According to researchers at The University of Texas MD Anderson Cancer Center, evaluating change over time of carbohydrate antigen 125 or CA-125, the protein long-recognized for predicting ovarian cancer recurrence, shows promise as a screening tool for early-stage disease. CA-125, a protein that is a so-called tumor marker or biomarker, is present in greater concentration in ovarian cancer cells than in other cells.

The findings showing a potential benefit in early detection are published in August 26, 2013 edition of Cancer. [1] The preliminary data were first presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting. [2] If a larger study shows survival benefit, the simple blood test could offer a much-needed screening tool to detect ovarian cancer in its early stages ? even in the most aggressive forms ? in post-menopausal women at average risk for the disease.

…[In the near future]… we may be able to offer a screening method that can detect the disease in its earliest, curable stages

Researchers at the MD Anderson Cancer Center have a long history in the research of the important biomarker. In the 1980s, Robert Bast, M.D., vice president for translational research at MD Anderson Cancer Center and co-investigator on the ASCO study, discovered CA-125 and its predictive value of ovarian cancer recurrence.The original application of CA 125 was in monitoring the response of ovarian cancer during chemotherapy and in detecting persistent disease after primary treatment. [3]Since then, researchers at MD Anderson Cancer Center have been trying to determine its role in early disease detection. The marker, however, can become elevated for reasons other than ovarian cancer, leading to false positives in early screening.

Early detection
“Over the last ten years, there’s been a lot of excitement over new markers and technologies in ovarian cancer,” said Karen Lu, MD, professor and chair, Department of Gynecologic Oncology and the study’s corresponding author. “I and other scientists in the gynecologic oncology community thought we would ultimately find a better marker than CA-125 for the early detection of the disease. After looking at new markers and testing them head-to-head in strong, scientific studies, we found no marker better than CA-125.”

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According data from the American Cancer Society, 22,240 women will be diagnosed with ovarian cancer in 2013 and another 14,030 are expected to die from the disease. The challenge, explained Lu, is that more than 70% of women with ovarian cancer are diagnosed with advanced disease.

Holy Grail
“Finding a screening mechanism would be the Holy Grail in the fight against ovarian cancer, because when caught early it is not just treatable, but curable,” noted Lu, who is also the trial’s principal investigator.

Positive predictive value
For the prospective, single-arm, 11-year study, 4,051 women were enrolled from seven sites across the country, with MD Anderson Cancer Center serving as the lead site. All were healthy, post-menopausal women, ages 50-74, with no strong family history of breast or ovarian cancer. The study’s primary endpoint was specificity, or few false positives. In addition, the study looked at the positive predictive value, or the number of operations required to detect a case of ovarian cancer.

Each woman received a baseline CA-125 blood-test. Using the Risk of Ovarian Cancer Algorithm or ROCA, a mathematical model based on the patient’s age and CA-125 score, women were stratified to one of three risks groups, with the respective follow-up: “low,” came back in a year for a follow-up blood test; “intermediate,” further monitoring with repeat CA-125 blood test in three months; and “high,” referred to receive transvaginal sonography or TVS and to see a gynecologic oncologist.

Based on the women’s CA-125 change over time, the average annual rate of referral to the intermediate and high groups were 5.8% and .9%, respectively. Cumulatively, 85 women (2.9%) were determined to be high risk, and thereby received the TVS and were referred to a gynecologic oncologist. Of those women, 10 underwent surgery: four had invasive ovarian cancer; two had borderline disease; one had endometrial cancer and three had benign ovarian tumors ? a positive predictive value of 40%, which greatly surpasses the clinical benchmark of 10%, say the researchers. The specificity of the test was 99.9%, explained Lu. The screening failed to detect two borderline ovarian cancers.

“Of great importance”, Lu explained “Is that the four invasive ovarian cancers detected were high-grade epithelial tumors, the most aggressive form of the disease, and were caught early (stage IC or IIB), when the disease is not only treatable, but most often curable. Lu also noted that all four women found to have invasive disease were monitored at low risk for three years or more prior to a rising CA-125.”

Additional trials
“CA-125 is shed by only 80% of ovarian cancers,” explained Bast, the study’s senior author. “At present, we are planning a second trial that will evaluate a panel with four blood tests including CA-125 to detect the cancers we may otherwise miss with CA-125 alone. The current strategy is not perfect, but it appears to be a promising first step.”

Not practice-changing
While encouraging, the findings are neither definitive, nor immediately practice-changing, Lu stressed. She also noted that a large, randomized prospective screening trial still needs to be conducted. Such research is ongoing in the United Kingdom and these results, including more than 200,000 women, should be known by 2015.

“As a clinician treating women with this disease for more than ten years, I’ve become an admitted skeptic of ovarian cancer screening. Now, with these findings, I’m cautiously optimistic that in the not too distant future, we may be able to offer a screening method that can detect the disease in its earliest, curable stages and make a difference in the lives of women with this now-devastating disease.”

The study is ongoing and, as a follow-up, Lu and her team plan to look at combining other markers with CA-125 to determine the screening impact of their combined change over time.

For more information:
[1] Lu KH, Skates S, Hernandez MA, Bedi D, Bevers T, Leeds L, Moore R, et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer. 2013 Aug 26. doi: 10.1002/cncr.28183. [Epub ahead of print][Article][PubMed]
[2] Bast RC Jr. CA 125 and the detection of recurrent ovarian cancer: a reasonably accurate biomarker for a difficult disease.Cancer. 2010 Jun 15;116(12):2850-3. doi: 10.1002/cncr.25203.[Article][PubMed]
[3] Niloff JM, Bast RC Jr, Schaetzl EM, Knapp RC. Predictive value of CA 125 antigen levels in second-look procedures for ovarian cancer. Am J Obstet Gynecol.1985; 151:981 – 986. [PubMed]

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