Ovarian cancer risk factors

21% of ovarian cancer cases each year in the UK are linked to major lifestyle and other risk factors.[1]

Ovarian cancer risk is associated with a number of risk factors.[2-4]

Ovarian Cancer Risk Factors

Ovarian cancer risk is strongly related to age.

Ovarian cancer risk is associated with factors affecting lifetime number of (and breaks between) ovulations, and/or sex hormone levels (oestrogen, progesterone and androgens). Ovulation causes structural changes to the ovary which may stimulate cancer development, and hormonal factors may compound this or have their own independent effects.[1-3] Having more children, breastfeeding, or using oral contraceptives (OCs) decreases the number of ovulations.

Current use of postmenopausal oestrogen hormone replacement therapy (HRT) is classified by the International Agency for Research on Cancer (IARC) as a cause of ovarian cancer.[1] An estimated 1% of ovarian cancer cases in the UK are linked to HRT use.[2]

Ovarian cancer risk is 53% higher in long-term (5+ years) current oestrogen-only HRT users, compared with never users, a cohort study showed.[3]

Ovarian cancer risk is 17% higher in long-term (5+ years) oestrogen-progesterone HRT users, compared with never users, a cohort study showed.[3]

Ovarian cancer risk varies with circulating androstenedione levels, a nested case-control study showed; this association varies with ovarian cancer type and menopausal status.[1] Ovarian cancer risk is not associated with circulating testosterone levels.[1]

Tobacco smoking is classified by the International Agency for Research on Cancer (IARC) as a cause of ovarian cancer.[1] An estimated 3% of ovarian cancer cases in the UK are linked to smoking tobacco.[2]

Ovarian mucinous cancer risk is 31-49% higher in current smokers compared with never-smokers, meta- and pooled analyses have shown.[3,4] Risk increases with smoking duration.[3,4] Ovarian mucinous borderline malignant tumour risk is 83-125% higher in current versus never-smokers.[3,4]

Ovarian clear cell and ovarian endometrioid cancer risk may be lower in current versus never-smokers, but evidence is mixed.[3,4] Other ovarian cancer types are not associated smoking.[3,4]

Asbestos is classified by the International Agency for Research on Cancer (IARC) as a cause of ovarian cancer.[1]

Ovarian cancer mortality risk is higher in women occupationally exposed to asbestos, meta-analyses have shown; however the evidence is limited by erroneous inclusion of peritoneal mesothelioma with ovarian cancer cases, potential confounding by other risk factors, and lack of evidence for an association with ovarian cancer incidence.[2,3]

Talc-based body powder used perineally  is classified by the International Agency for Research on Cancer (IARC) as a probable cause of ovarian cancer.[1]

Ovarian cancer risk is 24-35% higher in women who have ever used body powder perineally/genitally versus those who have not, meta- and pooled analyses of case-controls studies have shown.[2,3] However, recall bias (cases more likely than controls to recall exposure to possible risk factors) may have influenced this, as ovarian cancer risk is not associated with perineal powder use in cohort studies.[3,4] Ovarian cancer risk is not associated with non-genital talc-based body powder use.[5]

This association with ovarian cancer risk may be due to the mineral talc in body powders, though not all body powders today contain talc; it may also be due to asbestos traces in some body powders made before the 1970s.[3]

X radiation and gamma radiation is classified by the International Agency for Research on Cancer (IARC) as a probable cause of ovarian cancer.[1]

A very small number of ovarian cancer cases may be associated with radiotherapy for previous cancer, specifically breast cancer.[2] However associations between breast and ovarian cancers are probably due more to shared genetic or hormonal risk factors; indeed radiotherapy has been associated with decreased ovarian cancer risk in breast cancer survivors.[3]

Around 3% of ovarian cancer cases occur in women with a family history of ovarian cancer, a cohort study showed.[1] Ovarian cancer risk is 2.7-3.5 times higher in women whose mother or sister has/had ovarian cancer, compared with women with no such family history, cohort studies have shown; risk may be higher if the affected relative was diagnosed at a younger age.[2,3]

Ovarian cancer risk is higher in women whose sibling has/had stomach, liver, breast, prostate, or connective tissue cancer, or melanoma; or whose parent has/had breast or liver cancer, a cohort study showed.[1] Ovarian cancer risk is higher in families with a history of breast cancer compared with the general population, even when when BRCA1  or BRCA2 mutations are not present, a cohort study showed.[2]

Inherited conditions account for 5-15% of ovarian cancer cases; the majority of these hereditary cases are linked with BRCA1/2 mutations.[1]

Ovarian cancer risk is up to 65% higher in women with BRCA1 mutation, and up to 35% higher in women with BRCA2 mutation, versus women without these genes.[2,3] Ovarian cancer risk among BRCA1 mutation carriers is lower in those who have given birth to 4+ children versus none, those who have used oral contraceptives for a year or more, and those who have had tubal ligation; but is not associated with other reproductive factors, or hormone replacement therapy (HRT) use, a meta-analysis showed.[4] Ovarian cancer risk among BRCA2 mutation carriers is lower in oral contraceptives users but is not associated with reproductive factors or HRT use.[4]

Around 7% of women with Lynch syndrome  develop ovarian cancer by age 70, a pooled analysis showed.[1] Around 21% of women with Peutz-Jeghers syndrome develop ovarian cancer aged 15-64, a meta-analysis showed.[2]

Body fatness is classified by the International Agency for Research on Cancer (IARC) and World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) as a cause of ovarian cancer (WCRF/AICR classify the evidence on body fatness and ovarian cancer as probable).[1,2]

Ovarian cancer risk among hormone replacement therapy (HRT) never-users is 10% higher per 5-unit body mass index (BMI) increment, a meta-analysis showed. [3] Ovarian cancer risk among HRT ever-users (presumably postmenopausal) is 5% lower per 5-unit BMI increment.[3] Ovarian cancer risk may only be increased in women with BMI above 28, a meta-analysis showed.[4]

Greater adult attained height (as a marker of factors that promote linear growth in childhood) is classified by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) a probable cause of ovarian cancer.[1]

Ovarian cancer risk is 7-10% higher per 5cm increment in height, meta-analyses and a pooled analysis of Nordic data showed.[2-4]

Ovarian cancer risk is 27-80% higher in women with endometriosis , versus women without the disease and the general population respectively, a meta-analysis showed.[1] The association may differ by tumour type.[1]

Ovarian cancer risk is 20-55% higher in diabetics compared with non-diabetics, meta-analyses have shown.[1,2]

Ovarian cancer risk among diabetics may be slightly higher in insulin users versus non-users.[3] Ovarian cancer risk among diabetics is not associated with metformin or pioglitazone use versus non-use.[4,5]

Ovarian cancer risk is 24% higher in breast cancer survivors compared with the general population, a cohort study showed.[1] Ovarian cancer risk among breast cancer survivors is higher in those diagnosed with breast cancer at a younger age versus those diagnosed older, and higher risk is limited to oestrogen-receptor  (ER)-negative or ER-unknown breast cancer.[1]

Ovarian cancer risk is higher in bowel cancer survivors compared with the general population, a cohort study showed; this is limited to those diagnosed with bowel cancer at a younger age, and largely limited to the period very shortly after bowel cancer diagnosis.[1]

These associations between primary breast and bowel cancers and subsequent ovarian cancer probably reflects the impact of BRCA mutations and Lynch syndrome, or shared hormonal risk factors.[1,2]

Oral contraceptives (OCs) are classified by the International Agency for Research on Cancer (IARC) as protective against ovarian cancer.[1] An estimated 9% more ovarian cancer cases would occur each year in the UK, but for current and past use of OCs.[2]

Ovarian cancer risk is 25-28% lower in women who have ever used OCs compared with never-users, a meta-analysis showed.[3] Risk reduces further with longer duration of OC use; it is more than halved with 10+ years' use, a meta-analysis showed.[3] Ovarian cancer risk in OC ever-users remains reduced for at least 30 years after last use of OCs, though the protection may diminish over time.[3,4]

Among BRCA1/2 mutation carriers, ovarian cancer risk is almost halved among OC ever-users compared with never-users, a meta-analysis showed.[3,5]

Breastfeeding is classified by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) as possibly protective against ovarian cancer, based on limited-suggestive evidence.[1] An estimated 18% of ovarian cancers in the UK are linked to women breastfeeding each of their children for fewer than 6 months.[2]

Ovarian cancer risk is 24-30% lower in women who have ever breastfed, versus those who have never done so, meta-analyses have shown; risk decreases further with longer breastfeeding duration.[3-6] Breastfeeding and higher parity may have a synergistic effect on decreased ovarian cancer risk.[6]

Consumption of non-starchy vegetables is classified by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) as possibly protective against ovarian cancer, based on limited evidence.[1]

Consumption of cruciferous vegetables and vegetables overall is not associated with ovarian cancer risk, meta- and pooled analyses have shown.[2,3]

Ovarian cancer risk is lower in women with the following reproductive or medical factors, meta-and pooled analyses or systematic reviews have shown:

• Higher parity (number of children given birth to).[1-4] Nulliparity (bearing no children) plus not breastfeeding are probably the mechanisms underlying higher ovarian cancer risk in infertile women, including those treated with ovarian stimulating drugs.[5-7]
• Hysterectomy  – 27-31% lower risk (though some evidence of higher risk in women undergoing hysterectomy in more recent years, perhaps due to changes in average age at hysterectomy, surgical technique, or use of hormone replacement therapy (HRT) following hysterectomy).[8,9]
• Tubal ligation – 30% lower risk, with variation by ovarian cancer subtype.[8]
• Statins – 21% lower risk in users versus non-users, even lower risk in long-term (5+ years) users.[10]
• Systemic lupus erythematosus  – 34% lower risk versus general population[10] (though some evidence of no association[12]).

The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) make no judgement on the association between ovarian cancer risk and vegetables; fruits; pulses (legumes); red meat; processed meat; poultry; fish; eggs; milk and dairy products; vegetarian and individual level dietary pattern; coffee; tea; dietary fibre; carbohydrates; protein; total fat; saturated, monounsaturated, and polyunsaturated fatty acids; vegetable and animal fat; trans fatty acids; dietary cholesterol; alcohol; folate; vitamin A; lycopene; vitamin C; vitamin E; serum vitamin D; lactose; calcium; acrylamide; physical activity; abdominal fatness; and energy intake, due to limited evidence.[1]

Ovarian cancer risk is not associated with the following factors, meta- and pooled analyses or systematic reviews have shown:

• Older age at menarche (though some evidence of lower risk in case-control studies).[2]
• Polycystic ovary syndrome (PCOS) and ovarian cysts (though limited evidence of higher risk in younger women with PCOS).[3-6]
• Aspirin[7,8] (though some evidence of lower risk particularly with daily low-dose aspirin[9,10]).
• Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs)[7,8,10] (though some evidence of lower risk of mucinous ovarian cancer[8]).
• Paracetamol (acetaminophen).[9,11,12]
• Physical activity (though some evidence of lower risk in case-control studies).[13]
• Birth weight.[14]
• Vitamin D levels.[15,16]
• Alcohol (though evidence is inconsistent).[17-19]
• Coffee.[20]
• Red and processed meat.[21]
• Fish.[22]
• Dietary lycopene (postmenopausal women).[23]
• Dairy products.[24,25]
• Total dietary fat (though some evidence of higher risk, particularly for animal fats[26,27]).[28]
• Fruit.[29]
• Eggs (though some evidence of higher risk in case-control studies).[30]
• Nitrate and nitrite.[31]
• Systemic lupus erythematosus.[32]