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.
Highlights
A key component of cancer control is screening, and significant research is underway to develop highly sensitive and specific tests that are minimally invasive
22 interval invasive epithelial ovarian and/or tubal cancer (iEOC) occurred within 1 year of screening, of which one was detected by risk of ovarian cancer algorithm (ROCA) but was managed conservatively after clinical assessment
The sensitivity and specificity of multimodal strategy (MMS) for detection of iEOCs were 85.8% and 99.8%, respectively, with 4.8 surgeries per iEOC
Summary
A key component of cancer control is screening, and significant research is underway to develop highly sensitive and specific tests that are minimally invasive. Circulating biomarkers have a major role in this effort. Many are not specific to the cancer because they are altered in other malignant or benign conditions. It is essential to carefully define the cutoff for abnormality. Biomarker levels are interpreted by using a single-threshold rule developed in the context of differential diagnosis of Serial Biomarker Levels Improve Detection of Ovarian Cancer. Assessed for eligibility (N = 1,243,282) Excluded. Not meeting inclusion criteria (n = 79,627). Not recruited as target reached (n = 10,192). Allocated to control group: nonintervention (n = 101,359). Allocated to multimodal group: intervention (n = 50,640).
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