RISK ASSESSMENT FOR OVARIAN CANCER

Although scientists' understanding about the early carcinogenic events of ovarian cancer is incomplete (see Chapter 2), researchers have identified several factors associated with either an increased or a decreased risk of developing ovarian cancer (see Table 3-1). While some of these risks factors cannot be modified (e.g., age and ancestry), a number of others (e.g., hormone use and diet) can be altered through lifestyle changes, pharmacological interventions, or surgery. A critical drawback, however, is that nearly all of the identified risk factors are associated predominantly with the less common and less lethal ovarian cancer subtypes and not with the most common and lethal type—high-grade serous carcinoma (HGSC). Ovarian cancer risk factors can also vary by histologic subtype, and thus a given risk factor may increase risk for one subtype while decreasing risk for another.

TABLE 3-1

Risk Factors for Ovarian Cancer.

Inherited Genetic Risk

A family history of ovarian cancer has a strong association with risk for ovarian cancer, and having a large number of first-degree biological relatives with an ovarian carcinoma increases a woman's risk (Jervis et al., 2014; Soegaard et al., 2009; Stratton et al., 1998; Werness and Eltabbakh, 2001). As a result, specific germline (inherited) genetic mutations are among the most well-established risk factors associated with ovarian cancer (Shulman and Dungan, 2010). Many women with a family history of cancer have a hereditary cancer syndrome (Garber and Offit, 2005). Table 3-2 describes some common genetic mutations and hereditary cancer syndromes that are found among women with ovarian cancer. Inherited genetic mutations are associated with approximately 5 to 15 percent of all ovarian carcinomas, though their distribution varies by subtype (Lynch et al., 2009). In some studies, inherited mutations have been found in up to 25 percent of women with HGSC, but up to half of these women did not have a family history of breast or ovarian cancer (Schrader et al., 2012; Walsh et al., 2011).

TABLE 3-2

Examples of High-Risk Ovarian Cancer Susceptibility Genes and Cancer Syndromes.

High- and Moderate-Risk Gene Mutations

BRCA1 and BRCA2 are the most recognizable of the genes that increase the risk of ovarian cancer. These genes were identified in the mid-1990s as breast and ovarian cancer–risk genes, and in recent years the effect that the BRCA1 and BRCA2 mutations have on the risk of breast and ovarian cancers has been established (Miki et al., 1994; Rebbeck et al., 2015; Wooster et al., 1994). Germline mutations in these genes are present in approximately 10 to 15 percent of all women diagnosed with invasive ovarian carcinomas and in approximately 15 to 23 percent of women diagnosed with HGSC (Alsop et al., 2012; Pal et al., 2005; Risch et al., 2006; Zhang et al., 2011). Recently discovered single-nucleotide polymorphisms (SNPs) in other genes appear to have a role in modulating the risk of ovarian cancer in those women who have an inherited BRCA1 or BRCA2 mutation (Ramus et al., 2011, 2012).

Lynch syndrome is caused by deleterious mutations in DNA mismatch repair genes (see Table 3-2). The lifetime risk of ovarian cancer associated with Lynch syndrome mutations is around 8 percent, with the greatest risks associated with MLH1 or MSH2 (Lu and Daniels, 2013). Many of the genes in Table 3-2 are typically included in the multiplex gene panels currently offered by commercial laboratories, and National Comprehensive Cancer Network (NCCN) guidelines suggest various interventions when a woman has one or more of these genes. For example, NCCN recommends risk-reducing surgeries (e.g., bilateral salpingo-oophorectomy) for women with mutations in BRCA1, BRCA2, and genes associated with Lynch syndrome (NCCN, 2015). Risk-reducing surgeries are discussed later in this chapter. Other moderate-risk cancer susceptibility genes often included in the panels are CHEK2, PALB2, RAD51 family, BRIP1, and BARD1 (Walsh et al., 2011). RAD51C and RAD51D mutations appear to confer a lifetime risk of 10 to 15 percent for ovarian cancer (Lancaster et al., 2015).

Advances in DNA-sequencing technologies have dramatically reduced the cost of genetic testing, and in 2013 the U.S. Supreme Court ruled that, with few exceptions, patents on naturally isolated DNA sequences are invalid.¹ The confluence of these events led to the rapid development and release of genetic tests that sequence multiple genes simultaneously—the so-called multiplex gene panels—and to the possibility of performing whole-genome sequencing (Rahman, 2014; Robson et al., 2015). With multiplex gene panels it may be possible to identify more individuals with hereditary cancer gene mutations than with testing for BRCA1 and BRCA2 alone (Desmond et al., 2015). However, the ability to find more mutations does not necessarily lead to a better understanding of disease risk, as little is known about the clinical impacts of a large fraction of these variants or mutations. In these cases where the clinical implications are unknown, the mutations are referred to as “variants of unknown significance” (Domchek and Nathanson, 2014; Eccles et al., 2015).

Recently, the American Society of Clinical Oncology (ASCO) recognized that for women with a personal or family history of cancer, multigene testing may be an efficient way to evaluate multiple high-penetrance genes of established clinical utility (Robson et al., 2015). ASCO further stated that providers with expertise in cancer risk assessment need to be involved in ordering and interpreting multigene panels when genes of uncertain clinical utility are included and that patients must give informed consent and be provided with pretest counseling prior to any genetic testing. ASCO also commented on the specific components that should be included in multigene panel testing.

Technological and legislative advances have combined to make genetic testing for BRCA1 and BRCA2 mutations much more accessible. The Patient Protection and Affordable Care Act² requires health plans beginning on or after September 23, 2010, to cover genetic counseling and testing for BRCA1 and BRCA2 mutations in women whose family history indicates a high risk for cancer. The law does not specifically cover testing using multiplex gene panels or genome-wide sequencing, and testing is not required to be covered for women whose family history does not indicate an increased risk (Nelson et al., 2005, 2014). Two testing issues that the act leaves unaddressed are that BRCA1 and BRCA2 mutations alone do not fully account for genetic risk and that many women with inherited cancer-predisposing mutations do not have a strong family history of breast or ovarian cancer (Jervis et al., 2014; Schrader et al., 2012; Walsh et al., 2011).

Women who test positive for germline genetic mutations associated with greatly increased risk for developing ovarian cancer may benefit from enhanced screening, risk-reducing prophylactic surgery, or chemoprevention. For instance, women with a known BRCA1 or BRCA2 mutation who have prophylactic bilateral salpingo-oophorectomy (BSO) can reduce their risk of ovarian cancer by more than 90 percent (and, for premenopausal women, can reduce their risk for breast cancer by 50 percent) (Domchek et al., 2010).

Low-Penetrance Alleles

Genome-wide association studies have identified some common low-penetrance alleles (genes associated with a low risk) that can also contribute to the familial risk associated with ovarian cancer (Song et al., 2014). Studies using consortia have identified as many as 17 low-penetrance SNP alleles associated with ovarian cancer risk (Bojesen et al., 2013; Bolton et al., 2010; Goode et al., 2010; Kuchenbaecker et al., 2015; Permuth-Wey et al., 2013; Pharoah et al., 2013; Song et al., 2009). In general, most of the risk alleles have been more strongly associated with serous tumors, but these associations may reflect the fact that there are relatively many cases of such tumors, making it easier to find risk alleles associated with them. Using consortia increases the number of cases available for study, which may lead to more associations being uncovered, especially for the less common subtypes. For example, one study of mucinous carcinomas using consortia identified several risk alleles that had not been identified in previous studies that included multiple histologic subtypes (Kelemen et al., 2015).

Genetic Testing Guidelines and Recommendations

Cancer genetic consultation services can provide an evaluation of personal and family history for possible features of hereditary cancer syndromes, a consideration of diagnoses, genetic testing if indicated and available, recommendations for the prevention and management of cancer, and information for at-risk relatives (Hampel et al., 2015). The American College of Surgeons (ACS) Commission on Cancer³ has issued standards for the provision of cancer risk assessment, genetic counseling, and genetic testing services (ACS, 2012). Several other clinical societies and organizations have also developed guidelines and recommendations for when referrals should be made to cancer genetic consultation (see Table 3-3). With the exception of the U.S. Preventive Services Task Force (USPSTF), all of the organizations recommend that all women diagnosed with ovarian carcinoma receive referral for genetic counseling and testing regardless of their family history. Guidelines from the Society of Gynecologic Oncology (SGO), the National Society of Genetic Counselors (NSGC), the American College of Medical Genetics and Genomics (ACMG), and the NCCN all recommend referral to a cancer genetics professional for women without a personal history of cancer but with a family history strongly suggestive of hereditary breast and ovarian cancer (HBOC) (Lancaster et al., 2015; NCCN, 2015).

TABLE 3-3

Current Recommendations for Cancer Genetic Consultation and Germline Genetic Testing for Individuals with Personal or Family History of Ovarian Cancer, 2013–2015.

In spite of the benefits of germline genetic testing for women diagnosed with ovarian cancer, the rate of referral to genetic counseling and testing in accordance with existing guidelines still remains low (Febbraro et al., 2015; Powell et al., 2013a). For example, one study of women with ovarian cancer found that only 14.5 percent of women who should have been counseled according to NCCN guidelines actually were referred to genetic counseling (Febbraro et al., 2015). Further, only 59.5 percent of the women who were referred actually did follow up with the genetic counseling, although of those who did receive counseling, approximately 95 percent ultimately underwent genetic testing.

One objective of Healthy People 2020⁴ is that a greater percentage of women with a significant family history of breast or ovarian cancer receive genetic counseling (HHS, 2013). From 2006 to 2010 the proportion of women receiving genetic counseling rose from 34.6 to 52.9 percent (HHS, 2013). While this was a large increase, still nearly half of all eligible women are not receiving the recommended counseling. There are various patient-, provider-, and system-level barriers that make cancer genetics referrals less likely, including patients being unaware of a family history of cancer, the limited time that providers have to collect family history, and referral criteria that are complex and that vary by group (Hampel et al., 2015).

Relying on a patient's family history alone to consider whether genetic testing should take place will inevitably overlook some women with inherited mutations that put them at risk for ovarian cancer. As mentioned previously, many women with inherited mutations do not have a significant family history for cancer. Furthermore, family history may not indicate a high risk for women with few close female relatives, women with female relatives who underwent risk-reducing surgery at early ages, women who may be adopted and thus do not know their biological family's cancer history, or women who otherwise do not know the family health history of one or both parents (Lancaster et al., 2015).

Cascade Testing

Cascade testing is a sequential process of identifying and testing close blood relatives of individuals who are at increased risk for genetic conditions; the process minimizes the number of tests and costs (George et al., 2015). If an individual has a known deleterious mutation, further genetic testing of close blood relatives requires testing only for the specific mutation rather than testing for the entire gene or doing multigene testing. Only single-site testing is needed for family members unless they are in a population with common and known founder mutations, such as Ashkenazi Jews. For relatives who are negative for the specific mutation, it is likely that their risk of cancer and their offspring's risk of inheriting the mutation are no greater than the risk for the general population. For relatives who have the same mutation, the cascade testing continues with testing their close blood relatives, and so on. Asymptomatic women with a known mutation are often referred to as previvors (FORCE, 2008). Figure 3-1 illustrates how cascade genetic testing might be carried out for individuals at high risk for HBOC syndrome.

FIGURE 3-1

Cascade genetic screening of BRCA mutation for HBOC syndrome. NOTE: HBOC = hereditary breast and ovarian cancer. SOURCE: George et al., 2015.

Several of the clinical societies and organizations in Table 3-3 recommend that biological relatives of an individual with a deleterious mutation for BRCA1, BRCA2, or the Lynch syndrome genes be referred for genetic consultation. The Centers for Disease Control and Prevention (CDC) also promotes cascade testing as an important public health intervention among family members at risk for HBOC syndrome and Lynch syndrome (Bowen et al., 2012).

RISK FACTORS AND TUMOR SUBTYPES

While some factors affect risk for all ovarian cancer subtypes, many factors appear to affect risk for different ovarian cancer subtypes in different ways, including increasing risk for one or more subtypes and decreasing risk for others (Yang et al., 2012). Generally, studies have used histology with or without tumor grade as a surrogate for tumor type. The inability to demonstrate clear associations for certain risk factors may be due in part to the limited power of individual studies to assess associations by tumor type.

The complex associations that these factors have with ovarian cancer risk are driven in part by the differing etiologies for the diverse ovarian cancer subtypes. Many of the studies described earlier in this chapter used the Type I and Type II classification dichotomy. This schema has greater power to detect associations (by increasing the number of cases in each category), but it ignores the unique biology of each subtype and thereby likely masks particular associations.

RISK PREDICTION MODELS

Risk prediction models for women at average genetic risk are important tools for informing women of their 5- and 10-year risk for ovarian cancer, for improving clinical decision making, and for identifying women for enrollment in prevention studies (Freedman et al., 2005). Table 3-4 outlines four studies that have developed risk prediction models for ovarian cancer among women at average genetic risk. Overall, these studies do not demonstrate a strong predictive ability that would be meaningful in clinical decision making, most likely because of the relative rarity of ovarian cancer and the somewhat modest effect sizes of the known risk factors. Improving the discriminatory ability of these models will likely require the consideration of differential associations by tumor subtype and the identification of new risk factors.

TABLE 3-4

Risk Prediction Models for Ovarian Cancer in Average Risk Populations.

PREVENTION STRATEGIES

Most medical strategies designed to prevent the occurrence of ovarian cancer are structured around modulating female hormone cycles and the surgical removal or modification of gynecological tract components, including the fallopian tubes (salpingectomy), ovaries (oophorectomy), and uterus (hysterectomy).

Bilateral Salpingo-Oophorectomy (BSO)

BSO, also known as risk-reducing salpingo-oophorectomy (RRSO), is the surgical removal of the fallopian tubes and ovaries, which dramatically reduces the risk of ovarian cancer in women at average risk and high risk due to inherited genetic susceptibility (see Table 3-5). The USPSTF and SGO advocate RRSO for women at high genetic risk, but it may also be effective for women at average or unknown genetic risk (Evans et al., 2009; Nelson et al., 2014; Walker et al., 2015). The GOG-0199 study, also known as the National Ovarian Cancer Prevention and Early Detection Study, a number of factors linked to a higher risk of ovarian cancer were found during RRSO, including being postmenopausal or having mutated BRCA1 or BRCA2 genes, abnormal CA-125 test results, and abnormal transvaginal ultrasound (TVU) results (Sherman et al., 2014). However, the risk reduction achieved with RRSO is not 100 percent, and the procedure is not without inherent risks and side effects, including early menopause, osteoporosis, cardiovascular disease, and increased overall mortality (Finch et al., 2014). As such, no formal body has recommended RRSO for the primary prevention of ovarian cancer for the general population.

TABLE 3-5

Risk Reduction After Bilateral Salpingo-Oophorectomy.

EARLY DETECTION

As discussed in Chapter 1, one of the chief causes of the significant morbidity and mortality from ovarian cancer is the late stage at which most women are diagnosed (see Figure 1-5), which is partly due to the lack of clear and unique ovarian cancer–specific symptoms. Because of this absence of specific symptoms, researchers have investigated other strategies for early ovarian cancer detection, such as assaying for one or more biomarkers, often in combination with imaging technologies. While the use of these strategies in large screening trials has resulted in more women being diagnosed with ovarian cancer at earlier stages, to date these strategies have not reduced overall mortality. Furthermore, because some ovarian carcinoma subtypes originate away from the ovaries, it is difficult to know where to look to detect the earliest lesions associated with ovarian cancer. Because this is an issue specific to ovarian cancer, it is difficult to draw on early detection methods from other heterogeneous cancers. Thus developing effective and reliable early detection strategies for ovarian cancer will require ongoing research aimed at better understanding the early molecular and genetic events associated with the carcinogenesis of each subtype of ovarian cancer, along with better assessment of disease-specific symptoms.

CHALLENGES TO EARLY DETECTION OF OVARIAN CANCER

Because of the marked heterogeneity of ovarian carcinomas, it is likely that no single tumor biomarker will be sufficient to aid in the early detection of all the histologic subtypes. Research shows, for instance, that the distinct carcinoma subtypes express different sets of post-translationally modified proteins and microRNAs (Hua et al., 2013; Lee et al., 2009). There are also questions concerning the timing and type of patient samples that will need to be collected in clinical studies, although one screening trial suggests that serial biomarker measurements have better predictive power than single-time-point sampling (see detailed discussion in next section) (Cohen et al., 2014; Menon et al., 2015). It is becoming clearer that a more individualized approach to measuring CA-125 may be needed rather than having a single threshold for all women (Skates et al., 2011). This individualized approach could include longitudinal biomarker, genetics, and epidemiologic results in order to more accurately assess the risk for ovarian cancer. Another outstanding challenge is determining which marker or combination of markers meets the sensitivity and specificity requirements for early detection of a rare and heterogeneous disease. The difficulties of performing such validation studies are exacerbated by the low incidence of ovarian cancer, especially when separating out the different subtypes. However, recent screening trials (e.g., GOG-0199) actively collected DNA, serum, plasma, and tissue samples from high-risk women, which resulted in a valuable repository of samples for future studies (Greene et al., 2008).

Several challenges stand in the way of developing reliable and accurate early detection technologies for ovarian carcinomas. Imaging technologies have improved markedly over the years—including becoming less invasive and providing finer resolution of images—but a major challenge remains in the incomplete understanding of early carcinogenesis. While other types of cancer also have multiple subtypes, ovarian cancer is distinct in that the different subtypes likely develop from different tissues of origin. Once researchers have a better understanding of the cell of origin for each of the ovarian carcinoma subtypes, they may then have more success with the use of imaging technologies to find these ovarian carcinomas at earlier stages.

SCREENING FOR OVARIAN CANCER

Screening—checking for disease when there are no symptoms (NCI, 2015)—is a key tool in the early detection of disease. In general, the effectiveness of a screening test is evaluated in terms of the ability of the test to identify those individuals who truly have the disease in question and to rule out those individuals who do not have the disease. Furthermore, a standard goal is that no more than 10 exploratory diagnostic operations are performed for every 1 actual case of ovarian cancer (Bast, 2003). Establishing these minimum targets is important primarily to avoid an unacceptable level of unnecessary and potentially harmful surgical or chemotherapeutic interventions (Etzioni et al., 2013; Jacobs and Menon, 2004).

No reliable screening method exists to detect ovarian cancer at earlier stages, and, as a result, no professional organization recommends screening in the general population. Current methods for detecting ovarian cancer include physical examination, assessment of symptoms, imaging methods (e.g., TVU), and the use of serum levels of CA-125 (as described previously) (Bast et al., 1998; Fishman et al., 2005; Higgins et al., 1990; Kinkel et al., 2000).

Ovarian Cancer Screening Trials

Early detection screening trials evaluate the effectiveness of screening strategies in reducing the morbidity and mortality from a disease. General screening strategies have proved to be effective in detecting early-stage disease for several forms of cancer (e.g., breast and colon cancer) in both general and high-risk populations (Nelson et al., 2009; Schoen et al., 2012). However, there is limited evidence to suggest that these strategies significantly decrease the short- or long-term mortality from these cancers (Harding et al., 2015). Several large trials have been conducted to determine whether screening for ovarian cancer within either the high-risk or the general population helps reduce mortality from the disease (see Table 3-6).

TABLE 3-6

Ovarian Cancer Prospective Screening Trials Results Summary.

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which used CA-125 screening and TVU, showed no reduction in disease-specific mortality in women at average risk for ovarian cancer (Buys et al., 2011). However, an increase in invasive medical procedures and associated harms was observed. One limitation of this study was its use of a single fixed cutoff for CA-125 serum levels. Follow-up modeling studies of the PLCO study's results suggest that nearly 20 percent of ovarian cancer could have been detected at an earlier point if a CA-125 level trajectory had been taken into account that used the risk ROCA employed in later trials, although using the trajectory would have not affected mortality (Buys et al., 2011; Drescher et al., 2013; Pinsky et al., 2013). ROCA is based on annual measurements of CA-125 evaluated in a serial fashion so that each woman serves as her own baseline (Menon et al., 2005).

To study the predictive value of biomarkers beyond CA-125, the PLCO trial distributed sets of Phase III patient serum samples that were collected prior to the clinical diagnosis of ovarian cancer (Cramer et al., 2011). Although researchers analyzed 35 different biomarkers that had been identified in PLCO trial specimens for use in ovarian cancer screening, CA-125 remained the single best biomarker among the samples tested (Cramer et al., 2011).

United Kingdom Collaborative Trial of Ovarian Cancer Screening

The UKCTOCS is the largest randomized controlled ovarian cancer screening trial to date, with 200,000 women enrolled and each assigned to one of three arms in order to compare two screening strategies (Sharma et al., 2012). The first strategy used ROCA to evaluate the trajectory of CA-125 serum concentration over time, starting from a baseline concentration (measured prior to diagnosis) and using concentrations measured annually throughout the 10-year screening period (Skates et al., 1995, 2001). This longitudinal sampling contrasts with the single fixed cutoff used in previous screening trials. In the first screening arm, the CA-125 trajectory was evaluated, and TVU was used as a second line test for women who had significantly elevated CA-125 levels. The second screening arm used only an annual TVU imaging, while the third, control arm used no intervention at all. In addition to evaluating patient survival, the UKCTOCS collected data on the cost of screening, acceptance of screening modalities by patients, and a variety of physiological and psychosocial comorbidities linked to screening with TVU and measuring CA-125 levels.

The UKCTOCS found that using ROCA and TVU resulted in a notable improvement in the early detection of ovarian cancer at earlier stages (Menon et al., 2015) (see Table 3-6). Compared to using different fixed cutoffs for CA-125 concentration, screening with ROCA doubled the number of ovarian or tubal carcinomas detected in the trial. However, as most of the cancer detected at earlier stages was not of the deadly HGSC subtype, this improvement in early diagnosis may not lead to a similarly significant improvement in mortality. Recently published mortality data indicated that there was a 15 percent mortality reduction with CA-125 plus TVU and an 11 percent mortality reduction in TVU alone compared with no screening over 14 years (Jacobs et al., 2015). When the analysis was restricted to years 7 through 14, when most of the mortality occurred, the benefits of the CA-125 and TVU screening were more obvious, as it reduced mortality by 23 percent in this time frame. Although these results are promising, the current methods still need further refining, and it is likely that distinct multimodal approaches will be needed in order to detect each of the various subtypes at their earliest stages.

Japanese Shizuoka Cohort

The Shizuoka Cohort Study of Ovarian Cancer Screening prospective randomized controlled trial involved more than 80,000 asymptomatic postmenopausal women who were enrolled between 1985 and 1999 (Kobayashi et al., 2008). Nearly half of the women were assigned to the intervention arm, which consisted of annual screening with pelvic ultrasound and CA-125 serum measurement. The control arm included no screening. The ultrasound techniques used for the prevalence or first incidence scans were TVU (in the majority of cases screened after 1990) or transabdominal ultrasound. Women with abnormal ultrasound findings or elevated CA-125 levels (or both) were referred for further medical evaluation or investigative surgery by gynecologic oncologists. The trial closed in December 2002 with a mean follow-up period of 9.2 years. A higher proportion of women with Stage I ovarian cancer were identified in the screened group than in the control group, but it was not statistically significant (Kobayashi et al., 2008).

Kentucky Screening Study

Between 1987 and 2005, more than 25,000 women participated in a screening study at the University of Kentucky (van Nagell et al., 2007). In this single-arm study, women received annual TVU screening. The 5-year survival rate in women whose screens were positive and who were diagnosed with invasive ovarian carcinoma was significantly higher than among women treated at the University of Kentucky during the same time period who did not undergo screening (75 versus 54 percent). As improved therapies continue to be developed, even a modest improvement in detection time may improve survival rates.

KEY FINDINGS AND CONCLUSIONS

The committee offers the following findings and conclusions:

• Given the relative rarity of ovarian cancer and the heterogeneity of the disease, consortia are likely to be necessary to achieve the statistical confidence (power) to evaluate risk factor associations by tumor histologic subtype.
• While several risk factors for ovarian cancer have been identified, their associations with specific histologic subtypes require further clarification.
• Not all women who carry germline genetic mutations in cancer-predisposition genes have an apparent family history.
• The contribution that known mutations in the BRCA1 and BRCA2 genes, as well as others linked to hereditary cancer syndromes (e.g., Lynch syndome), make to inherited genetic risk is well characterized, yet it does not account for all of the inherited risk for ovarian cancer.
• New mutations identified in recent sequencing studies need further risk quantification before they can be integrated into clinical practice.
• The current understanding of risk factors has limited utility in accurately predicting risk at the individual level; thus, there is a clear need for improved and validated risk prediction models that can be used to screen the general population of women.
• BSO has been shown to drastically reduce a woman's risk of ovarian cancer and is recommended for women known to be at high genetic risk for developing ovarian cancer. Adverse side effects (e.g., surgical complications, loss of fertility, and premature menopause) and the low incidence of ovarian cancer in the general population preclude performance of these surgeries as part of a risk-reducing strategy in women at low or average genetic risk for ovarian cancer.
• The potential impact of opportunistic salpingectomy on reducing risk for women at high risk and average risk of developing ovarian cancer needs to be studied.
• Current imaging technologies for ovarian cancer screening are effective at detecting pelvic masses but are limited in their sensitivity to detect small, early lesions. Efforts to improve early detection through technology are hampered by an incomplete understanding of tumorigenesis, including knowledge about the cell or tissue of origin.
• Current screening methods have not had a substantial impact on overall mortality for general or high-risk populations irrespective of the biomarkers, imaging strategy, or risk prediction algorithms that have been used. In addition, the best currently available protocol for early detection of ovarian cancer (a combination of screening for elevated CA-125 and use of TVU) does not meet the risk–benefit ratio criteria for support by the USPSTF.
• The largest and most recent screening trial, UKCTOCS, has demonstrated a significant improvement in early detection, although the improvement in mortality was modest.
• No reliable biomarker or panel test exists for the detection of early-stage ovarian cancer.

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