The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125?

Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. More than 80% of patients present with advanced disease, with 5 year survival rates between 15% and 45%. In contrast, the survival rate for stage I disease, with malignancy confined to the ovary, is approximately 95%. Given the discrepancy in survival outcomes between early- and late-stage disease, strategies that would allow for the detection of ovarian cancer in its early stages would hold promise to significantly improve the mortality rate from ovarian cancer. Unfortunately, current screening methods for the detection of early stage ovarian cancer are inadequate. However, several recent proteomics-based biomarker discovery projects show promise for the development of highly sensitive and specific markers for gynecological malignancies, including ovarian cancer. In this review, we hope to provide an overview of the early detection ovarian cancer from traditional methods to recent promises in the proteomics pipeline.     

Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

The goal of ovarian cancer screening is to detect disease when confined to the ovary (stage I) and thereby prolong survival. We believe this is an elusive goal because most ovarian cancer, at its earliest recognizable stage, is probably not confined to the ovary. We propose a new model of ovarian carcinogenesis based on clinical, pathological, and molecular genetic studies that may enable more targeted screening and therapeutic intervention to be developed. The model divides ovarian cancer into 2 groups designated type I and type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well-established precursor lesions so-called borderline tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing, highly aggressive neoplasms that lack well-defined precursor lesions; most are advanced stage at, or soon after, their inception. These include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. The type II tumors are characterized by mutation of TP53 and a high level of genetic instability. Screening tests that focus on stage I disease may detect low-grade type I neoplasms but miss the more aggressive type II tumors, which account for most ovarian cancers. A more rational approach to early detection of ovarian cancer should focus on low volume rather than low stage of disease.     

卵巢癌的早期预警和早期诊断

围绝经期是卵巢癌的高发年龄。卵巢癌早期无明显临床症状,且缺乏有效诊断手段,其病死率居于妇科肿瘤首位。基因芯片、蛋白质组学和免疫组学等研究方法已成为目前卵巢癌早期诊断研究的热点,但尚无确切定论。因此,需要确定一种新的系统、高度敏感、特异的早期诊断卵巢癌的方法,在人群中进行早期卵巢癌的筛查,做到早诊断、早治疗,以进一步提高患者的生活质量。     

肿瘤标记物用于卵巢癌早期诊断的研究进展

卵巢癌是妇科常见的恶性肿瘤之一,早期无明显临床症状,且缺乏有效的诊断方法,其病死率居于妇科肿瘤首位。基因组学、蛋白质组学和免疫学等方法已成为目前卵巢癌早期诊断研究的热点,以期找到高度敏感、特异的用于卵巢癌早期诊断的标记物。综述与卵巢癌相关的新的肿瘤标记物的研究进展。     

Ovarialkarzinom

Ovarian cancer is diagnosed usually in advanced stages. Until now, minimal progress has been achieved to detect ovarian cancer at a more curable early stage. There is no proof that routine screening for ovarian cancer in the general and high risk population with serum markers, sonograms or pelvic examinations decrease mortality. There is no recommendation for routine ovarian cancer screening.     

Ovarian cancer screening and early detection in the general population

Worldwide, the estimated annual incidence of ovarian cancer is 204,000, with 125,000 deaths. In developed countries, ovarian cancer remains the most lethal of all gynecologic malignancies. One of the reasons for the high fatality rate is that more than 70% of women with ovarian cancer are diagnosed with advanced disease. There is a close correlation between stage at presentation and survival; therefore, early detection of ovarian cancer represents the best hope for mortality reduction and long-term disease control. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. The proteomic approach has yielded encouraging preliminary findings, but these findings are not mature enough for clinical use. At this time, clear recommendations cannot be made on the basis of the available data.     

Reducing ovarian cancer mortality through screening: Is it possible,and can we afford it?

ObjectiveOvarian cancer is a leading cause of cancer-related deaths among women. Given the low prevalence of this disease, the effectiveness of screening strategies has not been established. We wished to estimate the clinical impact and cost-effectiveness of potential screening strategies for ovarian cancer using population-specific data.MethodsA Markov state transition model to simulate the natural history of ovarian cancer in a cohort of women age 20 to 100. Age-specific incidence and mortality rates were obtained from SEER. Base-case characteristics of a potential screening test were sensitivity 85%, specificity 95%, and cost $50. Outcome measures were mortality reduction, lifetime number of false positive screening tests, positive predictive value, years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (ICER, in cost/YLS).ResultsModel-predicted lifetime risk of ovarian cancer (1.38%), lifetime risk of death from ovarian cancer (0.95%), and stage distribution (stage I-19%; stage II-7%; stage III, IV, or unstaged — 74%) closely approximated SEER data. Annual screening resulted in 43% reduction in ovarian cancer mortality, with ICER of $73,469/YLS (base case) and $36,025/YLS (high-risk population) compared to no screening. In the base case, the average lifetime number of false positive tests is 1.06. Cost-effectiveness of screening is most sensitive to test frequency, specificity and cost.ConclusionsAnnual screening for ovarian cancer has the potential to be cost effective, particularly in high-risk populations. Clinically acceptable positive predictive values are achieved if specificity exceeds 99%. Mortality reduction above 50% may not be achievable without screening intervals less than 12 months.     

Clinical evaluation of ovarian tumor antigen NB/70K: monoclonal antibody assays for distinguishing ovarian cancer from other gynecologic disease

Circulating human ovarian tumor antigen NB/70K levels were assessed with four monoclonal antibody radioimmunoassays. A total of 844 blood samples from patients with ovarian cancer and gynecologic control subjects was evaluated to determine the specificity of each of the four assays for ovarian cancer. It was determined that the mean and percent positivity for patients with ovarian cancer were significantly higher than those values for all control groups. When clinical parameters of the patients with ovarian cancer were examined, it was found that NB/70K appeared to be elevated in patients with all of the pathologic types of early stage, low-grade epithelial ovarian cancers studied. One of the four radioimmunoassays (the NB12123 assay) was capable of detecting elevated blood NB/70K levels in greater than 50% of patients with early stage ovarian malignancies. The NB12123 assay was also able to detect NB/70K in the blood of 45% (9 of 20) of patients with stage I, well-differentiated ovarian cancer. These results indicate that NB/70K may be a useful marker for the early detection of localized tumors as well as for monitoring patients with ovarian cancer, as has been demonstrated previously. In addition, NB/70K appears to be a marker for all stages, grades, and pathologic types of human ovarian epithelial tumors.     

CA125、D-二聚体在卵巢癌中的应用价值

卵巢癌发病率在妇科恶性肿瘤中居第3位,而病死率却居首位。卵巢癌起病隐匿,早期缺乏典型临床表现,易发生腹腔内播散转移,70%的患者就诊时已属晚期。虽然目前卵巢癌可经肿瘤细胞减灭术辅以化疗得到有效治疗,但因其复发率较高,晚期患者5年存活率仅为30%左右。早期诊断、有效治疗、降低复发对卵巢癌的预后有重要影响。研究者致力于寻找指标,如CA125、D-二聚体,以应用于卵巢癌的早期诊断、疗效观察及预后评估。综述CA125、D-二聚体在卵巢癌中的应用价值。     

循环肿瘤细胞在卵巢癌预测和预后中的应用价值

卵巢癌早期病变缺乏特异性症状及可靠的检测方法,约75%的卵巢癌患者初次诊断时已为肿瘤晚期,而晚期病变缺乏有效的监测、治疗方法,因此卵巢癌死亡率居高不下,约70%的患者存活不超过5年。肿瘤患者血液中的循环肿瘤细胞（CTCs）携带有与原肿瘤细胞一致的表观遗传学等生物信息学特性,是液体活检技术的核心内容,且在多种实体瘤中显示了重要的预测和预后价值。过去卵巢癌的主要转移途径被认为是腹腔直接转移,而远处转移仅发生在不到1/3的患者中,推测CTCs只有极少数脱落。最近研究证明了血源性传播在卵巢癌中的重要作用,因此通过检测CTCs可以无创、连续、实时监测肿瘤发生、发展过程中的突变情况,是卵巢癌早期诊断、个体化治疗评估及临床随访潜在的重要监测指标。本文综述CTCs在卵巢癌预测和预后中的应用价值,希望能给未来卵巢癌的液体活检道路奠定基础。     

Urinary mesothelin provides greater sensitivity for early stage ovarian cancer than serum mesothelin, urinary hCG free beta subunit and urinary hCG beta core fragment

OBJECTIVES: Early detection of ovarian cancer should improve overall survival. Multiple serum markers have been evaluated as possible tests to detect early stage disease, but few urine markers have been studied. Mesothelin has been detected in serum from patients with ovarian cancer, but has not been previously reported in urine. METHODS: Mesothelin was assayed in the serum and in the urine from 28 patients with early stage (I/II) invasive epithelial ovarian cancers, 111 with advanced stage (III/IV) invasive disease and 19 with tumors of low malignant potential. Marker values have been compared to those in healthy controls and 115 patients with benign pelvic masses. Thresholds were set to include 95% of mesothelin values for 127 sera and 89 urines from healthy women. Urine values were considered: (1) as assayed; (2) normalized using the ratio of serum to urine creatinine; and (3) normalized using the Cockroft-Gault formula for glomerular filtration rate (GFR). Urines were also assayed for human chorionic gonadotropin (hCG) free beta subunit and beta subunit core fragment and similarly normalized. RESULTS: Optimal sensitivity for early stage disease was obtained when urine mesothelin was normalized using GFR. A greater fraction of patients with early stage disease was detected with the mesothelin urine assay (42%) than with the serum assay (12%). Similarly, 75% of patients with advanced ovarian cancer had elevated mesothelin in urine compared to 48% in serum. Serum and urine levels of mesothelin correlated for early (p=0.02) and late (p<0.001) disease. Urine mesothelin exhibited greater sensitivity for early stage ovarian cancer than did hCG free beta subunit or beta subunit core fragment and complementarity was not observed. CONCLUSION: Urine mesothelin deserves further evaluation as a biomarker for detection of early stage ovarian cancer in combination with other urinary markers.     

B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression

OBJECTIVE: This study characterizes the expression of the novel biomarker B7-H4 in ovarian cancer tissue, normal ovaries, and benign ovarian tumors, and evaluates its relationship to CA125. METHODS: Ovarian tissue lysates from 251 patients with ovarian carcinoma were assessed for the levels of B7-H4 and CA125 by ELISA assays. For comparison, ovarian tissues from patients with benign ovarian tumors (n=43) and patients with normal ovaries (n=32) were tested. The marker concentrations were correlated with CA125 expression, clinicopathological variables, and patient outcome. RESULTS: Using a cut-off based on the 95th percentile of B7-H4 or CA125 concentration in the control group, B7-H4 was over-expressed in 48% of patients with stage I cancer, 55% of patients with stage II cancer, and 67% of patients with late stage cancer. CA125 was elevated in 31% patients with early stage cancer. B7-H4 was elevated in tumors of 30 patients with early stage cancer that were negative for CA125. The combination of B7-H4 and CA125 identified 56 early stage cancer patients (65%) as positive. Correlation of marker expression to clinical outcome showed that high B7-H4 levels were correlated with poor prognosis. However, the effect was not significant when outcome was adjusted for other clinicopathological variables. CONCLUSION: B7-H4 expression was low in normal ovaries and in benign tumors while half of early stage and two-thirds of late stage cancers over-expressed B7-H4. The data are consistent with previous observations and support further investigation of B7-H4 in the detection of early stage ovarian cancer either alone, or in combination with CA125.     

National Institutes of Health Consensus Development Conference Statement

The National Institutes of Health Consensus Development Conference on Ovarian Cancer—Screening, Treatment, and Follow-up brought together epidemiologists; obstetrician/gynecologists; gynecologic, medical, and radiation oncologists; and the public to address the following questions: (1) What is the current status of screening and prevention in ovarian cancer? (2) What is the appropriate management of early-stage ovarian cancer? (3) What is the appropriate management of advanced epithelial ovarian cancer? (4) What is the appropriate follow-up after primary therapy? and (5) What are the directions for future research? The consensus panel concluded that there is an evidence available as yet that the current screening modalities of CA 125 and transvaginal ultrasonography can be effectively used for widespread screening to reduce mortality from ovarian cancer nor that their use will result in decreased rather than increased morbidity and mortality. They recommended that further prospective research be done to evaluate this very important issue. Women with stage IA grade 1 and most IB grade 1 ovarian cancer do not require postoperative adjuvant therapy. Many remaining stage I patients do require chemotherapy. Subsets of stage I must be fully defined and ideal treatment must be determined. Women with stages II, III, and IV epithelial ovarian cancer (other than low malignant potential tumors) should receive postoperative chemotherapy. Physicians should be encouraged to discuss clinical trial participation with women, and women should be encouraged to participate. All women should have access to accurate and complete information regarding ovarian cancer. Furthermore, there must be no barriers to women's access to qualified specialists, optimal therapy, and protocols. The full text of the consensus panel's statement follows.     

Elevated serum levels of macrophage colony-stimulating factor and OVX1, 11 months prior to the diagnosis of stage IC ovarian cancer

In published trials, CA125 has been utilized to trigger ultrasound examination for the early detection of ovarian cancer. Although serum CA125 levels can be elevated prior to clinical detection of ovarian cancer, only approximately half of patients with stage I disease will have an abnormal value. A combination of CA125, macrophage colony-stimulating factor (M-CSF) and the mucin marker OVX1 will detect> 95% of stage I patients, but it is not known whether the markers can be elevated prior to clinical detection of the disease. A postmenopausal patient was found to have small unilocular bilateral cystic adnexal lesions during an abdominal ultrasound examination. No pelvic abnormality could be palpated. Serum levels of the CA125 antigen were within the normal range. Progressive ultrasound changes prompted a laparotomy II months later, and the diagnosis of a stage IC serous cystadenocarcinoma of the ovary was established. A retrospective analysis of stored serum samples revealed that this patient had elevated serum levels of M-CSF and OVX1 at the time of the original ultrasound scan. Interpreted within the context of a potential screening strategy for ovarian cancer, these data illustrate that either or both of these tumor markers and/or ultrasound could have identified this ovarian cancer many months prior to the actual diagnosis, while the disease was at an early stage.     

Screening for ovarian cancer

The increased survival advantage for patients diagnosed with early stage ovarian cancer suggests that screening programs that detect early stage disease might have an impact on disease mortality. Attempts are being made to develop effective screening methods for early ovarian cancer in women without symptoms, using a variety of serum tumour markers, proteomic patterns and ovarian vascular and morphological features. Three main screening strategies have emerged, one utilising transvaginal scanning as the primary test (ultrasound strategy), one involving measurement of the serum tumour marker CA125 as the primary test with transvaginal scanning as the secondary test (multimodal strategy) and another utilising both transvaginal scanning and measurement of CA125 together as both a primary and secondary test (combined strategy). Large randomised trials are now underway to provide definitive data on the impact of screening on mortality and address morbidity, health economics and psychosocial issues.     

Fertility sparing therapy for ovarian cancer has inherent risks and benefits

Introduction: Fertility sparing therapy for epithelial ovarian cancer has been suggested for well-selected patients with early stage disease. The overall recurrence rate of 10% and 5-year disease free survival greater than 90% is similar in conservative and traditional surgical management of epithelial ovarian cancer. Thus, conservative approaches may be considered in young women diagnosed with FIGO stage I cancer who wish to preserve reproductive function. Subsequent use of assisted reproductive technologies (ART) may facilitate production of biologic offspring in these cancer survivors. However, each candidate requires unique consideration by subspecialists to avoid potentially fatal management errors. Case report: We present two cases in which fertility sparing therapy for early stage epithelial ovarian cancer was considered. The first case delineates the comprehensive work-up required to identify candidates for this therapy, while the second case illustrates the successful application of a fertility sparing approach. Discussion: The conservative management of early epithelial ovarian cancer and use of ART to obtain offspring are reviewed.     

Lymph node metastasis in stage I ovarian cancer]

One hundred and sixteen cases of stage I Ovarian cancer from nine hospitals in all the China during Sept. 1982-April 1991 were investigated for their lymph node metastasis. There were 70 epithelial tumors, 36 malignant germ cell tumors, 8 from gonadal stroma and 2 undifferentiated. In 89 patients the ovarian tumor was confined to one ovary (stage Ia); in 6 cases both ovaries were involved (stage Ib); 21 cases was documented stage Ic. Systemic lymphadenectomy covering all pelvic groups of node together with aortic lymph node accomplished in 82 cases. In the remaining 34 cases only pelvic lymph node dissection was performed. There was 10.3 percent incidence of lymphatic metastasis in this series. The most common lesion was serous cystadenocarcinoma. All patients were follow-up for at least half year. The mortality rate in patients without lymph node metastasis was 2.8%, but 8.3% for those with lymph node metastasis. The clinical significance of retroperitoneal lymphadenectomy in early ovarian cancer was discussed.     

NM23-H1B基因mRNA在卵巢上皮性肿瘤组织中表达的研究

目的研究NM23-H1B基因与卵巢上皮性肿瘤的相关性。方法收集2003年4月至2004年2月手术切除的卵巢上皮性肿瘤标本48份,其中卵巢上皮性癌（卵巢癌）40份,卵巢交界性上皮性肿瘤8份,正常卵巢组织标本8份。采用RT-PCR技术、RNA印迹（northern blot）法、原位杂交实验,检测NM23-H1B基因mRNA的表达。结果经RT-PCR方法检测在所有的标本中均有NM23-H1B基因mRNA的表达,在正常卵巢组织中表达较低,而在所有的卵巢肿瘤中表达均高于正常卵巢组织,早期（Ⅰ、Ⅱ期）卵巢癌中的表达高于晚期（Ⅲ、Ⅳ期）。northern blot法检测结果显示NM23．H1B基因mRNA在正常卵巢组织的表达较低,交界性肿瘤中的表达则与正常卵巢组织中相似,而在卵巢癌组织中表达明显增高,在早期卵巢癌中分化好（G1级）者表达明显高于分化较差（G2、G3级）者。原位杂交实验检测结果显示,在所有的卵巢癌标本中NM23-H1B基因mRNA阳性表达率为100％（40／40）,在正常卵巢组织中阳性表达率为0,在8份卵巢交界性肿瘤标本中,有2份NM230H1B基因表达阳性,阳性表达率为2／8。结论NM23-H1B基因与卵巢癌发生发展有相关性。     

Ovarian cancer screening: potential effect on mortality

Serum tumor markers and ultrasonography are being investigated as possible ovarian cancer screening tests. Data from the United States on ovarian cancer incidence and survival were used to estimate the potential benefit on ovarian cancer mortality from screening tests of various sensitivities. A test with 80% sensitivity could reduce ovarian cancer mortality by 50% if all screening-detected cases were to experience current stage I survival rates; the benefit would be greatest among women aged 45 or older. For each cancer detected there would be at least 50 false-positive screening tests unless test specificity is greater than 98%. If our most optimistic assumptions about screening could be met, then universal periodic screening of women aged 45 to 74 would result in about 5000 additional 5-year survivors of ovarian cancer annually. Uptake of existing screening tests is far less than universal; thus we would expect the impact of any ovarian cancer screening program to fall short of these projections.     

Familial ovarian cancer and early ovarian cancer: biologic, pathologic, and clinical features.

Women with ovarian cancer have poor overall survival rates, largely because the disease is so often diagnosed at an advanced, less curable stage. Because women with early ovarian cancer experience good survival rates, there is great interest in the study and detection of early disease. Familial ovarian cancer has been relevant to the study of early ovarian cancer in two different ways. First, women from ovarian cancer families often undergo prophylactic oophorectomy to prevent development of this disease. These ovaries have been studied for pathologic or molecular features that might represent early preinvasive disease. Second, screening tests to detect presymptomatic ovarian cancer have selectively targeted this population because of the increased positive predictive value of these tests in this population. A review of the clinical, pathologic, epidemiologic, and molecular biologic aspects of familial ovarian cancer provides a background to facilitate understanding these issues.