(a) Main significant risk factors for ovarian cancer. (b) Main significant protective factors for ovarian cancer.
1. Introduction
According to the American Cancer Society, in 2012 ovarian cancer is expected to account for 3% (22,280) of all new cases and 6% (15,500) of all female cancer deaths in the United States. The proportion of ovarian cancer among gynaecological cancers is increasing, also because of the decrease in cervical cancer as a result of pap smear screening programmes. On the other hand, survival from ovarian cancer is the poorest of all gynaecological cancers, with a five-year relative survival rate of 44% for all stages [1,2]. The main reasons for this poor survival are the lack of early detection strategies and an unfavourable anatomical situation. Thus, the vast majority of ovarian cancer is diagnosed at an advanced stage and therapy for this pathology is very complex [3-5]. Reduction in mortality rates could be gained both with new screening strategies and with ameliorations in surgical and medical treatments. However, neither of these approaches will affect cancer incidence, thus, it is clear that the prospects for making a major impact on the mortality from ovarian cancer lie more in the area of prevention.
The purpose of this chapter is to identify the evidence for the appropriate practical strategies to prevent ovarian cancer or the detection of cancer in the early stages in order to improve the overall survival. The search was restricted to full reports and guidelines published in English between 2000 and May 2012, in an attempt to summarize the principal findings regarding primary and secondary ovarian cancer prevention.
2. Primary prevention for ovarian cancer in general population
Primary prevention aims to prevent the disease before its biological onset, thus it is based on avoiding risk factors and increasing protective factors.
A summary of the most significant risk and protective factors, with relative hazard ratio, for epithelial ovarian cancer is summarized in Tables 1a and1b,
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Schorge JO et al. [6] | White race | 1.35 (1.08-1.50) | ||
Schouten LJ et al. [7] | Height≥160 cm | 1.38 (1.16-1.65) | ||
Lahmann PH et al. [8] | BMI≥25 | 1.33 (1.05-1.68) | ||
Camargo MC et al. [9] | Asbestos exposure | 1.77 (1.37-2.28) | ||
Cramer DW [10] | early age at menarche | 1.74 (1.28-2.18) | ||
Cramer DW [10] | late menopause | 1.61 (1.15-2.08) | ||
Beral V et al. [11] | HRT | 1.20 (0.98-1.32) | ||
Melin A et al. [12] | Endometriosis | 1.43 (1.19-1.71) | ||
Chen S et al. [13] | BRCA1 BRCA2 |
42.4 (15-119.6) 20.6 (7.75-57.2) |
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Watson P et al. [14] | MMR | 19 (5.0-30.0) | ||
(a) | ||||
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Trudel D et al. [15] | green tea components | 0.66 (0.54-0.80) | ||
Collaborative Group on Epidemiological Studies of Ovarian Cancer [16] | hormonal contraceptive use | 0.73 (0.70-0.76) | ||
Ness RB et al. [17] | Multiparity(≥ 4 pregnancies) | 0.40 (0.30-0.50) | ||
Danforth KN et al. [18] | breastfeeding | 0.98 per month ( 0.97-1.00) |
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Hankinson SE et al. [19] | bilateral tube ligation | 0.33 (0.16-0.64) | ||
Hankinson SE et al. [19] | hysterectomy | 0.67 (0.45-1.00) | ||
(b) |
The average age at diagnosis is approximately 60 years, but the overall incidence of ovarian cancer rises with increasing age up to 75-84 years, due to the accumulation of random genetic alterations, before declining slightly among women beyond 84 years [20]. Women residing in North America, Northern Europe or in any industrialized Western country have a higher risk of developing ovarian cancer. Conversely, women residing in developing countries have shown the lowest rate [6]. The exact reasons for this distribution are unknown but discrepancies in parity, rates of gynaecologic surgery and dietary habits may account for some differences [21]. In particular, regarding dietary habits, a comprehensive meta-analysis of the observational studies published up to September 2011 provided no evidence of a material association between alcohol drinking and epithelial ovarian cancer risk [22]. Finally, a recent study provided some suggestion that soy and phytoestrogen consumption may decrease ovarian cancer risk, although the results did not reach statistical significance [23].
Exposure to radiation may increase the risk of ovarian cancer and the risk increases with increasing dose. The Life Span Study incidence data for ovarian cancer demonstrated a borderline significant association [24], and mortality data showed a significant positive association between exposure to radiation and ovarian cancer [25].
With regards to reproductive factors, early age at menarche and late menopause have been consistently associated with an increased risk of ovarian cancer, likely due to an increase in ovulation and in oestrogen exposure [26]. The effect of combined hormonal contraceptive use on the risk of ovarian cancer has been long discussed. In 2007, the IARC review concluded that women who had at least for a period used combined hormonal contraceptives orally had an overall reduced risk for ovarian cancer, which persists for at least 20 years after cessation of use, and an inverse relationship was observed with duration of use [27]. These results have been confirmed by the Collaborative Group on Epidemiological Studies of Ovarian Cancer [16] that reported an overall reduction in ovarian cancer risk in users versus non-users of 27%, which was not confined to any particular type of oral formulation nor to any histological type of ovarian cancer, although it was less consistent for mucinous than for other types of ovarian cancer. On this basis, the “incessant menstruation” hypothesis was postulated, which concludes that the use of oral contraceptives (OC) should be favoured for prolonged periods of time, especially in women with endometriosis, a population at doubled risk of ovarian cancer [28]. On the other hand, in the Million Women Study HRT after menopause was shown to increase the risk of ovarian cancer [11].
Women who have never had children are at increased risk of developing ovarian cancer [29]. Regarding fertility drug use, previous studies have provided conflicting results. Recent data demonstrated that fertility drug use does not significantly contribute to ovarian cancer risk among the majority of women. However, women who despite their use remain nulliparous may have an increased risk [30]. The role of breastfeeding as a protective factor against ovarian cancer has been long discussed. Finally, the risk of ovarian cancer decreases in women who underwent bilateral tube ligation or hysterectomy, probably because these surgical interventions do not allow the carcinogenic agents to enter the body from the vagina and reach the ovaries [19, 31]. For instance, a number of observational studies (largely case-control) conducted over the last two decades suggested an association between use of talc powders on the female perineum and increased risk of ovarian cancer, although the weak statistical associations observed in a number of epidemiological studies do not support a causal association between cosmetic talc use and ovarian cancer [32,33].
Endometriosis represents another considerable risk factor for epithelial ovarian cancer. In particular, self-reported endometriosis was associated with a significantly increased risk of clear-cell, low-grade serous and endometrioid invasive ovarian cancers. No association was noted between endometriosis and risk of mucinous or high-grade serous invasive ovarian cancers or borderline tumours of either subtype [34]. Also, pelvic inflammatory disease has been suggested to double the risk of epithelial ovarian cancer [35], but few studies have been done and the conclusions are inconsistent.
The most important risk factor still remains a family history of breast or ovarian cancer. Up to 10% of ovarian cancer patients may have inherited a germline mutation that places them at increased risk of the disease. Mutations in the breast and ovarian cancer-susceptibility genes
The mechanism to repair the double-strand DNA breaks is shown in Fig.2.
Heterozygous germline mutation leads to genetic instability as shown in the Fig.3, modified by Brodie
However,
However, most of the common risk and protective factors only slightly influence the risk of developing ovarian cancer, thus, to date; the knowledge of these factors has still not been translated into practical strategies to prevent ovarian cancer.
3. Primary prevention for ovarian cancer in high risk women
Some women have a high risk of developing ovarian cancer due to hereditary conditions associated to BRCA syndrome and Lynch syndrome. Thus, when one of these forms of hereditary or familial breast and/or ovarian cancer is suspected in clinical practice, the general practitioner should refer the patient to a cancer centre specialising in cancer-specific genetic counselling for the identification, definition and management of risk. Genetic counselling, defined by the American Society of Human Genetics as ‘a communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family’, involves one or more professional figures to help the affected individuals or families [41-44]. Genetic counselling in the oncological setting (cancer-specific genetic counselling) should also provide sufficient information to enable the user to make a fully informed choice as to course of action, particularly with regards to prevention, in the case of the identification of a mutation or of a familial cancer risk [45, 46].
A recent review investigated the impact of cancer genetic risk assessment on outcomes, including perceived risk of inherited cancer and psychological distress. The review found favourable outcomes for patients after risk assessment for familial breast cancer, suggesting that cancer-specific genetic risk assessment services help to reduce distress, improve the accuracy of the perception of risk of ovarian cancer, and increase the knowledge of ovarian cancer and genetics. However, there were too few papers to make any significant conclusions on how best to deliver cancer genetic risk assessment services. Further research is needed, assessing the best means of delivering cancer risk evaluation, by different health professionals, in different ways and in alternative locations [47].
Women at increased risk of breast and ovarian cancer are advised to consider risk-reducing strategies; however, such methods vary in their effectiveness. These strategies include chemoprevention and prophylactic surgery (risk-reducing salpingo-oophorectomy, RRSO). Risk-reducing strategies have been shown to have associations with a lengthening of life expectancy in
3.1. Risk-reducing salpingo-oophorectomy (RRSO)
Women who have inherited mutations in the
RRSO has also been demonstrated to decrease the risk of both breast and ovarian cancer in
Similar findings were observed in a prospective study of 170
A summary of published studies on RRSO is presented in Table 2.
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Rebbeck et al., 2002 [55] | RC | 261/292 | 8.5 | 96 | 53 |
Kauff et al., 2008 [56] | PC | 509/283 | 3.2 | 85 | 72 |
Finch et al., 2006 [57] | RC | 1041/779 | 3.5 | 80 | NA |
Chang-Claude et al., 2007 [58] | RC | 55/1601 | 65,675 PY | NA | 44 |
Rutter et al., 2003 [60] | RC | 5/223 | NA | 67 | NA |
Kauff et al., 2002 [61] | PC | 98/72 | 2.0 | 85 | 68 |
A synopsis of different management strategies available for
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Chemoprevention | OC | Likely 30-60% reduction in ovarian cancer risk | Potential increase in risk of breast cancer |
Screening | TVUS, CA 125 | Avoids RRSO | Unproven efficacy |
Risk-reducing surgery | Bilateral salpingo-oophorectomy | Substantial decrease in risk of ovarian and fallopian tube cancers | Premature menopause and iatrogenic infertility |
The National Comprehensive Cancer Network (NCCN) guidelines and other institutions concerning this method, recommend RRSO “for women with a known BRCA1/2 mutation, ideally between 35 and 40 years or upon completion of child bearing” or at an adjusted age based on earliest age of ovarian cancer diagnosis in the family” [62].
Also ACOG, the Committee on Genetics and the Society of Gyneacologic Oncologists, recommends RRSO for women with
The National Cancer Institute (NCI) [64] on the clinical management of
For the European Society of Medical Oncology ESMO [66], RRSO is associated with a reduction in risk of breast cancer in premenopausal
The significantly reduced risk of breast cancer by RRSO seems to be higher in
However, it should be noted that the NCCN and other institutions couch these recommendations within a multidisciplinary consultative process in which reproductive desires, assessment of cancer risk, and the pros and cons of surgery along with the potential sequelae of surgery are fully discussed.
The recommendations of different organizations regarding surgical primary prevention for
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RRSO | Between 35 and 40 years or upon completion of child bearing | By the age of 40 years or when childbearing is complete | Considered but age is not indicated | After age 35 and when childbearing decisions are complete |
Bilateral salpingectomy | - | - | Considered but age is not indicated | - |
3.2. Chemoprevention
Women at increased risk, based on their personal or family history of breast and/or ovarian cancer including
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OC USERS | BRCA 1/2 | Users | 5 | 1503 | 0.50 (0.33-0.75) |
BRCA 1 | 5 | 1251 | 0.51 (0.40-0.65) | ||
BRCA 2 | 4 | 286 | 0.52 (0.31-0.87) | ||
DURATION OF USE | BRCA 1/2 | 1 year | 4 | 1336 | 0.96 (0.94-0.97) |
5 years | 0.80 (0.73-0.88) | ||||
10 years | 0.64 (0.53-0.78) |
Another meta-analysis of cohort, case-control and case-case studies published in English up to December 2009 confirmed a significantly decreased ovarian cancer risk in
Other chemopreventative agents such as retinoids, vitamin D, cyclo-oxygenase inhibitors and peroxisome proliferator activated receptor-gamma ligands have shown promise in early investigations of disease prevention [71].
Retinoids, a class of compounds comprising vitamin A, its natural derivatives, and synthetic analogs, have been extensively studied in both the prevention and treatment of gynaecologic malignancies [72]. One of the most promising retinoids to be used in chemoprevention trials is the synthetic amide of retinoic acid fenretinide,
The most important study where 4-HPR was administrated was a multicentric phase III randomized trial, coordinated by the Istituto Nazionale dei Tumori in Milan, which started in 1987. Most notably, the younger the women were, the greater the benefit of 4-HPR. Such a benefit was associated with a remarkable 50% risk reduction in women aged 40 years or younger, whereas it disappeared after 55 years of age. Interestingly, the incidence of ovarian cancer during the 5-year intervention period was significantly lower in the treatment arm [74].
The role of analgesic drug use in the development of ovarian cancer is still widely discussed.
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Costa et al., 1989 [75] | Phase I, Randomized, Placebo controlled (60) | Orally: 100, 200 and 300mg x 6 months subsequently at 200mg for another 6 months. | Tolerability | Recommended dose for chemoprevention trials of HPR is 200mg/die. |
Formelli et al., 1989 [76] | Phase II, Randomized, Placebo controlled (60) | Orally: 100, 200 and 300mg x 6 months subsequently at 200mg for another 6 months. | Pharmacokinetic | HPR treatment lowers retinol and RPB plasma concentrations. Effect related to HPR levels and reversible on cessation of HPR administration. |
Veronesi et al., 1999 [77] | Phase III, Randomized (2867) | Orally 200mg versus no treatment x 5 years. | Second breast cancer prevention | No statistically significant effect but a possible benefit in premenopausal women. |
Veronesi et al., 2006 [78] | Phase III, Randomized, 15-year follow-up (1879) | Orally 200mg versus no treatment x 5 years: 15-years followup. | Second breast cancer prevention | 4-HPR induces a significant reduction of risk of second breast cancer in premenopausal women, which is remarkable at younger ages, and persists several years after treatment cessation. |
A recent population-based case-control study, carried out in Denmark in the period 1995-1999, analysed the association between analgesic drug use and ovarian cancer risk using multiple logistic regression models. The study showed that regular use of non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAID), paracetamol or other analgesics did not decrease ovarian cancer risk. In contrast, use of any analgesics (OR = 0.72; 95% CI 0.53-0.98) or aspirin (OR = 0.60; 95% CI 0.36-1.00) resulted in a statistically significant decreased risk of serous ovarian cancer but not mucinous or other ovarian tumours [79]. On the other hand, recent data reported by the Multiethnic Cohort Study did not find compelling evidence to support an association between use of NSAID and risk of ovarian and endometrial cancers in a multiethnic population. The RR (95% CI) for ovarian cancer associated with aspirin, non-aspirin NSAID, and acetaminophen were 0.87 (0.68, 1.14), 0.97 (0.74, 1.26), and 0.86 (0.67, 1.12), respectively. No heterogeneity across ethnic groups (P's ≥0.29) or dose-response relation with increased duration of use (P's for trend ≥0.16) was observed [80]. Finally, in an attempt to review and summarize the evidence provided by longitudinal studies on the association between NSAID use and ovarian cancer risk, a comprehensive literature search for articles published up to December 2011 was performed (Table 7). The meta-analysis found no evidence of an association between aspirin or NA-NSAID use and ovarian cancer risk, based on a random-effects model or a fixed-effects model. Furthermore, the analysis did not show strong association between frequency or duration of NA-NSAID use and ovarian cancer, leading to the conclusion that there is no strong evidence of an association between aspirin/NA-NSAID use and ovarian cancer [81].
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RR | (95% CI) | RR | (95% CI) | |||
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All studies | 17 | 0,94 | (0,87-1,01) | 0,91 | (0,82-1,01) | 0,046 |
C-C studies | 14 | 0,94 | (0,87-1,02) | 0,90 | (0,79-1,03) | 0,015 |
Cohort studies | 3 | 0,92 | (0,77-1,09) | 0,92 | (0,77-1,10) | 0,456 |
Regular Use | 7 | 0,86 | (0,73-1,03) | 0,83 | (0,65-1,05) | 0,119 |
Irregular Use | 7 | 1,07 | (0,96-1,20) | 1,07 | (0,96-1,21) | 0,421 |
Duration > 5 yrs | 5 | 0,91 | (0,67-1,24) | 0,89 | (0,63-1,25) | 0,332 |
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All studies | 7 | 0,86 | (0,76-0,98) | 0,89 | (0,74-1,08) | 0,089 |
C-C studies | 4 | 0,88 | (0,75-1,03) | 0,97 | (0,73-1,28) | 0,042 |
Cohort studies | 3 | 0,82 | (0,64-1,04) | 0,89 | (0,74-1,08) | 0,283 |
Regular Use | 3 | 1,45 | (1,07-1,98) | 1,47 | (0,95-2,27) | 0,153 |
Irregular Use | 3 | 0,96 | (0,69-1,33) | 0,93 | (0,49-1,76) | 0,038 |
Duration > 5 yrs | 3 | 1,65 | (1,13-2,41) | 1,56 | (0,92-2,65) | 0,21 |
4. Secondary prevention for ovarian cancer
This is based on diagnosing and treating extant disease in the early stages before it causes significant morbidity. CA125 (or MUC16) glycoprotein is the most studied tumour marker, alone and/or in combination with other biomarkers, for ovarian cancer screening. However, false positive CA125 levels can occur in women with benign conditions, including menstruation, appendicitis, benign ovarian cysts, endometriosis and pelvic inflammatory disease, as well as with other malignancies, including breast, lung, endometrial and pancreatic cancers. Thus, a large number of false-positive screening tests can occur, potentially leading to unnecessary surgeries and subsequent issues of morbidity and cost [82]. Consequently, multimodal strategies, in particular the combination of CA125 with pelvic ultrasound, have been examined, in order to improve sensitivity and positive predictive value of ovarian cancer screening.
4.1. Transvaginal ultrasound
In the general population, TVUS appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in the interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found no reduction in mortality with the annual use of combined TVUS and CA125 in screening asymptomatic, postmenopausal women at average risk of ovarian cancer [83].
Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experiments with ovarian cancer screening in high-risk women using TVUS with or without CA125 [84-90].
However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether the cancers detected were incident or prevalent. One of the largest reported studies included 888
A similar study reported the results of annual TVUS and CA125 combined-screening in a cohort of 312 high-risk women (152
The first prospective study of TVUS and CA125 with survival as the primary outcome was completed in 2009. Out of 3,532 high-risk women screened, 981 were
4.2. Serum CA125
Serum CA125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section [84-90].
The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA125 screening every 6 to 12 months, beginning at the age of 35 years [91]. The Cancer Genetics Studies Consortium task force recommends that female carriers of a deleterious
NCCN for those patients who have not chosen RRSO, consider concurrent TVUS (preferably day 1-10 menstrual cycle women in premenopausal women) + CA125 (preferably after day 5 of menstrual cycle women in premenopausal women) every 6 months starting at the age of 30 years or 5-10 years before the earliest age of first diagnosis of ovarian cancer in the family [93].
Although there are retrospective data indicating that annual ovarian cancer screening using TVUS and measurement of serum CA125 levels is neither an effective strategy for the early detection of ovarian tumours nor a reasonable substitute for a bilateral RRSO, the effectiveness of these interventions is limited to six-monthly screening. Investigational imaging and screening studies may be considered for this population.
4.3. Proton Magnetic Resonance Spectroscopy (MRS)
MRS has proved to be a reliable technique for probing metabolic patterns, biochemical effects of tumour microenvironment, and the action of therapy in cancer cells, both in vivo and in vitro [94]. In particular, an increase in the total choline-containing compounds (tCho) content allows to distinguish malignant from benign lesions in the breast [95].
Moreover, some studies have also shown alterations of the phospholipid metabolism in vitro using epithelial ovarian carcinoma cell lines [96,97], and demonstrated the feasibility of 3D CSI MRS to detect a choline peak in ovarian lesions in vivo at 1.5 T.
Then, the metabolic meaning of a high concentration of choline in ovarian tumours merits some consideration. This topic has been extensively reviewed by Podo
Based on peer-reviewed published data, several institutions established the Guidelines to facilitate clinical management of patients with a suggestive personal or family history of breast and/or ovarian cancer, in particular individuals from a family with a known deleterious BRCA1/2 mutation. Screening options include transvaginal ultrasonography (TVUS), and serum CA125, while prevention options include medical therapy with drugs and surgery such as RRSO. The guidelines, summarized in Table 8, include age ranges for which these options should be begun and how often screening should take place. [53].
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TVU+CA125 | Every 6 months starting at age 30 years |
Periodic screening beginning between the ages 30 years and 35years | Every 6 to 12 months, beginning at age 35 years | Not considered |
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RRSO | Between 35 and 40 years or upon completion of child bearing | By age 40 years or when childbearing is complete | Considered but age is not indicated | After age 35 and when childbearing decisions are complete |
Bilateral salpingectomy | - | - | Considered but age is not indicated | - |
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Considered | Considered | Considered | Not considered |
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Considered | Considered | Considered | Not considered |
4.4. Human Epididymis Protein 4 (HE4)
Additional potential serum biomarkers have been studied for the detection of ovarian cancer. For instance, human epididymis protein 4 (HE4) is a secreted glycoprotein over-expressed by serous and endometrioid ovarian cancers and expressed by 32% of ovarian cancers lacking CA125 expression.
To define the clinical utility of HE4, a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and non-ovarian tissues by immunohistochemistry was performed and published in 2005. In comparison with normal surface epithelium, which does not express the protein, HE4 was widely found in cortical inclusion cysts lined by metaplastic Mullerian epithelium. These findings suggested that the formation of Mullerian epithelium is a prerequisite step in the development of some types of epithelial ovarian cancer. Moreover, the expression was restricted to certain histologic subtypes: 93% of serous and 100% of endometrioid epithelial ovarian cancers expressed HE4, while only 50% and 0% of clear cell carcinomas and mucinous tumours, respectively, were positive. HE4 protein expression is restricted in normal tissue to the reproductive tracts and respiratory epithelium. In fact, tissue microarrays revealed that the majority of non-ovarian carcinomas do not express HE4 [100].
In 2008 the Food and Drug Administration (FDA) approved HE4 to monitor disease recurrence and this marker was recently incorporated into the clinical evaluation of ovarian cancer patients. Recently, Moore
In the last few years, several multi-modal screenings of women at high risk, combining different approaches, were carried out to improve ovarian cancer diagnostic test performance [103,104]. In 2010, a prospective case-control study was designed to evaluate the independent contributions of HE4, CA125 and the Symptom Index (SI) to predict ovarian cancer status in a multivariate model [105]. The SI is a screening tool that evaluates specific symptoms in conjunction with their frequency and duration to identify women who are at risk of ovarian cancer [106]. The SI, HE4 and CA125 all made significant independent contributions to ovarian cancer prediction. A rule for the positive cut-off based on anyone of the three tests being positive had a sensitivity of 95% with specificity of 80%. A rule based on any two of the three tests being positive had a sensitivity of 84% with a specificity of 98.5%. The SI alone had sensitivity of 64% with specificity of 88%. If the SI index is used to select women for CA125 and HE4 testing, specificity is 98.5% and sensitivity is 58% using the 2-of-3-positive positive cut-off rule. A comparison between different markers in ovarian cancer early diagnosis is presented in Table 9.
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CA125 | CA125 was dichotomized at 95th percentile in the control group. Subjects with a marker value above that threshold were considered to be positive for CA125. |
HE4 | HE4 was dichotomized at 95th percentile in the control group. Subjects with a marker value above that threshold were considered to be positive for HE4. |
Symptom Index (SI) | The SI was considered to be positive if the patient had at least one of the following symptoms for less than one year but more than 12 times per month: bloating or increased abdominal size, abdominal or pelvic pain, difficulty eating or feeling full quickly. |
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CA125 or HE4 | Screen considered positive if CA125, HE4 or both were positive. |
SI or CA125 | Screen considered positive if either the SI or CA125 was positive, or if both were positive. |
SI or HE4 | Screen considered positive if either the SI or HE4 was positive, or if both were positive. |
Any 1 of 3 tests positive | Screen considered positive if any one of the SI or CA125 or HE4 was positive, or if two or more tests were positive. |
Any 2 of 3 tests positive | Screen considered positive if both the SI and CA125 were positive, or if both the SI and HE4 were positive, or if both CA125 and HE4 were positive, or if all three tests were positive. |
SI and at least 1 additional test positive | Classified as positive if SI was positive in addition to either a positive CA125 or a positive HE4, or if all three tests were positive. |
4.5. Proteomic profiling of ovarian cancer for biomarker discovery
Unfortunately, current diagnostic tools have had very limited success in early detection. The search for an ovarian cancer screening method with improved specificity and sensitivity has led to the examination of serum biomarker patterns using new ‘omic’ technologies [107-110]. In recent years, the advancing techniques for proteomics have accelerated the research for ovarian cancer biomarkers. Numerous proteomics-based molecular biomarkers/panels have been identified and hold great potential for diagnostic applications, but they need further development and validation.
Several studies have analysed the proteomic profiles of ovarian tumour tissue, cell lines, urine, ascites fluid and blood samples from ovarian cancer patients (Table 10) [111- 114].
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An et al.,(2006)[111] | NM23-H1 | ↑ |
Annexin-1 | ↑ | |
Protein phosphatase-1 | ↑ | |
Ferritin light chain | ↑ | |
Proteasome alpha-6 | ↑ | |
NAGK (N-acetyl glucosamine kinase) | ↑ | |
Petri et al., (2009) [112] | fibrinogen alpha fragment | ↑ |
collagen alpha 1 (III) fragment | ↑ | |
fibrinogen beta NT fragment | ↑ | |
Li et al., (2009) [113] | prx-II | ↓ |
prx-III | ↑ | |
hsp27 | ↑ | |
hsp60 | ↑ | |
mitochondrial short-chain enoyl-CoA hydratase | ↑ | |
Prohibitin | ↑ | |
Cortesi et al.,(2011) [114] | Annexin-5 (ANXA5) | ↓ |
Phosphatidylethanolamine-biding protein 1 (PEBP) | ↓ | |
glutathione S-transferase A2 (GSTA2) | ↓ | |
galectin-3 (LEG3) | ↓ | |
protein S100-A8-calgranulin A (S100A8) | ↑ | |
retinol binding protein (RET1) | ↓ |
An
A recent comparative proteomic study investigated and defined protein expression patterns associated with advanced stage ovarian cancer, to define a panel of diagnostic and/or prognostic markers. The study also investigated proteins secreted by the cancer cell into the interstitial fluid, as cancer growth and progression also depends on stromal factors present in the tumour microenvironment. Moreover, many biomarkers present in biopsied cancer tissues can also be found in blood serum, representing potential biomarkers of the disease. Proteomic profiling of differentially expressed proteins in cancer ovarian tissue, tumoral interstitial fluid (TIF) and ascitic fluid, compared with healthy tissue samples and normal interstitial fluid (NIF), allowed the identification of protein spots consistently differentially expressed between normal and cancer samples. Protein expression/identification was evaluated by 2-DE (two-dimensional gel electrophoresis) and MS (mass spectrometry) analysis and was confirmed by immunohistochemistry. Six proteins showed differential expression in tumoral interstitial fluid and tumour tissue compared to normal interstitial fluid and healthy tissue. Differential protein expression between tumoral and normal ovarian tissue is presented in Table 11.
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ANXA5 | -1,88 ± -0,48 | <0,0001 | -5,605 ± -3,29 | <0,01 |
PEBP | -4,21 ± -2,90 | <0,01 | -2,82 ± -0,69 | <0,0001 |
GSTA2 | -4,67 ± -1,88 | <0,0001 | -27,39 ± -21,24 | <0,01 |
LEG3 | -2,19 ± -0,69 | <0,0001 | -5,10 ± -4,42 | <0,05 |
S100A8 | 3,67 ± 1,50 | <0,001 | 3,58 ± 1,11 | <0,0001 |
RET1 | -6,33 ± -3,30 | <0,001 | -5,01 ± -4,28 | <0,05 |
Five were found to be down-regulated and identified as galectin 3, glutathione S-transferase A-2, retinol binding protein 1, phosphatidylethanolamine-binding protein and annexin 5, while the calgranulin, was significantly up-regulated in all pathological samples, including the ascitic fluid. This is the first study to report an over-expression of calgranulin by 2-DE analysis combined with MS/MS on surgical biopsy. As previously reported, the reduced expression of galectin 3 and retinol binding protein 1 in cystic fluid and serum of patients with early stage disease is confirmed in this study. The results highlight alterations in proteins that control cell-cycle progression and apoptosis, as well as factors that modulate the activity of signal transduction pathways. Moreover, this study suggests that calgranulin expression may be used as a diagnostic and/or prognostic biomarker [114].
However, critical assessment of the results has shown significant shortcomings and uncertainties with regard to the reproducibility of the findings and identity of the proteins behind the peak patterns, thus, the validation of the newly discovered biomarkers still remains the most challenging aspect of clinical proteomics. The advancing techniques for proteomics have shown promise in a variety of studies and have provided new insights into ovarian cancer diagnosis, but few have turned out to be useful in the clinic. At present, the development of an effective strategy for early detection of ovarian cancer is still a work in progress [110].
5. Discussion
Primary and secondary prevention of ovarian cancer play a crucial role in the attempt to improve the overall survival from the disease. In particular, primary prevention is based on avoiding risk factors and increasing protective factors. Despite the identification of several risk and protective factors among the general population, most of the common factors described to date only slightly influence the risk of developing ovarian cancer, thus, the knowledge of these factors has still not been translated into practical strategies to prevent ovarian cancer.
On the other hand, primary prevention could represent a good opportunity for high-risk women. Women who inherit a mutation in either the
Regarding radiological methods to investigate ovaries and their adnexes, new techniques besides TVUS need to be explored. Pelvic Magnetic Radiological Imaging could be of interest even if it is difficult to imagine such an expensive technique being employed in the screening of high-risk women. For high-risk women, recommended cancer screening strategies, which need to be adjusted depending on the earliest age of onset in a family, have not been assessed by randomized trials or case-control studies. Ovarian cancer screening relies on a combination of annual or semi-annual pelvic examination, annual or semi-annual transvaginal ultrasound examination with colour Doppler, and annual measurement of serum CA125 concentrations.
Current approaches are a futile attempt to detect ovarian cancer in the early stages, but future research should be directed to better characterizing critical pathways in ovarian carcinogenesis and to identifying appropriate surveillance programs based on biomarker tests and/or radiological investigations, in order to improve overall survival, which dramatically decreases in the first 5 years. Due to the fact that an analysis of potentially thousands of proteins which could be simultaneously altered is necessary, comparative proteomics is a promising mode of potential biomarker discovery for cancer detection and monitoring. A better estimation of the biological importance of certain proteins with regard to the progression from pre-neoplastic tissue alterations to malignant tumours, as well as the prediction of the metastasis-forming potential by biomarkers, will be a necessary prerequisite to provide a more detailed insight and understanding of tumour progression.
Acknowledgments
The authors thank the “Angela Serra” Association for Cancer Research (Modena, Italy) and the “Fondazione Cassa di Risparmio “of Modena, Italy for financial support. A special thanks to Dr Adriano Benedetti and Dr Daniela Manzini (C.I.G.S., University of Modena and Reggio Emilia) for skilled assistance in protein analysis by ESI-Q-TOF MS. This work was supported by grants from the Italian Minister of University and Research, PRIN 2008 (20088RFCMH).
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