Predisposing risk factors for ovarian cancer and its prevention
Qilu Hospital of Shandong University (Jinan, 250012) Beihua Kong Kun Song
Abstract: Epithelial ovarian cancer (EOC) ranks first in the mortality rate of malignant tumors of the female reproductive system. Its etiology is unknown, but several risk factors for ovarian cancer have been confirmed by research findings. Among them, hereditary factors are the main and most certain high-risk factors. For people with BRCA1/2 gene mutation, prophylactic bilateral adnexal resection is currently considered the most effective ovarian cancer prevention measure. Besides, pregnancy, breastfeeding, oral contraceptives, tubal ligation and hysterectomy are considered as protective factors for ovarian cancer; while hormone replacement therapy, talc, smoking and obesity are high-risk factors for ovarian cancer, which should be avoided with care. Song Kun, Department of Gynecology, Qilu Hospital, Shandong University
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer deaths. Although the etiology of ovarian cancer is unclear, many Chief among these is the family history of the disease. Based on the identification of these risk factors, the incidence of ovarian cancer can be reduced by pregnancy, lactation, the oral contraceptive pill and tuberculosis, Some evidence suggests the risk can also be reduced by eating a diet rich in fruit and vegetables, avoiding smoking, avoiding being overweight and tubal ligation. Some evidence suggests the risk can also be reduced by eating a diet rich in fruit and vegetables, avoiding smoking, avoiding being overweight and avoiding long-term use of unopposed hormonal replacement therapy (HRT). Strategies available to high-risk women include screening and prophylactic salpingo-oophorectomy, which is the most effective method of cancer risk Besides, more and more evidence shows that oral contraceptives is also protective to ovarian cancer.
In the United States, 21,550 new cases of ovarian cancer and 14,600 deaths were estimated in 2009, ranking the second highest incidence of female reproductive malignancies and the first highest death rate [1]. Ovarian cancer has an insidious onset, and most patients are diagnosed at an advanced stage with poor prognosis. Therefore, it is a major test for gynecologic oncologists to explore the risk factors for ovarian cancer, screen the high-risk groups for ovarian cancer, and prevent the occurrence of ovarian cancer. Over the years, scholars at home and abroad have devoted themselves to the screening and prevention of ovarian cancer high-risk factors and have made definite research results, which are introduced as follows.
1. High-risk factors of ovarian cancer
1.1 Fertility factors
At present, it is generally believed that “persistent ovulation” (incessant ovulation) can lead to ovarian epithelial damage and induce malignant transformation of epithelial cells. Based on this theory, women who have not yet given birth, have early menarche, or have delayed menopause are at increased risk of ovarian cancer due to excessive ovulation during their lifetime. Conversely, prolonged anovulation of the ovaries during pregnancy and lactation is a protective factor for ovarian cancer. One study showed a decreased risk of ovarian cancer in menstruating women compared to women who did not have children, with a dominance ratio (Odds Ratios, ORs) of 0.3 to 0.7, and the risk continued to decrease with increasing number of deliveries, with a 10-15% reduction in ovarian cancer risk per pregnancy. In addition, abortion or preterm delivery has been found to slightly reduce the risk of ovarian cancer; pregnancy also has a protective effect on borderline ovarian tumors (BOTs), but its protective effect is weaker than that of epithelial tumors [2-4]. -4].
Breastfeeding reduces the risk of breast cancer, as well as the risk of ovarian cancer due to suppressed ovarian function and persistent anovulation during lactation. Data from two prospective cohort studies showed that women who breastfed for a mean of 9 months had a reduced risk of ovarian cancer compared to the non-lactating group (RR = 0.86), but the difference was not significant, while women who breastfed for a mean of 18 months or more had a significantly lower risk (RR = 0.66). However, some studies have also shown no significant correlation between the duration of breastfeeding and the risk of morbidity [5].
A large number of statistics show that age at menarche and menopause are associated with the risk of ovarian cancer. Women with early menarche or delayed menopause have an increased lifetime total number of ovulations and an increased risk of ovarian cancer. Some studies have shown a moderate increase in ovarian cancer risk in women with menarche age less than 12 years compared to women older than 14 years; women with delayed menopause have an ovarian cancer risk of 1.5 to 2.9 compared to women with younger menopause age [6, 7]. However, some studies have also concluded that menstruation is not associated with ovarian cancer.
Similar to infertile women, patients with infertility have an increased risk of ovarian cancer per se (RR = 2.67). However, it has been suggested that the risk of ovarian cancer is increased only in infertile women who have never had a pregnancy and delivery, and that there is no increased risk in treated infertile women who have a successful pregnancy and delivery compared to the general population. Frequent use of ovulation-promoting drugs such as clomiphene, HCG, and HMG in infertility patients theoretically exacerbates ovarian epithelial damage and increases the risk of ovarian cancer. However, data from studies have shown that the risk of ovarian cancer does not increase with the use of ovulation-promoting drugs. Because of the complex etiology of infertility and the many factors affecting it, it is difficult to thoroughly evaluate the effect of ovulation-promoting drugs on the risk of ovarian cancer in women with infertility [8-10].
Hormone replacement therapy
Most studies have concluded that hormone replacement therapy (HRT) can increase the risk of ovarian cancer. In the well-known Women Health Initiative (WHI) study, the Hazard Ratio (HR) for ovarian cancer in women treated with sequential HRT with estrogen and progestin compared to the placebo group was 1.58 [11]. Replacement Therapy (ERT) was associated with a significantly higher risk of ovarian cancer (RR = 1.6) and the risk value was related to the duration of ERT: 10-19 years on hormones, RR = 1.8; more than 20 years on hormones, their RR value was up to 3.2, with a statistically significant difference in ovarian cancer risk between the two groups of women (p < 0.001). The RR increased by 7% for each additional year of average estrogen use. The study also reported a relative risk of ovarian cancer of 1.5 in women who had previously used estrogen alone and later switched to combined estrogen-progestin therapy, compared with a relative risk of 1.1 in women who started with combined estrogen-progestin therapy [12]. The results of another study in the United States showed that the risk of ovarian cancer was significantly higher in women who did not use an allopathic progestin in the HRT regimen compared to those who used progestin (OR 1.8 vs. 1.1), suggesting that progestin allopathy has some protective effect against ovarian cancer [13]. A Swedish study further reported that progestin regimens were also associated with ovarian cancer risk, with women receiving sequential progestin therapy having an increased risk of ovarian cancer compared to those not receiving HRT (OR = 1.53); while women receiving continuous progestin HRT had no increased risk of ovarian cancer (OR = 1.02) [14]. The results of the million women study in the UK were recently published in the Lancet. Nearly one million postmenopausal women participated in this study (n = 948,576), 30% of whom were receiving HRT and 20% of whom had previously received HRT. 5.3 years of follow-up were given for common cases, with 2273 cases of ovarian cancer occurring during the follow-up period; 6.9 years of follow-up were given for deaths, with 1591 deaths occurring during the follow-up period. The results of the study showed that women who were receiving HRT had an increased risk of ovarian cancer (RR=1.2) and an increased risk of death (RR=1.23) compared with those who had never received HRT, and the risk increased as the duration of HRT increased. Another important finding of this study was that the risk of ovarian cancer was inconsistent among different tissue subtypes, with a statistically significant difference of 1.53, 0.72, 1.05 and 0.77 for plasmacytoma, mucinous carcinoma, endometrioid carcinoma and clear cell carcinoma, in that order. According to the article calculations, from 1991 to 2006, because of the application of HRT increased the number of ovarian cancer in the UK by 1300, of which 1000 died [15].
The reason for the high risk of ovarian cancer due to HRT has not been clarified. It has been suggested that it is related to the long-term stimulation by estrogen. Progestin inhibits ovarian epithelial proliferation and promotes cell differentiation and apoptosis, which has a protective effect against ovarian cancer, and the progestin-containing HRT regimen in the above study reduced the risk of ovarian cancer supporting this theory. In addition, one study found that women who underwent ERT after hysterectomy did not have an increased risk of ovarian cancer [14]; therefore, it is speculated that menstrual reflux caused by withdrawal bleeding after HRT is associated with an increased risk of ovarian cancer.
Gynecologic surgery
Hysterectomy and tubal ligation are considered to be protective factors against ovarian cancer. Women with prior hysterectomy have a reduced risk of ovarian cancer, with studies reporting ORs of 0.58 to 0.78; data from several studies suggest that tubal ligation may reduce the risk of ovarian cancer by 10-80%.JAMA reported the results of a prospective U.S. study in which 121,700 registered nurses participated (Nurses’ Health Study). Health Study), in which women with previous tubal ligation had a significantly lower risk of ovarian cancer (RR = 0.33) and women with previous hysterectomy also had a lower risk of ovarian cancer (RR = 0.67) [16].
Bilateral oophorectomy undoubtedly reduces the risk of ovarian cancer, but there is no definitive conclusion as to whether the ovaries should be removed at the same time as conventional hysterectomy. It is generally accepted that postmenopausal women should routinely have their ovaries removed at the same time to prevent ovarian cancer or other ovarian diseases, but it has also been suggested that removal of the ovaries leads to endocrine disruption and that the side effects are even higher than the positive effects. “In a follow-up report of the Nurses’ Health Study, 29,380 nurses had undergone hysterectomy, 16,345 (55.6%) had their ovaries removed at the same time, and 13,035 (44.4%) had their ovaries preserved. However, the risk of lung cancer (HR = 1.26) and overall cancer mortality (HR = 1.17) increased after removal of the ovaries, and the risk of other diseases such as coronary heart disease and cerebral hemorrhage increased (HR = 1.17). (HR = 1.17, 1.14), and overall mortality (HR = 1.12) [17].
Gynecological diseases
Endometriosis is a benign gynecological disease, and the cyclic alteration of its lesions can induce local inflammatory responses to secrete mediators such as cytokines, which has been suggested as a potential risk factor for ovarian cancer. Unlike other risk factors for ovarian cancer, endometriosis is mainly associated with endometrioid and clear cell carcinoma [18]. One study reported an increased risk of ovarian cancer in women with previous endometriosis compared to controls (OR = 1.6), particularly an almost threefold increase in the risk of endometrioid and clear cell carcinoma [19]. Another Canadian study also confirmed an increased risk of ovarian cancer in endometriosis (RR = 1.6), where endometrioid and clear cell carcinomas accounted for 24.4% and 21.9% of ovarian cancers associated with endometriosis, respectively, significantly higher than the proportion of both in pathological subtypes of ovarian cancer in the normal population [20]. Other benign gynecological diseases such as pelvic inflammatory disease and polycystic ovary syndrome have been reported to be associated with ovarian cancer, but there is no consistent conclusion and more studies are needed to confirm this.
Environmental factors
Talcum powder is a potential risk factor for ovarian cancer. Exposure to talcum powder in the female reproductive tract increases the risk of ovarian cancer by approximately 30%, and it mainly increases the risk of ovarian plasma cancer. In vitro cytological experiments revealed that talc particles promote the proliferation and transformation of ovarian mesenchymal and epithelial cells, and animal experiments confirmed that after vulvovaginal exposure to talcum powder it can migrate upward to the abdominal cavity and wrap around the ovarian surface epithelium, inducing a response similar to ovulation, which further induces cancer [21].
Smoking is a high risk factor for several cancers, but there is insufficient evidence to elucidate its effect on ovarian cancer. The results of a Meta-analysis found a 1-fold increased risk of ovarian mucinous carcinoma in women who smoked, but their risk decreased to normal population levels after smoking cessation [22]. The relationship between alcohol and ovarian cancer is not yet clear, and it is generally believed that there is no correlation between the two. High-dose alcohol consumption has been reported to increase the risk of mucinous carcinoma of the ovary.
Dietary factors
High fat diet and obesity are high risk factors for ovarian cancer, while people who consume more vegetables and fruits and other vegetarian foods have a lower risk of ovarian cancer. The incidence of ovarian cancer is higher in developed countries than in developing countries, where the diet is more meat-based. Data from the study showed that women who ate more meat had an increased risk of ovarian cancer compared to those who ate the least meat (OR = 1.53); in contrast, vegetables and fruits were protective against ovarian cancer (OR = 0.81). In an Australian study, overweight and obesity were shown to be high risk factors for ovarian cancer (OR = 1.5).
It has been suggested that coffee and sugar can increase the risk of ovarian cancer, while tea consumption has a protective effect on ovarian cancer, and the protective effect becomes stronger as the duration of tea consumption increases. Other dietary factors such as fiber, carotenoids, and vitamins have been suggested to reduce ovarian cancer risk to some extent, but are not conclusive [23].
Ethnic economic factors
The incidence of ovarian cancer is higher in developed Western countries such as Europe and North America than in developing countries. Study data reported that the highest global ovarian cancer incidence rate is 14.9/10,0000 in Sweden and 13.3/10,0000 in the United States, while the incidence rate of ovarian cancer in India is only 4.6/10,0000.
As an immigrant country, the United States has a wide variation in ovarian cancer incidence rates by race within the country. Data from the North American Consortium of Tumor Registries indicate that of the 59,277 patients with invasive ovarian cancer, 90.2% were white women, 6.1% were black, 2.7% were Asian, and 0.1% were Indian. This difference may be related to race, but also to economic factors, cultural differences, and diet [23].
Genetic factors
Among all the risk factors, genetic factors are most definitely associated with the risk of epithelial ovarian cancer. With the development of the disciplines of genetics, molecular genetics, and molecular biology, there is increasing evidence that fully demonstrates the role of genetic factors in the development of ovarian cancer. NIH data suggest that the lifetime risk of ovarian cancer for women in the general population is 1.4%, while the increased risk for ovarian cancer is 5% if one first-degree relative has had ovarian cancer and 7.2% if two to three first-degree relatives have had ovarian cancer [24]. 7.2 % [24].
Over the years, two major hereditary ovarian cancer syndromes have been identified through extensive genetic studies: Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNCCS). Polyposis Colorectal Cancer Syndrome (HNPCC), which is also known as Lynch type II syndrome. Site-specific Ovarian Cancer Syndrome (SOSOC), originally considered a third hereditary ovarian cancer syndrome, is now classified as HBOC, in which family members develop only ovarian cancer without a high risk of breast cancer. For women in families with hereditary ovarian cancer syndrome, the lifetime risk of ovarian cancer is as high as 40% [25].
HBOC accounts for approximately 75-90% of hereditary ovarian cancers and its occurrence is associated with BRCA1/2 gene mutations, with BRCA1 gene mutations accounting for 90% of cases. Data from studies show that the lifetime risk of ovarian cancer is 37-62% for women with BRCA1 mutations and 11-23% for those with BRCA2 mutations, and that BRCA1 mutation carriers develop ovarian cancer at a younger age than those with BRCA2 mutations. The median age at the onset of ovarian cancer was earlier in HBOC compared with the general population (48 vs. 62 years), and the tissue type of ovarian cancer was mainly plasmacytoma.HNPCC family members can develop a variety of tumors including colon cancer, endometrial cancer, and gastric cancer, and their risk of ovarian cancer is 3.5-8 times higher than that of the general population, accounting for 2% of all familial ovarian cancer patients, and its occurrence is mainly related to MSH2 gene mutation [26].
2. Preventive measures for ovarian cancer
Unlike cervical cancer, ovarian cancer has an unknown etiology and insidious onset, making it difficult to identify effective preventive and screening measures. Although ovarian cancer has the highest morbidity and mortality rate in the female reproductive system, its incidence is not high and screening for ovarian cancer in the general population is not currently feasible for health economics reasons. In particular, there is no effective screening tool for ovarian cancer to date. Gynecologic examination and transvaginal ultrasound combined with CA125 testing are the classical ovarian cancer screening tools. The results of the UK Collaborative Ovarian Cancer Screening Trial suggest that transvaginal ultrasound combined with CA125 may improve the diagnosis of early-stage ovarian cancer, but this has also been reported to be negative. Even in high-risk groups, such as family members with hereditary ovarian cancer syndrome, there is no evidence that these combined screening tests improve the early diagnosis of ovarian cancer.
Prophylactic surgery
Prophylactic Bilateral Salpingo-Oophorectomy (PBSO) is currently considered the most effective measure to reduce the risk of ovarian cancer in families with hereditary ovarian cancer syndromes with clear BRCA1/2 gene mutations. Given the high risk of ovarian cancer in family members with hereditary ovarian cancer syndrome, it is necessary to perform genetic diagnosis, screen for high-risk groups, and take measures to reduce their ovarian cancer risk. Currently, screening of high-risk individuals is divided into four major steps: risk assessment, genetic counseling, and BRCA1/2 genetic testing, and finally, appropriate medical interventions. For those diagnosed as BRCA1/2 positive, prophylactic bilateral oophorectomy at an appropriate time after childbirth has been shown to significantly reduce the risk of ovarian cancer (85-100%) and breast cancer (46-68%), and has been reported to reduce overall mortality. Data from these studies have been published in prestigious journals such as NEMJ, Lancet, and JAMA [27,28]. In the largest prospective study to date reported by the Canadian Hereditary Ovarian Cancer Clinical Study Group, 1828 women with BRCA1/2 mutations were enrolled, 1045 (57%) underwent prophylactic bilateral oophorectomy, 783 (43%) were monitored at a median follow-up of 3.5 years, and the incidence of ovarian, fallopian tube, and peritoneal cancers in the surgical group was 18.5%. The median follow-up was 3.5 years. 18 cases of ovarian, fallopian tube and peritoneal cancers occurred in the surgical group (11 cases were diagnosed at the time of surgery) and 32 cases in the control group. The findings suggest that PBSO may reduce the risk of ovarian cancer by 80% [29]. The results of another small prospective study were similar, with an 85% reduction in ovarian cancer risk and a 70% reduction in breast cancer risk after PBSO [30].
With bilateral oophorectomy alone, cancer can still occur in the residual fallopian tubes, and it has been suggested that ovarian and peritoneal cancers can originate in the fallopian tube tissue, so prophylactic tubo-ovarian resection is recommended. Even so, primary peritoneal cancer still occurs in 3-4% of women after tubo-ovariectomy [27,28]. Patients with BRCA1/2 mutations have a significantly higher risk of developing malignancies at other sites such as rectal, pancreatic, esophageal, and gastric cancers than the general population, and therefore need to be closely monitored after PBSO. Current data show that the risk of cancer is most significantly reduced by PBSO before the age of 40, so it is recommended that PBSO be performed after childbirth in high-risk women over the age of 35. HRT can be used for a short time after surgery to treat symptoms associated with estrogen deficiency [27,28].
Prophylactic drugs
In addition to prophylactic surgery, other preventive measures for ovarian cancer include close surveillance, avoidance of the above-mentioned high-risk factors, and pharmacological prophylaxis. There are several medications that are considered to reduce the risk of ovarian cancer, including vitamin D, nonsteroidal anti-inflammatory drugs, and oral contraceptives. Among them, oral contraceptives are the most widely studied and are considered to be the most effective.
Oral Contraceptives (OCs) inhibit ovulation and their protective effect against ovarian cancer has been confirmed by numerous studies. The protective effect of OCs on ovarian cancer is limited to plasma cancers, but not to other types such as mucinous cancers. A Meta-analysis showed that the risk of ovarian cancer was significantly lower in women who had used oral contraceptives compared to women who had never used oral contraceptives (RR = 0.64) [31]. In general, the longer the duration of OCs use, the greater the ovarian cancer protective effect. Data from a recent study showed a 50% reduction in ovarian cancer risk with OCs for more than 5 years, and another study showed a 10-12% reduction in ovarian cancer risk with each additional year of OCs use. The Nurses’ Health Study in the United States followed 107,900 registered nurses for 28 years and found 612 cases of ovarian cancer, with a significant reduction in the risk of ovarian cancer in women who had been taking oral contraceptives for 5-20 years (RR = 0.58) [32]. The protective effect persisted after discontinuation of OCs, with several case-control studies confirming a 50% reduction in ovarian cancer risk 15 years after discontinuation of OCs compared with the control population. In 2008, the Collaborative Ovarian Cancer Epidemiology Study Group analyzed 45 epidemiological studies from 21 countries, including 23,257 ovarian cancer patients and 87,303 controls, and concluded that OCs significantly reduced the risk of developing ovarian cancer. According to the article’s projections, the application of OCs has prevented 200,000 ovarian cancer cases and 100,000 patient deaths since their introduction, and they are expected to prevent 30,000 new cases of ovarian cancer each year in the future. The findings of this study were published as a cover article in the Lancet [33].
In conclusion, although the etiology of ovarian cancer is unknown, several ovarian cancer risk factors have been identified through numerous epidemiological studies. Among them, hereditary factors are by far the most certain and major high-risk factors. In addition, pregnancy, breastfeeding, oral contraceptives, tubal ligation and hysterectomy are protective factors for ovarian cancer; while hormone replacement therapy, talcum powder, smoking and obesity are high-risk factors for ovarian cancer, which should be avoided with care. For people with high risk of familial ovarian cancer, monitoring should be strengthened and genetic counseling and diagnosis should be conducted. Prophylactic bilateral adnexal resection is the most effective ovarian cancer prevention measure for women with confirmed BRCA1/2 gene mutation.
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