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Current Cancer Drug Targets, 2018, 18, 522-537

REVIEW ARTICLE
ISSN: 1568-0096
eISSN: 1873-5576

Towards Prevention of Ovarian Cancer Impact

Factor:
2.992

BENTHAM
SCIENCE

Aus Tariq Ali*

Department of Pathology, Tygerberg Hospital and Stellenbosch Medical School, Cape-Town, South Africa

Abstract: Ovarian cancer is the leading cause of death of all gynaecological cancers. To date, there
is no reliable, specific screening procedure for detecting ovarian cancer. The risk factors of ovarian
cancer include modifiable and non-modifiable factors. The main goal of the ovarian cancer preven-
tion program is to significantly reduce the risk of development of ovarian cancer and other cancers
such as breast and/or peritoneal cancer. The application of non-surgical preventive approaches such
as oral contraceptives, parity and breastfeeding has been shown to be highly protective against ovar-
ARTICLE HISTORY ian cancer development. Targeting inflammation has been also reported to be associated with a pro-
tective trend against ovarian cancer and can be achieved through either non-steroidal anti-
Received: June 23, 2017
Revised: November 20, 2017 inflammatory drugs (NSAIDs) such as aspirin or lifestyle modifications or both. Lifestyle modifica-
Accepted: November 24, 2017 tion that includes regular exercise, healthy diet supplemented with anti-oxidants and anti-
DOI: inflammatory elements reduces the risk of the disease even further. Surgical protective approaches
10.2174/1568009618666180102103008 include; tubal ligation, hysterectomy and prophylactic bilateral salpingo-oophorectomy and the for-
mer is the most effective approach to protect against ovarian cancer. A better understanding of the
risk factors of ovarian cancer and the current approaches to prevent it may increase the awareness
and help decrease the incidence of ovarian cancer, increase the five-year survival rate and decrease
Current Cancer Drug Targets

the mortality rate significantly in the general population especially among those at high risk for
ovarian cancer. This review is an attempt to outline a potential program of ovarian cancer preven-
tion and the potential challenges.

Keywords: Aspirin, breastfeeding, contraceptives, ovarian cancer, parity, physical activity, prophylactic surgery.

1. INTRODUCTION procedures and chemotherapy, ovarian cancer remains the

most lethal gynaecologic cancer worldwide. The longer sur-
Ovarian cancer is a heterogeneous disease and is more vival time is influenced by younger age at the time of diag-
common in developed countries. Epithelial ovarian cancer nosis, early stage of the tumor, low-grade and nonserous
represents about 90% of ovarian cancer and can arise from histology [4]. Since most patients are diagnosed in the ad-
the epithelium cells of the ovary, peritoneum and fallopian vanced stages (III and IV), the survival rate is extremely low.
tube. The remaining percentage of ovarian tumors originate Epidemiological studies have showed that the risk of ovarian
from germ cells and gonadal stromal cells [1]. Mutation in cancer mainly increases with age progression [5], genetic
epithelial ovarian DNA is responsible for 10-15% of epithe- predisposition [6-9], family history of ovarian cancer [10-
lial ovarian cancer cases [2]. Various factors involved in the 12], late age of menopause [12, 13], nulliparity [14, 15],
development of ovarian cancer have been postulated and the hormone replacement therapy (HRT) [12, 16], obesity [17-
most common hypotheses are displayed in Fig. (1). Epithe- 20] and dietary fat [21-24]. Since the focus of this article is
lial ovarian cancer is composed of five major histological on preventive approaches, only the main risk factors for
types; high-grade serous carcinoma, accounting for most of ovarian cancer is discussed (Table 1).
the cases; clear cell, endometrioid, mucinous and low-grade
serous carcinomas. The fallopian tube is currently believed A protective trend has been shown to be associated with
to be the source of high-grade serous carcinoma which is the non-surgical approaches such as: oral contraceptives [5, 25-
most common disease subtype. The other two prevalent sub- 27], parity [27-29], breastfeeding [5, 15, 30-32], targeting
inflammation with aspirin [33-38], a healthy diet [21, 39-41]
types are clear cell and endometrioid that are derived from
and regular exercise [42, 43]. Surgical approaches involve
endometria that had passed into the peritoneal cavity and
tubal ligation [44-46], salpingectomy [3, 47] hysterectomy
implanted on the ovaries [3].
[44, 45], hysterectomy with unilateral oophorectomy [45]
Early ovarian cancer is an asymptomatic disease and and bilateral salpingo-oophorectomy [6, 48]. For women
despite the development in screening technology, surgical with a family history of ovarian cancer or those with a ge-
netic predisposition (BRCA mutations), bilateral salpingo-
oophorectomy could be the only available solution. It should
*Address correspondence to this author at the Department of Pathology,
Tygerberg Hospital and Stellenbosch Faculty of Medicine and Health Sci-
however, be taken in consideration that the risk of peritoneal
ences P.O. Box 19113, Tygerberg 7505, Cape Town, South Africa; cancer is reported to be increased following bilateral
Tel: +27 21 938 6144; Fax: +27 21 938 4640; E-mail: atali@sun.ac.za salpingo-oophorectomy [48].

1873-5576/18 $58.00+.00 © 2018 Bentham Science Publishers

Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 523

Hypotheses Explaining Ovarian Cancer Development

Fallopian tube Hormonal imbalance Incessant ovulation Inflammation

Ovarian cancer is either Ovarian cancer is due to Ovarian cancer is due to Ovarian cancer is due to
originate from fallopian long exposure to non-stop ovulation inflammation
tube or passing through it unopposed oestrogen

Supported by; Supported by; Supported by; Supported by;

*Increased ovarian cancer risk *The ovarian epithelium is a *Increased ovarian cancer *Cancers arise at tissue
with increased exposure of hormonally responsive target incidence/prevalence among with chronic inflammation.
ovaries to carcinogens that are organ. nulliparous women.
transported to the peritoneal *Cancer risk is increased in
cavity through the fallopian *Imbalance of the hormonal many chronic inflammatory
tubes. environment increases the risk *A great increase in the risk of diseases.
of ovarian cancer. ovarian cancer is associated with
* The simultaneous presence of increased number of ovulation *Chemical mediators of
serous tubal intraepithelial * Increased risk of ovarian (i.e. laying chicken). inflammation are up-
carcinomas in patients at high cancer incidence/prevalence regulated in many cancers.
risk for ovarian cancer or with among postmenopausal *Decreased ovarian cancer
sporadic or familial ovarian women who used hormone incidence/prevalence among *Inhibition of the inflammatory
cancer. replacement therapy women using contraceptives, or chemical mediators inhibits
containing oestrogen alone. multi-parous and breast feeding cancer progression and
*Decreased ovarian cancer women. metastasis.
among women with tubal
ligation and salpingectomy.

Fig. (1). Most popular hypotheses explain the development of ovarian cancer and their supportive evidences.
The 4 major hypotheses that explain the development of ovarian cancer are; incessant ovulation, inflammation, hormonal imbalance and the
fallopian tube. Each of these hypotheses has supportive evidences as shown above.

Table 1. Selected risk factors for ovarian cancer and their contribution towards the occurrence of the disease.

Author/Year Risk Factor Reported Risk

The lifetime risk of ovarian cancer varies from 36% to 46% among BRCA 1 mutation carriers compared
BRCA1 to 1.3% for general population.
Rebbeck et al., 2009 [6]
BRCA2 The lifetime risk of ovarian cancer varies from 10% to 27% among BRCA 2 mutation carriers compared
to 1.3% for general population.

Compared with women who never used HRT, the incidence rate for current users of HRT was 1.38 (95%
Mørch et al., 2009 [16] HRT
CI: 1.26-1.51) for all ovarian cancers and 1.44 (95%, CI: 1.30-1.58) for epithelial ovarian cancer.

There is 1.42 fold increase in the risk of ovarian cancer in nulliparous women compared with parous
Park et al., 2016 [15] Nulliparity
women.

Bhaskaran et al., 2014 Each 5 kg/m2 increase in BMI is associated with a 0.09 increased risk of ovarian cancer [HR 1.09,
Obesity
[19] (99%CI: 1.04-1.14)].

Compare with normal BMI women, obese (BMI≥30 kg/m2) women were at an increased risk of develop-
Liu et al., 2016 [20] Obesity
ing epithelial ovarian cancer [HR: 2.44 (95% CI: 1.37-4.35)].

The high consumption animal fat is associated with 4.6 fold increase in ovarian cancer risk [OR: 4.6
Zhang et al., 2002 [21] Animal fat
(95% CI: 2.2-9.3)] compared to low consumption.

Kolahdooz et al., 2009 Compared with low consumption of meat and fat, the high consumption of meat and fat is associated
Meat and fat
[22] with a 2.49 increased risk of ovarian cancer [OR: 2.49 (95% CI: 1.75-3.55)].

Shanmughapriya et al., Compared with women consumed vegetarian diet, those who consumed dietary fat diet showed a 6 fold
Dietary fat
2016 [23] increase in cancer risk [OR: 6.286 (95% CI: 0.779-50.701)].
524 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

A successful prevention program must lead to a signifi- Ovarian cancer is more common in developed compared
cant reduction in ovarian cancer and the development of with non-developed countries. The westernisation of lifestyle
other cancers such as breast and /or peritoneal cancer [48] and changes in socio-demographic behavior in industrialised
and other related complications [49]. This review presents an and developing countries may explain the gradual escalation
overview of ovarian cancer prevention strategies, highlight- in ovarian cancer incidence. The former assumption is sup-
ing the obstacles and the most convenient approaches in or- ported by an earlier study that reported a high incidence rate
der to reduce the risk of the disease in the general population of ovarian cancer among Japanese immigrants to the USA
and prevent it among high risk populations. [56]. Worldwide, there are more than 200 000 cases of ovar-
ian cancer diagnosed every year and more than half of these
2. SELECTION OF ARTICLES FOR THIS REVIEW die yearly due to the disease [57]. In developed countries, the
USA ranks first in terms of the number of new cases and
This review includes epidemiological, experimental and mortality rate with about 22 000 women diagnosed with
clinical studies that targeted ovarian cancer risk and preven- ovarian cancer every year with 14,270 deaths due to the dis-
tion. After an intensive search through PubMed using com- ease [50].
binations of specific key words representing, diagnosis and
prognosis, risk factors or prevention methods for ovarian Ovarian cancer data from most developing countries are
cancer, the relevant English language publications on ovar- scarce due to registration deficiencies, and this causes geo-
ian cancer up to October 2017, were selected. Articles that graphical differences in the incidence, prevalence and death
were not accessible or not found through the university’s rate from ovarian cancer between countries. Increased hys-
electronic library were requested directly from the authors. terectomy and prophylactic bilateral salpingo-oophorectomy
Out of the total number of chosen articles, only articles that regardless of whether a woman has a family history of ovar-
considered basic research roles such as appropriate sample ian cancer, affect the prevalence of ovarian cancer and may
size and appropriate methodology were selected. Studies that create differences in observed rates among countries. Thus,
exhibited methodological weaknesses and case reports were such practices may affect the number of women at risk (the
excluded. denominator) and lead to underestimation of ovarian cancer
rates. Part of the international differences in ovarian cancer
3. THE SIZE OF THE PROBLEM prevalence is due to differences in the distribution of the
main risk factors of ovarian cancer (i.e. BRCA mutations,
Although ovarian cancer accounts for only one quarter of obesity) and differences in the exposure to preventive fac-
the gynaecologic cancer, it is responsible for more than half tors. Although it might have a small effect, increased lethal
of the deaths due to gynaecological cancer [50]. The main diseases such as the human immunodeficiency virus infec-
public health challenges are represented by firstly, the lack tion and acquired immune deficiency syndrome (HIV-
of adequate diagnostic or screening strategies, thus most AIDS), tuberculosis (TB) and other viral diseases (i.e. hepa-
women are diagnosed at advanced stages and mostly be- titis B and C) may affect the prevalence of ovarian cancer in
tween stage III and IV [51]. Secondly, the recurrence of the African countries, as most women with these diseases die
disease that is often chemo-resistant which negatively affects before reaching the age when ovarian cancer is common [58,
the 5 year survival rate. Thirdly, the majority of ovarian can- 59].
cer tumors (90%) are diagnosed in women who are not in an
identifiable high-risk group [7], and almost one-third of the
4. MAIN RISK FACTORS
cases diagnosed with ovarian cancer due to mutations have
no family history with cancer [52], affecting the detection of Ovarian cancer is a multifactorial disease. Generally, the
the disease earlier. Currently, no reliable and specific screen- main risk factors for ovarian cancer include modifiable and
ing procedure for detecting ovarian cancer exists. Conse- non-modifiable factors.
quently, ovarian cancer is associated with a low five year
survival rate.
5. NON-MODIFIABLE RISK FACTORS
Available screening methods include measurement of se-
rum tumor markers (CA125), detection of ovarian morpho- Ovarian cancer is mostly seen in postmenopausal women
logical abnormalities by transvaginal ultrasound, symptom [34, 37]. Thus, as a woman gets older her risk of developing
indexes, color Doppler ultrasound scanning and other imag- ovarian cancer increases and elderly women are more likely
ing modalities [53]. Ovarian cancer cannot be prevented by than younger women to be in an advanced stage of the dis-
screening, because of lack of precancerous states, but the ease at initial diagnosis. Family history of ovarian cancer
goal of screening is to reduce mortality. In contrast, there is confers a three to fourfold increased risk of the disease for
preliminary evidence that serous tubal intraepithelial carci- women with a single first-degree relative affected with ovar-
noma (STIC) is a precursor lesion for high-grade serous tu- ian cancer [11]. Nevertheless, genetic factors represent only
mours. Nonetheless, the use of screening approaches has no 10% of ovarian cancer and the majority of genetic related
significant effect on the death rate [54] and is usually associ- ovarian cancer is due to the presence of BRCA1 and BRCA2
ated with either false negatives or false positives. While false mutations [9]. Mutations of DNA mismatch repair genes are
negatives underestimate the risk, false positive results lead to more frequently associated with mucinous and endometrioid
unnecessary testing and biopsies sometimes resulting in seri- ovarian cancers [60], and mutations in BRCA1 and BRCA2,
ous complications [55]. Ovarian cancer cannot be eliminated which are involved in double strand DNA break repair, lead
completely even after prophylactic oophorectomy, as there is to the development of serous cancers [61]. There are other
still a risk of peritoneal cancer, albeit with a low incidence genes that have also been linked to ovarian cancer such as
rate [48]. HNPCC or Lynch syndrome and Peutz-Jeghers syndrome
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 525

Increased insulin demand Overweight/ Obese/

Normal weight -
metabolically obese

Insulin resistance Hyperinsulinemia

Vicious circle

Body weight ↑ Unopposed estrogen↑

Visceral fat ↑

Hormonal Disturbances

Hormonal Disturbances Chronic inflammation

Vicious circle Oxidative stress

Inflammation ↑ Chances for mutation ↑

Cytokines (TNFα , IL6) ↑
Estrogen biosynthesis ↑

Ovarian cancer

Fig. (2). A proposed mechanism describing the relationship between obesity and the development of ovarian cancer.
There is an increase demand for insulin in overweight, obese and normal but metabolically obese women. The pancreas responds by increas-
ing insulin secretion and as a result, the body will deposit more fat, and more weight requires more insulin. Increased insulin secretion in
these groups will lead mostly to insulin resistance and hyperinsulinaemia will develop. The body enters a vicious cycle where more insulin
resistance forces the pancreas to secrete more insulin. Consequently, the body starts to direct the extra fat to the abdominal cavity to be de-
posited as visceral fat. This will cause hormonal disturbances, increased cytokines and inflammation, as well as increase oestrogen secretion
from fat tissue. Chronic inflammation will developed leading to oxidative stress, which increases the chances for mutation and ultimately
increasing the risk of ovarian cancer development.

[8]. A woman with a family history of ovarian cancer has a 1·66)] and endometrioid tumors [RR: 1·42, (1·20-1·67)]. The
2.9 fold increased risk of developing ovarian cancer [OR: 2.9 risk is diminished after stopping the use of HRT [12]. High
(95% CI: 1.5-5.8)] compared with a woman with no family BMI is associated with increased risk of ovarian cancer [20,
history of the disease [5]. Although younger age at menarche 65], and obese women have more than two fold increase in
is considered to be an important risk factor for breast and the risk [HR: 2.44 (95% CI: 1.37-4.35)] compared with nor-
endometrial cancer, it is modestly associated with ovarian mal weight women [20], and more ovarian cancer cases are
cancer risk and was only reported in a limited number of reported to be overweight or obese [37]. A previous study
studies and in the general population [62]. In contrast, stud- reported a 10% increase in the risk of ovarian cancer [RR:
ies on patients with BRCA gene mutations reported no asso- 1.10 (95% CI: 1.07-1.13)] per 5kg/m2 increase in body mass
ciation between ovarian cancer and age of menarche [63]. index [65]. In contrast, a recent systemic review reported that
On the other hand, late age at menopause has been shown to the relationship between obesity and the risk of ovarian can-
be strongly associated with the risk of ovarian cancer [12, cer was found to be smaller than expected [66]. This is be-
13]. cause the results could have been influenced by the study
design [17, 65]. When the relationship between obesity and
6. MODIFIABLE RISK FACTORS ovarian cancer was studied by histological subtype, this as-
sociation was stronger with borderline serous tumours, while
Nulliparity has been known for decades to be associated
no association was observed with serous invasive tumours
with increased reproductive cancer risks. Compared with
parous women, nulliparous women have a 1.42-fold higher [18].
risk for developing ovarian cancer [11]. Furthermore, the Obesity is associated with inflammation, insulin resis-
risk is related to the total number of years with ovulation and tance and increased levels of estrogen (Fig. 2). Persistent
a 7% to 8% increase in risk of nonmucinous tumors for each inflammation induced by TNF-α may encourage DNA dam-
year of ovulation, but no significant increased risk for muci- age, angiogenesis, invasion and metastasis, and immunosup-
nous tumors [64]. A meta-analysis consisting of 52 epidemi- pression at the inflammation sites [67]. Previous studies have
ological studies [17] reported a 43% increase in ovarian can- reported a significant relationship between ovarian cancer
cer risk [RR: 1·43, (95% CI 1·31-1·56)] among current users and dietary fat [21-23, 68] and especially animal fat but not
of HRT even when the duration of HRT use was less than 5 from plant sources [21, 24, 68]. Dietary fat increases cancer
years. However, when studied by subtypes increased ovarian progression and metastasis and decreases the survival rate
cancer risk only seen in serous [RR: 1·53, (95% CI 1·40- among patients with cancer in general. Thus, differences
526 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

Table 2. The protective effect of a selected reproductive factors against ovarian cancer development.

Author/Year Factor Reported Risk Reduction

Among BRCA1/2 carriers, any past use of a combined oral contraceptive was associated with a 43% risk
Oral
Cibula et al., 2011 [73] reduction [OR: 0.57 (95% CI: 0.47-0.70)] and the reduction trend is significantly associated with the
contraceptives
duration of use.

Havrilesky et al., 2013 Oral

Using oral contraceptives for 10 years was associated with a 50% decrease in ovarian cancer risk.
[25] contraceptives

Having four or more live births among BRCA1 mutation carriers was associated with a 58% risk reduc-
Friebel et al., 2014 [27] Parity
tion [the pooled effect estimated= 0.42 (95% CI: 0.20 - 0.88)].

Compared with parous women, nulliparous women has 0.4 fold increased risk [RR: 1.4(95% CI: 0.9-
Vachon et al., 2002 [29] Parity 2.4), while nulliparous with family history of breast or ovarian cancer has 2.7 fold increase in the risk of
ovarian cancer compared with parous women [RR:2.7(95% CI: 1.1-6.6)].

Huusom et al., 2006 Breastfeeding was associated with a 68% reduction in the risk of borderline tumors [OR: 0.32(95% CI:
Breastfeeding
[71] 0.11-0.95)] when the duration of breastfeeding exceeded 25 months.

Women with BRCA1 mutation who breastfed have a 26% risk reduction [OR: 0.74 (95% CI: 0.56-0.97)]
Gronwald et al., 2006
Breastfeeding compared with control. The risk reduction rose to 36% [OR: 0.64 (95% CI: 0.47-0.91)] with increasing
[74]
duration of breastfeeding to more than 1 year.

among countries in the consumption of dietary fat may ex- carriers was studied separately, a similar significant reduc-
plain partially the international differences in the prevalence tion in risk for BRCA1 and BRCA2 mutation carriers was
of different types of cancer including ovarian cancer. A observed [27, 73, 77]. The protective effect of contraceptives
meta-analysis study showed that the association between among BRCA1 and BRCA2 mutation carriers increased from
dietary fat and ovarian cancer varies by the type of fat con- 20% for three years use to 60% for six years of use [77],
sumed and histological subtypes of ovarian cancer and the however, Modan and colleagues reported that contraceptives
relation was more pronounced in case control than cohort have no effect on the risk of ovarian cancer among BRCA
studies [24]. Table 1 summaries some of the results reported mutation carriers [78].
previously.
10. THE IMPACT OF PARITY
7. CURRENT APPROACHES FOR THE PREVEN-
Parity protects against the development of ovarian cancer
TION OF OVARIAN CANCER in women in the general population [28, 69] and in those
The current strategies to prevent ovarian cancer include with BRCA1 mutations [27, 79], and the risk continues to
surgical and non-surgical approaches. decrease with increased numbers of births [28, 69] suggest-
ing an accumulative effect. An earlier study by Hankinson
and colleagues showed that compared to nulliparous woman,
8. NON-SURGICAL APPROACHES
parous women have a decreased risk for ovarian cancer after
Non-surgical approaches to prevent ovarian cancer in- birth of the first child, and the risk continued to decrease
clude; firstly, reproductive strategies (Table 2) such as oral after the second, third, fourth, fifth, and sixth or more chil-
contraceptives [25-27], parity [27, 28, 69, 70, 71], multipar- dren by about 7%, 32%, 47%, 56%, 59%, 65% respectively
ity [28, 69, 72] and breastfeeding [5, 15, 30-32]. Secondly, [69]. When studied by subtypes [72], the protection of higher
targeting inflammation with medication [33-37], diet modifi- parity (≥4 children) was 28% against serous [RR:0.72 (95%,
cation [21, 39, 40] and physical activity [42, 43]. CI: 0.63 to 0.81)], 66% against endometrioid [RR: 0.34
(95%, CI: 0.25 to 0.45)], 45% against mucinous [RR: 0.55
9. THE IMPACT OF ORAL CONTRACEPTIVES (95%, CI: 0.38 to 0.80)] and 86% against clear cell tumors
[RR: 0.14 (95%, CI: 0.08 to 0.25)]. Parity was associated
Oral contraceptives prevent ovarian cancer development with a protective effect among BRCA1 mutation carriers [27,
among tens of thousands of women worldwide every year 79]. Having live birth was 59% protective among BRCA1
[75]. The protective trend of oral contraceptives was consis- mutations carriers [HR: 0.41(95% CI: 0.18-0.94)] similar to
tent in earlier [5, 76], and most recent studies [25-27], and what was reported before [27] as seen in Table 4. No such
the protective effect increases with the duration of use [5, 25] relationship has been detected among women with BRCA2
and continue to be effective for at least 15 years after cessa- mutation carriers [79].
tion [25]. Compared with those who never used contracep-
tives, the risk reduction was 60% [OR: 0.4 (95% CI: 0.3- 11. THE IMPACT OF BREASTFEEDING
0.6)] among users [5]. The protection was 42% [OR: 0.58
(95% CI, 0.46 to 0.73)] among BRCA1 and BRCA2 muta- Breastfeeding is protective against ovarian cancer [5, 15,
tions carriers combined [26]. When the effect of contracep- 71] also shown in Table 2. Women who did not breastfeed
tives on ovarian cancer among BRCA1 and BRCA2 mutation their children had a 17% increased risk of ovarian cancer
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 527

Targeting inflammation as a strategy to prevent ovarian cancer

Regular exercise Healthy diet* Aspirin

Balancing hormonal level Total body fat ↓

Resting Metabolic Rate (RMR)↑ Muscle to fat % ↑ Inflammation ↓
Energy expenditure ↑ Visceral fat ↓ Cytokines (TNFα , IL6) ↓

Inflammation ↓
Normal body weight
Cytokines (TNFα , IL6) ↓
Oxidative stress ↓
Diabetes type2 ↓
Cardiovascular diseases ↓ Induce apoptosis
Stroke ↓ Inhibit angiogenesis
Cell ability to detect DNA damage ↑ Other types of cancer ↓ Increase immune response
Cell ability to repair DNA damage↑
Chances for mutation ↓
Quality of life ↑
5 year survival rates ↑
Total mortality rates ↓

Ovarian cancer risk reduced

Fig. (3). A proposed mechanism of the impact of targeting inflammation on ovarian cancer risk.
*Healthy diet is a diet that contains fruits, vegetables, fibers to ensure the existence of adequate amounts of vitamins, flavonoids and caro-
tenoids which have anti-oxidants and anti-inflammatory properties.
Targeting inflammation using aspirin, the regular consumption of heathy diet and regular exercise may cause a significant reduction in the
risk of ovarian cancer. Aspirin decreases cytokines and inflammation, as well as increases immune response, which are all in the favor of
decreasing ovarian cancer risk as well as type2 diabetes, CVD and stroke. At cellular level, aspirin inhibits angiogenesis and encourage apop-
tosis in cancer cells. Regular exercise helps to balance hormonal level, increases energy expenditure and increases Resting Metabolic Rate
(RMR). Consequently cytokines, inflammation will decreased significantly and with the help of healthy diet, a significant decrease in body
fat including visceral fat can be achieved. Combining these approaches is not only associated with more risk reduction, but also increase
quality of life.

[RR = 1.17 (95 % CI: 1.02-1.33)] compared to women who (diet and exercise). Fig. (3) displays the expected outcome of
have experienced breastfeeding. An Italian case control targeting inflammation in the prevention of ovarian cancer
study [5] has shown that, breastfeeding for more than 1 year plan. Targeting inflammation also decreases the risk of de-
was associated with a 50% reduction in the risk of ovarian veloping type2 diabetes and heart disease and improve the
cancer [OR: 0.5 (95% CI: 0.4-0.8)]. A similar protective quality of life, which can indirectly increase the 5-year sur-
effect by breastfeeding has been observed in women with vival rates and decrease mortality rates among patients with
BRCA1 and BRCA2 mutation carriers [30]. The protective ovarian cancer [80].
effect was found to be significantly increased with increased
duration of breastfeeding more than one year [30, 31, 32, 13. THE IMPACT OF MEDICATION
74]. Among BRCA1 and BRCA2 mutation carriers breast-
feeding for 12 months or less was associated with a 17% Previous studies [33-37] have provided satisfactory evi-
[OR: 0.83 (0.67-1.04)] and 21% [OR: 0.79 (95% CI: 0.51- dence that aspirin is associated with a significant reduction in
1.23)] in the risk decrease in ovarian cancer respectively, the risk of ovarian cancer. Although the exact mechanism of
while breastfeeding for more than 12 month was associated these medications on ovarian cancer is not elucidated yet,
with a 38% [OR: 0.62 (95% CI: 0.48-0.79)] and 50% [OR: experimental studies have shown that aspirin may induce
0.50 (95% CI: 0.29-0.84)] reduction in the risk of ovarian apoptosis, inhibit the growth of ovarian cancer cells and an-
cancer among BRCA1 and BRCA2 mutation carriers, respec- giogenesis in cell culture and encourage cellular immune
tively [30]. responses [36, 81]. The regular intake of aspirin was associ-
ated with a 44% reduction in ovarian cancer risk [34, 37].
12. TARGETING INFLAMMATION Aspirin was also associated with a significant reduction in
the risk of breast, colon and lung cancer [35]. Paracetamol
Since chronic inflammation is a corner stone in cancer also has been reported to have a similar effect of protection
initiation and progression, targeting inflammation has be- against ovarian cancer although it is not considered as an
come an essential approach in order to reduce disease risk anti-inflammatory drug since it’s not associated with signifi-
and associated mortality rates. Inflammation can be targeted cant reduction in inflammation [82-84]. Table 3 summarises
directly via using medications such as aspirin, ibuprofen, and the results of studies that examined the protective effect of
other NSAIDs or indirectly through lifestyle modification aspirin and paracetamol in the prevention of ovarian cancer.
528 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

Table 3. The protective effect of aspirin and paracetamol against ovarian cancer development.

Author, Year Type of Medication Reported Risk Reduction

A modest significant reduction in risk of invasive ovarian cancer with aspirin [RR: 0.93, (95% CI
Baandrup et al., 2013 [82] Aspirin 0.84-1.02)]. However, the risk of invasive ovarian cancer was significantly reduced with use of
aspirin [RR: 0.88 (95% CI 0.79-0.98)].

Regular intake of paracetamol was associated with a 30% risk reduction [RR: 0.70, (95% CI: 0.51-
Bonovas et al., 2006 [84] Paracetamol
0.95)] in comparison with non-usage.

Ammundsen et al., 2012 Regular aspirin intake was associated with 32 % reduction in the risk [OR: 0.68 (95% CI: 0.46 -
Aspirin
[85] 1.02)] in comparison to the control group.

The risk reduced by 18% [OR: 0.82(95% CI: 0.74 - 0.92)] and more risk reduction was achieved
Baandrup et al., 2014 [83] Paracetamol
with long-term (≥10 years), high-intensity paracetamol use [OR: 0.45(95% CI: 0.24-0.86)].

Compared to non-users, a 9% risk reduction was achieved [OR: 0.91(95%, CI: 0.84 - 0.99)]. The
Trabert et al., 2014 [33] Aspirin reduction escalated to 20% when authors relied on seven studies with frequent data [OR: 0.80,
(95%, CI: 0.67 - 0.96)].

Compared to non-users, the use of 150 mg aspirin tablets was associated with 18% risk reduction
[OR: 0.82 (95% CI: 0.68-0.99)], and 23% reduction was achieved with long-term use (≥5 years) of
Baandrup et al., 2015 [34] Aspirin
low-dose aspirin [OR: 0.77, (95% CI: 0.55-1.08)]. Continuous long-term use of low-dose aspirin,
was associated with a 44% risk reduction [OR: 0.56, (95% CI: 0.32-0.97)].

Compared to control group, aspirin was associated with a 44% risk reduction [OR: 0.56(95%, CI:
Peres et al., 2016 [37] Aspirin 0.35-0.92)]. The strongest risk reduction was observed among women taking aspirin to prevent
cardiovascular disease.

An inverse significant association was observed between aspirin use and the risk of ovarian cancer
Zhang et al., 2016 [38] Aspirin
[RR per 1time/week: 0.94, (95% CI: 0.89-1.00), n=2)].

14. LIFESTYLE MODIFICATION tive trend against ovarian cancer [88]. In the Women’s
Health Initiative study, a reduction in dietary fat was associ-
The other strategy to target inflammation is through sig- ated with a 40% decrease in the risk of ovarian cancer [89].
nificant modification in lifestyle, which includes the con-
sumption of healthy diet and the performance of regular ex-
ercise (Fig. 3). 16. THE IMPACT OF PHYSICAL ACTIVITY
Regular exercise in general is vital to maintain health and
improve quality of life (Fig. 3). Physical activity is associ-
15. THE IMPACT OF DIET
ated with a significant reduction in the risk of ovarian cancer
Developed countries have brought prosperity, but with [42, 43, 90] (Table 4). Furthermore, the risk of ovarian can-
significant increases in caloric intake, dietary fat consump- cer tends to decline with increasing duration by 87% [OR
tion and physical inactivity. Furthermore, westernised diets 0.13 (95% CI: 0.03-0.64)], and 55% [OR 0.45 (95% CI 0.24-
have low fiber content with less fruits and vegetables com- 0.85)] among pre-menopausal women and post-menopausal
pared to diets in developing countries. People who include women respectively [90]. Physical activity decreases obesity
vegetables and fruits in their diet are less prone to develop and especially abdominal obesity [91]. A Swedish study
cancer compared with the general population [14]. showed that increased physical activity level at age 18-30
years was associated with a significant reduction in ovarian
Increased dietary fat consumption was also shown to in- cancer [43], consistent with other findings [42, 92]. To the
crease ovarian cancer risk [21-23]. In contrast, Mediterra- contrary, physical inactivity is associated with a significant
nean populations have less cancer in general compared to the increase in the risk of epithelial ovarian cancer and increased
USA population despite that their daily intake of fat (as olive mortality rates [93, 94] and a similar association was ob-
oil) is more, suggesting an important role of this type of fatty served with other types of ovarian cancer.
acid content. The traditional Mediterranean diet is a plant-
based diet. It includes fruits and vegetables, olive oil and
high amounts of essential fatty acids (EFA), mono unsatu- 17. SURGICAL APPROACHES
rated fat, fibers, antioxidants and vitamins which have been The surgical approaches include: tubal ligation [45, 46],
shown to be associated with a lower risk of ovarian cancer salpingectomy [3, 47], hysterectomy [45] and bilateral
[39, 41] and cancer in general [41, 86]. Furthermore, fruits salpingo-oophorectomy [95]. Bilateral salpingo-oophorecto-
and vegetables contain a high amount of flavonoids and ca- my is generally performed for the following reasons: firstly,
rotenoids which have anti-cancer properties [87]. Table 4 an elective choice at time of hysterectomy for benign condi-
summarises some of previous studies’ results. Increasing the tions (i.e. endometriosis), secondly, as a preventive approach
consumption of fish and poultry is associated with a protec-
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 529

Table 4. The impact of type of diet and physical activity on ovarian cancer development.

Author, Year Factor Reported Risk Reduction

Compared with women at the lowest quartile intake of dietary fiber, those at the highest quartile
Zhang et al., 2004 [39] Dietary fiber
have 64% reduction in the risk of ovarian cancer [OR; 0.36 (95% CI: 0.2-0.6)].

Compared with the control group, dietary fiber consumption was associated with a 27% risk reduc-
Tzonou et al., 1993 [41] Dietary fiber
tion [OR; 0.73 (95% CI: 0.61-0.87)].

Women in the upper quartile range who consume vegetables and fruits have 76 % [OR: 0.24 (95%
Zhang et al., 2002 [21] Vegetables and fruits CI: 0.1-0.5)] and 64% [OR: 0.36 (95% CI: 0.2-0.7)] reduction in the risk of ovarian cancer respec-
tively, compared with women in the lower quartile.

Compared with women in the lowest quartile, women in the highest quartile of total vegetable and
Pan et al., 2004 [40] Vegetables cruciferous vegetable intake have 23% [OR: 0.77 (95% CI: 0.60-1.04)] and 24% [OR: 0.76 (95%
CI: 0.56-0.99)] risk reduction in ovarian cancer respectively.

Comparing highest versus the lowest quartile of intake, alpha-carotene was associated with a 61%
risk reduction [OR : 0.39 (95 % CI: 0.23-0.66)], beta-carotene was associated with a 49% risk re-
Zhang et al., 2007 [87] Flavonoids/carotenoids duction [OR: 0.51 (95 % CI: 0.31-0.84)], beta-cryptoxanthin was associated with a 49% risk reduc-
tion [OR: 0.51 (95 % CI: 0.31-0.83)], 55% risk reduction for lutein and zeaxanthin [ OR: 0.45 (95
% CI: 0.27-0.76)] and 67% risk reduction [0.33 (95 % CI: 0.20-0.56)] for total carotenoids.

When compared with women in the lowest tertile of moderate physical activity, those in the highest
Pan et al., 2005 [42] Physical activity
tertile have a 33% risk reduction [OR: 0.67(95%, CI: 0.50-0.88)].

Compared to women in the lowest physical activity level, those in the highest physical activity level
Riman et al., 2004 [43] Physical activity
have a 33% reduction in ovarian cancer risk [OR: 0.67 (95%, CI: 0.52-0.87)].

in individuals with high risk of ovarian and breast cancer and 19. THE IMPACT OF SALPINGECTOMY
lastly due to malignancy.
Opportunistic salpingectomy has been increased at the
time of pelvic surgery for benign indications and has been
18. THE IMPACT OF TUBAL LIGATION recommended in countries like Canada as a preventive ap-
The increased number of ovarian cancer cases had been proach against ovarian cancer [3]. A meta-analysis study
explained to be due to increase in the exposure of ovaries to [47] reported a 49% decrease in the risk of ovarian cancer
carcinogens that are transported through the fallopian tubes among patients that underwent prophylactic bilateral
(Fig. 1). The significant reduction in ovarian cancer risk fol- salpingectomy compared to the controls [OR=0.51(95% CI:
lowing tubal ligation [46, 63, 96, 97] and salpingectomy [3, 0.35-0.75)].
47] strongly supported this hypothesis. In addition, and as
mentioned earlier, the fallopian tube is believed to be the 20. THE IMPACT OF HYSTERECTOMY
origin of the most common subtype of ovarian cancer [3]. A
meta-analysis consisting of 13 case control, retrospective and Previous studies [44, 45] have shown that hysterectomy
prospective studies reported a 34% reduction in the risk of was associated with a significant reduction of ovarian cancer.
ovarian cancer [RR: 0.66(95% CI: 0.60-0.73)] following Nevertheless, hysterectomy was not associated with ovarian
tubal ligation [96], while in The Million Women Study a cancer in patients with BRCA mutations [63]. To prevent the
20% risk reduction was achieved [RR=0.80(95% CI: 0.76- development of ovarian cancer among women over the age
0.85)] following the same surgical approach [97]. The pro- of 45 years, bilateral oophorectomy at the time of hysterec-
tective effect of tubal ligation varies by histologic subtype of tomy for benign disease has been recommended [48, 99]. A
ovarian cancer. Thus, the risk reduction was 34% for endo- meta-analysis of 24 case control, retrospective and prospec-
metrioid cancer [OR: 0.66(95% CI: 0.47-0.93)], and 13% tive studies found that the risk reduction after simple hyster-
[OR: 0.87(95% CI: 0.78-0.98)] for epithelial ovarian cancer, ectomy and hysterectomy with unilateral oophorectomy was
while no effect on borderline ovarian tumors was observed 38% and 40% respectively [(Relative Risk (RR):0.62 (95%
following tubal ligation [46], while another study observed a CI: 0.49-0.79)] and [RR: 0.60 (95% CI: 0.47-0.78)] respec-
40% [RR: 0.60 (95% CI: 0.41-0.88)] and 65%[RR: 0.35 tively [44]. Similar results were observed in the Nurses’
(95% CI:0.18-0.69)] decrease in endometrioid and clear cell Health Study [45].
tumors respectively following the same approach [72]. Tubal
ligation was associated with 58% risk reduction in women 21. THE IMPACT OF PROPHYLACTIC SALPINGO-
with BRCA1 mutations [63]. The risk was reduced to 72% OOPHORECTOMY
[OR: 0·28 (95% CI: 0·15-0·52)], when tubal ligation was
combined with the past use of an oral contraceptive [98]. Bilateral salpingo-oophorectomy is considered to be the
However, studies including small numbers of BRCA2 carri- most definitive method for preventing ovarian cancer for
ers reported that tubal ligation had no effect on the risk of high risk women (i.e. BRCA mutation carriers). A meta-
ovarian cancer in this group [63, 98]. analysis [6] showed that salpingo-oophorectomy associated
530 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

with a significant reduction in the risk of BRCA1/2- thus selection bias may influence the results since the con-
associated ovarian or fallopian tube cancer [HR: 0.21(95% trols might have a higher frequency of aspirin use than the
CI: 0.12-0.39)], similar to what was achieved later [100]. general population. Another problem with results obtained
Although bilateral salpingo-oophorectomy protect against from case control studies, is the effect of different uncon-
the development of ovarian cancer, it may be followed by trolled confounders which usually over estimate or underes-
short and long term health consequences [101, 102]. timate the effect of aspirin [82].
The other way to reduce inflammation is through lifestyle
22. CAN WE PREVENT OVARIAN CANCER? modification (Fig. 3). Regular exercise or physical activity
[42, 43, 90, 92] as well as maintaining a normal BMI are
In order to prevent ovarian cancer, a prevention program
associated with ameliorating inflammation and significant
must be designed and the most appropriate interventions that reduction in ovarian cancer [19, 20]. Although results ob-
decrease ovarian cancer risk must be implemented as dis-
tained from case control studies [42, 43, 90, 92] may be in-
cussed below:
fluenced by recall bias, but such a drawback shouldn’t dis-
suade women from participating moderate or vigorous exer-
23. DESIGNING A PREVENTION PROGRAM cise on daily bases since exercise is associated with increase
quality of life (Fig. 3). Inactive women have a higher risk of
A well designed prevention program for ovarian cancer developing ovarian cancer [93] and high death rate [94]. Fur-
must take the following aspects into account; firstly, the ma-
thermore, the link between excess weight, increased waist
jority of ovarian cancers are cancers of the epithelial surface.
circumference with cancer risk has been reported for several
Secondly, most identified cases of ovarian cancer (around
sites including breast [20], endometrial [20] and ovarian can-
90%) are not genetically related. Thirdly, a significant reduc-
cer [19, 20]. Central adiposity or visceral fat has been par-
tion in ovarian cancer risk is associated with a decreased
ticularly implicated in promoting metabolic conditions ame-
number of ovulations and vice versa. Fourthly, protective nable to carcinogenesis. Data from previous studies have
factors for ovarian cancer have accumulative effect when
shown that obesity among patients with ovarian cancer af-
combined and the protective effect of each factor correlates
fects survival rate, thus obese patients have a worse outcome
positively with the duration of use. Lastly, the disease is sig-
with a significant decrease in survival rate as compared to
nificantly decreased among aspirin users. A simple preven-
patients with normal BMI [106]. The mechanisms explaining
tion program may suggest avoiding the risk factors and in-
this association among ovarian cancer patients is perhaps due
crease the adoption of factors associated with a protective to the strong association between obesity and inflammation
effect. As most women are not necessarily aware of all the
(Fig. 2) with increased inflammatory cytokines such as
factors linked to ovarian cancer, a starting point in any pre-
TNFα and IL6 promoting cancer invasion and metastasis
vention program must be educating women and highlighting
[67, 107, 108].
the epidemiology of ovarian cancer in order to increase
awareness in the general population. This may help to mini- In addition, considering a diet containing antioxidants
mize the time that women are exposed to certain risk factors and substances with anti-inflammatory properties is funda-
and promote increased exposure to protective factors. mental in cancer prevention in general and ovarian cancer is
no exception. Thus, decreasing the consumption of dietary
24. MINIMISING INFLAMMATION fat especially animal fat, red meat, processed food in general
and increasing the consumption of white meat (i.e. poultry,
In most of the cases, ovarian cancer initiation and pro- fish) and fruits and vegetables may also help in reducing the
gression cannot emerge without the presence of chronic in- risk of ovarian cancer even further [21, 22, 39, 41, 68, 87,
flammation. Thus, targeting inflammation must become a 88]. However, findings from cohort and meta-analysis stud-
strategy in any ovarian cancer prevention program due to its ies seem less supportive [24, 109, 110]. Furthermore, when
beneficial effects (Fig. 3). Although aspirin has been associ- dietary fat effect classified by type of fat, the increased ovar-
ated with a protective trend against ovarian cancer [33-37], ian cancer risk was only seen with animal fat, but not with
the application of such medications faces some challenges plant fat [21, 24, 68] and the relationship continued to be
including, firstly increased side effects associated with aspi- higher in case control compared to cohort studies [24]. Thus,
rin use (i.e. gastrointestinal bleeding, increased mortality the significant reduction in ovarian cancer risk reported in
among patients without CVD history) may limit the use of case control studies could be affected by recall bias. A recent
aspirin [103, 104]. Secondly, since previous studies were study reported that decreasing dietary saturated fat intake
case control [33-37], there is a need to confirm the previous and replacing it with polyunsaturated vegetable oil resulted
results with well-designed large prospective cohort studies. in about 30% reduction in CVD [111]. Furthermore, avoid-
The daily intake of low dose (100-150 mg) aspirin benefits ing dietary fat and increasing the consumption of healthy diet
for prevention of cardiovascular diseases (CVD) and stroke will also decrease the risk of breast and colon cancer [110].
in identified individuals with high risk and will have a sig- As a consequence woman will avoid the chemotherapy and
nificant impact on decreasing mortality rates [80, 104, 105]. radiation used to treat these cancers, which may escalate the
Unfortunately, among those without a previous history of risk of ovarian cancer in the long run [112]. Increasing the
CVD, no protection was observed among daily aspirin users consumption of dietary fiber, fruits and vegetables and
[HR:1.06 (1.02-1.11)], and the risk of mortality due to CVD avoiding dietary saturated fat will have a positive impact on
was increased 29% [HR:1.29 (1.19-1.39)] among individuals general health by improving lipid profiles, which reflects
taking aspirin twice daily or more [104]. In case control stud- directly on the liver and cardiovascular system performance
ies, controls may not be representative of general population, (Fig. 3).
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 531

A systemic review reported that the higher intake of (95% CI: 1.6-6.7)] [117], and carriers of the BRCA gene mu-
vegetables and fish was associated with a 21% decrease in tation [73, 118]. Thus, an alternative option was suggested
overall mortality among cancer survivors [RR, 0.79; 95 %( by replacing or combining oral contraceptives for the pre-
CI: 0.71-0.89)]. In contrast, a 51% increase in the risk of vention of ovarian cancer. Retinoids was amongst these op-
overall mortality was observed [RR: 1.51; 95 %( CI: 1.24- tions, due to their pivotal role in cell differentiation and their
1.85)], among cancer survivors who consumed a westernised ability to inhibit carcinogenesis [119]. The most studied
diet [113]. Unhealthy of diet is associated with higher body forms of retinoids is fenretinide N-[4-hydroxyphenyl] reti-
mass index and obesity [110]. Since obesity is associated namide (4-HPR), which is a synthetic retinoid proven to pre-
with increased mortality in women with ovarian cancer [106, vent ovarian cancer occurrence throughout the period of in-
114], weight reduction becomes crucial in order to increase tervention. However, such a protective effect diminished
survival rates. In addition, such changes in lifestyle will de- after a period of stopping the treatment [120].
crease type 2 diabetes and associated complications includ-
ing CVD, and will have a pivotal impact in improving the 26. PROPHYLACTIC SURGERIES
quality of life and decreasing mortality rates among patients
with ovarian cancer [80]. Unfortunately, a healthy diet and The protective effect of tubal ligation is 20 to 34% [96,
access to sport facilities may not be affordable for women of 97]. Among women with BRCA1 mutations, the protective
middle and low socioeconomic classes in many parts of the effect increases from 50% to 72% when combined with oral
world. Furthermore, in many countries, women are not able contraceptive use [98]. Tubal ligation interrupts the transfer
to perform any type of exercise either because it is prohibited of growth factors of endometrial cells, carcinogen chemicals
by traditional and religious constraints or sport centers do not and infectious agents to the ovary. Increasing evidence on
exist. the role of fallopian tubes in ovarian cancer development and
progression has led to the recommendation of opportunistic
salpingectomy as a strategy for the prevention of ovarian
25. REPRODUCTIVE INTERVENTIONS cancer in the general population in the USA and British Co-
lombia in Canada [3, 47]. Opportunistic salpingectomy is a
Historically, women had avoided breast, endometrial and
safe approach, cost effective for decreasing ovarian cancer
ovarian cancer via large numbers of pregnancies, which used
risk when done concurrently with hysterectomy instead of
to be followed by prolonged periods of breast feeding. The
tubal ligation [121]. Hysterectomy has also been proven to
large number of children that a woman of developing coun-
be protective against ovarian cancer [44, 45], and the protec-
tries has can explain the significant differences in ovarian
tive effect of hysterectomy increased significantly when per-
cancer incidence/prevalence between developed and devel-
formed with a unilateral oophorectomy [122]. Hysterectomy
oping countries. A previous study reported a 65% decrease
with bilateral salpingectomy is an ideal option for women of
in ovarian cancer after the sixth delivery [69]. With further
the general population who completed their childbearing.
reduction gained from prolonged periods of breast feeding
Unfortunately, hysterectomy among patients with high risk
[74], women who are not at high risk may prevent the dis-
mutations was not associated with any protection against
ease with the more children they have. However, one must ovarian cancer [63]. Comparing the previous surgical ap-
consider the likely overall impact of childbearing on the proaches, Falconer and colleagues found that bilateral
woman’s health - in some low-resource settings, the risk of salpingectomy was associated with 65% risk reduction in
maternal death from complications of pregnancy and birth comparison to 21% and 28% risk reduction following hys-
are likely to outweigh any potential benefit in reduced risk of terectomy and tubal ligation respectively [123].
ovarian cancer. Although breastfeeding is a protective
against ovarian cancer [5, 15, 30-32], women in developed The remaining option for individuals at high risk is bilat-
countries are rarely practicing breastfeeding compared to eral salpingo-oophorectomy, preferably after completing
women in developing countries [115]. A significant reduc- childbearing, as it is the definitive method for preventing
tion of ovarian cancer risk among parous women with ovarian cancer [3, 48]. Although, bilateral salpingo-
BRCA1 mutations has been reported in previous studies [79]. oophorectomy is cost effective and may protect women at
However, it is difficult to predict that these women will have high risk, the application of this approach faces many chal-
an outcome similar to multiparous women without genetic lenges including; firstly, the absence of a screening method
predisposition, even when BRCA1 mutation carriers give to identify individuals at risk, secondly, the willingness of
birth to the same number of children. In addition, the role of the patient/family to go through such surgery and lastly, the
parity in women with BRCA2 mutations is not fully eluci- possible development of health consequences such as prema-
dated as yet [79]. ture menopause, peritoneal cancer, bone mineral loss and
CVD [101, 102, 124]. The development of primary perito-
In the general population, women who are satisfied with neal cancer has been observed in previous studies in patients
one, two or three children can decrease their risk of ovarian that underwent bilateral salpingo-oophorectomy [48, 125].
cancer drastically through the exposure to contraceptives, Furthermore, observations from epidemiological studies
tubal ligation or salpingectomy. Unfortunately, the use of showed an increase in mortality rate due to heart disease.
oral contraceptives for long periods was associated with a The risk of heart disease significantly increases with younger
slight but significant increase in the risk of breast cancer age at oophorectomy [126, 127]. Compared with women
[OR, 1.08(95% CI: 1.00-1.17)], and the risk increased with who had oophorectomy after the age of 45 years, those who
more recent use [0-5 years since previous use OR: 1.21(95% had oophorectomy before the age of 40 years have 7 times
CI: 1.04-1.41)] [116]. Furthermore, the risk increases more increased risk of ischaemic heart disease [128]. Individuals
than threefold among women (sisters and daughters of the from families with a history of heart diseases are expected to
probands) with a family history of breast cancer [RR, 3.3 have an even higher risk due to risk accumulation.
532 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

27. WHO MUST BE TARGETED FIRST? nulliparous and women with a low fertility rate must be edu-
cated towards ovarian cancer risk and prevention.
The key success in any ovarian cancer prevention pro-
gram is careful targeting. Since the primary aim of any ovar-
ian cancer prevention program is to decrease the risk of the CONCLUSION
disease (and other related cancers), then those who must be Ovarian cancer is the most fatal of all gynaecologic can-
targeted first are women at high risk and this include; women cers. The risk of ovarian cancer can be reduced naturally by
with family history of breast and ovarian cancer and women multiple pregnancies and longer duration of breast feeding.
with history of breast cancer. Family members of an identi- Although such an approach has been adopted naturally in the
fied patient must go through genetic testing to detect any third world, however, the overall impact of childbearing on
possibility of mutation. Women testing positive must be the woman’s health need to be highlighted. Prevention
monitored and any preventive approach must consider their strategies should start with educating women in general and
age, their reproductive status, future reproductive plans, and to improve their awareness of the epidemiology of ovarian
the extent of the risk and to calculate and balance between cancer. Oral contraceptives is an excellent approach for those
benefits and risks. A geneticist should assess the family satisfied with a limited number of children, however it
pedigree for at least three generations with carefully main- should be avoided among women at high risk of developing
tained medical records of all women. Women with family breast cancer. Targeting inflammation is vital in any ovarian
history of breast and ovarian cancer, women with a history of cancer prevention plan, healthy diet and physical activity and
breast cancer or those testing positive for BRCA gene muta- maintaining normal weight (or BMI) are achievable strate-
tions and wish to maintain their fertility or maintain their gies to increase protection, decrease death rate and increase
reproductive system after menopause must perform periodic the quality of life. Pelvic surgeries such as hysterectomy, a
transvaginal ultrasonography preferably twice a year. De- tubal ligation or opportunistic bilateral salpingectomy may
spite the fact that this method is very sensitive, it is associ- provide considerable protection. Bilateral salpingectomy
ated with high false positive rates [129]. should be proposed to premenopausal women of the general
Although genetic screening is a costly approach, it may population who have completed their childbearing when
result in a significant decrease in the number of women go- hysterectomy for benign conditions is performed. The defini-
ing through bilateral salpingo-oophorectomy which ulti- tive preventive approach for women at high risk (i.e. BRCA
mately reduce the nation’s long-term health care cost. A re- mutation carriers) is bilateral salpingo-oophorectomy. How-
cent study from the United Kingdom has shown that ever, such surgery is associated with possible development
BRCA1/BRCA2 testing for all women with epithelial ovar- of primary peritoneal cancer and other health risks, thus it
ian cancer is a cost effective approach and is associated with should not be performed before weighing up the risks and
increased survival rates [130], but whether this is applicable benefits.
for other countries is questionable. Population-based genetic
testing was found to be very effective compared with family CONSENT FOR PUBLICATION
history-based testing which is not sensitive enough to detect Not applicable.
a high proportion of BRCA carriers. A previous study has
shown that population-based genetic testing picked up to CONFLICT OF INTEREST
56% additional BRCA mutation carriers compared with fam-
ily history-based testing [131, 132]. These results suggested The author declares no conflict of interest, financial or
that population based testing would be more accurate and otherwise.
cost effective than family based genetic testing.
ACKNOWLEDGEMENTS
The increased number of genetic testing for breast and
ovarian cancer has been associated with an increase in the Declared none.
number of variant uncertain significance (VUS). When ge-
netic testing identified such cases, parental samples must be
available for testing and provide information that enables the REFERENCES
laboratory to re-classify the variant. A specialized laboratory [1] Singh, N.; Gilks, C.B.; Hirschowitz, L.; Kehoe, S.; McNeish, I.A.;
may reclassify the VUS into being either benign or patho- Miller, D.; Naik, R.; Wilkinson, N.; McCluggage, W.G. Primary
genic. Follow up screening in other family members to see if site assignment in tubo-ovarian high-grade serous carcinoma: Con-
the VUS segregates with the cancer. Most VUS are not asso- sensus statement on unifying practice worldwide. Gynecol. Oncol.,
2016, 141(2), 195-198.
ciated with a high risk of ovarian cancer but misinterpreting
[2] Köbel, M.; Kalloger, S.E.; Lee, S.; Duggan, M.A.; Kelemen, L.E.;
the results can lead to mismanagement of the patients and Prentice, L.; Kalli, K.R.; Fridley, B.L.; Visscher, D.W.; Keeney,
cause harm for both patients and their families. Patients with G.L.; Vierkant, R.A.; Cunningham, J.M.; Chow, C.; Ness, R.B.;
high pathogenic variants can make informed decisions about Moysich, K.; Edwards, R.; Modugno, F.; Bunker, C.; Wozniak,
prophylactic surgery. Due to reduced penetrance, some E.L.; Benjamin, E.; Gayther, S.A.; Gentry-Maharaj, A.; Menon, U.;
women with mutations may not have cancer and vice versa. Gilks, C.B.; Huntsman, D.G.; Ramus, S.J.; Goode, E.L. Biomarker-
based ovarian carcinoma typing: a histologic investigation in the
Thus, up to date there is no particular suggestions, with re- ovarian tumor tissue analysis consortium. Cancer Epidemiol. Bio-
gards to surveillance and prophylactic management in markers Prev., 2013, 22(10), 1677-1686.
women with a low-moderate risk variant [133]. [3] McAlpine, J.N.; Tone, A.A.; Hanley, G.E. Opportunistic
Salpingectomy: We chose to act, not wait. J. Obstet. Gynaecol.
Finally, women in general and those with modesty risk Can., 2016, 38(5), 425-427.
such as overweight and obese women, less active women,
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 533

[4] Cress, R.D.; Chen, Y.S.; Morris, C.R.; Petersen, M.; Leiserowitz, W. Prospective cohort study of general and central obesity, weight
G.S. Characteristics of long-term survivors of epithelial ovarian change trajectory and risk of major cancers among Chinese women.
cancer. Obstet. Gynecol., 2015, 126(3), 491-497. Int. J. Cancer, 2016, 139(7), 1461-1470.
[5] Greggi, S.; Parazzini, F.; Paratore, M.P.; Chatenoud, L.; Legge, F.; [21] Zhang, M.; Yang, Z.Y.; Binns, C.W.; Lee, A.H. Diet and ovarian
Mancuso, S.; La Vecchia, C. Risk factors for ovarian cancer in cen- cancer risk: a case-control study in China. Br. J. Cancer, 2002,
tral Italy. Gynecol. Oncol., 2000, 79(1), 50-54. 86(5), 712-717.
[6] Rebbeck, T.R.; Kauff, N.D.; Domchek, S.M. Meta-analysis of risk [22] Kolahdooz, F.; Ibiebele, T.I.; van der Pols, J.C.; Webb, P.M. Die-
reduction estimates associated with risk-reducing salpingo- tary patterns and ovarian cancer risk. Am. J. Clin. Nutr., 2009,
oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl. 89(1), 297-304.
Cancer Inst., 2009, 101(2), 80-87. [23] Shanmughapriya, S.; Senthilkumar, G.; Arun, S.; Das, B.C.; Nata-
[7] Tinelli, A.; Malvasi, A.; Leo, G.; Vergara, D.; Pisanò, M.; Cic- rajaseenivasan, K. Risk factors for epithelial ovarian carcinoma in
carese, M.; Chiuri, V.E.; Lorusso, V. Hereditary ovarian cancers: India: A case control study in low-incidence population. Interna-
from BRCA mutations to clinical management. A modern ap- tional Journal of Cancer Research, 2016, 12(1), 61-68.
praisal. Cancer Metastasis Rev., 2010, 29(2), 339-350. [24] Qiu, W.; Lu, H.; Qi, Y.; Wang, X. Dietary fat intake and ovarian
[8] Lynch, H. T.; Snyder, C.; Casey, M. J. Hereditary ovarian and cancer risk: a meta-analysis of epidemiological studies. Oncotar-
breast cancer: what have we learned? Ann. Oncol., 2013, 8, viii83- get, 2016, 7(24), 37390-37406.
viii95. [25] Havrilesky, L.J.; Gierisch, J.M.; Moorman, P.G.; Coeytaux, R.R.;
[9] Toss, A.; Tomasello, C.; Razzaboni, E.; Contu, G.; Grandi, G.; Urrutia, R.P.; Lowery, W.J.; Dinan, M.; McBroom, A.J.; Wing, L.;
Cagnacci, A.; Schilder, R.J.; Cortesi, L. Hereditary ovarian cancer: Musty, M.D.; Lallinger, K.R.; Hasselblad, V.; Sanders, G.D.;
not only BRCA 1 and 2 genes. BioMed Res. Int., 2015, 2015, Myers, E.R. Oral contraceptive use for the primary prevention of
341723. ovarian cancer. Evid. Rep. Technol. Assess. (Full. Rep), 2013,
[10] Granström, C.; Sundquist, J.; Hemminki, K. Population attributable (212), 1-514.
fractions for ovarian cancer in Swedish women by morphological [26] Moorman, P.G.; Havrilesky, L.J.; Gierisch, J.M.; Coeytaux, R.R.;
type. Br. J. Cancer, 2008, 98(1), 199-205. Lowery, W.J.; Peragallo Urrutia, R.; Dinan, M.; McBroom, A.J.;
[11] Stratton, J.F.; Pharoah, P.; Smith, S.K.; Easton, D.; Ponder, B.A.J. Hasselblad, V.; Sanders, G.D.; Myers, E.R. Oral contraceptives and
A systematic review and meta-analysis of family history and risk of risk of ovarian cancer and breast cancer among high-risk women: a
ovarian cancer. Br. J. Obstet. Gynaecol., 1998, 105(5), 493-499. systematic review and meta-analysis. J. Clin. Oncol., 2013, 31(33),
[12] La Vecchia, C. Ovarian cancer: epidemiology and risk factors. Eur. 4188-4198.
J. Cancer Prev., 2017, 26(1), 55-62. [27] Friebel, T.M.; Domchek, S.M.; Rebbeck, T.R. Modifiers of cancer
[13] Li, K.; Hüsing, A.; Fortner, R.T.; Tjønneland, A.; Hansen, L.; risk in BRCA1 and BRCA2 mutation carriers: systematic review
Dossus, L.; Chang-Claude, J.; Bergmann, M.; Steffen, A.; Bamia, and meta-analysis. J. Natl. Cancer Inst., 2014, 106(6), dju091.
C.; Trichopoulos, D.; Trichopoulou, A.; Palli, D.; Mattiello, A.; [28] Merritt, M.A.; De Pari, M.; Vitonis, A.F.; Titus, L.J.; Cramer,
Agnoli, C.; Tumino, R.; Onland-Moret, N.C.; Peeters, P.H.; Bueno- D.W.; Terry, K.L. Reproductive characteristics in relation to ovar-
de-Mesquita, H.B.; Gram, I.T.; Weiderpass, E.; Sánchez-Cantalejo, ian cancer risk by histologic pathways. Hum. Reprod., 2013, 28(5),
E.; Chirlaque, M.D.; Duell, E.J.; Ardanaz, E.; Idahl, A.; Lundin, E.; 1406-1417.
Khaw, K.T.; Travis, R.C.; Merritt, M.A.; Gunter, M.J.; Riboli, E.; [29] Vachon, C.M.; Mink, P.J.; Janney, C.A.; Sellers, T.A.; Cerhan,
Ferrari, P.; Terry, K.; Cramer, D.; Kaaks, R. An epidemiologic risk J.R.; Hartmann, L.; Folsom, A.R. Association of parity and ovarian
prediction model for ovarian cancer in Europe: the EPIC study. Br. cancer risk by family history of breast or ovarian cancer in a popu-
J. Cancer, 2015, 112(7), 1257-1265. lation-based study of postmenopausal women. Epidemiology, 2002,
[14] Boyle, P.; Maisonneuve, P.; Autier, P. Update on cancer control in 13(1), 66-71.
women. Int. J. Gynaecol. Obstet., 2000, 70(2), 263-303. [30] Kotsopoulos, J.; Lubinski, J.; Gronwald, J.; Cybulski, C.; Demsky,
[15] Park, B.; Park, S.; Shin, H.R.; Shin, A.; Yeo, Y.; Choi, J.Y.; Jung, R.; Neuhausen, S.L.; Kim-Sing, C.; Tung, N.; Friedman, S.; Senter,
K.W.; Kim, B.G.; Kim, Y.M.; Noh, D.Y.; Ahn, S.H.; Kim, J.W.; L.; Weitzel, J.; Karlan, B.; Moller, P.; Sun, P.; Narod, S.A. Factors
Kang, S.; Kim, J.H.; Kim, T.J.; Kang, D.; Yoo, K.Y.; Park, S.K. influencing ovulation and the risk of ovarian cancer in BRCA1 and
Population attributable risks of modifiable reproductive factors for BRCA2 mutation carriers. Int. J. Cancer, 2015, 137(5), 1136-1146.
breast and ovarian cancers in Korea. BMC Cancer, 2016, 16, 5. [31] Li, D.P.; Du, C.; Zhang, Z.M.; Li, G.X.; Yu, Z.F.; Wang, X.; Li,
[16] Mørch, L.S.; Løkkegaard, E.; Andreasen, A.H.; Krüger-Kjaer, S.; P.F.; Cheng, C.; Liu, Y.P.; Zhao, Y.S. Breastfeeding and ovarian
Lidegaard, O. Hormone therapy and ovarian cancer. JAMA, 2009, cancer risk: a systematic review and meta-analysis of 40 epidemi-
302(3), 298-305. ological studies. Asian Pac. J. Cancer Prev., 2014, 15(12), 4829-
[17] Beral, V.; Gaitskell, K.; Hermon, C.; Moser, K.; Reeves, G.; Peto, 4837.
R. Menopausal hormone use and ovarian cancer risk: individual [32] Sung, H.K.; Ma, S.H.; Choi, J.Y.; Hwang, Y.; Ahn, C.; Kim, B.G.;
participant meta-analysis of 52 epidemiological studies. Lancet, Kim, Y.M.; Kim, J.W.; Kang, S.; Kim, J.; Kim, T.J.; Yoo, K.Y.;
2015, 385(9980), 1835-1842. Kang, D.; Park, S. The effect of breastfeeding duration and parity
[18] Olsen, C.M.; Nagle, C.M.; Whiteman, D.C.; Ness, R.; Pearce, C.L.; on the risk of epithelial ovarian cancer. A systemic review and
Pike, M.C.; Rossing, M.A.; Terry, K.L.; Wu, A.H.; Risch, H.A.; meta -analysis. J. Prev. Med. Public Health, 2016, 49(6), 349-366.
Yu, H.; Doherty, J.A.; Chang-Claude, J.; Hein, R.; Nickels, S.; [33] Trabert, B.; Ness, R.B.; Lo-Ciganic, W.H.; Murphy, M.A.; Goode,
Wang-Gohrke, S.; Goodman, M.T.; Carney, M.E.; Matsuno, R.K.; E.L.; Poole, E.M.; Brinton, L.A.; Webb, P.M.; Nagle, C.M.; Jor-
Lurie, G.; Moysich, K.; Kjaer, S.K.; Jensen, A.; Hogdall, E.; dan, S.J.; Risch, H.A.; Rossing, M.A.; Doherty, J.A.; Goodman,
Goode, E.L.; Fridley, B.L.; Vierkant, R.A.; Larson, M.C.; M.T.; Lurie, G.; Kjær, S.K.; Hogdall, E.; Jensen, A.; Cramer,
Schildkraut, J.; Hoyo, C.; Moorman, P.; Weber, R.P.; Cramer, D.W.; Terry, K.L.; Vitonis, A.; Bandera, E.V.; Olson, S.; King,
D.W.; Vitonis, A.F.; Bandera, E.V.; Olson, S.H.; Rodriguez- M.G.; Chandran, U.; Anton-Culver, H.; Ziogas, A.; Menon, U.;
Rodriguez, L.; King, M.; Brinton, L.A.; Yang, H.; Garcia-Closas, Gayther, S.A.; Ramus, S.J.; Gentry-Maharaj, A.; Wu, A.H.; Pearce,
M.; Lissowska, J.; Anton-Culver, H.; Ziogas, A.; Gayther, S.A.; C.L.; Pike, M.C.; Berchuck, A.; Schildkraut, J.M.; Wentzensen, N.
Ramus, S.J.; Menon, U.; Gentry-Maharaj, A.; Webb, P.M. Obesity Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and
and risk of ovarian cancer subtypes: evidence from the Ovarian acetaminophen use and risk of invasive epithelial ovarian cancer: a
Cancer Association Consortium. Endocr. Relat. Cancer, 2013, pooled analysis in the Ovarian Cancer Association Consortium. J.
20(2), 251-262. Natl. Cancer Inst., 2014, 106(2), djt431.
[19] Bhaskaran, K.; Douglas, I.; Forbes, H.; Dos-Santos-Silva, I.; Leon, [34] Baandrup, L.; Kjaer, S.K.; Olsen, J.H.; Dehlendorff, C.; Friis, S.
D.A.; Smeeth, L. Body-mass index and risk of 22 specific cancers: Low-dose aspirin use and the risk of ovarian cancer in Denmark.
a population-based cohort study of 5·24 million UK adults. Lancet, Ann. Oncol., 2015, 26(4), 787-792.
2014, 384(9945), 755-765. [35] Vaughan, L.E.; Prizment, A.; Blair, C.K.; Thomas, W.; Anderson,
[20] Liu, Y.; Warren Andersen, S.; Wen, W.; Gao, Y.T.; Lan, Q.; K.E. Aspirin use and the incidence of breast, colon, ovarian, and
Rothman, N.; Ji, B.T.; Yang, G.; Xiang, Y.B.; Shu, X.O.; Zheng,
534 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

pancreatic cancers in elderly women in the Iowa Women’s Health [55] Erekson, E.A.; Martin, D.K.; Ratner, E.S. Oophorectomy: the de-
Study. Cancer Causes Control, 2016, 27(11), 1395-1402. bate between ovarian conservation and elective oophorectomy.
[36] Huang, Y.; Lichtenberger, L.M.; Taylor, M.; Bottsford-Miller, J.N.; Menopause, 2013, 20(1), 110-114.
Haemmerle, M.; Wagner, M.J.; Lyons, Y.; Pradeep, S.; Hu, W.; [56] Herrinton, L.J.; Stanford, J.L.; Schwartz, S.M.; Weiss, N.S. Ovar-
Previs, R.A.; Hansen, J.M.; Fang, D.; Dorniak, P.L.; Filant, J.; Dial, ian cancer incidence among Asian migrants to the United States
E.J.; Shen, F.; Hatakeyama, H.; Sood, A.K. Antitumor and Antian- and their descendants. J. Natl. Cancer Inst., 1994, 86(17), 1336-
giogenic Effects of Aspirin-PC in Ovarian Cancer. Mol. Cancer 1339.
Ther., 2016, 15(12), 2894-2904. [57] Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin,
[37] Peres, L.C.; Camacho, F.; Abbott, S.E.; Alberg, A.J.; Bandera, D.M. Estimates of worldwide burden of cancer in 2008: GLOBO-
E.V.; Barnholtz-Sloan, J.; Bondy, M.; Cote, M.L.; Crankshaw, S.; CAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
Funkhouser, E.; Moorman, P.G.; Peters, E.S.; Schwartz, A.G.; [58] O’Brien, D.; Spelman, T.; Greig, J.; McMahon, J.; Ssonko, C.;
Terry, P.; Wang, F.; Schildkraut, J.M. Analgesic medication use Casas, E.; Mesic, A.; Du Cros, P.; Ford, N. Risk factors for mortal-
and risk of epithelial ovarian cancer in African American women. ity during antiretroviral therapy in older populations in resource-
Br. J. Cancer, 2016, 114(7), 819-825. limited settings. J. Int. AIDS Soc., 2016, 19(1), 20665.
[38] Zhang, D.; Bai, B.; Xi, Y.; Wang, T.; Zhao, Y. Is aspirin use asso- [59] Velen, K.; Charalambous, S.; Innes, C.; Churchyard, G.J.;
ciated with a decreased risk of ovarian cancer? A systematic review Hoffmann, C.J. Chronic hepatitis B increases mortality and com-
and meta-analysis of observational studies with dose-response plexity among HIV-coinfected patients in South Africa: a cohort
analysis. Gynecol. Oncol., 2016, 142(2), 368-377. study. HIV Med., 2016, 17(9), 702-707.
[39] Zhang, M.; Lee, A.H.; Binns, C.W. Reproductive and dietary risk [60] Domanska, K.; Malander, S.; Måsbäck, A.; Nilbert, M. Ovarian
factors for epithelial ovarian cancer in China. Gynecol. Oncol., cancer at young age: the contribution of mismatch-repair defects in
2004, 92(1), 320-326. a population-based series of epithelial ovarian cancer before age
[40] Pan, S.Y.; Ugnat, A.M.; Mao, Y.; Wen, S.W.; Johnson, K.C. A 40. Int. J. Gynecol. Cancer, 2007, 17(4), 789-793.
case-control study of diet and the risk of ovarian cancer. Cancer [61] Lakhani, S.R.; Manek, S.; Penault-Llorca, F.; Flanagan, A.; Arnout,
Epidemiol. Biomarkers Prev., 2004, 13(9), 1521-1527. L.; Merrett, S.; McGuffog, L.; Steele, D.; Devilee, P.; Klijn, J.G.;
[41] Tzonou, A.; Hsieh, C.C.; Polychronopoulou, A.; Kaprinis, G.; Meijers-Heijboer, H.; Radice, P.; Pilotti, S.; Nevanlinna, H.; But-
Toupadaki, N.; Trichopoulou, A.; Karakatsani, A.; Trichopoulos, zow, R.; Sobol, H.; Jacquemier, J.; Lyonet, D.S.; Neuhausen, S.L.;
D. Diet and ovarian cancer: a case-control study in Greece. Int. J. Weber, B.; Wagner, T.; Winqvist, R.; Bignon, Y.J.; Monti, F.;
Cancer, 1993, 55(3), 411-414. Schmitt, F.; Lenoir, G.; Seitz, S.; Hamman, U.; Pharoah, P.; Lane,
[42] Pan, S.Y.; Ugnat, A.M.; Mao, Y. Physical activity and the risk of G.; Ponder, B.; Bishop, D.T.; Easton, D.F. Pathology of ovarian
ovarian cancer: a case-control study in Canada. Int. J. Cancer, cancers in BRCA1 and BRCA2 carriers. Clin. Cancer Res., 2004,
2005, 117(2), 300-307. 10(7), 2473-2481.
[43] Riman, T.; Dickman, P.W.; Nilsson, S.; Nordlinder, H.; Magnus- [62] Pajenga, E.; Rexha, T.; Çeliku, S.; Bejtja, G.; Pisha, M. Hormonal
son, C.M.; Persson, I.R. Some life-style factors and the risk of in- risk factors for ovarian cancer in the Albanian case-control study.
vasive epithelial ovarian cancer in Swedish women. Eur. J. Epide- Bosn. J. Basic Med. Sci., 2013, 13(2), 89-93.
miol., 2004, 19(11), 1011-1019. [63] Antoniou, A.C.; Rookus, M.; Andrieu, N.; Brohet, R.; Chang-
[44] Rice, M.S.; Murphy, M.A.; Tworoger, S.S. Tubal ligation, hyster- Claude, J.; Peock, S.; Cook, M.; Evans, D.G.; Eeles, R.; Nogues,
ectomy and ovarian cancer: A meta-analysis. J. Ovarian Res., C.; Faivre, L.; Gesta, P.; van Leeuwen, F.E.; Ausems, M.G.; Oso-
2012, 5(1), 13. rio, A.; Caldes, T.; Simard, J.; Lubinski, J.; Gerdes, A.M.; Olah, E.;
[45] Rice, M.S.; Hankinson, S.E.; Tworoger, S.S. Tubal ligation, hyster- Fürhauser, C.; Olsson, H.; Arver, B.; Radice, P.; Easton, D.F.;
ectomy, unilateral oophorectomy, and risk of ovarian cancer in the Goldgar, D.E. Reproductive and hormonal factors, and ovarian
Nurses’ Health Studies. Fertil. Steril., 2014, 102(1), 192-198.e3. cancer risk for BRCA1 and BRCA2 mutation carriers: results from
[46] Madsen, C.; Baandrup, L.; Dehlendorff, C.; Kjaer, S.K. Tubal the International BRCA1/2 Carrier Cohort Study. Cancer Epide-
ligation and salpingectomy and the risk of epithelial ovarian cancer miol. Biomarkers Prev., 2009, 18(2), 601-610.
and borderline ovarian tumors: a nationwide case-control study. [64] Soegaard, M.; Jensen, A.; Høgdall, E.; Christensen, L.; Høgdall,
Acta Obstet. Gynecol. Scand., 2015, 94(1), 86-94. C.; Blaakaer, J.; Kjaer, S.K. Different risk factor profiles for muci-
[47] Yoon, S.H.; Kim, S.N.; Shim, S.H.; Kang, S.B.; Lee, S.J. Bilateral nous and nonmucinous ovarian cancer: results from the Danish
salpingectomy can reduce the risk of ovarian cancer in the general MALOVA study. Cancer Epidemiol. Biomarkers Prev., 2007,
population: A meta-analysis. Eur. J. Cancer, 2016, 55, 38-46. 16(6), 1160-1166.
[48] Finch, A.; Beiner, M.; Lubinski, J.; Lynch, H.T.; Moller, P.; Rosen, [65] Ovarian cancer and body size: individual participant meta-analysis
B.; Murphy, J.; Ghadirian, P.; Friedman, E.; Foulkes, W.D.; Kim- including 25,157 women with ovarian cancer from 47 epidemiol-
Sing, C.; Wagner, T.; Tung, N.; Couch, F.; Stoppa-Lyonnet, D.; ogical studies. PLoS Med., 2012, 9(4), e1001200.
Ainsworth, P.; Daly, M.; Pasini, B.; Gershoni-Baruch, R.; Eng, C.; [66] Foong, K.W.; Bolton, H. Obesity and ovarian cancer risk: A sys-
Olopade, O.I.; McLennan, J.; Karlan, B.; Weitzel, J.; Sun, P.; tematic review. Post Reprod. Health, 2017, 23(4), 183-198.
Narod, S.A. Salpingo-oophorectomy and the risk of ovarian, fallo- [67] Szlosarek, P.W.; Balkwill, F.R. Tumour necrosis factor α: a poten-
pian tube, and peritoneal cancers in women with a BRCA1 or tial target for the therapy of solid tumours. Lancet Oncol., 2003,
BRCA2 Mutation. JAMA, 2006, 296(2), 185-192. 4(9), 565-573.
[49] Parker, W.H.; Broder, M.S.; Chang, E.; Feskanich, D.; Farquhar, [68] Blank, M.M.; Wentzensen, N.; Murphy, M.A.; Hollenbeck, A.;
C.; Liu, Z.; Shoupe, D.; Berek, J.S.; Hankinson, S.; Manson, J.E. Park, Y. Dietary fat intake and risk of ovarian cancer in the NIH-
Ovarian conservation at the time of hysterectomy and long-term AARP Diet and Health Study. Br. J. Cancer, 2012, 106(3), 596-
health outcomes in the nurses’ health study. Obstet. Gynecol., 602.
2009, 113(5), 1027-1037. [69] Hankinson, S.E.; Colditz, G.A.; Hunter, D.J.; Willett, W.C.;
[50] Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer statistics, 2014. CA Stampfer, M.J.; Rosner, B.; Hennekens, C.H.; Speizer, F.E. A pro-
Cancer J. Clin., 2014, 64(1), 9-29. spective study of reproductive factors and risk of epithelial ovarian
[51] Bell, R.; Petticrew, M.; Luengo, S.; Sheldon, T.A. Screening for cancer. Cancer, 1995, 76(2), 284-290.
ovarian cancer: a systematic review. Health Technol. Assess., 1998, [70] McGuire, V.; Hartge, P.; Liao, L.M.; Sinha, R.; Bernstein, L.;
2(2), i-iv, 1-84. Canchola, A.J.; Anderson, G.L.; Stefanick, M.L.; Whittemore, A.S.
[52] Chen, S.; Parmigiani, G. Meta-analysis of BRCA1 and BRCA2 Parity and oral contraceptive use in relation to ovarian cancer risk
penetrance. J. Clin. Oncol., 2007, 25(11), 1329-1333. in older women. Cancer Epidemiol. Biomarkers Prev., 2016, 25(7),
[53] Menon, U.; Jacobs, I. Screening for ovarian cancer. Best Pract. 1059-1063.
Res. Clin. Obstet. Gynaecol., 2002, 16(4), 469-482. [71] Huusom, L.D.; Frederiksen, K.; Høgdall, E.V.; Glud, E.; Christen-
[54] Lai, T.; Kessel, B.; Ahn, H.J.; Terada, K.Y. Ovarian cancer screen- sen, L.; Høgdall, C.K.; Blaakaer, J.; Kjaer, S.K. Association of re-
ing in menopausal females with a family history of breast or ovar- productive factors, oral contraceptive use and selected lifestyle fac-
ian cancer. J. Gynecol. Oncol., 2016, 27(4), e41.
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 535

tors with the risk of ovarian borderline tumors: a Danish case- [85] Ammundsen, H.B.; Faber, M.T.; Jensen, A.; Høgdall, E.; Blaakaer,
control study. Cancer Causes Control, 2006, 17(6), 821-829. J.; Høgdall, C.; Kjaer, S.K. Use of analgesic drugs and risk of ovar-
[72] Wentzensen, N.; Poole, E.M.; Trabert, B.; White, E.; Arslan, A.A.; ian cancer: results from a Danish case-control study. Acta Obstet.
Patel, A.V.; Setiawan, V.W.; Visvanathan, K.; Weiderpass, E.; Ad- Gynecol. Scand., 2012, 91(9), 1094-1102.
ami, H.O.; Black, A.; Bernstein, L.; Brinton, L.A.; Buring, J.; But- [86] Giacosa, A.; Barale, R.; Bavaresco, L.; Gatenby, P.; Gerbi, V.;
ler, L.M.; Chamosa, S.; Clendenen, T.V.; Dossus, L.; Fortner, R.; Janssens, J.; Johnston, B.; Kas, K.; La Vecchia, C.; Mainguet, P.;
Gapstur, S.M.; Gaudet, M.M.; Gram, I.T.; Hartge, P.; Hoffman- Morazzoni, P.; Negri, E.; Pelucchi, C.; Pezzotti, M.; Rondanelli, M.
Bolton, J.; Idahl, A.; Jones, M.; Kaaks, R.; Kirsh, V.; Koh, W.P.; Cancer prevention in Europe: the Mediterranean diet as a protective
Lacey, J.V., Jr; Lee, I.M.; Lundin, E.; Merritt, M.A.; Onland- choice. Eur. J. Cancer Prev., 2013, 22(1), 90-95.
Moret, N.C.; Peters, U.; Poynter, J.N.; Rinaldi, S.; Robien, K.; Ro- [87] Zhang, M.; Holman, C.D.; Binns, C.W. Intake of specific caro-
han, T.; Sandler, D.P.; Schairer, C.; Schouten, L.J.; Sjöholm, L.K.; tenoids and the risk of epithelial ovarian cancer. Br. J. Nutr., 2007,
Sieri, S.; Swerdlow, A.; Tjonneland, A.; Travis, R.; Trichopoulou, 98(1), 187-193.
A.; van den Brandt, P.A.; Wilkens, L.; Wolk, A.; Yang, H.P.; Zele- [88] Kolahdooz, F.; van der Pols, J.C.; Bain, C.J.; Marks, G.C.; Hughes,
niuch-Jacquotte, A.; Tworoger, S.S. Tworoger, S. S. Ovarian can- M.C.; Whiteman, D.C.; Webb, P.M. Meat, fish, and ovarian cancer
cer risk factors by histologic subtype: an analysis from the ovarian risk: Results from 2 Australian case-control studies, a systematic
cancer cohort consortium. J. Clin. Oncol., 2016, 34(24), 2888- review, and meta-analysis. Am. J. Clin. Nutr., 2010, 91(6), 1752-
2898. 1763.
[73] Cibula, D.; Zikan, M.; Dusek, L.; Majek, O. Oral contraceptives [89] Prentice, R.L.; Thomson, C.A.; Caan, B.; Hubbell, F.A.; Anderson,
and risk of ovarian and breast cancers in BRCA mutation carriers: a G.L.; Beresford, S.A.; Pettinger, M.; Lane, D.S.; Lessin, L.; Yas-
meta-analysis. Expert Rev. Anticancer Ther., 2011, 11(8), 1197- meen, S.; Singh, B.; Khandekar, J.; Shikany, J.M.; Satterfield, S.;
1207. Chlebowski, R.T. Low-fat dietary pattern and cancer incidence in
[74] Gronwald, J.; Byrski, T.; Huzarski, T.; Cybulski, C.; Sun, P.; Tul- the Women’s Health Initiative Dietary Modification Randomized
man, A.; Narod, S.A.; Lubinski, J. Influence of selected lifestyle Controlled Trial. J. Natl. Cancer Inst., 2007, 99(20), 1534-1543.
factors on breast and ovarian cancer risk in BRCA1 mutation carri- [90] Zhang, M.; Lee, A.H.; Binns, C.W. Physical activity and epithelial
ers from Poland. Breast Cancer Res. Treat., 2006, 95(2), 105-109. ovarian cancer risk: A case-control study in China. Int. J. Cancer,
[75] Beral, V.; Doll, R.; Hermon, C.; Peto, R.; Reeves, G. Ovarian can- 2003, 105(6), 838-843.
cer and oral contraceptives: collaborative reanalysis of data from [91] Ross, R.; Dagnone, D.; Jones, P.J.; Smith, H.; Paddags, A.; Hud-
45 epidemiological studies including 23,257 women with ovarian son, R.; Janssen, I. Reduction in obesity and related comorbid con-
cancer and 87,303 controls. Lancet, 2008, 371(9609), 303-314. ditions after diet-induced weight loss or exercise-induced weight
[76] McGuire, V.; Felberg, A.; Mills, M.; Ostrow, K.L.; DiCioccio, R.; loss in men. A randomized, controlled trial. Ann. Intern. Med.,
John, E.M.; West, D.W.; Whittemore, A.S. Relation of contracep- 2000, 133(2), 92-103.
tive and reproductive history to ovarian cancer risk in carriers and [92] Tavani, A.; Gallus, S.; La Vecchia, C.; Dal Maso, L.; Negri, E.;
noncarriers of BRCA1 gene mutations. Am. J. Epidemiol., 2004, Pelucchi, C.; Montella, M.; Conti, E.; Carbone, A.; Franceschi, S.
160(7), 613-618. Physical activity and risk of ovarian cancer: an Italian case-control
[77] Narod, S.A.; Risch, H.; Moslehi, R.; Dørum, A.; Neuhausen, S.; study. Int. J. Cancer, 2001, 91(3), 407-411.
Olsson, H.; Provencher, D.; Radice, P.; Evans, G.; Bishop, S.; Bru- [93] Cannioto, R.; LaMonte, M.J.; Risch, H.A.; Hong, C.C.; Sucheston-
net, J.S.; Ponder, B.A. Oral contraceptives and the risk of heredi- Campbell, L.E.; Eng, K.H.; Brian Szender, J.; Chang-Claude, J.;
tary ovarian cancer. N. Engl. J. Med., 1998, 339(7), 424-428. Schmalfeldt, B.; Klapdor, R.; Gower, E.; Minlikeeva, A.N.; Zirpoli,
[78] Modan, B.; Hartge, P.; Hirsh-Yechezkel, G.; Chetrit, A.; Lubin, F.; G.R.; Bandera, E.V.; Berchuck, A.; Cramer, D.; Doherty, J.A.;
Beller, U.; Ben-Baruch, G.; Fishman, A.; Menczer, J.; Struewing, Edwards, R.P.; Fridley, B.L.; Goode, E.L.; Goodman, M.T.; Hog-
J.P.; Tucker, M.A.; Wacholder, S. Parity, oral contraceptives, and dall, E.; Hosono, S.; Jensen, A.; Jordan, S. Kjaer, S. K.; Matsuo,
the risk of ovarian cancer among carriers and noncarriers of a K.; Ness, R. B.; Olsen, C. M.; Olson, S. H.; Leigh Pearce, C.; Pike,
BRCA1 or BRCA2 mutation. N. Engl. J. Med., 2001, 345(4), 235- M. C.; Anne Rossing, M.; Szamreta, E. A.; Thompson, P. J.; Tseng,
240. C. C.; Vierkant, R. A.; Webb, P. M.; Wentzensen, N.; Wicklund,
[79] Milne, R.L.; Osorio, A.; Ramón y Cajal, T.; Baiget, M.; Lasa, A.; K. G.; Winham, S. J.; Wu, A. H.; Modugno, F.; Schildkraut, J. M.;
Diaz-Rubio, E.; de la Hoya, M.; Caldés, T.; Teulé, A.; Lázaro, C.; Terry, K. L.; Kelemen, L. E.; Moysich, K. B. Chronic recreational
Blanco, I.; Balmaña, J.; Sánchez-Ollé, G.; Vega, A.; Blanco, A.; physical inactivity and ovarian cancer risk: evidence from the ovar-
Chirivella, I.; Esteban Cardeñosa, E.; Durán, M.; Velasco, E.; ian cancer association consortium. Cancer Epidemiol. Biomarkers
Martínez de Dueñas, E.; Tejada, M.I.; Miramar, M.D.; Calvo, Prev., 2016, 25(7), 1114-1124.
M.T.; Guillén-Ponce, C.; Salazar, R.; San Román, C.; Urioste, M.; [94] Cannioto, R.A.; LaMonte, M.J.; Kelemen, L.E.; Risch, H.A.; Eng,
Benítez, J. Parity and the risk of breast and ovarian cancer in K.H.; Minlikeeva, A.N.; Hong, C.C.; Szender, J.B.; Sucheston-
BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. Treat., Campbell, L.; Joseph, J.M.; Berchuck, A.; Chang-Claude, J.;
2010, 119(1), 221-232. Cramer, D.W.; DeFazio, A.; Diergaarde, B.; Dörk, T.; Doherty,
[80] Zhang, D.; Zhao, Y.; Wang, T.; Xi, Y.; Li, N.; Huang, H. Diabetes J.A.; Edwards, R.P.; Fridley, B.L.; Friel, G.; Goode, E.L.; Good-
mellitus and long-term mortality of ovarian cancer patients. A sys- man, M.T.; Hillemanns, P.; Hogdall, E.; Hosono, S.; Kelley, J.L.;
tematic review and meta-analysis of 12 cohort studies. Diabetes Kjaer, S.K.; Klapdor, R.; Matsuo, K.; Odunsi, K.; Nagle, C.M.; Ol-
Metab. Res. Rev., 2017, 33(4). sen, C.M.; Paddock, L.E.; Pearce, C.L.; Pike, M.C.; Rossing, M.A.;
[81] Rodriguez, G.C.; Turbov, J.M.; Berchuck, A.; Stack, M.S.; Hur- Schmalfeldt, B.; Segal, B.H.; Szamreta, E.A.; Thompson, P.J.;
teau, J.A.; Thaete, L.G.; Barry, C.P. Nonsteroidal antiinflammatory Tseng, C.C.; Vierkant, R.; Schildkraut, J.M.; Wentzensen, N.;
drugs and progestins synergistically enhance cell death in ovarian Wicklund, K.G.; Winham, S.J.; Wu, A.H.; Modugno, F.; Ness,
epithelial cells. Am. J. Obstet. Gynecol., 2012, 206(3), 253.e1- R.B.; Jensen, A.; Webb, P.M.; Terry, K.; Bandera, E.V.; Moysich,
253.e9. K.B. Recreational physical inactivity and mortality in women with
[82] Baandrup, L.; Faber, M.T.; Christensen, J.; Jensen, A.; Andersen, invasive epithelial ovarian cancer: evidence from the Ovarian Can-
K.K.; Friis, S.; Kjaer, S.K. Nonsteroidal anti-inflammatory drugs cer Association Consortium. Br. J. Cancer, 2016, 115(1), 95-101.
and risk of ovarian cancer: systematic review and meta-analysis of [95] Finch, A.; Evans, G.; Narod, S.A. BRCA carriers, prophylactic
observational studies. Acta Obstet. Gynecol. Scand., 2013, 92(3), salpingo-oophorectomy and menopause: clinical management con-
245-255. siderations and recommendations. Womens Health (Lond), 2012,
[83] Baandrup, L.; Friis, S.; Dehlendorff, C.; Andersen, K.K.; Olsen, 8(5), 543-555.
J.H.; Kjaer, S.K. Prescription use of paracetamol and risk for ovar- [96] Cibula, D.; Widschwendter, M.; Májek, O.; Dusek, L. Tubal liga-
ian cancer in Denmark. J. Natl. Cancer Inst., 2014, 106(6), dju111. tion and the risk of ovarian cancer: review and meta-analysis. Hum.
[84] Bonovas, S.; Filioussi, K.; Sitaras, N.M. Paracetamol use and risk Reprod. Update, 2011, 17(1), 55-67.
of ovarian cancer: a meta-analysis. Br. J. Clin. Pharmacol., 2006, [97] Gaitskell, K.; Coffey, K.; Green, J.; Pirie, K.; Reeves, G.K.; Ah-
62(1), 113-121. med, A.A.; Barnes, I.; Beral, V. Tubal ligation and incidence of 26
536 Current Cancer Drug Targets, 2018, Vol. 18, No. 6 Aus Tariq Ali

site-specific cancers in the Million Women Study. Br. J. Cancer, tients treated with breast conserving surgery and radiation therapy.
2016, 114(9), 1033-1037. Ann. Surg. Oncol., 2013, 20(5), 1514-1521.
[98] Narod, S.A.; Sun, P.; Ghadirian, P.; Lynch, H.; Isaacs, C.; Garber, [113] Schwedhelm, C.; Boeing, H.; Hoffmann, G.; Aleksandrova, K.;
J.; Weber, B.; Karlan, B.; Fishman, D.; Rosen, B.; Tung, N.; Neu- Schwingshackl, L. Effect of diet on mortality and cancer recurrence
hausen, S.L. Tubal ligation and risk of ovarian cancer in carriers of among cancer survivors: a systematic review and meta-analysis of
BRCA1 or BRCA2 mutations: a case-control study. Lancet, 2001, cohort studies. Nutr. Rev., 2016, 74(12), 737-748.
357(9267), 1467-1470. [114] Rodriguez, C.; Calle, E.E.; Fakhrabadi-Shokoohi, D.; Jacobs, E.J.;
[99] Whiteman, M.K.; Hillis, S.D.; Jamieson, D.J.; Morrow, B.; Thun, M.J. Body mass index, height, and the risk of ovarian cancer
Podgornik, M.N.; Brett, K.M.; Marchbanks, P.A. Inpatient hyster- mortality in a prospective cohort of postmenopausal women. Can-
ectomy surveillance in the United States, 2000-2004. Am. J. Obstet. cer Epidemiol. Biomarkers Prev., 2002, 11(9), 822-828.
Gynecol., 2008, 198(1), 34.e1-34.e7. [115] Victora, C.G.; Bahl, R.; Barros, A.J.; França, G.V.; Horton, S.;
[100] Marchetti, C.; De Felice, F.; Palaia, I.; Perniola, G.; Musella, A.; Krasevec, J.; Murch, S.; Sankar, M.J.; Walker, N.; Rollins, N.C.
Musio, D.; Muzii, L.; Tombolini, V.; Panici, P.B. Risk-reducing Breastfeeding in the 21st century: epidemiology, mechanisms, and
salpingo-oophorectomy: a meta-analysis on impact on ovarian can- lifelong effect. Lancet, 2016, 387(10017), 475-490.
cer risk and all cause mortality in BRCA 1 and BRCA 2 mutation [116] Gierisch, J.M.; Coeytaux, R.R.; Urrutia, R.P.; Havrilesky, L.J.;
carriers. BMC Womens Health, 2014, 14, 150-, 14, 150. Moorman, P.G.; Lowery, W.J.; Dinan, M.; McBroom, A.J.; Has-
[101] Bober, S.L.; Recklitis, C.J.; Bakan, J.; Garber, J.E.; Patenaude, selblad, V.; Sanders, G.D.; Myers, E.R. Oral contraceptive use and
A.F. Addressing sexual dysfunction after risk-reducing salpingo- risk of breast, cervical, colorectal, and endometrial cancers: a sys-
oophorectomy: Effects of a brief, psychosexual intervention. J. Sex. tematic review. Cancer Epidemiol. Biomarkers Prev., 2013,
Med., 2015, 12(1), 189-197. 22(11), 1931-1943.
[102] Hibler, E.A.; Kauderer, J.; Greene, M.H.; Rodriguez, G.C.; Alberts, [117] Grabrick, D.M.; Hartmann, L.C.; Cerhan, J.R.; Vierkant, R.A.;
D.S. Bone loss after oophorectomy among high-risk women: an Therneau, T.M.; Vachon, C.M.; Olson, J.E.; Couch, F.J.; Anderson,
NRG oncology/gynecologic oncology group study. Menopause, K.E.; Pankratz, V.S.; Sellers, T.A. Risk of breast cancer with oral
2016, 23(11), 1228-1232. contraceptive use in women with a family history of breast cancer.
[103] Yuhara, H.; Corley, D.A.; Nakahara, F.; Nakajima, T.; Koike, J.; JAMA, 2000, 284(14), 1791-1798.
Igarashi, M.; Suauki, T.; Mine, T. Aspirin and non-aspirin NSAIDs [118] Narod, S.A.; Dubé, M.P.; Klijn, J.; Lubinski, J.; Lynch, H.T.;
increase risk of colonic diverticular bleeding: a systematic review Ghadirian, P.; Provencher, D.; Heimdal, K.; Moller, P.; Robson,
and meta-analysis. J. Gastroenterol., 2014, 49(6), 992-1000. M.; Offit, K.; Isaacs, C.; Weber, B.; Friedman, E.; Gershoni-
[104] Huang, W.Y.; Daugherty, S.E.; Shiels, M.S.; Purdue, M.P.; Freed- Baruch, R.; Rennert, G.; Pasini, B.; Wagner, T.; Daly, M.; Garber,
man, N.D.; Abnet, C.C.; Hollenbeck, A.R.; Hayes, R.B.; Silver- J.E.; Neuhausen, S.L.; Ainsworth, P.; Olsson, H.; Evans, G.; Os-
man, D.T.; Berndt, S.I. Aspirin use and mortality in two contempo- borne, M.; Couch, F.; Foulkes, W.D.; Warner, E.; Kim-Sing, C.;
rary U.S. cohorts. Epidemiology, 2017. Olopade, O.; Tung, N.; Saal, H.M.; Weitzel, J.; Merajver, S.;
[105] Xie, M.; Shan, Z.; Zhang, Y.; Chen, S.; Yang, W.; Bao, W.; Rong, Gauthier-Villars, M.; Jernstrom, H.; Sun, P.; Brunet, J.S. Oral con-
Y.; Yu, X.; Hu, F.B.; Liu, L. Aspirin for primary prevention of car- traceptives and the risk of breast cancer in BRCA1 and BRCA2
diovascular events: meta-analysis of randomized controlled trials mutation carriers. J. Natl. Cancer Inst., 2002, 94(23), 1773-1779.
and subgroup analysis by sex and diabetes status. PLoS One, 2014, [119] Decensi, A.; Costa, A. Recent advances in cancer chemopreven-
9(10), e90286. tion, with emphasis on breast and colorectal cancer. Eur. J. Cancer,
[106] Nagle, C.M.; Dixon, S.C.; Jensen, A.; Kjaer, S.K.; Modugno, F.; 2000, 36(6), 694-709.
deFazio, A.; Fereday, S.; Hung, J.; Johnatty, S.E.; Fasching, P.A.; [120] De Palo, G.; Mariani, L.; Camerini, T.; Marubini, E.; Formelli, F.;
Beckmann, M.W.; Lambrechts, D.; Vergote, I.; Van Nieu- Pasini, B.; Decensi, A.; Veronesi, U. Effect of fenretinide on ovar-
wenhuysen, E.; Lambrechts, S.; Risch, H.A.; Rossing, M.A.; Do- ian carcinoma occurrence. Gynecol. Oncol., 2002, 86(1), 24-27.
herty, J.A.; Wicklund, K.G.; Chang-Claude, J.; Goodman, M.T.; [121] Dilley, S.E.; Havrilesky, L.J.; Bakkum-Gamez, J.; Cohn, D.E.;
Ness, R.B.; Moysich, K.; Heitz, F.; du Bois, A.; Harter, P.; Michael Straughn, J., Jr; Caughey, A.B.; Rodriguez, M.I. Cost-
Schwaab, I.; Matsuo, K.; Hosono, S.; Goode, E.L.; Vierkant, R.A.; effectiveness of opportunistic salpingectomy for ovarian cancer
Larson, M.C.; Fridley, B.L.; Høgdall, C.; Schildkraut, J.M.; Weber, prevention. Gynecol. Oncol., 2017, 146(2), 373-379.
R.P.; Cramer, D.W.; Terry, K.L.; Bandera, E.V.; Paddock, L.; Rod- [122] Rice, M.S.; Murphy, M.A.; Vitonis, A.F.; Cramer, D.W.; Titus,
riguez-Rodriguez, L.; Wentzensen, N.; Yang, H.P.; Brinton, L.A.; L.J.; Tworoger, S.S.; Terry, K.L. Tubal ligation, hysterectomy and
Lissowska, J.; Høgdall, E.; Lundvall, L.; Whittemore, A.; McGuire, epithelial ovarian cancer in the New England Case-Control Study.
V.; Sieh, W.; Rothstein, J.; Sutphen, R.; Anton-Culver, H.; Ziogas, Int. J. Cancer, 2013, 133(10), 2415-2421.
A.; Pearce, C.L.; Wu, A.H.; Webb, P.M. Obesity and survival [123] Falconer, H.; Yin, L.; Grönberg, H.; Altman, D. Ovarian cancer
among women with ovarian cancer: Results from the Ovarian Can- risk after salpingectomy: a nationwide population-based study. J.
cer Association Consortium. Br. J. Cancer, 2015, 113(5), 817-826. Natl. Cancer Inst., 2015, 107(2), dju410.
[107] Balkwill, F. TNF-alpha in promotion and progression of cancer. [124] Guidozzi, F. Hormone therapy after prophylactic risk-reducing
Cancer Metastasis Rev., 2006, 25(3), 409-416. bilateral salpingo-oophorectomy in women who have BRCA gene
[108] Schafer, Z.T.; Brugge, J.S. IL-6 involvement in epithelial cancers. mutation. Climacteric, 2016, 19(5), 419-422.
J. Clin. Invest., 2007, 117(12), 3660-3663. [125] Menkiszak, J.; Chudecka-Głaz, A.; Gronwald, J.; Cymbaluk-
[109] Tabung, F.K.; Huang, T.; Giovannucci, E.L.; Smith-Warner, S.A.; Płoska, A.; Celewicz, A.; Świniarska, M.; Wężowska, M.; Bedner,
Tworoger, S.S.; Poole, E.M. The inflammatory potential of diet and R.; Zielińska, D.; Tarnowska, P.; Jakubowicz, J.; Kojs, Z. Prophy-
ovarian cancer risk: results from two prospective cohort studies. Br. lactic salpingo-oophorectomy in BRCA1 mutation carriers and
J. Cancer, 2017, 117(6), 907-911. postoperative incidence of peritoneal and breast cancers. J. Ovarian
[110] Grosso, G.; Bella, F.; Godos, J.; Sciacca, S.; Del Rio, D.; Ray, S.; Res., 2016, 9, 11.
Galvano, F.; Giovannucci, E.L. Possible role of diet in cancer: sys- [126] Løkkegaard, E.; Jovanovic, Z.; Heitmann, B.L.; Keiding, N.; Otte-
tematic review and multiple meta-analyses of dietary patterns, life- sen, B.; Pedersen, A.T. The association between early menopause
style factors, and cancer risk. Nutr. Rev., 2017, 75(6), 405-419. and risk of ischaemic heart disease: Influence of Hormone Therapy.
[111] Sacks, F.M.; Lichtenstein, A.H.; Wu, J.H.Y.; Appel, L.J.; Creager, Maturitas, 2006, 53(2), 226-233.
M.A.; Kris-Etherton, P.M.; Miller, M.; Rimm, E.B.; Rudel, L.L.; [127] Rivera, C.M.; Grossardt, B.R.; Rhodes, D.J.; Brown, R.D., Jr;
Robinson, J.G.; Stone, N.J.; Van Horn, L.V. Dietary fats and car- Roger, V.L.; Melton, L.J., III; Rocca, W.A. Increased cardiovascu-
diovascular disease: A presidential advisory from the American lar mortality after early bilateral oophorectomy. Menopause, 2009,
Heart Association. Circulation, 2017, 136(3), e1-e23. 16(1), 15-23.
[112] Yi, M.; Cormier, J.N.; Xing, Y.; Giordano, S.H.; Chai, C.; Meric- [128] Finch, A.; Metcalfe, K.A.; Chiang, J.; Elit, L.; McLaughlin, J.;
Bernstam, F.; Vlastos, G.; Kuerer, H.M.; Mirza, N.Q.; Buchholz, Springate, C.; Esplen, M.J.; Demsky, R.; Murphy, J.; Rosen, B.;
T.A.; Hunt, K.K. Other primary malignancies in breast cancer pa- Narod, S.A. The impact of prophylactic salpingo-oophorectomy on
Towards Prevention of Ovarian Cancer Current Cancer Drug Targets, 2018, Vol. 18, No. 6 537

quality of life and psychological distress in women with a BRCA tions in the Ashkenazi-Jewish community: a randomized controlled
mutation. Psychooncology, 2013, 22(1), 212-219. trial. J. Natl. Cancer Inst., 2014, 107(1), 379.
[129] van Nagell, J.R., Jr; Hoff, J.T. Transvaginal ultrasonography in [132] Manchanda, R.; Legood, R.; Burnell, M.; McGuire, A.; Raikou,
ovarian cancer screening: current perspectives. Int. J. Womens M.; Loggenberg, K.; Wardle, J.; Sanderson, S.; Gessler, S.; Side,
Health, 2013, 6, 25-33. L.; Balogun, N.; Desai, R.; Kumar, A.; Dorkins, H.; Wallis, Y.;
[130] Eccleston, A.; Bentley, A.; Dyer, M.; Strydom, A.; Vereecken, W.; Chapman, C.; Taylor, R.; Jacobs, C.; Tomlinson, I.; Beller, U.;
George, A.; Rahman, N. A Cost-Effectiveness evaluation of germ- Menon, U.; Jacobs, I. Cost-effectiveness of population screening
line BRCA1 and BRCA2 testing in UK women with ovarian can- for BRCA mutations in Ashkenazi jewish women compared with
cer. Value Health, 2017, 20(4), 567-576. family history-based testing. J. Natl. Cancer Inst., 2014, 107(1),
[131] Manchanda, R.; Loggenberg, K.; Sanderson, S.; Burnell, M.; 380.
Wardle, J.; Gessler, S.; Side, L.; Balogun, N.; Desai, R.; Kumar, [133] Eccles, D.M.; Mitchell, G.; Monteiro, A.N.; Schmutzler, R.;
A.; Dorkins, H.; Wallis, Y.; Chapman, C.; Taylor, R.; Jacobs, C.; Couch, F.J.; Spurdle, A.B.; Gómez-García, E.B. BRCA1 and
Tomlinson, I.; McGuire, A.; Beller, U.; Menon, U.; Jacobs, I. BRCA2 genetic testing-pitfalls and recommendations for managing
Population testing for cancer predisposing BRCA1/BRCA2 muta- variants of uncertain clinical significance. Ann. Oncol., 2015,
26(10), 2057-2065.