Carcinoma of the Ovaries and Fallopian Tubes

Incidence

Globally, ovarian cancer is the third most common gynecologic malignancy after cervical and uterine corpus cancers and is the seventh most common female malignancy with 238,700 estimated new cases in 2012. In the United States, ovarian cancer is the second most common gynecologic malignancy after uterine corpus cancer. In 2017, it was estimated that there would be an estimated 22,440 new cases of ovarian cancer, accounting for 2.6% of all female malignancy cases. The lifetime risk of developing ovarian cancer is estimated at 1.3% based on 2011 to 2013 statistics.

Ovarian cancer is primarily a disease of older women with a median age of diagnosis of 63 years. The age-adjusted incidence rate is higher in more developed areas compared with less developed areas (9.1 versus 5.0 per 100,000 persons). In the United States, the age-adjusted incidence rate of ovarian cancer has been gradually decreasing in past decades from 16.3 in 1975 to 11.4 per 100,000 persons in 2013 ( Fig. 86.1A ). The incidence rate of ovarian cancer started declining in the late 1980s and further declined in the 2010s. This decline in the incidence rate of ovarian cancer is particularly evident in women aged 50 years or older ( Fig. 86.1B ). A decline in ovarian cancer incidence was also reported in other Northern European countries during this time. This decline is attributed to the introduction of oral contraceptive pills (OCPs; thought to decrease ovarian cancer risk by disrupting incessant ovulation and other incompletely understood mechanisms) in the 1960s and by a reduction in menopausal hormone therapy (MHT) use (removes estrogen exposure; see the risk factor section).

Mortality Rate

Worldwide, ovarian cancer is ranked as the second most common cause of death among gynecologic malignancies after cervical cancer with 151,900 estimated deaths in 2012. In the United States, ovarian cancer is the most common cause of death among gynecologic malignancies and is the fifth most common cause of death among all female malignancies. In 2017, it was estimated that there would be an estimated 14,080 deaths from ovarian cancer, which accounts for about 5% of all deaths from female malignancies in the United States. Globally, the age-standardized death rate of ovarian cancer in more developed areas was higher than in less developed areas (5.0 versus 3.1 per 100,000 persons). The number of survivors from ovarian cancer has continued to increase in the United States, with an estimated 235,200 survivors in 2016 and a projected 284,380 survivors in 2026. This estimated number of survivors from ovarian cancer is ranked as the third in gynecologic malignancies and as the ninth among all female malignancies. Cancer stage is an important determinant for survival outcome: stage I, 83.4% to 89.6%; stage, II 65.5% to 71.4%; stage III, 32.5% to 46.7%; and stage IV, 18.6% reported in the International Federation of Gynecology and Obstetrics (FIGO) 1999 to 2001 data.

Paralleling the decreasing incidence rate, the age-adjusted death rate from ovarian cancer has been steadily decreasing in the United States from 9.8 in 1975 to 7.2 per 100,000 persons in 2013 ( Fig. 86.1A ). The decrease in ovarian cancer incidence and a change in risk factors are the likely causes of this decrease. Women with ovarian cancer are more likely to die from ovarian cancer within 7 years from the initial diagnosis, and thereafter, women with ovarian cancer are likely to die from other causes. When survival of women with ovarian cancer is adjusted by a comparable group in the general population, all-cause mortality from ovarian cancer has actually improved in all stages, especially in stage III to IV disease between 1975 and 2011, and women with stage III to IV disease diagnosed in 2006 had a 51% lower mortality rate from ovarian cancer compared with those who were diagnosed in 1975. Regardless, the crude overall 5-year survival rate from ovarian cancer remains poor, reported as 46.2% based on 2006–2012 data in the United States. Whereas the mortality rate from ovarian cancer has not changed since the 1980s, the mortality rate from all types of malignancies has been decreasing in the past decades. This implies that further improvement in therapies for ovarian cancer are needed despite the recent major advances in surgical, chemotherapeutic, and biologically targeted treatment modalities.

Risk Factors

A summary of risk factors is shown in Table 86.1 . Aging is one of the strongest risk factors for developing ovarian cancer. The age-specific incidence rates of ovarian cancer per 100,000 women in 2013 were 0.6 in women younger than 20 years, 5.7 in 20- to 49-year-old women, 23.2 in 50- to 64-year-old women, 40.1 in 65- to 74-year-old women, and 43.6 in women aged 75 years or older. In addition, whereas older age was associated with higher prevalence of advanced-stage disease, younger age was associated with localized disease ( Fig. 86.2 ). Among ovarian cancer patients aged 65 years or older, 64.7% to 69.4% had distant metastatic disease; on the contrary, 20.9% to 42.3% of ovarian cancer patients younger than 50 years old had distant metastatic disease. Ovarian cancer is most commonly diagnosed in whites, but African Americans have the poorest prognosis.

Lifestyle and environmental factors play important roles in the tumorigenesis of ovarian cancer. First, obesity is associated with an increased risk of developing ovarian cancer. In analyses of systematic review of literature, obese women with a body mass index (BMI) of 30 kg/m ² or greater had a 30% increased risk of ovarian cancer compared with those with a normal BMI (BMI, 18.5 to 24.9 kg/m ² ). Similarly, overweight women (BMI, 25.0 to 29.9 kg/m ² ) had a 20% increased risk of ovarian cancer compared with those with a normal BMI. Nearly one-third of women with ovarian cancer are overweight, and more than 10% are obese, and one study found that women with BMIs of 40 kg/m ² or greater had a 50% increased risk of death from ovarian cancer compared with those with normal BMIs. Adipocytes are thought to function as the source of energy for tumor growth, promoting ovarian cancer metastasis, and vigorous and frequent exercise is reported to lower ovarian cancer mortality rates. A height of 170 cm or taller is associated with a 38% increased risk of ovarian cancer compared with a height less than 160 cm. The association of physical activity and ovarian cancer risk remains inconsistent across studies. With regard to diet, increased consumption of animal fat, α-linolenic acid, dairy foods, lactose products, and proinflammatory ingredients was related to an increased risk of ovarian cancer. Conversely, soy intake, certain flavonoids (isoflavones and flavonols), high-calcium consumption, and sun exposure are associated with a decreased ovarian cancer risk. However, these past studies examining the association between diet patterns and ovarian cancer remain insufficient to make solid recommendations on diet management.

For other lifestyle risk factors, longer sleep is reported to reduce the risk of ovarian cancer. Multiple systematic reviews have shown that cigarette use is associated with an increased risk of invasive mucinous ovarian cancer, but cigarette use is associated with a decreased risk of ovarian clear cell carcinoma. A patient's socioeconomic status correlates with disease status, and a lower education level was associated with an increased risk of metastatic disease at diagnosis. Diabetes mellitus is associated with a moderately increased risk of ovarian cancer of 17% compared with nondiabetics, and women with diabetes with ovarian cancer have poorer survival compared with their nondiabetic counterparts. Metformin may be associated with a decreased risk of ovarian cancer as shown in a meta-analysis of 53 studies. There has been a long-standing debate over talcum powder use and ovarian cancer risk, but recent evidence does not support the association between perineum exposure to talcum powder and risk of ovarian cancer.

Various reproductive hormonal factors are known to be the cause of increased risk of ovarian cancer. The two running hypotheses to support this causality are (1) disruption of müllerian-origin cell surface of the ovary by ovulation that can cause malignant transformation and (2) estrogen exposure that can be carcinogenic to the ovary. The two major factors supporting these hypotheses are the changes in ovarian cancer risk observed with oral contraceptive and MHT use. A collaborative analysis of 45 studies including 110,000 women demonstrated that oral contraceptive use is associated with a significantly decreased risk of ovarian cancer. Ever users had an approximately 30% reduction of developing ovarian cancer risk compared with never users, and there was a robust decrease in ovarian cancer risk with longer duration of oral contraceptive use: 22% reduction with 1 to 4 years of use, 36% reduction with 5 to 9 years of use, 44% reduction with 10 to 14 years of use, and 58% reduction with 15 years or longer use.

Menopausal hormone therapy use rapidly increased in the 1990s and then significantly decreased around 2000 because of the results of the Women's Health Initiative study reporting excess risk of breast cancer and cardiovascular events. In this study, there was no statistically increased risk of ovarian cancer between the MHT group and the placebo group, but the lower boundary of confidence interval (CI) was close to 1.0 (hazard ratio [HR], 1.6, 95% CI, 0.8 to 3.2). In a recent meta-analysis of 52 studies reported in 2015, MHT was associated with a 37% increased risk of ovarian cancer when comparing current or recent users versus never users in the prospective cohort, but there was no association seen in the retrospective observational cohort. Collectively, the current consensus is that the increased risk of ovarian cancer with MHT is likely causal, but the absolute risk is small. Among histologic subtypes, MHT use was associated with serous (53% increased risk) and endometrioid (42% increased risk) subtypes of ovarian cancer. Converse to the slightly increased risk of ovarian cancer with MHT, it may improve survival among women with ovarian cancer. A 5-year duration of MHT use among women with epithelial ovarian cancer who underwent surgical treatment including oophorectomy was associated with a 33% reduced risk of recurrence and a 37% reduced risk of all-cause mortality (median follow-up, 19 years). However, this study did not examine estrogen receptor status in the tumors.

Other reproductive factors for ovarian cancer development include parity, menopausal age, infertility, polycystic ovarian syndrome, endometriosis, breastfeeding, intrauterine device use, and pelvic inflammatory disease. Parous women had a 29% decreased risk of ovarian cancer with an 8% risk reduction with each additional pregnancy, and this protective effect of parity was strongest for endometrioid (22% reduction) and clear cell (32% reduction) subtypes. Menopausal age older than 52 years was associated with an approximately 50% increased risk of ovarian cancer compared with women undergoing menopause at age 45 years or younger, and endometrioid and clear cell types were associated with these menopausal age effects. Infertility confers an increased risk of ovarian cancer, and women with infertility longer than 5 years had more than a 2.5-fold increased risk of developing ovarian cancer compared with those with shorter than 1 year of infertility. However, ovulation induction is not associated with increased risk of invasive ovarian cancer as shown in a recent Cochrane review, and this finding was also observed in the genetically high-risk population. Increased risks of borderline ovarian tumors with ovulation induction are, however, suggested, and further study is warranted. Women with polycystic ovarian syndrome are at increased risks of developing ovarian cancer, particularly those aged 54 years or younger.

Endometriosis is reported as a risk factor for developing certain types of ovarian cancer (e.g., clear cell, endometrioid, and low-grade serous carcinomas). Genetic aspects of endometriosis-associated ovarian cancer are discussed in a separate section. Breastfeeding might reduce the risk of ovarian cancer as shown in a meta-analysis of 41 studies, and women with a history of breastfeeding for a longer duration had a 30% lower risk of developing ovarian cancer compared with those who did not breastfeed. Ovarian cancer risk starts sharply decreasing after a breastfeeding duration of 8 to 10 months. The protective effect of breastfeeding was also seen with borderline ovarian tumors. The association of intrauterine device use and ovarian cancer risk remains controversial. In an analysis of the Nurses' Health Study, the use of an intrauterine device was associated with a 76% increased risk of developing ovarian cancer during 28 years of follow-up ; however, another population-based study found that women who used levonorgestrel-releasing intrauterine device had a 40% decreased risk of ovarian cancer. In a population-based case-control study from Asia, an association between pelvic inflammatory disease and increased risk of ovarian cancer is reported.

Tubal factor is one of the crucial components of ovarian cancer risk. The Society of Gynecologic Oncology (SGO) recently made an evidence-based recommendation for five strategies for ovarian cancer prevention. These include (1) oral contraceptive use, (2) tubal sterilization, (3) risk-reducing salpingo-oophorectomy (RRSO) for high-risk genetic carriers, (4) improved identification of women at genetic risk, and (5) elective salpingectomy. Notably, three of the five strategies are related to tubal factors, supporting the importance of the fallopian tube in ovarian cancer development. The current consensus on the pathogenesis of ovarian cancer is that the fimbriated end of the distal fallopian tube is a major source of epithelial ovarian cancer (see the section on pathogenesis of ovarian cancer). A meta-analysis of 40 studies showed that tubal sterilization is protective for developing ovarian cancer by 34%, and this risk reduction was particularly evident for endometrioid subtype (60% reduction) followed by the serous type (27% reduction) but not for the mucinous type. Another large-scale meta-analysis found that elective salpingectomy reduces the risk of ovarian cancer by nearly 50%. Hysterectomy alone is reported to reduce the risk of nonserous type ovarian cancer, suggesting that hysterectomy and tubal sterilization share a similar protective mechanism via prevention of retrograde menstruation or reduction of blood supply to the ovaries.

Genetics is another major factor for developing ovarian cancer (details of genetic factors for ovarian cancer such as BRCA1 or BRCA2 gene mutations are described later). BRCA1 and BRCA2 mutation–negative women with a family history of breast cancer do not have an increased risk of ovarian cancer.

Inherited Genetic Risk

Because a family history of ovarian cancer in first-degree biological and other relatives increases a woman's risk of developing ovarian cancer, genetic counseling and testing should be offered to an unaffected woman if there are no surviving cancer relatives to test. Any woman with ovarian cancer regardless of family history should have multigene testing to evaluate for hereditary causes per National Comprehensive Cancer Network (NCCN) guidelines. When a mutation is known in a family, unaffected relatives should be tested for that specific mutation. Inherited genetic mutations account for approximately 5% to 25% of all ovarian carcinomas.

For the past 20 years, hereditary ovarian cancer was mainly attributed to mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2 , with a much smaller contribution from the mutations in the DNA mismatch repair (MMR) genes and TP53 causing Li-Fraumeni-syndrome. Women with a BRCA1 mutation have a lifetime risk of 35% to 60% of developing ovarian cancer during their lifetime compared with the population lifetime risk of 1.6%. Compared with BRCA2 mutation carriers, women with a BRCA1 mutation develop ovarian cancer earlier (at around 50 years of age). Additionally the penetrance for ovarian cancer is somewhat lower for BRCA2 , which confers a lifetime risk of 12% to 25%. BRCA1- or BRCA2 -associated ovarian carcinomas are typically of serous histology but can include endometrioid, clear cell, carcinosarcoma, and undifferentiated carcinoma. Additionally, BRCA1- or BRCA2 -related cancers have been associated with advanced stage with more visceral metastases, longer overall survival (OS), increased sensitivity to platinum-based chemotherapy, and increased sensitivity to therapy with poly-ADP-ribose polymerase (PARP) inhibitors compared with their sporadic counterparts. Other germline mutations that confer susceptibility to ovarian cancer, such as PALB2, BRIP1, BARD1, RAD51C , and RAD51D , all of which encode DNA repair proteins in the Fanconi anemia BRCA pathway, are becoming more clinically relevant. RAD51C and RAD51D mutations confer a lifetime risk of 10% to 15% for ovarian cancer.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is caused by deleterious mutations in DNA mismatch repair genes: MLH1 , MSH2, MSH6, PMS2, and EPCAM . In addition to a predisposition to the development of colorectal and endometrial cancer, women with this syndrome have an 8% to 10% lifetime risk of developing ovarian cancer, with the greatest risk associated with MLH1 or MSH2 mutations. HNPCC-associated ovarian cancers are diagnosed at stage I or II because of their endometrioid and clear cell histology. Additionally, genome-wide association studies have identified some common low-penetrance alleles such as 9p22.2, 2q31, 8q24, and 19p13 that can contribute to genetic risk associated with ovarian cancer.

According to the SGO, women affected with high-grade epithelial ovarian/tubal/peritoneal cancer (EOC), breast cancer at 45 years of age or younger, breast cancer in a close relative 50 years of age or younger or with EOC in a close relative, breast cancer at 50 years of age or younger with a limited family history, breast cancer with two or more close relatives at any age, breast cancer with two or more close relatives with pancreatic or aggressive prostate cancer (Gleason score ≥7), two breast primaries with the first diagnosed before 50 years of age, triple-negative breast cancer before 60 years of age, with breast cancer and Ashkenazi Jewish ancestry, pancreatic cancer with more than two close relatives with breast, EOC, pancreatic, or aggressive prostate cancer should receive genetic counseling and be offered genetic testing for BRCA and related hereditary breast and ovarian cancer gene mutations. Women unaffected with cancer but with a first-degree or several close relatives that meet the above criteria, a close relative with a known genetic mutation, or a close relative with male breast cancer should be offered genetic counseling and possible testing. Patients with an increased likelihood of HNPCC are as follows: patients with endometrial or colorectal cancer as evidenced by microsatellite instability or loss of DNA mismatch repair on immunohistochemistry, patients with a first-degree relative affected by endometrial or colorectal cancer who were diagnosed before age 60 years, or a known mismatch repair gene mutation in the family. If patients are suspected of having HNPCC by Amsterdam II criteria or the revised Bethesda criteria, they should be referred to a genetic counselor. With the advent of panel testing becoming more economical, this strategy is preferred to test for more genes unless a known mutation exists in the family.

Prevention

Most medical strategies to prevent ovarian cancer are focused on modulating the female hormonal cycle or surgical removal of the fallopian tubes and ovaries or hysterectomy in high-risk women.

For women with average risk of EOC, use of any OCPs is associated with a 40% to 50% lifetime risk reduction. Greater benefit is achieved with longer OCP use, and the benefit can last for 15 years after discontinuation of use. Similarly, women with BRCA1 or BRCA2 mutations should consider taking OCPs for a prolonged period of time to reduce their EOC risk. A meta-analysis of 18 case-control and retrospective cohort studies comprising a total of 2855 breast cancer cases and 1503 EOC cases in BRCA1 or BRCA2 mutation carriers identified a significant reduction in EOC for mutation carriers who used OCPs (summary relative risk [SRR], 0.50; 95% CI, 0.33 to 0.75). With each additional 10 years of OCP use, there was a 36% reduction in EOC incidence (SRR, 0.64; 95%CI, 0.88 to 1.45). An increased incidence of breast cancer was not found in lower dose OCP formulations. The data about OCP use and risk reduction of EOC after a bilateral salpingectomy in which ovaries are retained in BRCA1 or BRCA2 mutation carriers is unclear. Hence, OCPs have been recommended by the SGO for women to reduce the risk of ovarian cancer; however, the Centers for Disease Control has concluded that there is insufficient evidence to recommend the use of OCPs for ovarian cancer prevention.

Tubal ligation has been associated with a decreased risk of EOC. Cibula and colleagues concluded that a previous tubal ligation in women at average risk for EOC was associated with a 34% overall risk reduction. In BRCA1 mutation carriers, Antoniou and colleagues found a 57% risk reduction and Narod found that the addition of OCP use to tubal ligation decreased the odds ratio from 0.39 ( P = .002) to 0.28 (95% CI; 0.15 to 0.52). The reduction in risk was not confirmed for the BRCA2 subgroup. The risk reduction of tubal ligation was comparable to that with OCP use.

Risk-reducing salpingo-oophorectomy is the surgical removal of the fallopian tubes and ovaries, which definitively reduces the risk of ovarian cancer in high-risk women due to inherited genetic susceptibility. The SGO and the US Preventive Services Task Force (USPSTF) advocate RRSO between the age of 35 and 40 years of age, but this may be delayed for BRCA2 mutation carriers because of the later onset of EOC. Prospective studies have reported a 70% to 85% reduction in EOC and a 37% to 54% reduction in breast cancer as well as a reduction in cancer-related mortality and overall mortality. However, patients with RRSO need to be monitored for adverse effects of cardiovascular disease, osteopenia, osteoporosis, and menopause. Recently, there have been editorials discussing the potential role of interval salpingectomy after completion of childbearing followed by later oophorectomy in BRCA 1 or BRCA2 mutation carriers who decline standard recommendation of RRSO, but there is no actual data on this clinical paradigm and prospective trials are warranted before changing the recommendation of RRSO.

The ability to prevent EOC by salpingectomy in average-risk women undergoing hysterectomy, other pelvic surgery, and sterilization at the completion of childbearing is an attractive risk-reducing strategy that would still allow for the preservation of hormone production. This practice of opportunistic salpingectomy was supported by the SGO of Canada in 2011 and now is being adopted in the United States because it is feasible, does not affect short-term ovarian function, and has minimal increase in operative time or risk. In light of the evidence of the distal fallopian tube epithelium as the site of origin of at least some HGSCs, the SGO and American College of Obstetricians and Gynecologists (ACOG) have issued statements recommending consideration of opportunistic salpingectomy to reduce EOC mortality in the general population.

Early Detection

Because of the nonspecific symptoms related to ovarian cancer, efforts to assay for biomarkers in combination with radiographic imaging have been investigated as means to have earlier detection. CA-125 is elevated in nearly 80% of advanced-stage EOC patients and correlates with response to chemotherapy. For early detection, CA-125 is a predictive tool that becomes increasingly powerful with proximity to diagnosis and may signal the presence of precursor lesions. Using trends in CA-125 levels to select women for imaging may improve its screening performance. This strategy was tested in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which is discussed later. Other algorithms have included CA-125 with other biomarkers or diagnostic indicators such as OVA-1, the Risk of Ovarian Malignancy Algorithm (ROMA), and the Risk of Malignancy Index. However, the challenges to CA-125 for early detection or screening of EOC include its lack of sensitivity and specificity because it can be elevated in benign conditions or nonovarian malignancies. Additionally, in about 20% of patients with EOC, there is none or trace expression, and in only 50% of early-stage EOC patients is it significantly elevated above baseline. Another biomarker is HE4, which has similar sensitivity for detecting late-stage EOC but greater specificity in differentiating malignant from benign tumors. In 2011, the US Food and Drug Administration (FDA) approved the use of ROMA, which combines measurements of HE-4 and CA-125 with menopausal status to determine whether a woman presenting with a pelvic mass is at a high or low risk of malignancy. Similar to CA-125, elevated serum HE-4 levels can be seen in women with other nonovarian gynecologic and pulmonary tumors. Because of the substantial increases in HE-4 serum concentrations in women with EOC, it may be useful for early detection. OVA-1 measures levels of apolipoprotein A1, β ₂ microglobulin, CA-125, prealbumin, and transferrin and is another biomarker test. Currently, none of the FDA-approved protein tumor markers are approved as screening tests for EOC.

Imaging technologies have been evaluated in their role to detect earlier stages of ovarian cancer. TVU is the most widely used radiographic technique for examining pelvic organs. However, it has limited ability to discern malignant versus benign ovarian masses and hence is not a primary screening tool. In high-risk women or in conjunction with biomarkers for ovarian cancer screening, it may be useful. Even with the addition of Doppler and contrast-enhanced ultrasound to provide information on tissue vascularity and angiogenesis in an effort to improve differentiating between benign and malignant masses, the specificity and sensitivity are lower than TVU alone. ¹⁸ F-fluoro-deoxyglucose positron emission tomography (PET) combined with computed tomography (CT) is useful in distinguishing malignant from benign lesions compared with CT alone; however, for screening, PET has a higher chance of missing low-grade and borderline tumors, but the data are limited.

Several large trials have been conducted to determine whether screening for EOC in either high-risk or the general population would reduce the mortality rate from EOC. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial used one CA-125 level and TVU for screening and showed no reduction in disease-specific mortality in average risk women but did increase number of invasive medical procedures. The UKCTOCS is the largest randomized controlled ovarian cancer screening trial with 200,000 average-risk women enrolled and assigned to one of three arms. Arm 1 uses the Risk of Ovarian Cancer Algorithm (ROCA), which evaluates the trajectory of serum CA-125 levels over time, starting from a baseline concentration and using concentrations measured annually throughout the 10-year screening period. TVU was used as second-line test for women who had significantly elevated CA-125 levels. The second arm used only annual TVU imaging, and the third arm was the control using no intervention. The study found that ROCA and TVU resulted in an improvement in the early detection of ovarian cancer at earlier stages. Compared with using the fixed cut-offs for CA-125 concentrations, screening with ROCA doubled the number of ovarian and tubal cancers detected. Although most of the cancers were detected at an earlier stage, they were not of the high-grade serous subtype that would lead to improvement in mortality. Jacobs and colleagues reported that there was a 15% mortality rate reduction with CA-125 and TVU and 11% mortality rate reduction in TVU alone compared with no screening. Despite these promising results, refinement of the approach is needed to detect various subtypes at earlier stages. The Japanese Shizuoka Cohort evaluated the role of annual pelvic ultrasound and CA-125 to no screening in average risk women and found a higher proportion of stage I EOC with multiple histologic subtypes, but it was not statistically significant. In a smaller single-arm study from University of Kentucky, women were screened annually with TVU for 5 years, and the authors found that women who screened positive and had EOC had higher survival than nonscreened women with EOC treated at this institution during the time of the trial.

Routine screening for ovarian cancer in asymptomatic women is not recommended by the USPSTF based on the collective results noted. Currently, this recommendation against routine screening for ovarian cancer in asymptomatic postmenopausal women is also affirmed by other professional societies such as ACOG and the NCCN. The challenge to early detection of ovarian cancer is that it is a heterogeneous disease with multiple histologic subtypes for which early carcinogenesis may differ. Determining which marker or combination of markers meets sensitivity and specificity requirements for early detection of a rare disease is difficult. Performing validation studies in a disease with a low incidence adds additional barriers. With improved research to understand the early steps of carcinogenesis, better biomarkers and radiographic techniques can be developed for screening and early detection in average-risk women.

Other potential directions for novel biomarkers for early ovarian cancer detection may include microRNA and circulating cell-free DNA. MicroRNAs are small noncoding RNA molecules that regulate gene expression posttranscriptionally and have been implicated in the areas of treatment response and prognosis in ovarian cancer. MicroRNAs that modulate oncogenic pathways in ovarian cancer are potential targets as diagnostic markers, but this field is early in development. Cell-free DNA reflects both normal and tumor-derived DNA released into the circulation via cellular necrosis or apoptosis. Although ovarian cancer is historically known to spread intraperitoneally, a recent study found that ovarian cancer actually can spread hematogenously. An observational study found that occult bone marrow metastasis at ovarian cancer diagnosis is noted in 20% of stage I disease. These fundamental concepts support the possibility of using circulating cell-free DNA for ovarian cancer screening. Currently, screening efficacy of circulating cell-free DNA shows acceptable specificity in detecting ovarian cancer, but sensitivity needs to be improved. In addition, development and advances in nanotechnology to detect low-molecular-weight biomarkers for early detection of ovarian cancer, proteomics with mass spectrometry–based protein profiles to identify novel biomarkers for ovarian cancer diagnosis, and evaluation of ovarian cancer-specific DNA methylation changes as a diagnostic tool are possible next-generation strategies for early detection. A summary of possible diagnostic tools for ovarian cancer is shown in Table 86.2 .