This report originally appeard on the Sapient Health Network web site, which later became WebMD.

Special Report:
Tumor Marker CA 125

By Andrew Holtz 

Most women with ovarian cancer, as well as patients with other cancers, have very high levels of a protein antigen called CA 125 present in their blood serum. While almost all healthy people have CA 125 levels below 35 U/ml of serum, cancer patients may have CA 125 levels of 10-thousand to 20-thousand U/ml when they are diagnosed. The level of CA 125 has become a key measurement of the effectiveness of tumor treatment. 

Beginning with the first research linking CA 125 to ovarian cancer, published in 1981, there have been hopes of developing a screening test, especially since ovarian cancer usually produces no symptoms and is not diagnosed until it is far advanced. However, the attempts so far have been unsuccessful. 

The problem is that while CA 125 is produced by epithelial ovarian cancer cells, it is also made by normal cells. Some people have naturally high levels of CA 125. In many cases, inflammation or irritation of tissues in the abdomen, or conditions including uterine fibroids can cause CA 125 levels to rise. Endometriosis, liver ailments including hepatitis and cirrhosis, and pelvic inflammatory disease can also affect CA 125 levels. On the other hand, 10 to 20 percent of ovarian cancer patients have normal levels of CA 125 when their tumors are diagnosed. One study found that among patients with stage 1 ovarian cancer, fewer than half had abnormal levels of CA 125. 

Despite the obstacles to creating a screening test, physicians have come to rely on CA 125 as a way to gauge how well cancer treatment is working. A drop of 50 to 75 percent in CA 125 levels following initial chemotherapy has been shown to reliably define at least a partial response by the tumor. Generally the test is used along with other measures, including physical examinations, CT scans, and X-rays, in order to help guide treatment. Some patients may not feel symptoms or show any evidence of tumor on their scans, in which case the CA 125 may be the only available measure of tumor response. 

What is important is not so much the absolute level of CA 125, but rather the trend that appears with repeated testing. For instance, a cancer patient who has a CA 125 level of 2-thousand U/mL does not necessarily have a larger tumor or a poorer prognosis than a cancer patient with a CA 125 level of 1-thousand U/mL. But if the patient with the higher level sees her CA 125 test results drop during treatment, her tumor is more likely to be responding favorably than is the tumor of a patient who started with lower CA 125 levels that then rose during therapy. 

Experts stress that a single test is never definitive, and CA 125 levels must be followed over time. Patients may get CA 125 testing done once a month during treatment in order to establish a reliable trend. At the beginning of therapy, a patient's CA 125 level may actually rise. A temporary increase may merely indicate that cancer cells are releasing CA 125 as they die. But a CA 125 level that remains higher than normal throughout treatment indicates that cancer is still present. 

On the other hand, a return to a normal, or even below-normal, CA 125 level does not guarantee that the tumor has been eradicated. One study looked at patients who had normal CA 125 levels, as well as normal CT scans, following treatment. When the researchers performed what's known as a "second look laparatomy" to directly check for signs of cancer, they found that while one-third of the patients had no evidence of disease, a third still had visible tumors, and the remaining third of patients had miscroscopic disease. 

Ten to 20 percent of ovarian cancer patients (up to 50 percent of those with early stage tumors) have normal CA 125 levels when they are diagnosed, in which case the test may not be as useful in tracking tumor responses. 

After a patient has finished ovarian cancer treatment, CA 125 testing is often used to watch for recurrences of the tumor. Testing may be done at 3-month intervals at first, and then less frequently as time passes. 

Since CA 125 is produced by many types of tumors it can be used to monitor breast and other cancers. However, other tumor markers (such as CA 15-3) are being developed for breast cancer. What's more, physicians have a variety of tools, including mammography, to monitor breast cancer. CA 125's usefulness in the treatment of ovarian cancer stems in part from the relative lack of other options available to physicians; as well as the importance of monitoring the response of ovarian tumors to chemotherapy treatment. 

The fact that ovarian cancer has the highest mortality rate of all gynecologic cancers, leading to the deaths of an estimated 14,200 women in the United States in 1997 has prompted researchers to continue investigating its potential as one component of a screening program, despite the difficulties encountered so far. The National Cancer Institute is sponsoring the Prostate, Lung, Colorectum, and Ovary (PLCO) study, which includes comparing routine medical care with annual pelvic examination, CA 125, and ultrasound testing in 74-thousand women between the ages of 55 and 74. 

Discovery of the BRCA1 gene has also refocussed research into the use of CA 125 screening. Women who have a defective BRCA1 gene develop both breast and ovarian cancer at rates much higher than average. Eighty percent or more of women with the defective gene may develop breast cancer in their lifetimes. The risk of ovarian cancer may be about 50 percent. A consensus conference of the National Institutes of Health concluded that even though screening for ovarian cancer is not proven to save lives of women in families with hereditary ovarian cancer syndrome, they should nevertheless undergo CA 125 testing, along with pelvic examinations and ultrasound tests at least once a year, until they have completed childbearing or reached the age of 35. At that time, since the risk of ovarian cancer is so high in these women, the consensus panel recommended prophylactic removal of the ovaries. 

In general, CA 125 raises too many false alarms, and not enough useful early warning alerts, to be effective as screening test for cancer. And while it is a routine and valuable part of monitoring the effectiveness of ovarian cancer treatment, physicians say it is just one part of their evaluation, so they urge patients not to pin their hopes, or their fears, to heavily on the results of blood tests for CA 125.

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Sources: 

Maurie Markman, M.D. 
Director, Cleveland Clinic Cancer Center 

Paul Kucera, M.D. 
Oregon Health Sciences University 

"Reactivity of a monoclonal antibody with human ovarian carcinoma," R.C. Bast, et al., Journal of Clinical Investigation, Vol. 68, pp. 1331-1337, 1981 

"Extreme elevation of CA-125 in a postmenopausal woman with benign uterine fibroid and a history of breast cancer," P. Rubin, et al., American Society of Clinical Oncology annual meeting, May 1997 

"The CA-125 tumor-associated antigen: A review of the literature," I. Jacobs, R.C. Bast, Human Reproduction, Vol. 4, pp.1-12, 1989. 

"Defining the Response of Ovarian Carcinoma to Initial Chemotherapy According to serum CA 125," Gordon Rustin, et al., Journal of Clinical Oncology, Vol. 14, pp. 1545-1551, 1996 

"Ovarian cancer: issues and managment," C.O. Granai, et al., The Cancer Journal, Vol. 7, No. 1, January 1994 

"Cancer Statistics, 1997," S.L. Parker, et al., Ca-A Cancer Journal for Clinicians, Vol. 47(1), pp. 5-27, 1997 

"A National Cancer Institute sponsored screening trial for prostatic, lung, colorectal, and ovarian cancers," B.S. Kramer, et al., Cancer, Vol. 71, pp. 589-593, 1993. 

"Ovarian Cancer: Screening, Treatment, and Followup," National Institutes of Health Consensus Development Conference Statement, April 5-7, 1994