Age as a risk factor for ovarian cancer needs to be placed within the context of other events in a woman's life. Overall, age is considered a risk factor because ovarian cancer is a disease of older women. The annual incidence of ovarian cancer worldwide, regardless of age, is 42 cases per 100,000. The annual incidence of ovarian cancer in women between the ages of 75 and 79 years in the United States is 61.3 per 100,000, higher than any other age group, when age is considered independent of all other risk factors. When all other risk factors are considered, incidence is highest in women between the ages of 60 and 64 years.
Age at menarche is considered a weak predictor of ovarian cancer risk. A moderate increase in risk for ovarian cancer occurs in women when menarche begins earlier than age 12 years.[1,15] No association was found when menarche begins after age 16 years.[16,20] Age at natural menopause has been studied. Positive associations were found with late age of natural menopause and risk for ovarian cancer.[15,16,17] Odds ratios for late natural menopause were reported as low as 1.19 and as high as 1.25 (95% CI, 0.95-1.49).[1,16] The ratios did not achieve statistical significance, but late natural menopause was associated with increased risk for ovarian cancer.
Recently, maternal age at last birth was implicated in decreasing the risk for ovarian cancer if the last birth was at age 35 years or older. This finding is important because it compared nulliparous (never pregnant) women with women who had late first-time live births. These findings suggest that regardless of age at first birth, pregnancy still confers a significant risk reduction for the development of ovarian cancer. The protective effects of pregnancy may be associated with the decrease in ovulation associated with higher levels of progestins.
Chronic Inflammation and Nonsteroidal Anti-inflammatory Drugs
Chronic inflammation caused by talc and/or asbestos is a known risk factor for ovarian cancer. In addition, patients with ovarian cancer have a higher incidence of endometriosis and pelvic inflammatory disease.[13,20] These inflammatory processes may contribute to the development of ovarian cancer through a variety of mechanisms. Much of the available data on inflammation and cancer come from studies that evaluated the effect of NSAIDs on cancer risk.[24,25,26,27,28]
Nonsteroidal anti-inflammatory drugs have strong anticarcinogenic effects, and experimental evidence suggests that NSAIDs can impact the tumorigenic pathways in cancers of the small and large bowel. Four studies examined the relationship between aspirin use and ovarian cancer.[24,25,26,27] In three (Refs. 25, 26, and 28) of the 4 studies, as aspirin use increased, ovarian cancer risk decreased. Mechanistically, NSAIDs have many physiological effects. Three of these may be pertinent to the development of ovarian cancer. First, NSAIDs interrupt the synthesis of prostaglandins, which decreases inflammation. Second, NSAIDs cause apoptosis (ie, cell death) of human epithelial cancer cells. Finally, NSAID use may reduce the local inflammatory processes associated with endometriosis and pelvic inflammatory disease.[20,28]
Data on the protective effects of NSAID use in relationship to ovarian cancer in premenopausal women are confounded by the high frequency of use of these medications in women of this age. It is difficult to determine the exact mechanisms by which NSAIDs decrease ovarian cancer risk, because NSAID use has never been measured prospectively in patients who later developed the cancer. All of the retrospective studies [25,26,27] had small samples and did not quantify the exact dose of NSAIDs used. Future research needs to clarify the role of inflammation in the development of ovarian cancer before routine use of NSAIDs as preventative agents can be recommended.
The protective effects of fruits and vegetables have been investigated in other cancers and are of interest to ovarian cancer researchers. The role of milk and other dairy products, meat consumption, fat consumption, carbohydrate intake, and alcohol use have been investigated. However, only a few studies have evaluated the impact of dietary factors on ovarian cancer risk.[29,30,31,32,33,34,35,36,37,38,39]
One of the first studies to examine the association between dietary factors and the risk for ovarian cancer was conducted in northern Italy. This study described the influence of red meat, alcohol, dietary fat, vegetable oil, and butter consumption on ovarian cancer risk. This case-control study compared 455 patients with ovarian cancer with 1,385 age-matched controls. No relationship was found between alcohol use and ovarian cancer risk. Dietary factors that increased the relative risk (RR) for ovarian cancer included meat consumption of more than 7 portions versus less than 4 portions per week (RR, 1.6; 95% CI, 1.21-2.12) and butter versus fat consumption (RR, 1.9; 95% CI, 1.20-3.11). However, disparate measures of body weight, socioeconomic status, parity, and contraceptive use confounded these analyses. Dietary factors that decreased ovarian cancer risk included consumption of whole-grain bread and pasta (RR, 0.60; 95% CI, 0.41-0.88).
A larger cohort study in the United States that enrolled 29,083 postmenopausal women found that ovarian cancer risk was not associated with dietary fat intake, but did find that eggs increased the RR when consumed 2 to 4 times per week (RR, 2.04; 95% CI, 1.23-3.36). This study found that green leafy vegetables were strongly associated with decreased risk for ovarian cancer (RR, 0.44; 95% CI, 0.25-0.79). No consistent association was found with meats, breads, cereals, and starches. However, this study did find statistically significant associations between increased risk for ovarian cancer and intake of sweets and dairy.
Whereas 6 population-based studies[30,36,37,38,39,43,54] have examined the relationship between alcohol intake and ovarian cancer risk, only one found a statistically significant association. However, this study showed that an intake of 10 g/d of alcohol decreased the risk for ovarian cancer by 50%. At the present time, no definitive conclusions can be drawn about the association between alcohol consumption and ovarian cancer risk.
Only a few studies have reported differences in the incidence of ovarian cancer among ethnic groups, primarily because of their small sample sizes. However, data from 2 meta-analyses[18,19] suggest that the rates of epithelial ovarian cancer are higher in white women (OR, 0.70; 95% CI, 0.52-0.94) compared with black women (OR, 0.62; 95% CI, 0.24-1.6). An examination of potential ethnic differences in ovarian cancer rates and other factors, such as breast-feeding, OCP use, and parity, found that ethnicity explained only a small proportion of why the ovarian cancer rates were higher in white women.
Ovarian cancer seems to be the only gynecologic malignancy in which race does not impact overall survival, as mortality is high across all racial groups. Ethnicity does play a role in incidence, as women of Ashkenazi Jewish descent are at greater risk for BRCA1/2 mutations, which gives them an overrepresentation in the numbers of HOC cases.
Hormone Replacement Therapy
Several studies[40,41,42] have tried to determine whether the use of postmenopausal HRT is associated with increased risk for developing ovarian cancer. However, these studies have yielded inconclusive results. Several variables need to be considered when reviewing the literature about HRT including duration of use, type of hormones, circumstances of use (eg, surgical menopause vs natural menopause), reproductive history, and previous history of cancer in any organ.
Hormone replacement therapy is defined as any hormone orally ingested in combination (estrogen-E4 plus progesterone-P2) or E4. Other routes of administration (ie, creams, injections, patches) are not included in this definition, as these methods of HRT delivery have not been included in research studies that have attempted to understand HRT use and cancer risk.
It was originally thought that postmenopausal women would benefit from the supplemental use of exogenous estrogen and progesterone. Until the Women's Health Initiative, it was believed that the protective effects to the cardiovascular system and the prevention of bone loss outweighed the risks of HRT. However, several meta-analyses have questioned data originally used to support postmenopausal HRT use and risk for ovarian cancer.[40,41]
As previously discussed in the prophylactic oophorectomy section, hysterectomy confers a decrease in ovarian cancer risk.[23,40,42] In a large case-control study, risk for ovarian cancer was decreased by 36% (RR, 0.64; 95% CI, 0.48-0.85), and tubal ligation decreased risk by 39% (RR, 0.61; 95% CI, 0.46-0.85). In high-risk women, hysterectomy has also been studied, which decreases ovarian cancer risk by 50%.[13,22,42]
Infertility Drug Use
Clomiphene was approved in 1967 to treat primary infertility. Several epidemiological studies have questioned if ovarian hyperstimulation mimics "incessant ovulation" and therefore increases the risk for ovarian cancer.[43,44,45,46,47,60] The use and doses of clomiphene and human gonadotropins (eg, menotropins [Pergonal and Humegon] and urofollitropin [Metrodin]) were not reported consistently in infertility research studies. This inconsistency in reporting makes meta-analytic procedures difficult to use to estimate the true relationship between infertility drug use and ovarian cancer. Initial studies estimated that the risk for epithelial ovarian cancer associated with the use of infertility drugs was as high as 27-fold for nulligravida women (95% CI, 2.3-315.6). A subsequent, larger, and more rigorous study found that the use of clomiphene resulted in a 2.3 increased risk for ovarian cancer in nulligravida women (95% CI, 0.5-11.4).
Three studies[45,46,47] did not find an increased risk for ovarian cancer when clomiphene and gonadotropins were evaluated. These studies were rigorously designed, included an analysis of all hormonal stimulants, and followed up patients through in vitro fertilization for up to 15 years. However, a large Danish study that enrolled 684 cases and 1,721 controls found an increased incidence of cancer in women with a history of infertility. The overall OR in all women in the study with known fertility status for ovarian cancer was 1.54 (95% CI, 1.22-1.95). The unadjusted OR for ovarian cancer in infertile nulliparous women who were not treated for infertility was 3.13 (95% CI, 1.60-6.08). This 3-fold increase was observed even after adjustment for infertility treatment, drug type, and pregnancy outcome (ie, miscarriage, induced abortion, ectopic pregnancy), where the adjusted OR was 2.71 (95% CI, 1.33-5.52).
A large, retrospective, cohort study was conducted to determine if a true association existed between fertility drug use and increased risk for ovarian cancer. This study enrolled 12,193 women, and data included a survey of death records, registry data, historical medical records, interviews with patients, follow-up of in vitro fertilization clinic data, and mailed surveys. The standardized incidence ratio (IR) was 1.98 (95% CI, 1.4-2.6), where women exposed to clomiphene (ie, IR, 0.82; 95% CI, 0.4-1.5) or gonadotropins (ie, IR, 1.09; 95% CI, 0.4-2.8) had a decreased risk for ovarian cancer.
Ovarian hyperstimulating drugs have been used in the United States for only 37 years. Therefore, many women who have used these drugs have not reached the median age of highest-incidence ovarian cancer. Future studies need to follow up these women throughout their menopausal experience to determine the true risk for ovarian cancer.
Obesity is a risk factor for ovarian cancer because of its relationship to sex steroid hormones. Obesity is known to increase adrenal secretion of androgens, enhance conversion of gonadal and adrenal androgens to biologically active estrogens, and reduce sex hormone-binding globulin capacity, which increases the amount of free, biologically active estradiol. Adipose tissue is the primary source of endogenous estrogens in postmenopausal women.[50,51]
Several studies have evaluated the impact of obesity on ovarian cancer risk using body mass index (BMI) as the measure of obesity.[48,49,50,51] Body mass index is defined as weight in kilograms divided by height in meters squared. Several studies have reported a 70% increased risk for ovarian cancer in obese patients (OR, 1.7; 95% CI, 1.1-2.7). However, these estimates were based on cutoffs where BMI of less than 19.8 kg/m2 was considered "normal" weight and BMI of greater than 24.1 kg/m2 was considered obese. Current guidelines from the National Heart, Lung, and Blood Institute define a normal BMI to be 18.5 to 24.9 kg/m2; overweight, 25 to 29.9 kg/m2; obesity class 1, 30 to 34.9 kg/m2; obesity class 2, 35 to 39.9 kg/m2; and extreme obesity as greater than 40 kg/m2. Another study using the new guidelines and with a larger sample confirmed the association between obesity and increased risk for ovarian cancer at 70%. In addition, obesity was associated with increased mortality in lesbian women with ovarian cancer.
Oral Contraceptive Use
As previously discussed, OCP use confers significant risk reduction for ovarian cancer. Other routes of hormonal contraception, including the Ortho Evra (Ortho-McNeil-Janssen Pharmaceuticals, Raritan, NJ) patch, Nuva Ring (Organon, Shering-Plough, Kenilworth, NJ), Mirena (Bayer Healthcare Pharmaceuticals, Wayne, NJ) IUD, and medroxyprogesterone acetate/Depo Provera (Pfizer, NY, NY), have not been studied in terms of risk association in ovarian cancer. Future research needs to determine if other routes of administration of hormonal contraception confer similar protective effects.
The American College of Obstetrics and Gynecology developed standardized nomenclature to refer to the pregnancy history of women. Gravidity refers to the number of times a woman was pregnant in her lifetime. Parity refers to numbers of births. Parous women have a lower risk for ovarian cancer than nulliparous women (OR, 0.76; 95% CI, 0.63-0.93).[13,16] Women with term pregnancies (OR, 0.87; 95% CI, 0.76-0.91) versus failed pregnancies (OR, 0.93; 95% CI, 0.59-1.48) have lower ORs, with a risk reduction of about 14% for each subsequent pregnancy after the first. Data suggest a 40% decrease in the risk for epithelial ovarian cancer with the first live birth.[13,16] These data support theories that suggest that the hormonal changes associated with pregnancy provide a respite from continuous ovarian exposure to estrogen, a known mitogen.
Although cigarette smoking as a causative factor for other gynecologic cancers is well documented,[1,2] the relationship between smoking and ovarian cancer is not as clear. However, metabolites of nicotine, including cotinine and benzo[a]pyrene-DNA (B[a]P-DNA) adducts, have been found in ovarian follicular cells. In addition, polycyclic hydrocarbons such as dimethylbenzanthracene are known to induce ovarian cancer in rodents. The theoretical mechanisms that may explain how cigarette smoke impacts malignant ovarian transformation include altering steroid metabolism and concentration and impairing ovarian function. Seven studies have examined the relationship between smoking and ovarian cancer risk.[51,54,55,56,57,58,59] Five of these studies were conducted outside the United States and found a statistically significant relationship between smoking and increased risk for ovarian cancer.[51,53,57,58,59] However, 2 studies conducted in the United States failed to confirm this finding.[55,57]
Talc Use/Asbestos Exposure
Talcum powder (talc) use was implicated in ovarian cancer risk in the early 1960s when it was found to be biologically similar to asbestos, a known carcinogen. Women exposed to asbestos in their reproductive years have a 2-fold increased risk for ovarian and other cancers of the pelvis in a dose-dependent manner. Several studies found a positive association between talc use and increased risk for ovarian cancer.[61,62,63,64] These studies evaluated perineal application; use of talc in sanitary napkins/pads as well as first application at birth, at puberty, or in adulthood; and exposure to asbestos. A meta-analysis of 16 studies that included 11,933 patients examined the effect of talc use and increased risk for ovarian cancer. The use of talc conferred a 33% increased risk for ovarian cancer (RR, 1.33; 95% CI, 1.16-1.45). Two mechanisms are responsible for the increased risk for ovarian cancer in peritoneal talc users. The first mechanism is that the talc particles become entrapped in the ovarian surface epithelium, causing physiological responses similar to incessant ovulation. The second mechanism postulates that the presence of talc during ovulation allows it to be absorbed into the pelvic cavity where it is found in inclusion cysts. The foreign body in the inclusion cyst ultimately forms a granuloma and initiates an acute inflammatory response. It is this inflammatory response that is thought to lead to DNA damage, beginning the cascade of events necessary for tumorigenesis.
Cancer Nurs. 2009;32(4):281-288. © 2009 Lippincott Williams & Wilkins
Cite this: Epidemiological and Genetic Factors Associated With Ovarian Cancer - Medscape - Jul 01, 2009.