Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study

Introduction: Epidemiologic and biomarker studies suggest that inflammation is associated with ovarian cancer. Periodontal disease is an inflammatory response to microbial biofilms in dental plaque, affecting 30-35% of adult US population and potentially leading to loss of periodontal bone tissue and teeth loss. It is associated with several inflammation-related diseases, including cardiovascular disease, lung cancer, and pancreatic cancer. In this study we investigated the association between periodontal bone loss, a marker for advanced periodontal disease, and risk of epithelial ovarian cancer, in the Nurses’ Health Study, a prospective cohort of US-based nurses. Methods: Periodontal bone loss was self-reported by participants in 1998 and updated in 2000. This analysis included women with baseline information on periodontal bone loss, with no previous history of bilateral oophorectomy, pelvic radiation, or cancer (except non-melanoma skin cancer). Detailed information on relevant lifestyle and reproductive factors was updated every two years and participants were followed for incident ovarian epithelial cancer cases until June 2010. Relative risks (RR) and 95% confidence intervals (CI) for the association of periodontal bone loss with risk of ovarian cancer were assessed using Cox proportional hazards models adjusted for age and other potential confounders, listed below. Results: During follow-up (1998-2010), 352 incident epithelial ovarian cancer cases were identified among the 55,554 women who provided information on periodontal bone loss in 1998. In the main analysis, adjusted for age, duration of oral contraceptive use, tubal ligation, parity and family history of ovarian or breast cancer, periodontal disease was associated with a suggestively decreased risk of ovarian cancer (RR: 0.83; 95% CI: 0.61-1.13). While there was no association (RR=1.51, 95% CI: 0.82-2.81) between periodontal bone loss and non-serous ovarian cancer, participants with periodontal bone loss were at significantly lower risk of serous ovarian cancer than those with no bone loss (RR=0.64, 95% CI: 0.43-0.98). We observed no evidence of confounding by duration and type of menopausal hormone therapy, regularity of menstrual periods, diet quality (as measured by the alternative healthy eating index), physical activity, body mass index (BMI), diabetes, vitamin D status, NSAID use, smoking, or intakes of caffeine, alcohol, or lactose. The association was similar when stratifying by smoking, history of diabetes, use of hormone therapy, or BMI. History of periodontal bone loss was inversely associated with risk of ovarian cancer in women younger than 68 (median age; RR: 0.61, 95% CI: 0.36-1.00), but not in older women (RR: 1.09, 95% CI: 0.74-1.62)(P-heterogeneity = 0.08). Conclusions: This is the first study to investigate the association between ovarian cancer and periodontal health. We observed that women with history of advanced periodontal disease, as reflected by periodontal bone loss, may be at decreased risk of serous ovarian cancer, particularly for younger women. Future studies should confirm these findings and investigate the underlying mechanism. Citation Format: Ana Babic, Elizabeth M. Poole, Kathryn L. Terry, Shelley S. Tworoger. Periodontal bone loss and risk of epithelial ovarian cancer in nurses’ health study [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1201.

There is epidemiological evidence that parity is associated with a reduced risk of ovarian cancer, although few studies are large enough to adequately explore variation by histological subtype. Evidence of association with breastfeeding is varied, and often subject to significant residual confounding by parity. We explored the association between ovarian cancer and childbearing patterns (parity and breastfeeding) in a large prospective cohort of UK women. Information on exposures was obtained from the baseline questionnaire. Using a Cox proportional hazards model, we estimated the relative risk (RR) of ovarian cancer in women with different childbearing patterns, after adjustment for potential confounding factors (including age, region, history of breast cancer, hysterectomy, tubal ligation, use of contraceptive or menopausal hormones, body mass index, smoking, and socioeconomic status). We used a competing risks approach to look at variation by histological subtype, and explored effects of the timing of births. Analyses of breastfeeding were restricted to parous women and stratified by parity. After excluding women with previous cancer, bilateral oophorectomy, and unknown parity, the study population included 1,146,985 women, aged 56 years on average at recruitment. 7570 incident cases of ovarian cancer accrued, after an average of 13.0 years of follow-up. Overall, women with one child had an estimated 20% reduction in the relative risk of ovarian cancer compared to nulliparous women (RR: 0.80, 95%CI: 0.74-0.87). However, this showed significant heterogeneity by histological subtype (p-het = 0.005). There was strong evidence of a reduced risk of clear cell (n = 156, RR: 0.57, 95%CI: 0.41-0.79) and endometrioid tumours (n = 220, RR: 0.64, 95%CI: 0.49-0.84), but no statistically significant reduction of mucinous (n = 234, RR: 0.82, 95%CI: 0.63-1.06) or serous tumours (n = 916, RR: 0.92, 95%CI: 0.81-1.05). Amongst parous women, each additional birth was associated with an estimated 9% reduction in the relative risk of ovarian cancer (RR: 0.91, 95%CI: 0.88-0.94), without significant subtype heterogeneity (p-het = 0.1). We found no evidence of a significant association with the age at first or last birth. After careful adjustment for parity, we found limited evidence for a reduction in ovarian cancer risk with breastfeeding. Overall, breastfeeding (ever vs never) was not associated with ovarian cancer (RR: 0.94, 95%CI: 0.89-1.00, p = 0.07), and no variation was seen by histological subtype (p-het = 0.7). However, there was a significant trend with duration of breastfeeding (p-trend <0.001). In this largest prospective study of ovarian cancer to date, our results provide new reliable evidence that childbearing has different effects on different subtypes of ovarian cancer. Citation Format: Kezia Gaitskell, Jane Green, Kirstin Pirie, Gillian Reeves, Valerie Beral. Parity, breastfeeding and ovarian cancer in the Million Women Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 873. doi:10.1158/1538-7445.AM2015-873

Wine Consumption and Epithelial Ovarian Cancer

Epithelial ovarian cancer is an insidious disease, and women are often diagnosed when the disease is beyond curative treatment. Accordingly, identifying modifiable risk factors is of paramount importance. Inflammation predisposes an individual to cancer in various organs, but whether pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer has not been fully determined. This study aimed to investigate a possible association between clinically verified pelvic inflammatory disease and the risk of epithelial ovarian cancer. In this national population-based case-control study, all women in Sweden diagnosed with epithelial ovarian cancer between 1999 and 2020 and 10 controls for each were identified, matched for age and residential district. Using several Swedish nationwide registers, data on previous pelvic inflammatory disease and potential confounding factors (age, parity, educational level, and previous gynecologic surgery) were retrieved. Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression. Histotype-specific analyses were performed for the subgroup of women diagnosed with epithelial ovarian cancer between 2015 and 2020. Moreover, hormonal contraceptives and menopausal hormone therapy were adjusted in addition to the aforementioned confounders. This study included 15,072 women with epithelial ovarian cancer and 141,322 controls. Most women (9102 [60.4%]) had serous carcinoma. In a subgroup of cases diagnosed between 2015 and 2020, high-grade serous carcinoma (2319 [60.0%]) was identified. A total of 168 cases (1.1%) and 1270 controls (0.9%) were diagnosed with pelvic inflammatory disease. Previous pelvic inflammatory disease was associated with an increased risk of epithelial ovarian cancer (adjusted odds ratio, 1.39; 95% confidence interval, 1.17-1.66) and serous carcinoma (adjusted odds ratio, 1.46; 95% confidence interval, 1.18-1.80) for the entire study population. For the subgroup of women diagnosed in 2015-2020, pelvic inflammatory disease was associated with high-grade serous carcinoma (adjusted odds ratio, 1.43; 95% confidence interval, 1.01-2.04). The odds ratios of the other histotypes were as follows: endometrioid (adjusted odds ratio, 0.13; 95% confidence interval, 0.02-1.06), mucinous (adjusted odds ratio, 1.55; 95% confidence interval, 0.56-4.29), and clear cell carcinoma (adjusted odds ratio, 2.30; 95% confidence interval, 0.90-5.86). A dose-response relationship was observed between the number of pelvic inflammatory disease episodes and the risk of epithelial ovarian cancer (Ptrend<.001). A history of pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer and a dose-response relationship is evident. Histotype-specific analyses show an association with increased risk of serous epithelial ovarian cancer and high-grade serous carcinoma and potentially also with clear cell carcinoma, but there is no significant association with other histotypes. Infection and inflammation of the upper reproductive tract might have serious long-term consequences, including epithelial ovarian cancer.

Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study. Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques. Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity&amp;gt;0.05). Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer. Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2195.

Introduction: Recently, intrauterine device (IUD) use has increased and oral contraceptive (OC) use has decreased. While OC use is known to reduce epithelial ovarian cancer (EOC) risk, previous studies of IUD use and EOC risk have shown inconsistent associations. Here, we examined the association between primarily non-hormonal IUD use and EOC risk by leveraging harmonized individual-level data from 11 case-control studies, 10 in the Ovarian Cancer Association Consortium and the African American Cancer Epidemiology Study, and 7 prospective cohort studies from the Ovarian Cancer Cohort Consortium. Methods: Contraception use was self-reported through questionnaires. Study-specific odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression (case-control studies) or time varying polytomous logistic regression models (cohort studies), adjusted for age, duration of OC use, parity, and family history of breast or ovarian cancer. Heterogeneity between studies was assessed for case-control and cohort studies separately using Cochran Q. There was no evidence of heterogeneity between studies, thus, data were pooled within each study design. Case-control and cohort pooled results were combined by random effects meta-analysis. Associations were estimated for overall EOC risk and by histotype (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous). Heterogeneity across histotypes was evaluated using a Wald test for case-control and cohort models separately. Results: Among case-control studies, data were pooled for 11, 033 cases and 13, 358 controls. A total of 1, 933 (17.5%) cases reported ever IUD use compared to 2, 656 (19.9%) controls. Among cohort studies, data were pooled for 629, 008 participants with 3, 549 incident cases. A total of 72, 546 (11.5%) participants reported ever IUD use at enrollment. The associations of ever vs. never IUD use and EOC risk were similar in case-control (pooled OR: 0.92; 95% CI: 0.86-0.98) and cohort studies (pooled OR: 1.00; 95% CI: 0.88-1.13). When meta-analyzed, there was a suggestive 5% lower odds of overall EOC among IUD users (OR: 0.94; 95% CI: 0.88-1.01; p-het = 0.26). We observed heterogeneity by histotype in case-control studies (p=0.0001) but not in cohort studies (p=0.77). After meta-analysis, results suggested that IUD use was associated with a lower risk of mucinous (OR: 0.85; 95% CI: 0.73-0.98), clear cell (OR: 0.69; 95% CI: 0.64-0.86), and low grade serous EOC (OR: 0.75; 95% CI: 0.55-1.01). Conclusion: IUD use was not associated with an increased risk of EOC in this analysis of over 12, 000 ovarian cancer cases. Our findings suggest there may be an inverse association between IUD use and risk of mucinous, clear cell, and low grade serous EOC. Analyses are ongoing and will include assessment of effect modification by parity and birth cohort, as well as consideration of timing of IUD use. Citation Format: Jennifer M. Mongiovi, Ana Babic, Allison F. Vitonis, Naoko Sasamoto, Mark K. Townsend, Brett M. Reid, Mollie E. Barnard, Holly R. Harris, Lauren Peres, Britton Trabet, Brooke L. Fridley, Katie M. O'Brien, Anita Koushik, Renee Turzanski Fortner, Jennifer A. Doherty, Joelle M. Schildkraut, Shelley S. Tworoger, Kathryn L. Terry, Ovarian Cancer Association Consortium, Ovarian Cancer Cohort Consortium. Intrauterine device use and ovarian cancer risk among 11 case-control studies and 7 prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7377.

This case-control study evaluated the risk of epithelial ovarian cancer associated with genital exposure to various forms of powder application. Cases included all women aged 20-79 years in three counties of western Washington who were diagnosed with borderline or invasive ovarian cancer from 1986 through 1988; 64.3% of eligible cases were interviewed. A sample of similarly aged women who lived in these counties, identified by random digit dialing, served as controls. The overall response among control women was 68.0%. Information on powder application and other potential risk factors was ascertained during the in-person interview. Overall, ovarian cancer cases (n = 313) were more likely than controls (n = 422) to ever have used powder (age-adjusted relative risk (RR) = 1.5, 95% confidence interval (CI) 1.1-2.0). After adjustment for age and other methods of genital powder application (none vs. any), an elevated relative risk of ovarian cancer was noted only for women with a history of perineal dusting (RR = 1.6, 95% CI 1.1-2.3) or use of genital deodorant spray (RR = 1.9, 95% CI 1.1-3.1). These results offer support for the hypothesis, raised by prior epidemiologic studies, that powder exposure from perineal dusting contributes to the development of ovarian cancer, and they suggest that use of genital deodorant sprays may do so as well. Limitations of the present study include the fairly low proportion of eligible women who participated and the potential differential recall of powder usage.

Estrogen Replacement Therapy and Ovarian Cancer

If instead of the title "Prophylactic Oophorectomy: Reducing the U.S. Death Rate from Epithelial Ovarian Cancer," the title were "Drug X Reducing the U.S. Death Rate from Epithelial Ovarian Cancer," there would be great media and medical attention worldwide to such a report. Correctly so. Regrettably, there probably is no new Drug X in the foreseeable future that will significantly reduce the death rate from ovarian cancer, be it Taxol&reg;, taxotere, topotecan, gemcitabine, or liposomal doxorubicin-although each may result in significant responses and some prolongation of median survival. Epithelial ovarian cancer is a much more complex disease than anyone envisioned, when it was believed that extensive debulking surgery and the newest cytotoxic chemotherapy would radically reduce the death rate from ovarian cancer in the United States. Over 20 years after the first patient was treated with cisplatin for epithelial ovarian cancer, the annual death rate from ovarian cancer continued to increase. Just in the past decade, the number of women in the United States dying from ovarian cancer has increased 18% (Fig. 1) [1]. Although ovarian cancer is estimated to account for 26,700 cases and 14,800 deaths in 1996, it is a low-prevalence disease in comparison with breast cancer, which in 1996 is estimated to account for 185,700 cases and 44,560 deaths. Inexplicably, similar to breast cancer, the lifetime risk for ovarian cancer in the United States continues to increase. The most recent Surveillance, Epidemiology and End Results (SEER) calculations of lifetime risk for ovarian cancer are that 1 in 55 women will develop ovarian cancer over their lifetime, or 1.8%, up from the 1970 figures of 1 in 70, or 1.4% [2]. The 1.8% baseline lifetime risk for the general population is used to estimate the lifetime risk of known ovarian cancer risk factors (Table 1). Even utilizing what are now believed to be two of the most effective cytotoxic drugs against stage III and IV epithelial ovarian cancer, Taxol&reg; and cisplatin, researchers reported that this resulted in an increase in the median disease-free survival of only five months, as compared with those women allocated to receive cisplatin and cyclophosphamide (median disease-free survival of 18 and 12.9 months, respectively), felt then to be the standard therapy [3]. Patients treated with Taxol&reg; and cisplatin survived a median of 14 months longer than those treated with cisplatin and cyclophosphamide. These results may improve in women whose cancers were optimally debulked to </=1 cm residual disease, since the current study included only women with residual cancer greater than 1 cm. Given these sobering statistics, the public health issue is whether prophylactic oophorectomy for two select groups of women may be one measure in reducing the mortality from ovarian cancer in the United States. The two groups of women are: A) women age 40 or older who undergo hysterectomy for non-cancerous uterine conditions and B) those with a family history of ovarian cancer. PROPHYLACTIC OOPHORECTOMY AT THE TIME OF HYSTERECTOMY IN WOMEN AGE 40 OR OLDER: Concerning the first group of women, researchers from the University of Miami reported that 4.5%-14.1% of women develop ovarian cancer after prior hysterectomy for non-ovarian conditions (Table 2) [4-9]. Utilizing their University of Miami experience and the three other similar series in the literature, they were able to determine the number of ovarian cancer patients who had previously undergone hysterectomy at age 40 or older for non-cancerous uterine conditions. Of the 2,632 ovarian cancer cases, they predicted that 5.2% (138) of the ovarian cancers could have been prevented if prophylactic oophorectomy were performed in women 40 years or older at the time of hysterectomy for benign disease. Confirming these results is a recent survey of the American College of Surgeons which reported that of 12,316 cases of ovarian cancer studied, 18.2% of these women had had a previous hysterectomy for benign disease with ovarian preservation, 57.4% of which were performed in women over the age of 40 [10]. Prophylactic oophorectomy in such cases has not been a uniformly accepted practice because it has been assumed that preserved ovaries continue to function normally and thus delay both the onset of osteoporosis and menopause with its effect on the cardiovascular system. However, as many as 30% of women have postmenopausal symptoms within 24 months of hysterectomy with preservation of the ovaries [11]. In addition, in an important cross-sectional study of bone density of premenopausal women who had undergone hysterectomy with ovarian conservation compared with a matched group which had not had hysterectomy, investigators reported that bone density in the hysterectomy group was significantly reduced [12]. They concluded that premenopausal women who had undergone hysterectomy with ovarian preservation will have a significantly low bone density, somewhat negating the value of ovarian preservation. Women age 40 or over who undergo prophylactic oophorectomy at the time of hysterectomy for benign uterine conditions can be started immediately on hormone replacement therapy, thus helping to prevent loss of bone density and the onset of osteoporosis. PROPHYLACTIC OOPHORECTOMY IN WOMEN WITH A FAMILY HISTORY OF OVARIAN CANCER: Since familial (also known as site-specific or hereditary) ovarian cancer is considered to be an autosomal dominant inheritance with variable penetrance, sisters and daughters of families with a history of familial ovarian cancer (two or more first-degree relatives [mother, sister, daughter-who share one-half of one's genes]) may have as high as a 50% chance of inheriting the deleterious gene. Easton has estimated that for women with a BRCA1 mutation, the lifetime risk for developing ovarian cancer by age 70 is 63% [13]. The lifetime risk for BRCA2 mutations has not yet been calculated [14]. We have included women with two or more first-degree or a first- and second-degree relative with epithelial ovarian cancer as having a history of familial ovarian cancer. However, the Breast Cancer Linkage Consortium stated that "families with three or more cases of ovarian cancer are generally considered to be examples of hereditary ovarian cancer" [15]. In 1982, we first recommended prophylactic oophorectomy in women with a history of familial ovarian cancer. This definition included any woman with two or more first-degree or first- and second-degree relatives with epithelial ovarian cancer [16]. Because of what appeared to be an apparent increase in frequency of familial ovarian cancer in the 1970s, the Familial Ovarian Cancer Registry was formed in 1981 to further evaluate familial ovarian cancer syndrome. The Registry, renamed the Gilda Radner Familial Ovarian Cancer Registry in 1989 in memory of the late comedienne after her death from ovarian cancer, has registered as of June 1996, 1,376 families with ovarian cancer. A report on the first 1,000 families was recently published [17]. Previously, it was estimated that 5%-10% of all ovarian cancers are hereditary. However, scientists from the University of Pennsylvania believed the estimate of ovarian cancer cases that are hereditary may be as high as 20%, based on their recent report of germline BRCA2 mutations in women with ovarian cancer but without a family history of ovarian cancer [18]. In the CASH study, researchers compared 493 women with ovarian cancer to 2,465 matched controls [19]. The relative risk for ovarian cancer for any first-degree relative was 3.6, resulting in a lifetime risk of 6.5% (Table 1). However, if the mother was the first-degree relative with ovarian cancer, the relative risk was 4.3 and the lifetime risk was 7.5%. Although the latter risk is almost four times that of the general population, it is currently not recommended that women with only one first-degree relative with ovarian cancer undergo prophylactic oophorectomy. This recommendation would also be applicable to women with a strong family history of breast cancer but only one case of ovarian cancer in their family and to hereditary non-polyposis colorectal cancer (Lynch Syndrome II) if there were only one case of ovarian cancer. However, if a first-degree relative in a family with only one case of ovarian cancer carries the same BRCA1 or BRCA2 mutation as the germline mutation in the patient with ovarian cancer, prophylactic oophorectomy would be indicated. Using complex segregation analysis in evaluating the observed number of cases of ovarian cancer as compared with the expected number of cases during the same time period in England and Wales, researchers from the Ovarian Cancer Screening Clinic at Kings College Hospital in the United Kingdom studied 391 ovarian cancer family pedigrees [20]. The overall risk for any first-degree relative (8.1%) was almost exactly the same as that of the CASH study (Table 1). However, if the mother developed ovarian cancer before the age of 45, the relative risk was 14.2 with a calculated lifetime risk of 25%. This young age is consistent with an inherited cancer even with only one first-degree relative. If this study can be confirmed by other researchers, then prophylactic oophorectomy in women who have one first-degree relative who developed ovarian cancer before the age of 45 would indeed be indicated. As previously stated, we have used the definition of familial ovarian cancer as any family with two or more first-degree (mother, sister, daughter) or first- and second-degree relatives (grandmother, aunt) with epithelial ovarian cancer, and, further, that these women are candidates for prophylactic oophorectomy after age 35 if they have completed their family and desire the surgery. In contrast, the Breast Cancer Linkage Consortium studying inherited ovarian and breast cancer stated that "families with three or more cases of ovarian cancer are generally considered to be exa

Frequency of Ovulation Increases Ovarian Cancer Risk: Purdie DM, Bain CJ, Siskind V, Webb PM, Green AC. Ovulation and the Risk of Epithelial Ovarian Cancer. Int J Cancer 2003;104:228–32.

To estimate the relative risks and population attributable risks of ovarian cancer associated with family histories of cancer at several sites. A matched case-control analytic study (662 cases, 2647 controls), employing the Utah Population Database, a genealogy of approximately 1 million individuals linked to cancer incidence data from the Utah Cancer Registry. Family history was assessed using kinship order and a kinship-weighted familial standardized incidence ratio statistic. Family histories of ovarian, uterine, breast, and pancreatic cancer were significantly associated with increased risk of ovarian cancer. The relative risk of ovarian cancer was 4.31 (95% confidence interval [CI], 2.35 to 7.90) for women with a first-degree relative with ovarian cancer, 2.12 (95% CI, 1.19 to 3.78) for women with an affected second-degree relative, and 1.48 (95% CI, 0.98 to 2.24) for women with an affected third-degree relative. The odds ratio (OR) was 2.06 (95% CI, 1.44 to 2.93) for those with the highest familial standardized incidence ratio. No age differences were observed between cases with and without a family history of ovarian cancer. There was substantial heterogeneity of family history effects by cell type. Increased parity was not protective among women with a strong family history of cancer at the sites studied (OR, 1.11; 95% CI, 0.38 to 3.26), although it was protective among women without a family history of these cancers (OR, 0.29; 95% CI, 0.11 to 0.62). The risk of ovarian cancer was substantially increased among women with family histories of ovarian, uterine, pancreatic, and, to a lesser degree, breast cancer. Among women with family histories of any of these cancers, the risk of ovarian cancer is not diminished by high parity.

Carotenoids, found in fruits and vegetables, have the potential to protect against cancer because of their properties, including their functions as precursors to vitamin A and as antioxidants. We examined the associations between intakes of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin and lycopene and the risk of invasive epithelial ovarian cancer. The primary data from 10 prospective cohort studies in North America and Europe were analyzed and then pooled. Carotenoid intakes were estimated from a validated food frequency questionnaire administered at baseline in each study. Study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Among 521,911 women, 2,012 cases of ovarian cancer occurred during a follow-up of 7-22 years across studies. The major carotenoids were not significantly associated with the risk of ovarian cancer. The pooled multivariate RRs (95% confidence intervals) were 1.00 (0.95-1.05) for a 600 microg/day increase in alpha-carotene intake, 0.96 (0.93-1.03) for a 2,500 microg/day increase in beta-carotene intake, 0.99 (0.97-1.02) for a 100 microg/day increase in beta-cryptoxanthin intake, 0.98 (0.94-1.03) for a 2,500 microg/day increase in lutein/zeaxanthin intake and 1.01 (0.97-1.05) for a 4,000 microg/day increase in lycopene intake. These associations did not appreciably differ by study (p-values, tests for between-studies heterogeneity >0.17). Also, the observed associations did not vary substantially by subgroups of the population or by histological type of ovarian cancer. These results suggest that consumption of the major carotenoids during adulthood does not play a major role in the incidence of ovarian cancer.

The continued use of oral contraceptives has historically been believed by users to increase their risk of developing ovarian cancer. This belief has not been widely supported. Researchers have identified two factors that are associated with increased risk of epithelial ovarian cancer: family health history and nulliparity. This paper reports on a study of OC use and associated ovarian cancer risk levels. Data used in this investigation were from a US case-control study of breast ovarian and endometrial cancer initially conducted by the Cancer and Steroid Hormone Study. OC use among 494 women diagnosed with epithelial ovarian cancer was compared to 4238 women who were cancer-free. Four groups were studied for cancer incidence rates: parous women nulliparous women and women with and women without a family history of cancer. Three age groups (ages 40 50 and 55) were summarized for rate comparison. Effect of duration of OC use was also figured in and analyzed with a weighted least-squares regression. Researchers estimated that 1 year of OC use would reduce the relative risk of ovarian cancer by 17% 5 years of use would reduce risk by 48% and 10 years of use would reduce risk by 60%. Cancer rate estimates for nulliparous non-OC-using women yielded 165 cancer cases per 100000 nulliparous women by age 40 543/100000 by age 50 and 862/100000 by age 55.

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR≥4vs.0: 1.74, 95% CI: 1.20–2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR≥4vs.0: 1.99, 95% CI: 1.06–3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR≥4vs.0: 1.46, 95% CI: 0.68–3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.

We studied the association between cigarette smoking and ovarian cancer in a population-based case control study. A total of 794 women with histologically confirmed epithelial ovarian cancer who were aged 18-79 years and resident in one of three Australian states were interviewed, together with 855 controls aged 18-79 years selected at random from the electoral roll from the same states. Information was obtained about cigarette smoking and other factors including age, parity, oral contraceptive use, and reproductive factors. We estimated the relative risk of ovarian cancer associated with cigarette smoking, accounting for histologic type, using multivariable logistic regression to adjust for confounding factors. Women who had ever smoked cigarettes were more likely to develop ovarian cancer than women who had never smoked (adjusted odds ratio (OR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Risk was greater for ovarian cancers of borderline malignancy (OR = 2.4; 95% CI = 1.4-4.1) than for invasive tumors (OR = 1.7; 95% CI = 1.2-2.4) and the histologic subtype most strongly associated overall was the mucinous subtype among both current smokers (OR = 3.2; 95% CI = 1.8-5.7) and past smokers (OR = 2.3; 95% CI = 1.3-3.9). These data extend recent findings and suggest that cigarette smoking is a risk factor for ovarian cancer, especially mucinous and borderline mucinous types. From a public health viewpoint, this is one of the few reports of a potentially avoidable risk factor for ovarian cancer.