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A 21-year update of the Normal Risk Ovarian Cancer Screening Study () supports a strategy for early detection of ovarian cancer using sequential monitoring of CA125 and other blood biomarkers to trigger use of transvaginal sonography (TVS) in a small fraction of healthy postmenopausal women at average genetic risk for the disease. Findings of an abnormal ultrasound, in turn, would then suggest use of surgery to remove early-stage (I-II) ovarian cancer in a greater fraction of women than would occur without screening.

Robert C. Bast, Jr., MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues explained in the study in the that while neither CA125 nor TVS used individually is sufficiently sensitive nor specific for screening given the prevalence of ovarian cancer, studies have shown that no more than two to four operations are required to detect each case of ovarian cancer, indicating that both modalities are adequately specific when used sequentially.

In the following interview, Bast, who is vice president for Translational Research and director of the Department of Translational Molecular Pathology, elaborates on the results.

What does this study add to the literature?

Bast: An from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) in 2015 indicated that a mortality reduction might be observed in women screened on the trial for several years. In a with longer follow-up in 2021, there was no mortality reduction with CA125 followed by TVS or with TVS alone. A published in 2023 indicated, however, that chemotherapy for ovarian cancer on the UKCTOCS was inadequate.

In the UKCTOCS, screening with CA125 followed by TVS in the 2021 report increased [detection of] stage I-II disease by 10%, whereas, relative to the UKCTOCS control, the NROSS observed a 42% increase in stage I-II disease. The reasons for this dramatic difference are not clear, but may relate to the fact that blood was separated and frozen on the same day at each screening site in the NROSS but shipped at ambient temperature for up to 5 days before processing and freezing at a central facility in London for the UKCTOCS.

A published audit of TVS in the UKCTOCS indicated that the ovaries and fallopian tubes were visualized in only 50% of women screened. Figures from a published study in the U.S. indicate that TVS should visualize 75% of ovaries and tubes.

What are the main highlights of your study?

Bast: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study. Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors, with 12 of the 17 in early stage. In addition, seven endometrial cancers were detected, with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal Risk of Ovarian Cancer Algorithm (ROCA), the sensitivity for detecting ovarian invasive and borderline cancer was 74%, and 70% of ROCA-detected cases were in stage I-II.

NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with U.S. SEER [Surveillance, Epidemiology, and End Results] values. The positive predictive value (PPV) was 50% for detecting ovarian cancer and 74% for any cancer, far exceeding the minimum acceptable study end point of 10% PPV. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

What are the specifics of detecting ovarian cancer at an earlier stage?

Bast: When cancer is still confined to the ovary (stage I), 90% of patients are alive after 5 years and 84% after 10 years (). If cancer has spread to the pelvic organs, 70% survive 5 years and 59% survive 10 years. Thus, the majority of patients whose disease is diagnosed in stage I or II are likely to be cured.

When disease has spread throughout the abdominal cavity (stage III) or invaded the liver or spread outside the abdomen (stage IV), 5-year survival falls to less than 50% and 10-year survival to 23% (Stage III) and 8% (Stage IV). Without screening, only 25-30% of ovarian cancers are diagnosed in stage I and II. Computer simulations suggest that mortality might be reduced by 10-30% if a greater fraction of patients were diagnosed in early stage.

What is the next step in your research?

Bast: With renewed support from the National Cancer Institute-Early Detection Research Network, we are initiating the NROSS-2 trial to measure the specificity and sensitivity of the 4-biomarker algorithm for detecting early-stage ovarian cancer over the next 4 years at 11 U.S. sites in approximately 4,500 postmenopausal women. If positive, we will need to join or organize a larger randomized study to observe a reduction in mortality.

During NROSS2 we will observe the behavior of the anti-TP53, anti-CTAG1, and anti-IL-8 autoantibodies, but not use them to trigger TVS until their specificity is better documented.

What is your main message for practicing oncologists?

Bast: Early detection of ovarian cancer holds great promise, but is still an unmet medical need. Sequential use of blood tests followed by TVS has adequate specificity and a 4-biomarker test could improve sensitivity, leading to a large, randomized mortality study with optimal therapy for patients detected in early stage.

Read the study here.