Ov ca prevention jeddah

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Ovarian cancer prevention Zainab M. Al-Talal Gyne.Oncologist King abdulaziz,NGH,hasa

Transcript of Ov ca prevention jeddah

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Ovarian cancer prevention

Zainab M. Al-TalalGyne.Oncologist

King abdulaziz,NGH,hasa

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• Ovarian cancer is still the most frequent cause of death by gynecological malignancy for women in developed countries.

• The lifetime probability for developing ovarian cancer is less than 2 percent .

• The incidence of ovarian cancer increases with age.

Presenter
Presentation Notes
The incidence of ovarian cancer increases with age; the highest proportion of cases are diagnosed in women 50 to 59 years of age. To date, all attempted ovarian cancer screening strategies have failed.
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• One large-scale prospective clinical screening trial found that screening did not reduce mortality from ovarian cancer but did result in harm from consequent follow-up.

• There is a consensus that women at average risk for ovarian cancer should NOT undergo screening.

Presenter
Presentation Notes
Despite evidence to the contrary, a cross-sectional survey of physicians in the US found that one in three believed that screening for ovarian cancer was effective and commonly offered testing
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• Recently, a new classification of ovarian cancer in two different types of cancer has been introduced, where type II ovarian tumors are considered the most frequently diagnosed, aggressive, genetically instable and often advanced.

• One of the more important finding in last decade of gynecologic oncology is the confirmed theory that types II tumors derive from the epithelium of the Fallopian tube, whereas clear cell and endometrioidtumors derive from endometrial tissue that migrate to the ovary by retrograde menstruation.

Presenter
Presentation Notes
These observations are mainly collected from women that carry BRCA1/2 mutations and underwent prophylactic salpingo-oophorectomy, in which most of the incidentally diagnosed in situ carcinomas or intraepithelial precursors of cancers (STIC) were detected not in the ovary but in the fimbrial end of the fallopian tube [4], [5] and [6]. STIC were also subsequently diagnosed in many women not carrying BRCA mutations, thanks to an extended protocol of pathologic examination of the Fallopian tubes (SEE-FIM) of patients operated for sporadic HGSC
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RISK FACTORS

• Age• familial ovarian cancer syndrome/family

history of ovarian cancer• Infertility• Endometriosis• Perimenopausal or postmenopausal hormone

therapy

Presenter
Presentation Notes
Identification of women at high risk for ovarian cancer may help to select a group that would most benefit from screening strategies The likelihood that a case of ovarian cancer is attributable to a gene mutation decreases with increasing age at diagnosis familial ovarian cancer syndrome/" from the more common "family history of ovarian cancer” Over one-half of the women with BRCA1 mutations had unremarkable family histories A small family size may mask the presence of a hereditable disorde
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RISKS AND BENEFITS OF SCREENING

• The potential benefit of screening is its ability to identify ovarian cancer at a more localized and curable stage, leading to reduced mortality from the disease.

• Although ovarian cancer is an important cause of cancer death, its incidence and prevalence in the general population are relatively low. The problem of false-positive screening tests becomes critically important in diseases with low prevalence.

Presenter
Presentation Notes
Unless the test or sequence of tests is extremely accurate, a large number of healthy women would be at risk for unnecessary surgery
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Can ovarian cancer be prevented?

Presenter
Presentation Notes
Unfortunately, the options for ovarian cancer prevention and early detection are limited Thus, better methods to prevent, detect, and screen for ovarian cancer in all women, but particularly in high-risk women, are urgently needed Hypotheses
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The incessant ovulation hypothesis

• The incessant ovulation hypothesis states that tumors result from recurrent minor trauma at the time ovulation .

proliferationrepair

Presenter
Presentation Notes
and. The greater the number of repairs, the greater the chance of an aberrant repair process that can lead to a malignant cell. Any factor reducing that number would provide protection from the disease.
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The pituitary gonadotropin hormone hypothesis

• In contrast, the pituitary gonadotropin hormone hypothesis states that high levels of circulating gonadotropins result in the production of estrogen or estrogen precursors, which stimulate ovarian surface epithelial proliferate excessivelymalignant transformation.

Presenter
Presentation Notes
Any factor reducing the level of these hormones would be predicted to be protective against the disease.
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The inflammation hypothesis

• Ness and Cottreau have suggested that inflammation may play a role in the development of the disease. In support of this hypothesis:– talc– tubal ligation and hysterectomy– medical conditions associated with inflammation,

such as endometriosis and pelvic inflammatory disease have also been linked to ovarian cancer.

Presenter
Presentation Notes
While the evidence for the androgen/progesterone hypothesis is compelling, it does not fully account for all the epidemiologic data. For example, it fails to address the associations of talc use, endometriosis, and pelvic inflammatory disease with ovarian cancer. Finally, the use of anti-inflammatory agents, such as aspirin and nonsteroidals (NSAIDS) [145], [146], [147] and [148] also appear to protect against the disease. Although these data support the inflammation/ovarian cancer link, the evidence is not always complete. For example, the effects of talc use are not specific and there is no clear association with duration and frequency of use.
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Others..

• The androgen/progesterone hypothesis• The ovarian stromal hyperactivity hypothesis

Presenter
Presentation Notes
Androgens and progestins may play a role in ovarian cancer etiology. Androgens are produced by ovarian theca cells, are present in follicular fluid, and are the principal sex steroid of growing follicles. Postmenopause, a time when ovarian cancer rates sharply rise, the ovary is androgenic . OCs suppress ovarian testosterone production by 35–70% . In the CASH study, cases were more likely to have a history of polycystic ovary syndrome (OR = 2.4; 95% CI = 1.0–5.9) [107], a condition that causes elevated androgen levels [108], [109] and [110]. Finally, in a cohort study of 31,000 healthy women followed for more than 7 years, the risk of ovarian cancer increased with increasing waist-to-hip ratio (P = 0.03) [111], a marker of central obesity. Central obesity correlates with androgen levels in women Progestin-only oral contraceptives, which do not totally suppress ovulation, are as protective against ovarian cancer as estrogen–progestin formulas [123]. Finally, the presence of progesterone receptors in normal ovarian epithelial cells [124] further supports the activity of the hormone in epithelial tissue While both the androgen/progesterone and the inflammation hypotheses provide potential explanations for the protective effect of OC use in disease initiation, there is still the question of why both OC use and parity, behaviors in which women are engaged in their 20's and 30's, provide protection against the development of a disease some 30–40 years later. It is possible that OCs have a residual effect on gonadotropin levels [97]. By reducing the amount of menstrual bleeding, OCs may also reduce retrograde menstrual flow, which is associated with endometriosis [149], believed to be a precursor to some ovarian tumors [142]. Most recently, Cramer et al. [97] hypothesized that OCs may reduce “stromal hyperactivity.” In particular, during normal ovulation, granulosa and thecal cells proliferate to increase ovarian steroid production. Although it is believed that these cells undergo apoptosis, Cramer and colleagues hypothesize that some of the steroid-producing cells may in fact remain in the ovarian stroma. Hence, the greater the number of ovulatory cycles, the more follicles produced with granulosa–thecal cell compartments and the greater the number of residual (nonapoptosed) cells. These residual cells have been luteinized and may still retain steroid production capabilities. Hence, the more a woman ovulates, the greater the cumulative number of steroid-producing cells and potentially the greater cumulative lifetime exposure to ovarian steroids.
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STIC

• The detection of premalignant cells in the epithelium of the fallopian tube has resulted in revolutionary theories regarding the origin of epithelial ovarian cancer (EOC).

• Serous tubal intra-epithelial carcinomas (STIC ) have been detected in patients with BRCA 1 or 2 mutations and are considered as the most likely precursors of the high-grade serous ovarian cancer (HGSOC), which is the most common histological subtype.

Presenter
Presentation Notes
This hypothesis of the carcinogenesis of ovarian cancer has long been disputed, given that no pre-invasive lesions were known for its most common subtype: high-grade serous [4 ]. Only after the detection of ‘‘in situ’’ lesions in the fimbrial end of the fallopian tube (Table 1 ) [5 ] research was initiated to focus on the fallopian tube as a potential origin of EOC; most ‘apparent’ ovarian cancers might actually be of tubal origin after ‘‘drop metastases’’ of cancer cells on the ovarian surface or after dislocation of transformed fallopian tube. This tubal carcinogenesis most probably happens stepwise. Initiated by a so-called P53 signature, serous intra-epithelial carcinoma develops through a ‘‘proliferating P53 signature’’. The lesion, ‘Secretory Cell Outgrowth’ (SCOUT) equals a proliferation of secretory cells and is often regarded as a surrogate marker for precursor lesions. Due to their stemcell- like features, these lesions may also have a potential role in the pathogenesis of EOC [6 –17 ]. epithelial complexes at ovulation onto the ovarian cortex
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• The incidence of STIC detection in fallopian tube specimens after extensive histopathologicalprocessing is as follows:– 2–7 % in risk-reducing salpingo-

oophorectomies(BRCA1/2 positive or familial risk) – up to 80 % in surgical specimens of BRCA1/2

patients with HGSOC– 46 % in patients with sporadic ovarian cancer

Presenter
Presentation Notes
The development of EOC from a tubal precursor lesion cannot be established in 40–80 % of the cases especially when no BRCA 1/2 mutation exists. In the event of the coexistence of a STIC lesion together with invasive highgrade serous adenocarcinoma, a direct patho-genetical association is possible; however, an independent coexistence without a direct association of the two lesions is also plausible. It is therefore possible that not all HGSOCs find their origin in the fallopian tube, but that many parallel developmental pathways exist. For this reason, it is implausible that prophylactic salpingectomy as a risk-reduction procedure will prevent 100 % of all future invasive EOCs. The accuracy of detection of a tubal precursor lesion depends on the intensity of the histopathological assessment. Extensive labour intensive processing of the removed tubes is not suitable for daily clinical practice
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SO..

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BSO/Salpingectomy

• Preservation of the ovarian function is important both in the pre-menopausal age and in the post-menopause, due to the effective prevention of bone resorption, guaranteed by the intact ovaries .

• Furthermore, surgical menopause increases long-term risk of psychosexual, cognitive and cardiovascular dysfunctions and incidence of fatal and non-fatal coronary heart diseases.

Presenter
Presentation Notes
Prophylactic bilateral oophorectomy is associated with a lower risk of death from ovarian cancer, however, at no age oophorectomy was associated with a lower risk of other cause-specific or all-cause mortality in large prospective cohort studies [20 , 21 ]. Premenopausal women after bilateral oophorectomy have a significantly higher risk of osteoporosis and cardiovascular disease. This appears to be compensated for by the beneficial prophylactic effect [22 ]. No guidelines or recommendations exist to guide clinicians in determining the age at which prophylactic oophorectomy should be advised given the known risks and benefits. The prophylactic removal of the fallopian tubes at the time of the hysterectomy (for benign conditions) may have a negative impact on the vascular supply of the adjacent ovaries and hence result in degenerative changes which subsequently result in an earlier menopause .
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BSO/salpingectomy

• According to the existing literature, however, whether bilateral salpingectomy impairs ovarian reserve is still a matter of debate.

• Bilateral salpingectomy with ovarian preservation should be considered, as the best preventive strategy for women with low risk of ovarian cancer (not carrying BRCA mutations).

Presenter
Presentation Notes
, although it is mandatory to assess the effects and complications associated with it. Nevertheless, the effects of salpingectomy on ovarian functions are still controversial. To the best of our knowledge, there are no strong evidences on the effect of salpingectomy on surgical outcomes of a standard hysterectomy. This calculation would suggest that for 2.5 million hysterectomies with bilateral salpingectomy, 680 procedures would need to be performed to prevent one cancer. It is estimated that there will be a reduction in the incidence of all ovarian cancers by 2.3 % in 20 years if a concurrent salpingectomy is performed at every hysterectomy, and it is assumed that all serous ovarian cancers originate from the fallopian tube. If, however, we assume that there are also other alternative theories for the development of high-grade serous ovarian cancer (HGSOC), then the protective effect of the bilateral salpingectomy may be smaller than estimated. Furthermore, it is not clear to what extent the removal of the fallopian tubes can contribute to the prevention of other epithelial ovarian cancer subtypes such as endometrioid or clear cell histology. Epidemiological data have shown that even after tubal sterilisation, the risk of ovarian cancer is reduced, possibly through the prevention of carcinogen transport via fallopian tubes. If this is taken into account as a plausible mechanism, opportunistic salpingectomies may also decrease the incidence of non-serous histological subtypes.
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Chemoprevention

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Oral contraceptives

• Women who used oral contraceptives for 5 or more years have about a 50% lower risk of developing ovarian cancer compared with women who never used oral contraceptives.

• Further observation showed that progestin-only formulations, which do not suppress ovulation, are as protective as combined estrogen and progestin formulations.

Presenter
Presentation Notes
Elizabeth Poynor (Memorial Sloan-Kettering Cancer Center, New York, NY) gave a presentation regarding prophylactic approaches for ovarian cancer. There are data that support the role of oral contraceptives and prophylactic oophorectomy in preventing ovarian carcinoma in women at high risk. Peritoneal carcinomatosis has been reported in 1.9–10.7% of women undergoing prophylactic oophorectomy. More importantly, these animal data further suggest that progestin-based interventions may be useful postmenopausally, a time when ovarian cancer rates dramatically increase [158]. Indeed, progestin-containing hormone replacement therapy formulations used in a continuous regimen have recently been shown not to be associated with an increase in ovarian cancer risk, whereas both estrogen-only formulations and formulations in which the progestin component is used sequentially were both associated with an increased risk in that same study [159]. In particular, the animal data together with the data from this recent study implicate unopposed estrogens as risk factors for ovarian cancer. Clinically, progestin-containing HRT is prescribed only for women with an intact uterus in order to reduce the risk of endometrial cancer associated with unopposed estrogens. However, the primate data, in conjunction with emerging epidemiologic data, suggest that further study is needed to evaluate whether all postmenopausal women, regardless of their uterine status, should consider a progestin-containing HRT formulation used in a continuous regimen. This recommendation should be taken cautiously, because use of combined HRT formulations for extended periods of time has been associated with an increase in breast cancer risk [160]. Indeed, these conflicting data from the ovarian and breast cancer literature highlight the need for further investigation of specific progestin (and estrogen) formulations and their potential tissue-specific effects on the various hormone-sensitive tissues.
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Metformin

• Has strong anti-neoplastic effects in several cancers through activation of AMP-activated protein kinase which is a critical energy sensing pathway in cells.

• Metformin has a favorable effect both in the context of prevention and as an adjuvant treatment.

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NSAIDs

• The COX-2 inhibitors are a class of NSAIDS where activity against tumor development has been suggested for cancers of the ovary, colon, breast, lung, and cervix.

• Lower serum levels of VEGF were noted in some patients after treatment.

Presenter
Presentation Notes
Barnes conducted a pilot study to determine the feasibility of examining a COX-2 inhibitor (Celecoxib) as a chemopreventive agent in women at increase risk of ovarian cancer undergoing risk-reducing salpingo-oophorectomy.
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Retinol and vitamin A

• Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes.

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Green tea

• n vitro/in vivo studies assessed the use of green tea in EOC treatment, it showed promising properties such as the capacity to decrease the expression and/or activity of a large spectrum of cancer-related proteins.

Presenter
Presentation Notes
Although most women included in this study usually drank green tea before their diagnosis of EOC was established [44], only post-diagnosis green tea intake was evaluated [60]. As such, women who drank green tea daily after their diagnosis had a decreased risk of dying from EOC
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PA• Relative to obesity, previous pooled analyses have

demonstrated a significant direct association between BMI and EOC risk.

• Moderate-intensity PA may also decrease cancer risk by blunting chronic inflammation and enhancing immune surveillance .

• The most probable mechanisms linking with cancer risk and survival include decreased body fat, altered reproductive hormone levels, altered cytokine and growth factor milieu, and changes in immune function (including reduced inflammation and enhanced anti-tumor immunity) .

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Thank you