk (RR=0.87, 95% CI=0.72-1.06). Overall, tubal sterilization was not associated with breast cancer risk. However, a modest inverse association was observed at a time when the potentially destructive unipolar electrocautery method was commonly used, providing some support for an association between lower lifetime exposure to hormones and a decreased risk of breast cancer.     

Association between tubal ligation and endometrial cancer risk: A Swedish population‐based cohort study

Tubal ligation results in less advanced stages and lower risk of metastatic spread at diagnosis of endometrial cancer (EC) but the primary preventive effect of the procedure is unclear. In a Swedish nationwide population‐based cohort study, we crosslinked registry data for tubal ligation, EC, and death for Swedish women between 1973 and 2010. All women were followed until EC, emigration, hysterectomy for non‐cancerous reasons, death, or end of follow‐up. Primary outcome was incidence of EC and secondary outcome overall survival. We calculated adjusted incidence rates (IR) per 100,000 person‐years and hazard ratios (HR) using Cox regression models. A total of 35,711 cases of EC were identified among 5,385,186 women. The IR of EC among exposed was 17.7 (95% CI 15.7–19.9) versus 29.0 (95% CI 28.7–29.3) among unexposed (per 100,000 women years). Exposed individuals had significantly reduced risk of EC (HR 0.73, 95% CI 0.65–0.83). The mortality rate among women with EC was 72% lower in exposed compared to unexposed (IR 1,441; 95% CI 1,089–1,907 and IR 5,136; 95% CI 5,065–5,209, respectively) which following adjustment corresponded to a HR of 0.71 (95% CI 0.49–1.03). Tubal ligation was associated with lower risk of EC as well as mortality rates in women with EC. Elective tubal ligation may be adopted in future cancer preventive strategies but must be balanced against the irreversibility of the procedure, which preclude further unassisted reproduction.     

Tubal sterilization and risk of breast cancer mortality in US women

Objective: To investigate the hypothesis that tubal sterilization is associated with a reduced risk of breast cancer. Methods: We examined this hypothesis in a large prospective study of US adults. After 14 years of mortality follow-up, 3837 deaths from breast cancer were observed in a cohort of 619,199 women who were cancer-free at study entry in 1982. Results: Cox proportional hazards models (adjusted for multiple breast cancer risk factors) showed a significant inverse association between tubal sterilization and breast cancer mortality (adjusted rate ratio (RR) = 0.82, 95% confidence interval (CI) 0.70–0.96). Women who were sterilized before age 35 had a lower risk (adjusted RR = 0.69, 95% CI 0.53–0.88) than women who were sterilized at 35 years of age or older (adjusted RR = 0.92, 95% CI 0.75–1.13). Also, sterilizations performed before 1975 resulted in a lower risk (RR = 0.75, 95% CI 0.62–0.91) than those performed during or after 1975 (RR = 0.98, 95% CI 0.74–1.29), possibly reflecting the likelihood of greater tissue damage with earlier procedures. Conclusions: These results suggest that tubal sterilization may lower subsequent risk of breast cancer, especially among women who are sterilized at a relatively young age. Additional studies are needed to confirm or refute these findings.     

Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort

Background:

Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics.

Methods:

We conducted a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations.

Results:

We observed no association between IGF-I and EOC overall or by tumour characteristics.

Conclusions:

In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.     

Characterization of ovarian cancer survival by histotype and stage: A nationwide study in Norway

Contemporary population-based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1-, 3-, 5- and 7-year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry-based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non-epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7-year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7-year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high-grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5-year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non-epithelial cases was good (91.8% 5-year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments.     

Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study

New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in 1992. The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR = 1.85 (95% CI 1.08-3.16)] and those smoking more than 10 cigarettes per day had a doubling in risk [HR = 2.25(95% CI 1.26-4.03)] as did those who had smoked less than 15 pack-years of cigarettes [HR = 2.18 (95% CI 1.07-4.43)]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype.     

Alcohol intake and ovarian cancer risk: a pooled analysis of 10 cohort studies

Alcohol has been hypothesized to promote ovarian carcinogenesis by its potential to increase circulating levels of estrogen and other hormones; through its oxidation byproduct, acetaldehyde, which may act as a cocarcinogen; and by depletion of folate and other nutrients. Case-control and cohort studies have reported conflicting results relating alcohol intake to ovarian cancer risk. We conducted a pooled analysis of the primary data from ten prospective cohort studies. The analysis included 529 638 women among whom 2001 incident epithelial ovarian cases were documented. After study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then were pooled using a random effects model; no associations were observed for intakes of total alcohol (pooled multivariate RR=1.12, 95% CI 0.86-1.44 comparing > or =30 to 0 g day(-1) of alcohol) or alcohol from wine, beer or spirits and ovarian cancer risk. The association with alcohol consumption was not modified by oral contraceptive use, hormone replacement therapy, parity, menopausal status, folate intake, body mass index, or smoking. Associations for endometrioid, mucinous, and serous ovarian cancer were similar to the overall findings. This pooled analysis does not support an association between moderate alcohol intake and ovarian cancer risk.     

Infertility and ovarian cancer risk: Evidence from nine prospective cohort studies

Epidemiological studies have investigated the relationship between infertility and the risk of ovarian cancer (OC); however, the results have been inconsistent. We therefore conducted the first meta-analysis to update and quantify the aforementioned association based on prospective cohort studies. Studies were identified by searching PubMed, EMBASE and Web of Science databases up to January 8, 2020. We extracted data from the studies and performed quality assessments. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Publication bias, and subgroup, meta-regression and sensitivity analyses were also conducted. Nine prospective cohort studies with a total of 10 383 OC cases and 6 278 830 participants were included in the present study. The summary RR of the association between infertility and the risk of OC was 1.51 (95% CI: 1.35-1.69), with low heterogeneity. Positive associations were observed in most subgroup analyses stratified by predefined factors, including region, duration of follow-up, study quality, causes of infertility, invasiveness of OC, infertility treatment status and adjustment of potential confounding parameters. No significant publication bias was detected. Our findings suggest that infertility in women were associated with an increased risk of OC.     

Infertility and risk of fatal ovarian cancer in a prospective cohort of US women

Objectives: It is difficult to separate the possible role of fertility drugs from underlying infertility as risk factors for ovarian cancer. The present study examined the relationship between self-reported infertility and death from ovarian cancer among married women unlikely to have been exposured to fertility drugs.Methods: Women were selected for study from the 676,526 female participants in Cancer Prevention Study II (CPS-II). After twelve years of follow-up, 797 deaths from ovarian cancer were observed among women with no prior history of cancer or hysterectomy and 40 years of age or older in 1967 when ovulatory stimulants were approved in the United States. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors.Results: Overall, self-reported infertility was not significantly associated with ovarian cancer mortality (adjusted rate ratio (RR)=1.1, 95 percent confidence interval (CI)=0.9-1.3). Ovarian cancer death rates among nulligravid women with self-reported infertility, however, were 40 percent higher than for nulligravid women who never tried to become pregnant (RR=1.4, 95 percent CI=0.9-2.4). Multigravid women who reported infertility problems were not at increased risk.Conclusions: These results suggest that infertility itself, without concomitant exposure to fertility drugs, may increase risk of fatal ovarian cancer among nulligravid women.     

Birth spacing and maternal risk of invasive epithelial ovarian cancer in a Swedish nationwide cohort

Objective  Pregnancies reduce the risk of ovarian cancer, and among multiparous women, levels of circulating progesterone might be higher during pregnancies with wider birth spacing. We hypothesized that childbirth with wider birth spacing might reduce maternal risk of invasive epithelial ovarian cancer more than births with narrower spacing. Methods  We conducted a case–control study nested in a nationwide cohort of Swedish women from 1961 to 2001. We selected five individually age-matched controls for each case of invasive epithelial ovarian cancer, and analysis for the effect of birth spacing was performed for 5,341 cases and 29,047 controls. We applied unconditional logistic regression analyses adjusting for age, ages at childbirth, educational level, area of residence, and gender of offspring. Results  Relative risk of invasive epithelial ovarian cancer associated with each one-year increase in average birth spacing is 1.00 (95% CI = 0.98–1.01) among all women and 0.99 (0.98–1.01) among those born before 1935 and less likely to have used oral contraceptives. Further analyses on the biparous and triparous women did not find a consistent association between birth spacing and the risk of ovarian cancer. Conclusions  Birth spacing is unlikely to be a major determinant underlying the protective effects of childbirth on ovarian cancer risk.     

Dietary cadmium exposure and risk of epithelial ovarian cancer in a prospective cohort of Swedish women

Background:

The proposed cadmium-induced oestrogen mimicking effects in reproductive tissues, suggest a role of this widespread food contaminant in the development of hormone-dependent malignancies.

Methods:

We prospectively evaluated the association between tertiles of dietary cadmium exposure and epithelial ovarian cancer in 60 889 women from the population-based Swedish Mammography Cohort. Dietary cadmium was estimated using a food-frequency questionnaire at baseline (1987–1990) and in 1997. Multivariable-adjusted rate ratios (RR) were evaluated using Cox proportional hazards models.

Results:

During a mean follow-up of 18.9 years (1 149 470 person-years), we identified 409 incident cases of epithelial ovarian cancer, including 215 serous, 27 mucinous, 62 endometrioid and 12 clear cell tumours. We found no association between dietary cadmium exposure and the risk of ovarian cancer. Compared with the lowest tertile of cadmium exposure, the multivariable-adjusted RR for the highest tertile was 0.90 (95% confidence interval (CI): 0.71–1.15) for total epithelial ovarian cancer. Likewise, no association was observed in subtypes modelled with continuous dietary cadmium exposure; multivariable RR for each 1 μg per day increment of cadmium: 0.97 (95% CI: 0.93–1.02) for serous tumours, 0.94 (95% CI: 0.82–1.07) for mucinous tumours and 1.00 (95% CI: 0.92–1.08) for endometrioid and clear cell tumours.

Conclusion:

Our study suggests that dietary cadmium exposure is not likely to have a substantial role in ovarian cancer development.     

Wine drinking and epithelial ovarian cancer risk: a meta-analysis

Objective

Wine has been the focus in the prevention of epithelial ovarian cancer (EOC) development because resveratrol abundant in wine has anti-carcinogenic properties. However, epidemiologic results have been heterogenous in the chemopreventive effect of wine on the development of EOC. Thus, we performed a meta-analysis for comparing EOC risk between wine and never drinkers using previous related studies.

Methods

After extensive search of the literature between January 1986 and December 2008, we analyzed 10 studies (3 cohort and 7 case control studies) with 135,871 women, who included 65,578 of wine and 70,293 of never drinkers.

Results

In all studies, there was no significant difference in EOC risk between wine and never drinkers (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.92 to 1.38; random effects). When we performed re-analysis according to the study design, 3 cohort and 7 case control studies showed that there were also no significant differences in EOC risk between wine and never drinkers, respectively (OR, 1.44 and 1.04; 95% CI, 0.74 and 2.82 and 0.88 to 1.22; random effects). In sub-analyses using 2 case-control studies, EOC risk was not different between former and never drinkers (OR, 1.12; 95% CI, 0.87 to 1.44; fixed effect), and between current and former drinkers (OR, 0.74; 95% CI, 0.41 to 1.34; random effects).

Conclusion

Although resveratrol, abundantly found in wine, is a promising naturally occurring compound with chemopreventive properties on EOC in preclinical studies, this meta-analysis suggests the epidemiologic evidence shows no association between wine drinking and EOC risk.     

Twin births, sex of children and maternal risk of ovarian cancer: a cohort study in Norway

In a follow-up of 1,208,001 women aged 20-74 years, no significant association was found between twin births (112 cases) and risk, though those with twin girls had a non-significantly higher risk than those with singleton births; among the latter, those with girls only had a higher risk of endometrioid tumours (incidence rate ratio 1.35; 95% confidence interval 1.03-1.76, based on 475 cases) than women with boys only.     

Dairy foods and nutrients in relation to risk of ovarian cancer and major histological subtypes

Inconsistent results for the role of dairy food intake in relation to ovarian cancer risk may reflect the potential adverse effects of lactose, which has been hypothesized to increase gonadotropin levels, and the beneficial antiproliferative effects of calcium and vitamin D. Using data from the New England case–control study (1,909 cases and 1,989 controls), we examined dairy foods and nutrients in relation to risk of ovarian cancer overall, histological subtypes and rapidly fatal versus less aggressive disease. We used logistic regression and polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). In models that were simultaneously adjusted for total (dietary plus supplements) calcium, total vitamin D and lactose, we observed a decreased overall risk of ovarian cancer with high intake of total calcium [Quartile 4 (Q4, >1,319 mg/day) vs. Quartile 1 (Q1, <655 mg/day), OR = 0.62, 95% CI = 0.49–0.79]; the inverse association was strongest for serous borderline and mucinous tumors. High intake of total vitamin D was not associated overall with ovarian cancer risk, but was inversely associated with risk of serous borderline (Q4, >559 IU/day vs. Q1, <164 IU/day, OR = 0.51, 95% CI = 0.34–0.76) and endometrioid tumors (Q4 vs. Q1, OR = 0.55, 95% CI = 0.39–0.80). We found no evidence that lactose intake influenced ovarian cancer risk or that risk varied by tumor aggressiveness in the analyses of intake of dairy foods and nutrients. The overall inverse association with high intake of calcium and the inverse associations of calcium and vitamin D with specific histological subtypes warrant further investigation.     

Diet and ovarian cancer risk: a case-control study in Italy

To assess the dietary correlates of cancer of the ovary, the consumption of a wide range of food groups has been investigated in a case-control study conducted between January 1992 and September 1999 in 4 Italian areas. Cases were 1,031 women with incident, histologically confirmed epithelial ovarian cancer; controls were 2,411 women admitted to the same network of hospitals as the cases for acute, non-malignant and non-gynecological conditions, unrelated to hormonal or digestive tract diseases or to long-term modifications of diet. The subjects' usual diet was investigated through a validated food frequency questionnaire including 78 foods and recipes, then grouped into 18 food groups. Odds ratios (OR), and the corresponding 95% confidence intervals (CI) were estimated using unconditional multiple logistic regression models including terms for age, study center, education, year at interview, parity, oral contraceptive use and energy intake. Significant trends of increasing risk emerged for red meat (OR = 1.53 for the highest compared with the lowest quintile of consumption), whereas inverse associations were observed for consumption of fish (OR = 0.51), raw (OR = 0.47) and cooked vegetables (OR = 0.65), and pulses (OR = 0.77).     

Diet and ovarian cancer risk: a case-control study in China

This case-control study, conducted in Zhejiang, China during 1999-2000, investigated whether dietary factors have an aetiological association with ovarian cancer. Cases were 254 patients with histologically confirmed epithelial ovary cancer. The 652 controls comprised 340 hospital visitors, 261 non-neoplasm hospital outpatients without long-term diet modifications and 51 women recruited from the community. A validated food frequency questionnaire was used to measure the habitual diet of cases and controls. The risks of ovarian cancer for the dietary factors were assessed by adjusted odds ratios based on multivariate logistic regression analysis, accounting for potential confounding demographic, lifestyle, familial factors and hormonal status, family ovarian cancer history and total energy intake. The ovarian cancer risk declined with increasing consumption of vegetables and fruits but vice versa with high intakes of animal fat and salted vegetables. The adjusted upper quartile odds ratio compared to the lower quartile was 0.24 (0.1-0.5) for vegetables, 0.36 (0.2-0.7) for fruits, 4.6 (2.2-9.3) for animal fat and 3.4 (2.0-5.8) for preserved (salted) vegetables with significant dose-response relationship. The risk of ovarian cancer also appeared to increase for those women preferring fat, fried, cured and smoked food.