A review of the clinical utility of CA125 and other tumour markers in ovarian cancer

Abstract

A variety of tumour markers in epithelial ovarian cancer have been investigated and are currently under investigation, but CA125 (MUC16) is the most widely used tumour marker and considered the gold standard in clinical practice. CA125 is the antigen determinant identified by a murine monoclonal antibody that was raised specifically against non-mucinous epithelial ovarian cancer. The gene encoding CA125 has been cloned and CA125 found to have a number of features characteristic of a mucin and has been designated MUC16. CA125 is elevated in more than 80% of women with epithelial ovarian cancer and is used predominantly to monitor response to chemotherapy and detect disease recurrence. There are well accepted GCIG criteria to define progression based on a rising CA125 following chemotherapy as well as criteria to define response in clinical trials. CA125 is widely used to diagnose disease recurrence. One of the most controversial issues in gynaecological oncology is initiating chemotherapy in asymptomatic women with recurrent ovarian cancer on the basis of a rising CA125 alone. There is a lead time of between 3 and 9 months from CA125 rising to the development of clinical signs or symptoms and this will be discussed in more detail. CA125 has also been used as prognostic factor. There are studies to suggest that the rate of fall of CA125 (T ½ of 20 days) following initial treatment or the absolute levels after 2 or 3 cycles of chemotherapy correlate with survival, but this association has not been found in all studies. The CA125 levels at the third cycle of chemotherapy are not considered accurate enough to alter the management of individual patients whose levels have not fallen with a half-life than 20 days. CA125 is used to help in the differential diagnosis of a pelvic mass, particularly in post-menopausal women and specifically aid differentiating between benign and malignant tumours which should be referred to a gynaecological oncologist. Recently published European guidelines advocate that post-menopausal women with a CA125 >35 U/L should be referred on. The American College of Obstetricians and Gynaecologists advise that the cut-off for referral of premenopausal women should be >200 U/L. It should be noted that many benign diseases can also increase the CA125 in this age group and include endometriosis, fibroma, salpingitis and pelvic inflammatory disease. The role of CA125 to screen asymptomatic women for ovarian cancer is much more contentious and the available data suggest that CA125 has very limited, if any, benefit as a screening test. It lacks specificity, particularly in premenopausal women and has low sensitivity for early stage disease. Furthermore, the low prevalence of ovarian cancer in the general population means that CA125 has a low positive predictive value. There have been numerous attempts to enhance the utility of CA125 as a screening test and these include combining it with ultrasound as well using an algorithm based on patient age, rate of change of CA125 over time and the absolute level of CA125. The screening studies will be discussed in more detail as will the disappointing results of screening women at increased genetic risk. There is currently a lot of interest in using MUC16 and other mucins for radioimaging, radio-immunotherapy and targeted delivery of cytotoxic agents and this will be briefly discussed. Twenty per cent of epithelial ovarian cancers have little or no expression of CA125 and there has been an intense effort to identify other tumour markers. More than 30 have been evaluated either alone or in conjunction with CA125 and include HE4, mesothelin, MCSF, osteopontin, kallikrein, soluble EGF receptor and inhibin. Some groups are placing markers on multiplex platforms and mathematical models are being developed to analyse combinations of markers in an effort to improve on the sensitivity and specificity.The clinical utility of CA125 and other tumour markers in women with epithelial ovarian cancer will be reviewed.