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2002 Selected Articles

The Scientific Basis for the Accurate Detection of Early-stage Epithelial Ovarian Carcinoma
Part 2: The Future of Early Detection

David A. Fishman, MD; Leeber Cohen, MD; Kenny Bozorgi, MD; Diljeet Singh, MD; Anna O’Donnell, RN; MaryAnn Donnelly, RN; Jennifer O’Rourke, RN, MS; Kate Pfeifer, MS, CGC; Thanh Lu; Nita Maihle, PhD; Andre Baron, PhD; M. Sharon Stack, PhD; John Lurain, MD; Peter E. Schwartz, MD

Ovarian carcinoma is the leading cause of death from gynecologic malignancies, and is the fifth most common female cancer in the United States. Short of an effective ovarian-cancer—specific therapy, the timely detection of early-stage epithelial ovarian cancer is essential in decreasing the morbidity and mortality associated with the disease. In Part 1, the authors reviewed the scientific basis for the detection of early-stage disease, including identification and management of women at increased risk and the use of ultrasonography for early detection. In this concluding article, the future of early detection is discussed.

MECHANISMS OF ONCOGENIC TRANSFORMATION

The common epithelial ovarian cancers, which represent approximately 90% of all ovarian malignancies, arise from the two-cell layer of epithelium covering the external surface of the ovary. The neoplastic transition of normal ovarian surface epithelium requires a complex cascade of interrelated genetic, molecular, and biochemical events. Ovarian cancers accumulate genetic aberrations that affect cell cycle control, apoptosis, adhesion, angiogenesis, transmembrane signaling, DNA repair, and genomic stability. Specific genetic aberrations found in ovarian cancers include amplification and/or overexpression of the ErbB2 oncoprotein1 and phosphoinositide 3-kinase (PIK3CA).2 Some of these genes have been identified in ovarian cancers using comparative genomic hybridization (CGH) and analysis of allelic imbalance. Those regions of recurrent abnormality may encode genes that contribute to ovarian carcinoma progression when differentially expressed as a result of atypical copy number or mutation.1-5

The processes of cellular adhesion, migration, extracellular matrix degradation, directed invasion into host parenchyma, proliferation, and neovascularization are influenced by numerous regulatory molecules found within the tumor microenvironment. These include epidermal growth factor (EGF) and receptors (EGFR/ErbB), urinary-type plasminogen activator (uPA) and receptors (uPAR), matrix metalloproteinases (MMP-2, MMP-9), vascular endothelial growth factor (VEGF), cytokines such as interleukin-8 (IL-8), and biologically active lysophospholipids such as lysophosphatidic acid (LPA).6-18 Many of these factors regulate the expression of the others and initiate a cascade of extracellular and intracellular signaling that stimulates hematogenous, lymphatic, and intraperitoneal metastatic dissemination. Specifically, LPA, EGFR, VEGF, and IL-8 can act in both a paracrine and autocrine manner, affecting gene and protein expression and upregulating proteinase (uPA, MMP) expression and activation.

SERUM/PLASMA TUMOR MARKERS

CA-125

The ability to detect early-stage epithelial ovarian cancer by a simple blood test has yet to be achieved, despite tremendous clinical and scientific effort. While a variety of ovarian tumor markers have been studied, all have poor sensitivity and specificity for use as a screening tool in the general population. The most widely studied serum ovarian tumor marker is CA-125, an ovarian cancer cell surface-associated, high-molecular-weight glycoprotein that exists in forms ranging from 220 to more than 1,000 kDa, and is expressed in 80% of nonmucinous epithelial ovarian cancers.3,19 The normal physiologic function of CA-125 remains unknown, but it has been detected in both ascites from women with ovarian cancer and in fluids from healthy women. CA-125 is normally present on the cells that line the fallopian tubes, endometrium, endocervix, peritoneum, pleura, pericardium, and bronchus. Little or no CA-125 can be detected on healthy ovarian epithelium, although the antigen may exist in ovarian inclusion cysts, benign papillary excrescences, and tubal metaplasia.

The CA-125 antigen was initially defined by OC-125, a murine monoclonal antibody that was raised by immunizing a mouse with a human papillary serous ovarian carcinoma cell line. The presence of multiple, identical OC-125 binding sites on each CA-125 molecule has facilitated the development of a double-determinant immunoradiometric assay. This assay detects CA-125 levels exceeding 35 u/mL in 1% to 3% of apparently healthy nonpregnant women compared with 80% of patients with clinically apparent, advanced-stage epithelial ovarian cancer. The value of any screening test depends on its ability to differentiate between benign and malignant disease. At present, there are no commercially available serum markers that can be used to detect early-stage epithelial ovarian cancer, and CA-125 should not be used as a screening test in either the general or high-risk populations. Nonetheless, many patients fail to understand that CA-125 is not a specific marker for ovarian cancer.

Currently, the optimal clinical application of CA-125 is for surveillance of ovarian cancer after the diagnosis has been surgically confirmed because it is a sensitive indicator of persistent or recurrent disease. Among the histologic subtypes, mucinous ovarian cancers are less frequently associated with elevated CA-125 levels. Overall, more than 80% of women with advanced ovarian cancer have an elevated CA-125 level (more than 35 u/mL), but the test is not useful in the detection of early-stage disease.3,19,20 Elevated serum levels have been found in the majority of patients with metastatic endometrial, fallopian tube, endocervical, and pancreatic carcinomas, as well as those with gastric, breast, lung, and colon cancers. The highest incidence of CA-125 elevation in nongynecologic cancers is seen in pancreatic cancer. Therefore, CA-125 cannot be used to determine the origin of adenocarcinomas for which the primary site is not apparent.

CA-125 is even less reliable for the detection of occult ovarian cancer in premenopausal women. Serum CA-125 values are elevated in many nonmalignant gynecologic conditions, including normal and ectopic pregnancy, endometriosis, adenomyosis, benign ovarian cysts, leiomyomas, pelvic inflammatory disease, and normal menstruation. Nongynecologic conditions associated with elevated CA-125 include pancreatitis, cirrhosis, colitis, peritonitis, peritoneal tuberculosis, radiotherapy, intraperitoneal chemotherapy sequelae, and postsurgical inflammation. The US National Institutes of Health (NIH) Consensus Statement specified that CA-125 should not be used as a screening test in the general or high-risk population because an elevated value accurately detects malignancy in fewer than 3% of women.21,22 However, the utility of CA-125 testing is sufficiently increased in the postmenopausal patient such that any woman presenting with a complex adnexal mass and an elevated CA-125 level should be presumed to have ovarian cancer and referred to a gynecologic oncologist.

Despite these limitations, CA-125 has proved to be the most useful tumor marker currently available. Its clinical applications include monitoring the status of disease in women with metastatic gynecologic cancers, predicting the presence of residual disease at the completion of chemotherapy, detecting recurrent disease prior to clinical suspicion, and attempting to distinguish benign from malignant adnexal masses preoperatively.

The use of CA-125 in conjunction with ultrasonography is under clinical evaluation in the United States and England as a method for reducing ovarian cancer mortality through early detection.23,24 These longitudinal studies will assess the ability of both ultrasonography and CA-125 to detect early ovarian cancers in the general population by comparing the results of screening. Previously, Jacobs and associates23 reported that the use of CA-125 and ultrasonography led to the identification of 16 ovarian cancers in the screening group, but 11 of these malignancies were late-stage (III/IV). CA-125 had a positive predictive value of less than 10% as a single marker. The addition of ultrasonographic screening to CA-125 measurement has improved the positive predictive value to within the 20% range.25-29 Three-dimensional power Doppler ultrasonography can further improve the diagnostic accuracy for ovarian cancer prediction.30 However, neither CA-125 nor ultrasonography has proved to be sensitive or specific enough to accurately detect stage I ovarian cancer.25

Growth Factors

By individualizing the components of the metastatic cascade into tumor cell adhesion (cadherins and integrins), migration, matrix degradation (MMPs and uPA), and invasion and proliferation, a number of investigators have identified new serum and plasma biomarkers such as lysophospholipids that may be useful in the detection of early-stage epithelial ovarian cancer. The interrelationship among specific growth factors in the tumor microenvironment (lysophospholipids, EGFs, B-1 integrin ligation, MMPs, and uPA) play critical roles in the metastatic dissemination of ovarian cancer.6,7,10,16,18,20,31-51 The clinical relevance of these proteins and lipids in regulating ovarian carcinogenesis may permit the detection of early-stage disease and the development of new ovarian-cancer—specific therapies.

LPA.–Recently, attention has been focused on phospholipids such as LPA, lysophosphatidylserine (LPS), and sphingosylphosphorylcholine (SPC) as potential serum biomarkers for the early detection of epithelial ovarian carcinoma. These phospholipids function extracellularly to activate cells through specific cell membrane receptors, and have been found to induce proliferation of ovarian and breast cancer cells. Mills and colleagues32 reported that LPA induces a rapid and transient increase in cytosolic free calcium and stimulates tyrosine phosphorylation, including mitogen-activated protein kinase activation. Certain phospholipids appear to increase uPA and MMP expression and activation.33 Therefore, it appears that phospholipids may play a significant role in ovarian cancer metastasis. Treatment of ovarian cancer cells with LPA increases membrane fluidity, cellular adhesion to type I collagen, and B-1 integrin expression. A significant upregulation of MMP-dependent proMMP-2 activation was observed in LPA-treated cells, boosting pericellular MMP activity. This increase in MMP activity in turn enhanced haptotactic and chemotactic motility, in vitro wound closure, and invasion of a synthetic basement membrane. These data suggest that LPA contributes to metastatic dissemination of ovarian cancer cells via upregulation of MMP activity and subsequent downstream changes in MMP-dependent migratory and invasive behavior.32-34

The clinical application of LPA in ovarian cancer detection was initially reported by Xu and associates. 34 Women with ovarian cancer had elevated plasma levels of LPA compared with healthy controls, and elevated levels were observed in 9 of 10 women with stage I disease.34 The authors’ ongoing multi-institutional international study has also found elevated levels of LPA in the plasma and serum of women with advanced- and early-stage epithelial ovarian cancer, despite normal CA-125 values. These results suggest that plasma/serum LPA levels may be of value in detecting early-stage disease.

EGF/ErbB Receptor Family.–Overexpression of ErbB1, ErbB2, and ErbB3 receptors is common in human ovarian carcinoma-derived cell lines and tumors, and this growth factor receptor family is thought to play a critical role in tumor etiology and progression.10,37,38,49 Furthermore, ErbB1 overexpression is associated with disease recurrence and decreased survival in ovarian cancer patients. Several studies demonstrate that both normal and malignant cells synthesize soluble forms of ErbB1 receptors in addition to the transmembrane form of this molecule.10,37,38,49

Maihle and associates49 found that serum p110 sErbB1 levels are significantly lower in women with stage III or IV ovarian cancer prior to and shortly after cytoreductive staging laparotomy compared with age-matched healthy women.10,37,38,49 Serum sErbB1 levels can also increase after cytoreductive surgery, so that decreasing serum sErbB1 levels may predict disease recurrence. These studies demonstrate that altered and/or changing serum p110 sErbB1 levels may provide important diagnostic and/or prognostic information for patient management. Preoperative serum sErbB1 levels in women with stage III/IV carcinomas are significantly lower than those in age-matched healthy women, suggesting that epithelial ovarian tumors affect circulating sErbB1 levels and that sErbB1 may be a useful diagnostic biomarker for epithelial ovarian cancer.

Enzymes

Plasminogen Activators, MMPs, and Integrins.–Predominant among the proteinases produced by invading tumor cells are enzymes in the plasminogen activator and MMP families.13,29-31 Plasminogen activators are serine proteinases, which catalyze the conversion of the plasma zymogen plasminogen to the active proteinase plasmin. Plasmin is a broad-spectrum serine proteinase capable of degrading numerous extracellular matrix and matrix-associated proteins including fibrin, laminin, fibronectin, and vitronectin. As a large reservoir of potential proteolytic activity is available in the form of plasminogen, production of plasminogen activators provides a mechanism for amplifying tumor cell degradation of the extracellular matrix. Although the hematogenous invasion and spread of metastatic tumors is known to be mediated via the action of extracellular matrix-degrading proteinases, the role of proteolysis in intraperitoneal metastasis remains unclear.7,11-13,50-54

Proteolytic activity may be required both to disrupt the mesothelial cell layer while the implanted tumor invades the submesothelial basement membrane into the visceral organ stroma and to facilitate subsequent tumor-mediated angiogenesis. MMPs are zinc-dependent metalloendopeptidases that function in the degradation of collagen, gelatin, and other extracellular matrix macromolecules. Expression of gelatinolytic MMPs such as MMP-2 (gelatinase A, 72 kDa type IV collagenase) and MMP-9 (gelatinase B, 92 kDa type IV collagenase) has been linked to enhanced tumor invasion in numerous models.7,30,31,55-57 Established cultures of epithelial ovarian carcinoma cells secrete elevated quantities of uPA, co-express the cellular uPA receptor, and overexpress gelatinolytic MMPs relative to normal ovarian epithelium.7,11-13,50-54 However, gelatinolytic MMPs including MMP-2 and MMP-9 are secreted in large amounts by primary cells, regardless of the original anatomic source of the culture. Furthermore, whereas uPA production was regulated in part by cellular growth substratum, MMP secretion was not diminished by the cellular adhesive microenvironment. Together, these data suggest that initial production of MMPs may mediate the invasive behavior of epithelial ovarian carcinoma cells. MMP production is upregulated in ovarian cancer, and has been found to contribute to tumor invasion.

PROMISing Technologies

Proteomics

Low-molecular-weight serum protein profiling may reflect the pathologic state of organs and aid in the early detection of cancer. Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) and surface-enhanced laser desorption and ionization time-of-flight (SELDI-TOF) mass spectroscopy can profile proteins in this range.58-60 These profiles can contain thousands of data points, necessitating the use of sophisticated analytical tools. Bioinformatics has been employed to study physiologic outcomes and cluster gene microarray transcript profiles.61-64 A study sponsored by both the US Food and Drug Administration (FDA) and National Cancer Institute (NCI) confirmed that SELDI-TOF spectral analysis with a high-order analytical approach could define an optimal discriminatory proteomic pattern.65 A bioinformatics tool was developed and used to identify proteomic patterns in serum that distinguished between neoplastic and benign ovarian disease. The discriminatory pattern was developed using spectra from a training set of women with ovarian cancer and applied to a blinded series of samples from unaffected women, patients with early- and late-stage ovarian cancer, and patients with benign disorders. This pattern identified the presence of ovarian cancer in affected women using less than a drop of blood.

This study also found that serum proteomic patterns could correctly classify and distinguish ovarian cancers from nonmalignant disorders (50/50).65 All stage I cancers (confined to the ovary) were accurately identified. The positive predictive value (PPV) in their validation set was 94% (95% confidence interval [CI]: 84%-99%). By comparison, the PPV of CA-125, the most widely used serum marker for ovarian cancer, was 34% in this same validation set. The algorithm identified a cluster pattern that completely segregated patients with cancer from unaffected women in the training set. The discriminatory pattern correctly identified all 50 ovarian cancer cases in the validation set, including all 18 stage I cases. Of the 66 cases of nonmalignant disease, 63 were recognized as benign. This yielded a sensitivity of 100% (95% CI, 93%-100%), specificity of 95% (95% CI, 87%-99%), and PPV of 94% (95% CI, 84%-99%) compared with a PPV of 34% for CA-125 in this same cohort. These findings have led to the recently initiated prospective, population-based evaluation of proteomic pattern technology as a screening tool for ovarian cancer in both the high-risk and general population.

The Ovarian "Pap Test"

A 1984 study described the histologic evaluation of an ovary that revealed significant epithelial abnormalities that were neither malignant nor low malignant potential, thus introducing "ovarian dysplasia."66 Ovarian dysplasia has since been further characterized by morphometric methods revealing specific changes in the architecture and cytologic characteristics of ovarian surface epithelium.66-69 Retrospective analysis of ovarian tissues from women with stage I carcinoma looked for cellular and nuclear atypia in noncancerous tissue adjacent to the primary tumor. Atypia was more common in the cancer patients, and was defined as the presence of nuclear pleomorphism or irregular chromatin distribution with stratification or loss of polarity. This nuclear or cellular atypia is termed ovarian intraepithelial neoplasia (OIN), which is believed to precede the development of ovarian cancer. Methodology for the direct sampling of ovarian tissue (ie, in vivo testing) from women at increased risk for ovarian cancer is now available as an outpatient office laparoscopic procedure. With the advent of microlaparoscopic technology, visualization of the adnexa and peritoneal cavity can be achieved with laparoscopes less than 0.9 mm in diameter. The procedure requires anesthesia similar to that used for ovum retrieval. Ovarian cytology can accurately discern malignant from normal ovarian epithelium. The question remains as to whether the molecular taxonomy of ovarian carcinoma can be applied to histologically normal-appearing epithelium to detect occult carcinoma; it is hoped that some answers will emerge from the National Ovarian Cancer Early Detection Program (NOCEDP).

Conclusion

The NCI and FDA are committed to the development of early detection, effective chemoprevention, and ovarian-cancer—specific therapies. The clinical application of the biochemical, genetic, and molecular mechanisms of ovarian carcinogenesis, invasion, and metastasis is required to affect any significant reduction in the morbidity and mortality from epithelial ovarian cancer. The translational application of new technologies affords an opportunity to challenge established scientific paradigms, and has led to the identification of biologically relevant lipids, proteins, gene mutations, aberrant DNA methylation, and specific low-molecular-weight proteins and fragments in serum and/or plasma that may be useful for early detection and development of cancer-specific therapies. It is anticipated that the validation of these new detection tests and technologies will significantly improve women’s health care and quality of life.

For Further Information please contact:

The Gynecological Cancer Foundation
800-444-4441
http://www.wcn.org/gcf/

The American Board of Genetic Counseling
301-571-1825
http://www.faseb.org/genetics/abgc/abgcmenu.htm

The American Cancer Society
800-ACS-2345 (800-227-2345)
http://www.cancer.org/

National Ovarian Cancer Coalition
888-OVARIAN (888-682-7426)
http://www.ovarian.org/

Cancer Information Service
800-332-8615
http://cis.nci.nih.gov/

US Public Health Service Office of Women’s Health
202-690-7650
http://www.4woman.gov/owh/index.htm

The Gynecologic Cancer Foundation Women’s Cancer Network
312-644-6610
http://www.wcn.org/

cancer.gov (NCI Online)
800-4-CANCER (800-422-6237)
http://www.nci.nih.gov/

cancer.gov (Cancer Information)
800-4-CANCER (800-422-6237)
http://www.cancer.gov/cancer_information/

OncoLink
http://www.oncolink.com/

Introduction to Gynecologic Oncology
http://www.gyncancer.com/

Society of Gynecologic Oncologists
312-644-6610
http://www.sgo.org/

The National Ovarian Cancer Early Detection Program
312-926-6606
http://www.nmh.org/services/outpatient_services/national_ovarian_cancer_early_detection_program_at_northwestern.html

David A. Fishman, MD, director and principal investigator; director, gynecologic oncology research, Robert H. Lurie Cancer Center; board-certified gynecologic oncologist; professor of obstetrics and gynecology; Leeber Cohen, MD, chief gynecologic ultrasonologist; board-certified obstetrician-gynecologist; associate professor of obstetrics and gynecology; Kenny Bozorgi, MD, assistant professor of obstetrics and gynecology; Diljeet Singh, MD, MPH, assistant professor of obstetrics and gynecology; Anna O’Donnell, RN, coordinator of clinical research trials; MaryAnn Donnelly, RN, coordinator of clinical research programs; Jennifer O’Rourke, RN, MS, coordinator of communication and educational programs; Kate Pfeifer, MS, CGC, genetic counselor; instructor; M. Sharon Stack PhD, associate professor, Department of Cellular and Molecular Biology; John Lurain MD, section head, gynecologic oncology; board-certified gynecologic oncologist; professor of obstetrics and gynecology; Thanh Lu, grant administrator, data coordinator, all at Northwestern University Medical School, Chicago, Ill; Nita Maihle PhD, professor of biochem/molecular biology; Andre Baron PhD, member of the Mayo Clinic Cancer Center, both at the Mayo Clinic, Rochester, Minn.; and Peter E. Schwartz, MD, professor of obstetrics and gynecology, vice chairman, Department of Obstetrics and Gynecology, chief, section of gynecologic oncology, Yale University, New Haven, Conn.

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