Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening

Abstract

PurposeCancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates.Patients and MethodsIn the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves.ResultsAfter 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869).ConclusionScreening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk – Combined Results from Two Screening Trials

“…, among prevalent cases (first study-related CA125 test was elevated or part of a rising pattern). (35) Effective screening for incident cases, which arose during rather than before screening initiation, would be expected to yield an increased proportion of early-stage cases. Nine women were diagnosed with ovarian cancers at elective RRSO (none of their screening tests had produced a surgical recommendation); thus, we separated surgically-detected cases from screen-detected cases.…”

Evaluation and Management of Ultrasonographically Detected Ovarian Tumors in Asymptomatic Women

“…This more intensive surveillance establishes biomarker and morphology index patterns, which are helpful in predicting the risk of malignancy in an individual ovarian tumor. Menon et al, 9 for example, reported that a risk algorithm using serial CA 125 determinations detected twice the number of ovarian cancers when compared with a single CA 125 with a cutoff value of greater than 35 units/mL. Although prospective data have yet to be published on this subject, the authors believe that an increase in the Dmorphology index of 1 or greater in 1 month, or the doubling of serum CA 125 in 1 month, places an ovarian tumor in the high-risk category.…”

“…Likewise, serum biomarker patterns 8,9 and analysis of tumor blood flow 10,11 have been shown to be useful in selected cases. It is important to remember that ovarian tumors are usually in a dynamic state, increasing or decreasing in volume and complexity over time.…”

Diagnosis of ovarian cancer

“…The most recent results from the trial show that serial testing with the ROCA algorithm doubles the number of ovarian cancers detected compared with testing using single thresholds of CA125. 35 Given the recent understanding that the fimbrial end of the fallopian tube is the starting site of neoplastic transformation for many women, population based opportunistic postpartum salpingectomy is now being evaluated in British Columbia, Canada, as a prevention strategy for epithelial ovarian cancer. 36 Long term incidence and mortality data are expected in 10 years.…”