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Interventions to reduce the risk of ovarian and fallopian tube cancer: A European Menopause and Andropause Society Position Statement

      Highlights

      • Opportunistic bilateral salpingectomy may prevent ovarian cancer. Bilateral salpingectomy should be preferred to tubal ligation, and should be recommended in cases of hysterectomy for benign conditions.
      • Combined but not progestogen-only contraceptive medication reduces the risk of ovarian cancer.
      • Being overweight or obese increases the risk of ovarian cancer. There is no evidence that any particular diet reduces the risk of ovarian cancer.

      Abstract

      Background

      Ovarian cancer is a leading cause of female gynecological cancer-related death, and there are no effective screening procedures or early diagnostic approaches.

      Aims

      To examine risk factors and risk-reducing strategies for both sporadic and familial tumors.

      Materials and methods

      Literature review and consensus of expert opinion.

      Results and conclusions

      In women with a genetic predisposition to ovarian cancer, salpingo-oophorectomy reduces the risk of ovarian malignancy, and to a lesser degree of breast cancer. Opportunistic bilateral salpingo-oophorectomy and bilateral salpingectomy may also prevent epithelial ovarian cancer. In premenopausal women, bilateral salpingectomy should be preferred to tubal ligation, and be performed when hysterectomy is carried out for benign uterine disease. Hysterectomy and the use of combined oral contraceptives and non-steroid anti-inflammatory drugs are also recognized to reduce the risk of ovarian cancer, as do the prevention of obesity and smoking cessation.

      Keywords

      1. Background

      Approximately 1.3% of women will be diagnosed with ovarian cancer at some point during their life. Mortality is high, with a 5-year survival rate ranging from 36% to 46%, although there has been a net survival improvement during the last decades, especially among young and mid-aged women [
      • Surveillance E.
      • End Results Program (SEER)
      SEER Cancer Statistics Factsheets: Ovarian Cancer.
      ,
      • Chirlaque M.D.
      • Uhry Z.
      • Salmerón D.
      • Sánchez-Zapata M.I.
      • Zannoni G.F.
      • Navarro C.
      GRELL EUROCARE -5 Working Group. Trends in net survival from ovarian cancer in six European Latin countries: results from the SUDCAN population-based study.
      ].
      The incidence of ovarian cancer has decreased during recent years in countries in which more women have used oral contraceptives for long periods; moreover, where new therapeutic strategies have been introduced (particularly for germ cell cancers) there has been a reduction in mortality rates [
      • Malvezzi M.
      • Carioli G.
      • Rodriguez T.
      • Negri E.
      • La Vecchia C.
      Global trends and predictions in ovarian cancer mortality.
      ,
      • Rauh-Hain J.A.
      • Melamed A.
      • Wright A.
      • Gockley A.
      • Clemmer J.T.
      • Schorge J.O.
      • Del Carmen M.G.
      • Keating N.L.
      Overall survival following neoadjuvant chemotherapy vs primary cytoreductive surgery in women with epithelial ovarian cancer: analysis of the national cancer database.
      ]. The primary intervention is normally surgery, though even in early-stage disease many recommend adjuvant chemotherapy [
      • Kehoe S.
      • Hook J.
      • Nankivell M.
      • Jayson G.C.
      • Kitchener H.
      • Lopes T.
      • Luesley D.
      • Perren T.
      • Bannoo S.
      • Mascarenhas M.
      • Dobbs S.
      • Essapen S.
      • Twigg J.
      • Herod J.
      • McCluggage G.
      • Parmar M.
      • Swart A.M.
      Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.
      ,
      • Leary A.
      • Cowan R.
      • Chi D.
      • Kehoe S.
      • Nankivell M.
      Primary surgery or neoadjuvant chemotherapy in advanced ovarian cancer: the debate continues.
      ].
      The high mortality rate of ovarian cancer is largely due to its late stage at presentation, partly related to the lack of early symptoms and effective screening methods [
      • Pérez-López F.R.
      • Chedraui P.
      • Troyano-Luque J.M.
      Peri- and post-menopausal incidental adnexal masses and the risk of sporadic ovarian malignancy: new insights and clinical management.
      ,
      • Moyer V.A.
      • U.S. Preventive Services Task Force
      Screening for ovarian cancer: U.S. preventive services task force reaffirmation recommendation statement.
      ]. To date, screening asymptomatic women without a genetic predisposition has not been proven to reduce mortality, and yet it does increase the risk of healthy women undergoing unnecessary surgical procedures [
      • Moyer V.A.
      • U.S. Preventive Services Task Force
      Screening for ovarian cancer: U.S. preventive services task force reaffirmation recommendation statement.
      ], with the inevitable associated morbidity and risk of surgical mortality [
      • Buys S.S.
      • Partridge E.
      • Black A.
      • Johnson C.C.
      • Lamerato L.
      • Isaacs C.
      • Reding D.J.
      • Greenlee R.T.
      • Yokochi L.A.
      • Kessel B.
      • Crawford E.D.
      • Church T.R.
      • Andriole G.L.
      • Weissfeld J.L.
      • Fouad M.N.
      • Chia D.
      • O'Brien B.
      • Ragard L.R.
      • Clapp J.D.
      • Rathmell J.M.
      • Riley T.L.
      • Hartge P.
      • Pinsky P.F.
      • Zhu C.S.
      • Izmirlian G.
      • Kramer B.S.
      • Miller A.B.
      • Xu J.L.
      • Prorok P.C.
      • Gohagan J.K.
      • Berg C.D.
      Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial.
      ]. Hence, this position statement will examine the evidence regarding risk-reducing strategies.

      2. Histological types and carcinogenic trajectories

      Ovarian cancer types include:(1) epithelial ovarian carcinomas (EOCs) (90%), usually in postmenopausal women; (2) germ cell carcinomas (4%), more common in adolescents and women in their early 20s; (3) stromal carcinomas (teratomas, dysgerminomas and endodermal sinus tumors), diagnosed mostly at early stages; and (4) other primitive and metastatic malignant tumors, which are rarer. EOCs can arise not only from the ovarian surface but also from the fallopian tubes and the peritoneum [
      • Cannistra S.A.
      • Gershenson D.M.
      • Recht A.
      Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma.
      ,
      • Kurman R.J.
      • Carcangiu M.L.
      • Herrington C.S.
      • Young R.H.
      WHO classification of tumours of female reproductive organs.
      ,
      • Prat J.
      Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features.
      ,
      • Prat J.
      FIGO Committee on Gynecologic Oncology Staging classification for cancer of the ovary, fallopian tube, and peritoneum.
      ,
      • Singh N.
      • Gilks C.B.
      • Hirschowitz L.
      • Kehoe S.
      • McNeish I.A.
      • Miller D.
      • Naik R.
      • Wilkinson N.
      • McCluggage W.G.
      Primary site assignment in tubo-ovarian high-grade serous carcinoma: consensus statement on unifying practice worldwide.
      ,
      • Nasioudis D.
      • Alevizakos M.
      • Holcomb K.
      • Witkin S.S.
      Malignant and borderline epithelial ovarian tumors in the pediatric and adolescent population.
      ]. This knowledge creates a new scenario for opportunistic bilateral salpingectomy to prevent ovarian cancer, while preserving the ovarian endocrine function [
      • Madsen C.
      • Baandrup L.
      • Dehlendorff C.
      • Kjaer S.K.
      Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.
      ,
      • Falconer H.
      • Yin L.
      • Grönberg H.
      • Altman D.
      Ovarian cancer risk after salpingectomy: a nationwide population-based study.
      ,
      • Pérez-López F.R.
      • Chedraui P.
      Surgical prevention of epithelial ovary cancer without oophorectomy: changing the future.
      ,
      • Yoon S.H.
      • Kim S.N.
      • Shim S.H.
      • Kang S.B.
      • Lee S.J.
      Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: a meta- meta-analysis.
      ]. This is important for premenopausal women since bilateral oophorectomy has been related to higher all-cause mortality and death rates due to ischemic heart disease and cancer [
      • Mytton J.
      • Evison F.
      • Chilton P.J.
      • Lilford R.J.
      Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage.
      ].
      Each histologic variety of ovarian cancer is associated with a different clinical natural history, epidemiologic factors and genetic and familial influences [
      • Prat J.
      Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features.
      ,
      • Kommoss S.
      • Gilks C.B.
      • du Bois A.
      • Kommoss F.
      Ovarian carcinoma diagnosis: the clinical impact of 15 years of change.
      ,
      • Matz M.
      • Coleman M.P.
      • Carreira H.
      • Salmerón D.
      • Chirlaque M.D.
      • Allemani C.
      CONCORD Working Group: worldwide comparison of ovarian cancer survival: histological group and stage at diagnosis (CONCORD-2).
      ]. Although the precise causes of ovarian cancers are unknown, environmental, genetic, hormonal, and local genital factors have all been implicated. Some ovarian cancers cluster in families (hereditary ovarian cancer) and develop and progress earlier than sporadic (non-hereditary) tumors. Clinical and molecular studies suggest two different carcinogenic trajectories. Type I includes low-grade serous, clear cell, low-grade endometrioid, mucinous cancers and Brenner tumors, all of which are relatively stable from a genetic point of view. Type II includes high-grade epithelial serous, high-grade endometrioid and undifferentiated cancers and mixed mesodermal malignancies. These have a high genetic instability and a high p53 mutation prevalence [
      • Lim D.
      • Oliva E.
      Precursors and pathogenesis of ovarian carcinoma.
      ]. They arise from extra-ovarian tissue, mostly the fallopian tubes [
      • Prat J.
      FIGO Committee on Gynecologic Oncology Staging classification for cancer of the ovary, fallopian tube, and peritoneum.
      ,
      • Karnezis A.N.
      • Cho K.R.
      • Gilks C.B.
      • Pearce C.L.
      • Huntsman D.G.
      The disparate origins of ovarian cancers: pathogenesis and prevention strategies.
      ].
      Epithelial ovarian borderline tumors (EOBT) are of low malignant potential, are different from low-grade tumors and are typically diagnosed in young women [
      • Nasioudis D.
      • Alevizakos M.
      • Holcomb K.
      • Witkin S.S.
      Malignant and borderline epithelial ovarian tumors in the pediatric and adolescent population.
      ,
      • Lazarou A.
      • Fotopoulou C.
      • Coumbos A.
      • Sehouli J.
      • Vasiljeva J.
      • Braicu I.
      • Burger H.
      • Kuehn W.
      Long-term follow-up of borderline ovarian tumors clinical outcome and prognostic factors.
      ]. EOBT tumors usually require less radical treatments than frankly malignant ovarian cancers, and usually have a favorable prognosis, although they may recur even 20 years after primary diagnosis. The majority of these tumors are mucinous and serous. However, prognosis cannot be predicted by their histopathology [
      • Avril S.
      • Hahn E.
      • Specht K.
      • et al.
      Histopathologic features of ovarian borderline tumors are not predictive of clinical outcome.
      ]. During the last decades, the incidence of EOBT has increased 2- to 5-fold, probably due to greater histopathological experience [
      • Skírnisdóttir I.
      • Garmo H.
      • Wilander E.
      • Holmberg L.
      Borderline ovarian tumors in Sweden 1960–2005: trends in incidence and age at diagnosis compared to ovarian cancer.
      ,
      • Hannibal C.G.
      • Huusom L.D.
      • Kjaerbye-Thygesen A.
      • Tabor A.
      • Kjaer S.K.
      Trends in incidence of borderline ovarian tumors in Denmark 1978–2006.
      ].
      Pelvic inflammation may be associated with both borderline ovarian tumors and cancers, and this risk may increase for women who experience multiple inflammatory episodes [
      • Lin H.W.
      • Tu Y.Y.
      • Lin S.Y.
      • Su W.J.
      • Lin W.L.
      • Lin W.Z.
      • Wu S.C.
      • Lai Y.L.
      Risk of ovarian cancer in women with pelvic inflammatory disease: a population-based study.
      ,
      • Rasmussen C.B.
      • Jensen A.
      • Albieri V.
      • Andersen K.K.
      • Kjaer S.K.
      Increased risk of borderline ovarian tumors in women with a history of pelvic inflammatory disease: a nationwide population-based cohort study.
      ].

      3. Familial cancer

      A family history of ovarian cancer (and related syndromes) is a well-recognized risk factor. Thus, the presence of an ovarian cancer in one first-degree relative increases women’s lifetime risk by 5%; the risk increases up to 7% if there are 2 such relatives [
      • U.S. Preventive Services Task Force
      Screening for ovarian cancer: recommendation statement. U.S. preventive services task force.
      ]. The risk is also high in families with hereditary breast and ovarian cancer syndromes in association with autosomal dominant mutations of the BRCA1 and BRCA2 genes (such syndromes are also associated with TP53 genes, but at a lesser frequency). However, other genes also seem to play a significant role (along with lifestyle factors) in the genesis of different subtypes of EOCs [
      • Cuellar-Partida G.
      • Lu Y.
      • Dixon S.C.
      Australian Ovarian Cancer Study., Fasching PA, et al. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.
      ].

      3.1 BRCA1 and BRCA2 gene mutations

      BRCA1 and BRCA2 gene mutations increase ovarian and breast cancer risk, and also to a lesser degree the risk for fallopian tube, peritoneal, and pancreatic cancers. The risk of ovarian cancer is higher in BRCA1 carriers (two-fold) than in BRCA2 carriers [
      • Petrucelli N.
      • Daly M.B.
      • Feldman G.L.
      Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2.
      ]. Furthermore, women with fallopian tube cancer frequently have BRCA1 or BRCA2 gene mutations [
      • Vicus D.
      • Finch A.
      • Cass I.
      • Rosen B.
      • Murphy J.
      • Fan I.
      • Royer R.
      • McLaughlin J.
      • Karlan B.
      • Narod S.A.
      Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube.
      ]. Some women with BRCA mutations have lower survival rates, and this has been related to a higher FIGO disease stage at diagnosis and more aggressive serous variants, suggesting that familial cancers are more aggressive than non-familial cancer types [
      • Lee M.
      • Reilly M.
      • Lindström L.S.
      • Czene K.
      Differences in survival for patients with familial and sporadic cancer.
      ]. In contrast, the risk of endometrial cancer in families with BRCA gene mutations is nearly the same as that found in the general population without such mutations. Nonetheless, BRCA mutation carriers may also have a slightly increased risk of serous and/or serous-like endometrial carcinomas (but not endometrioid type) [
      • Shu C.A.
      • Pike M.C.
      • Jotwani A.R.
      • Friebel T.M.
      • Soslow R.A.
      • Levine D.A.
      • Nathanson K.L.
      • Konner J.A.
      • Arnold A.G.
      • Bogomolniy F.
      • Dao F.
      • Olvera N.
      • Bancroft E.K.
      • Goldfrank D.J.
      • Stadler Z.K.
      • Robson M.E.
      • Brown C.L.
      • Leitao Jr, M.M.
      • Abu-Rustum N.R.
      • Aghajanian C.A.
      • Blum J.L.
      • Neuhausen S.L.
      • Garber J.E.
      • Daly M.B.
      • Isaacs C.
      • Eeles R.A.
      • Ganz P.A.
      • Barakat R.R.
      • Offit K.
      • Domchek S.M.
      • Rebbeck T.R.
      • Kauff N.D.
      Uterine cancer after risk-Reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations.
      ]. In some BRCA1 mutation carriers, the increased risk of endometrial cancer has been related to the use of tamoxifen [
      • Segev Y.
      • Iqbal J.
      • Lubinski J.
      • Gronwald J.
      • Lynch H.T.
      • Moller P.
      • Ghadirian P.
      • Rosen B.
      • Tung N.
      • Kim-Sing C.
      • Foulkes W.D.
      • Neuhausen S.L.
      • Senter L.
      • Singer C.F.
      • Karlan B.
      • Ping S.
      • Narod S.A.
      Hereditary Breast Cancer Study Group. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study.
      ]. Therefore, women considering salpingo-oophorectomy (e.g. those who are BRCA positive) should also envisage hysterectomy, especially if it is anticipated that they will take tamoxifen for a long period.
      Preventive surgery should be individualized to the woman’s specific circumstances, including her age and reproductive desires, and the presence of uterine pathology. Prophylactic oophorectomy (preferentially a salpingo-oophorectomy), which may be combined with hysterectomy, can be offered to women aged over 35 years who have completed childbearing. Preventive salpingo-oophorectomy is associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality [
      • Finch A.
      • Bacopulos S.
      • Rosen B.
      • Fan I.
      • Bradley L.
      • Risch H.
      • McLaughlin J.R.
      • Lerner-Ellis J.
      • Narod S.A.
      Preventing ovarian cancer through genetic testing: a population-based study.
      ]. However, intra-abdominal carcinomatosis of ovarian serous malignancies has been reported after bilateral salpingo-oophorectomy in women with BRCA mutations [
      • Finch A.
      • Beiner M.
      • Lubinski J.
      • Lynch H.T.
      • Moller P.
      • Rosen B.
      • Murphy J.
      • Ghadirian P.
      • Friedman E.
      • Foulkes W.D.
      • Kim-Sing C.
      • Wagner T.
      • Tung N.
      • Couch F.
      • Stoppa-Lyonnet D.
      • Ainsworth P.
      • Daly M.
      • Pasini B.
      • Gershoni-Baruch R.
      • Eng C.
      • Olopade O.I.
      • McLennan J.
      • Karlan B.
      • Weitzel J.
      • Sun P.
      Narod SA; Hereditary Ovarian Cancer Clinical Study Group Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation.
      ,
      • Kauff N.D.
      • Domchek S.M.
      • Friebel T.M.
      • Robson M.E.
      • Lee J.
      • Garber J.E.
      • Isaacs C.
      • EvansD.G. Lynch H.
      • Eeles R.A.
      • Neuhausen S.L.
      • Daly M.B.
      • Matloff E.
      • Blum J.L.
      • Sabbatini P.
      • Barakat R.R.
      • Hudis C.
      • Norton L.
      • Offit K.
      • Rebbeck T.R.
      Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
      ]. Despite this small risk, bilateral salpingo-oophorectomy remains the most cost-effective prophylactic intervention and reduces all-cause mortality [
      • Finch A.
      • Bacopulos S.
      • Rosen B.
      • Fan I.
      • Bradley L.
      • Risch H.
      • McLaughlin J.R.
      • Lerner-Ellis J.
      • Narod S.A.
      Preventing ovarian cancer through genetic testing: a population-based study.
      ,
      • Marchetti C.
      • De Felice F.
      • Palaia I.
      • Perniola G.
      • Musella A.
      • Musio D.
      • Muzii L.
      • Tombolini V.
      • Panici P.B.
      Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers.
      ,
      • Stuckey A.R.
      • Onstad M.A.
      Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.
      ]. This intervention can also prevent breast cancer in premenopausal women with BRCA2 mutations, although not those with BRCA1 mutations [
      • Kotsopoulos J.
      • Huzarski T.
      • Gronwald J.
      • Singer C.F.
      • Moller P.
      • Lynch H.T.
      • Armel S.
      • Karlan B.
      • Foulkes W.D.
      • Neuhausen S.L.
      • Senter L.
      • Tung N.
      • Weitzel J.N.
      • Eisen A.
      • Metcalfe K.
      • Eng C.
      • Pal T.
      • Evans G.
      • Sun P.
      • Lubinski J.
      • Narod S.A.
      • Hereditary Breast Cancer Clinical Study Grou p.
      Bilateral oophorectomy and Breast cancer risk in BRCA1 and BRCA2 mutation carriers.
      ]. Premenopausal women with BRCA1 or BRCA2 mutations or with less frequent gene mutations, without prior breast cancer, undergoing oophorectomy should be advised to take menopausal hormone therapy (MHT) until the average age of natural menopause, since it does not appear to increase the risk of breast cancer [
      • Finch A.
      • Valentini A.
      • Greenblatt E.
      • Lynch H.T.
      • Ghadirian P.
      • Armel S.
      • Neuhausen S.L.
      • Kim-Sing C.
      • Tung N.
      • Karlan B.
      • Foulkes W.D.
      • Sun P.
      • Narod S.
      Hereditary Breast Cancer Study Group. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.
      ,
      • Li D.
      • Ding C.Y.
      • Qiu L.H.
      Postoperative hormone replacement therapy for epithelial ovarian cancer patients: a systematic review and meta-analysis.
      ,
      • Birrer N.
      • Chinchilla C.
      • Del Carmen M.
      • Dizon D.S.
      Is hormone replacement therapy safe in women with a BRCA mutation? A systematic review of the contemporary literature.
      ]. A meta-analysis indicates that in these women and among those undergoing prophylactic salpingo-oophorectomy before the age of 40, MHT should be individualized and closely monitored [
      • Birrer N.
      • Chinchilla C.
      • Del Carmen M.
      • Dizon D.S.
      Is hormone replacement therapy safe in women with a BRCA mutation? A systematic review of the contemporary literature.
      ]. This population may have an increased risk of endometrial cancer [
      • Shu C.A.
      • Pike M.C.
      • Jotwani A.R.
      • Friebel T.M.
      • Soslow R.A.
      • Levine D.A.
      • Nathanson K.L.
      • Konner J.A.
      • Arnold A.G.
      • Bogomolniy F.
      • Dao F.
      • Olvera N.
      • Bancroft E.K.
      • Goldfrank D.J.
      • Stadler Z.K.
      • Robson M.E.
      • Brown C.L.
      • Leitao Jr, M.M.
      • Abu-Rustum N.R.
      • Aghajanian C.A.
      • Blum J.L.
      • Neuhausen S.L.
      • Garber J.E.
      • Daly M.B.
      • Isaacs C.
      • Eeles R.A.
      • Ganz P.A.
      • Barakat R.R.
      • Offit K.
      • Domchek S.M.
      • Rebbeck T.R.
      • Kauff N.D.
      Uterine cancer after risk-Reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations.
      ,
      • Segev Y.
      • Rosen B.
      • Lubinski J.
      • Gronwald J.
      • Lynch H.T.
      • Moller P.
      • Kim-Sing C.
      • Ghadirian P.
      • Karlan B.
      • Eng C.
      • Gilchrist D.
      • Neuhausen S.L.
      • Eisen A.
      • Friedman E.
      • Euhus D.
      • Ping S.
      • Narod S.A.
      Hereditary Breast Cancer Study Group. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study.
      ]. In light of this evidence, the option to include a hysterectomy as part of the surgical preventive intervention may be considered but must be balanced against the extra surgical morbidity.
      Contraceptive interventions have been studied in women with BRCA gene mutations. Since many EOCs originate from fallopian tube lesions, the effect of tubal ligation and other contraceptive treatments has been studied though data are limited. In BRCA gene carriers, tubal ligation is associated with a non-significant reduction of fallopian tubal cancer while oral contraceptive use has a protective role [
      • Vicus D.
      • Finch A.
      • Rosen B.
      • Fan I.
      • Bradley L.
      • Cass I.
      • Sun P.
      • Karlan B.
      • McLaughlin J.
      Narod SA; Hereditary Ovarian Cancer Clinical Study Group: risk factors for carcinoma of the fallopian tube in women with and without a germline BRCA mutation.
      ].

      3.2 Other gene mutations related to an increased risk of ovarian cancer

      Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (or Cowden disease) is characterized by thyroid problems (including cancer) and breast cancer. These women also have an increased risk of serous EOC, which is related to gene mutations [
      • Modi D.A.
      • Tagare R.D.
      • Karthikeyan S.
      • Russo A.
      • Dean M.
      • Davis D.A.
      • Lantvit D.D.
      • Burdette J.E.
      PAX2 function, regulation and targeting in fallopian tube-derived high-grade serous ovarian cancer.
      ,
      • Smith I.N.
      • Briggs J.M.
      Structural mutation analysis of PTEN and its genotype-phenotype correlations in endometriosis and cancer.
      ]. Women with hereditary nonpolyposis colon cancer (Lynch syndrome) also have an increased risk of endometrial cancer and (to a lesser extent) ovarian cancer. Women with Lynch syndrome have a lifetime risk of ovarian cancer of about 10% and they represent up to 1% of all EOCs [
      • Adachi M.
      • Banno K.
      • Yanokura M.
      • Iida M.
      • Nakamura K.
      • Nogami Y.
      • Umene K.
      • Masuda K.
      • Kisu I.
      • Ueki A.
      • Hirasawa A.
      • Tominaga E.
      • Aoki D.
      Risk-reducing surgery in hereditary gynecological cancer: clinical applications in Lynch syndrome and hereditary breast and ovarian cancer.
      ,
      • Lancaster J.M.
      • Powell C.B.
      • Chen L.M.
      Richardson DL; SGO Clinical Practice Committee: society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      ].
      Peutz-Jeghers syndrome usually affects teenagers; they have a high risk of cancer at different digestive sites as well as of epithelial or sex cord ovarian cancers. This syndrome is related with the STK11 gene mutation [
      • Lancaster J.M.
      • Powell C.B.
      • Chen L.M.
      Richardson DL; SGO Clinical Practice Committee: society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions.
      ].
      The preventive management of gynecological cancer risk in all these gene-mutated syndromes (although risks are less than with BRCA mutations) includes bilateral salpingo-oophorectomy. In women with Lynch syndrome, hysterectomy should be also considered because of the increased risk of endometrial cancer.

      4. Surgical strategies to reduce ovarian cancer risk

      Prophylactic bilateral salpingo-oophorectomy has been used at the time of hysterectomy among postmenopausal women with benign conditions, although its use in premenopausal women seems a matter of controversy. In the premenopausal population, there has been a trend to change bilateral salpingo-oophorectomy to bilateral salpingectomy during the last decade [
      • Madsen C.
      • Baandrup L.
      • Dehlendorff C.
      • Kjaer S.K.
      Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.
      ,
      • Falconer H.
      • Yin L.
      • Grönberg H.
      • Altman D.
      Ovarian cancer risk after salpingectomy: a nationwide population-based study.
      ,
      • Mikhail E.
      • Salemi J.L.
      • Mogos M.F.
      • Hart S.
      • Salihu H.M.
      • Imudia A.N.
      National trends of adnexal surgeries at the time of hysterectomy for benign indication, United States, 1998–2011.
      ], in order to preserve ovarian function yet eliminate fallopian tubes as the source of the initial EOC. It seems that in women with an average risk of ovarian cancer, ovary preservation may have general health benefits, including the reduction of future cardiovascular risk, osteoporosis, sexual dysfunction, cognitive function and mental health, and impaired quality of life [
      • Mytton J.
      • Evison F.
      • Chilton P.J.
      • Lilford R.J.
      Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage.
      ,
      • Hickey M.
      • Ambekar M.
      • Hammond I.
      Should the ovaries be removed or retained at the time of hysterectomy for benign disease?.
      ].
      Fallopian tubal ligation and hysterectomy (if performed before age 35) reduce the risk of EOC, particularly non-serous types [
      • Rice M.S.
      • Murphy M.A.
      • Tworoger S.S.
      Tubal ligation, hysterectomy and ovarian cancer: a meta-analysis.
      ,
      • Rice M.S.
      • Hankinson S.E.
      • Tworoger S.S.
      Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the Nurses’ Health Studies.
      ]. An Australian Cancer Study, a Danish register-based case-control study, and the Million Women Study reported that tubal ligation has different preventive effects according to histologic types, the protection being greater for high-risk serous, endometrioid and clear cell carcinomas, while results are conflicting regarding mucinous carcinomas [
      • Madsen C.
      • Baandrup L.
      • Dehlendorff C.
      • Kjaer S.K.
      Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.
      ,
      • Sieh W.
      • Salvador S.
      • McGuire V.
      • Weber R.P.
      • Terry K.L.
      • Rossing M.A.
      • Risch H.
      • et al.
      Ovarian Cancer Association Consortium. Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies.
      ,
      • Merritt M.A.
      • De Pari M.
      • Vitonis A.F.
      • Titus L.J.
      • Cramer D.W.
      • Terry K.L.
      Reproductive characteristics in relation to ovarian cancer risk by histologic pathways.
      ].
      The effect of salpingectomy on ovarian cancer risk has been compared with that provided by tubal ligation. Madsen et al. [
      • Madsen C.
      • Baandrup L.
      • Dehlendorff C.
      • Kjaer S.K.
      Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.
      ] and Falconer et al. [
      • Falconer H.
      • Yin L.
      • Grönberg H.
      • Altman D.
      Ovarian cancer risk after salpingectomy: a nationwide population-based study.
      ] reported that salpingectomy reduced EOC in the Danish register-based case-control study and in a national US population-based study, respectively. The results suggest that opportunistic bilateral salpingectomy should be recommended when women are treated by hysterectomy for benign conditions and among those seeking sterilization [
      • Pérez-López F.R.
      • Chedraui P.
      Surgical prevention of epithelial ovary cancer without oophorectomy: changing the future.
      ,
      • Yoon S.H.
      • Kim S.N.
      • Shim S.H.
      • Kang S.B.
      • Lee S.J.
      Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: a meta- meta-analysis.
      ]. This approach means the preservation of ovarian function with the prevention of the all-cause mortality and death rate due to ischemic heart disease and cancer, associated with oophorectomy [
      • Mytton J.
      • Evison F.
      • Chilton P.J.
      • Lilford R.J.
      Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage.
      ]
      Hysterectomy alone due to benign conditions in young women, with conservation of the fallopian tubes and the ovaries, may also reduce the risk of ovarian cancer [
      • Rice M.S.
      • Hankinson S.E.
      • Tworoger S.S.
      Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the Nurses’ Health Studies.
      ,
      • Merritt M.A.
      • De Pari M.
      • Vitonis A.F.
      • Titus L.J.
      • Cramer D.W.
      • Terry K.L.
      Reproductive characteristics in relation to ovarian cancer risk by histologic pathways.
      ].

      5. Hormonal interventions and ovarian cancer risk

      Combined oral contraceptives (COC) reduce the risk of EOC. The use of oral contraceptives is associated with a reduction in ovarian cancer risk in the general population [
      • Webb P.M.
      • Green A.C.
      • Jordan S.J.
      Trends in hormone use and ovarian cancer incidence in US white and Australian women: implications for the future.
      ], probably related to anovulation (reduction of the risk of implantation of fallopian tube cancer cells). A meta-analysis of case-control and cohort studies reported a significant reduction in ovarian cancer risk whenever users are compared with never users. In addition, when use is for 10 or more years there is a reduction of more than 50% in the incidence [
      • Havrilesky L.J.
      • Moorman P.G.
      • Lowery W.J.
      • Gierisch J.M.
      • Coeytaux R.R.
      • Urrutia R.P.
      • Dinan M.
      • McBroom A.J.
      • Hasselblad V.
      • Sanders G.D.
      • Myers E.R.
      Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis.
      ]. However, COCs do not seem to affect the incidence of mucinous tumors [
      • Collaborative Group on Epidemiological Studies of Ovarian Cancer
      • Beral V.
      • Doll R.
      • Hermon C.
      • Peto R.
      • Reeves G.
      Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23, 257 women with ovarian cancer and 87, 303 controls.
      ]. On the other hand, the use of progestogen-only contraceptive pills does not seem to provide protection against ovarian cancer risk [
      • Faber M.T.
      • Jensen A.
      • Frederiksen K.
      • Glud E.
      • Høgdall E.
      • Høgdall C.
      • Blaakaer J.
      • Kjaer S.K.
      Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer.
      ]. Despite this, the levonorgestrel-releasing intrauterine system decreases the risk of mucinous, endometrioid and serous ovarian carcinomas [
      • Soini T.
      • Hurskainen R.
      • Grénman S.
      • Mäenpää J.
      • Paavonen J.
      • Pukkala E.
      Impact of levonorgestrel-releasing intrauterine system use on the cancer risk of the ovary and fallopian tube.
      ].
      The protective effect of COC is closely related to the dose of estrogen and treatment duration, although there is no accumulative effect of estrogen intake [
      • Faber M.T.
      • Jensen A.
      • Frederiksen K.
      • Glud E.
      • Høgdall E.
      • Høgdall C.
      • Blaakaer J.
      • Kjaer S.K.
      Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer.
      ], and the protective effect is not reduced with increasing age [
      • McGuire V.
      • Hartge P.
      • Liao L.M.
      • Sinha R.
      • Bernstein L.
      • Canchola A.J.
      • Anderson G.L.
      • Stefanick M.L.
      • Whittemore A.S.
      Oral contraceptive use in relation to ovarian cancer risk in older women.
      ]. COC use before the first full-term pregnancy has a protective effect on the risk of EOC. A case-control study of invasive EOC in parous women aged 40 or more reported a 9% risk reduction in those who used combined contraceptives before the first birth, suggesting a prolonged protective effect after cessation of COC use [
      • Cook L.S.
      • Pestak C.R.
      • Leung A.C.
      • Steed H.
      • Nation J.
      • Swenerton K.
      Combined oral contraceptive use before the first birth and epithelial ovarian cancer risk.
      ]. Combined hormone contraceptive use also has a significant inverse association with BRCA-related ovarian cancer risk, and the effect is similar when BRCA1 or BRCA2 mutation carrying women are analyzed separately [
      • Moorman P.G.
      • Havrilesky L.J.
      • Gierisch J.M.
      • Coeytaux R.R.
      • Lowery W.J.
      • PeragalloUrrutia R.
      • Dinan M.
      • McBroom A.J.
      • Hasselblad V.
      • Sanders G.D.
      • Myers E.R.
      Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.
      ].
      The incidence of EOC has been associated with the use of menopausal hormone therapy. The worldwide reduction in the prevalence of ovarian cancer during the last decade has been linked with the decline in MHT use [
      • Yang H.P.
      • Anderson W.F.
      • Rosenberg P.S.
      • et al.
      Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in the United States.
      ,
      • Collaborative Group On Epidemiological Studies Of Ovarian Cancer
      • Beral V.
      • Gaitskell K.
      • Hermon C.
      • Moser K.
      • Reeves G.
      • Peto R.
      Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies.
      ], although the causality of this association has been strongly refuted [
      • Webb P.M.
      • Green A.C.
      • Jordan S.J.
      Trends in hormone use and ovarian cancer incidence in US white and Australian women: implications for the future.
      ,
      • Pérez-López F.R.
      • Rees M.
      Menopausal hormone therapy and ovarian cancer: putting risk into perspective.
      ,
      • Shapiro S.
      • Stevenson J.C.
      • Mueck A.O.
      • Baber R.
      Misrepresentation of the risk of ovarian cancer among women using menopausal hormones Spurious findings in a meta-analysis.
      ]. No adverse effects have been shown with MHT use after diagnosis and treatment for ovarian cancer [
      • Kuhle C.L.
      • Kapoor E.
      • Sood R.
      • Thielen J.M.
      • Jatoi A.
      • Faubion S.S.
      Menopausal hormone therapy in cancer survivors: a narrative review of the literature.
      ]. However, there are concerns for women with advanced endometrioid adenocarcinomas who may have residual disease that is hormone-sensitive. While there is a lack of data regarding the use of MHT post-treatment for germ cell tumors, it is typically thought to be safe. Similarly, there are no data on the safety of MHT after treatment for granulosa cell tumors, but it is generally avoided as these tumors are frequently hormonally active [
      • Singh P.
      • Oehler M.K.
      Hormone replacement after gynaecological cancer.
      ].

      6. Non-hormonal interventions

      Non-steroidal anti-inflammatory drugs (NSAIDs) and some analgesics may have chemopreventive actions against cancer from different organs. Low-dose aspirin (150 mg/day for ≥5 years) may reduce the risk of EOC: with regard to histological types, the strongest inverse associations were seen for mucinous and endometrioid tumors [
      • Baandrup L.
      • Kjaer S.K.
      • Olsen J.H.
      • Dehlendorff C.
      • Friis S.
      Low-dose aspirin use and the risk of ovarian cancer in Denmark.
      ]. The African American Cancer Epidemiology Study on EOC risk analyzed the effect of aspirin, non-aspirin NSAIDs and acetaminophen on ovarian cancer risk and found that it was significant for NSAIDs (aspirin and non-aspirin) while acetaminophen had no protective effect. It is likely that ovarian follicle rupture during ovulation releases fluid containing prostaglandins and other compounds that induce inflammation, which can potentially be neutralized by NSAIDs [
      • Peres L.C.
      • Camacho F.
      • Abbott S.E.
      • Alberg A.J.
      • Bandera E.V.
      • Barnholtz-Sloan J.
      • Bondy M.
      • Cote M.L.
      • Crankshaw S.
      • Funkhouser E.
      • Moorman P.G.
      • Peters E.S.
      • Schwartz A.G.
      • Terry P.
      • Wang F.
      • Schildkraut J.M.
      Analgesic medication use and risk of epithelial ovarian cancer in African American women.
      ]. Therefore, small doses of NSAIDs may be a preventive intervention for women at high risk of ovarian cancer but more research is required.

      7. Diet and lifestyle

      Studies analyzing the association between dietary types or contents, alcohol consumption, and coffee or tea consumption have not provided any recommendation to prevent ovarian cancer. The effect of recreational physical activity on ovarian cancer risk is inconclusive or controversial. A meta-analysis reported a 12% increase in EOC risk for obese women (>30 kg/m2), after adjusting for different confounding factors such as MHT use [
      • Collaborative Group on Epidemiological Studies of Ovarian Cancer
      Ovarian cancer and body size: individual participant meta-analysis including 25, 157 women with ovarian cancer from 47 epidemiological studies.
      ]. Furthermore, another meta-analysis of prospective studies reported a non-linear increase in ovarian cancer for each 5 units of BMI increase, this rise starting with a BMI of 28 kg/m2 and above. In addition, there was no association between ovarian cancer and weight gain, hip circumference or waist–hip ratio [
      • Aune D.
      • Navarro Rosenblatt D.A.
      • Chan D.S.
      • Abar L.
      • Vingeliene S.
      • Vieira A.R.
      • Greenwood D.C.
      • Norat T.
      Anthropometric factors and ovarian cancer risk: a systematic review and nonlinear dose-response meta-analysis of prospective studies.
      ]. A recent study among African American women pointed out that ovarian cancer risk is significantly elevated in women with BMI ≥ 40 kg/m2 as compared with those with a BMI <25, and there is an association between this cancer risk and weight gain after age 18 comparing the highest versus the lowest quartile. In postmenopausal women (MHT users and non-users) ovarian cancer risk increased by 15% per 5 kg/m2 increase of BMI, or 6% per 5 kg of weight gain [
      • Bandera E.V.
      • Qin B.
      • Moorman P.G.
      • Alberg A.J.
      • Barnholtz-Sloan J.S.
      • Bondy M.
      • Cote M.L.
      • Funkhouser E.
      • Peters E.S.
      • Schwartz A.G.
      • Terry P.
      • Schildkraut J.M.
      Obesity, weight gain, and ovarian cancer risk in African American women.
      ]. For each 5 kg increase in adult weight, ovarian cancer risk increases in postmenopausal women, both in users and non-users of MHT [
      • Keum N.
      • Greenwood D.C.
      • Lee D.H.
      • Kim R.
      • Aune D.
      • Ju W.
      • Hu F.B.
      • Giovannucci E.L.
      Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies.
      ]. In addition, in postmenopausal women the risk is similar among MHT users and non-users. It is important to note that obesity does not seem to increase the risk of the most aggressive (or lethal) cancers, and that associations are similar in MHT users and non-users [
      • Olsen C.M.
      • Nagle C.M.
      • Whiteman D.C.
      • Ness R.
      • Pearce C.L.
      • Pike M.C.
      • Rossing M.A.
      • Terry K.L.
      • Wu A.H.
      • Australian Cancer Study (Ovarian Cancer)
      • Australian Ovarian Cancer Study Group
      • Risch H.A.
      • Yu H.
      • Doherty J.A.
      • Chang-Claude J.
      • Hein R.
      • Nickels S.
      • Wang-Gohrke S.
      • Goodman M.T.
      • Carney M.E.
      • Matsuno R.K.
      • Lurie G.
      • Moysich K.
      • Kjaer S.K.
      • Jensen A.
      • Hogdall E.
      • Goode E.L.
      • Fridley B.L.
      • Vierkant R.A.
      • Larson M.C.
      • Schildkraut J.
      • Hoyo C.
      • Moorman P.
      • Weber R.P.
      • Cramer D.W.
      • Vitonis A.F.
      • Bandera E.V.
      • Olson S.H.
      • Rodriguez-Rodriguez L.
      • King M.
      • Brinton L.A.
      • Yang H.
      • Garcia-Closas M.
      • Lissowska J.
      • Anton-Culver H.
      • Ziogas A.
      • Gayther S.A.
      • Ramus S.J.
      • Menon U.
      • Gentry-Maharaj A.
      • Webb P.M.
      Ovarian cancer association consortium. obesity and risk of ovarian cancer subtypes: evidence from the ovarian cancer association consortium.
      ]. These results suggest the importance of avoiding obesity in young women and preventing weight gain.
      Cigarette smoking has been associated with certain histologic subtypes of ovarian cancer [
      • Marchbanks P.A.
      • Wilson H.
      • Bastos E.
      • et al.
      Cigarette smoking and epithelial ovarian cancer by histologic type.
      ]. Women who smoked for more than 20 years had 3 times the risk of developing borderline EOCs as compared with never smokers, and there was an almost significant relation for mucinous tumors. In addition, there was also a significant dose–response effect with smoking intensity and duration for both borderline and serous tumors [
      • Gram I.T.
      • Braaten T.
      • Adami H.O.
      • Lund E.
      • Weiderpass E.
      Cigarette smoking and risk of borderline and invasive epithelial ovarian cancer.
      ,
      • Licaj I.
      • Jacobsen B.K.
      • Selmer R.M.
      • Maskarinec G.
      • Weiderpass E.
      • Gram I.T.
      Smoking and risk of ovarian cancer by histological subtypes: an analysis among 300 000 Norwegian women.
      ]. Another recent study reported that smoking is associated with an increased risk of mucinous cancers, and a decreased risk for clear cell cancers [
      • Wentzensen N.
      • Poole E.M.
      • Trabert B.
      • White E.
      • Arslan A.A.
      • Patel A.V.
      • Setiawan V.W.
      • et al.
      Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium.
      ]. Therefore, on these grounds alone, it is recommended that tobacco consumption is reduced or eliminated.

      8. Summary

      • Opportunistic bilateral salpingectomy may prevent ovarian cancer. Bilateral salpingectomy should be preferred to tubal ligation, and should be recommended in cases of hysterectomy for benign conditions.
      • Combined but not progestogen-only contraceptive medication reduces the risk of ovarian cancer.
      • Menopausal hormone therapy should be individualized in oophorectomized BRCA gene mutation carriers or among those with other genetic-related increased ovarian cancer risk.
      • NSAIDs, particularly aspirin, may reduce the risk of ovarian cancer but more research is required.
      • Being overweight or obese increases the risk of ovarian cancer. There is no evidence that any particular diet reduces the risk of ovarian cancer.

      Contributors

      Faustino R. Pérez-López prepared the initial draft, which was circulated to EMAS board members for comment and approval; production was coordinated by Irene Lambrinoudaki and Margaret Rees.

      Conflict of interest

      F. R. Pérez-López: None declared.
      I. Ceausu: None declared.
      H. Depypere: None declared.
      S. Kehoe: In the past year Dr Sean Kehoe has received speakers’ honoraria from Roche. He is member of the advisory Board of Roche.
      I. Lambrinoudaki: None declared.
      A. Mueck: None declared.
      L. M. Senturk: None declared.
      T. Simoncini: None declared.
      J. C. Stevenson: In the past year Dr. John C. Stevenson has received grants/research support from Mylan, consulting fees from Abbott and Mylan, and speakers honoraria from Mylan.
      P. Stute: In the past year Dr Petra Stute has received grants/research support from Medinova AG and Dr Kade/Besins Pharma GmbH, consulting fees from Max Zeller Söhne AG, Madaus GmbH, and speakers honoraria from MSD Merck Sharp & Dohme AG, Dr Kade/Besins Pharma GmbH and Max Zeller Söhne AG.
      M. Rees: None declared

      Funding

      No funding was received for the preparation of this position statement.

      Provenance and peer review

      This article is an EMAS position statement and was not externally peer reviewed.

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