Abstract
iStock/David Marchal
A single biomarker plus a fixed threshold may equal a missed diagnosis—actually, a great many missed diagnoses. But fixed thresholds aren't inevitable. For example, a serum biomarker used to screen women for ovarian cancer can yield more accurate results if it is assessed serially. This biomarker, called cancer antigen 125 (CA125), can detect cancer in 86% of women with invasive epithelial ovarian cancer (iEOC)—provided the pattern of CA125 concentration changes over time is assessed. If, however, CA125 figures in a simplistic “less than/greater than” metric, screen-detected cancers are just 41% or 48%, according to data from clinical trials or clinical practice, respectively.
The dramatic increase in cancer-screening accuracy was documented in the UK Collaborative Trial of Ovarian Cancer Screening. This trial, which was implemented over a period of 14 years, involved 202,638 postmenopausal women aged 50 or over. The women were randomly assigned to two different annual screening strategies (multimodal screening or transvaginal ultrasound) or no test at all.
Ultimately, 46,237 women continued to attend annual multimodal screening (MMS) following the first screen. Their blood was tested once a year for CA125 levels, and then a computer algorithm—the risk of ovarian cancer algorithm (ROCA)—was used to interpret their risk of ovarian cancer based on factors including the woman's age, the original levels of CA125, and how that level changed over time. The serial pattern was compared with known cases of cancer and controls to estimate the risk of having ovarian cancer.
The results of the trial appeared in the Journal of Clinical Oncology, in an article entitled, “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.”
“After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs),” the study indicated. A further 22 women were diagnosed with iEOC within a year of the last annual screen. “Of the 155 women with iEOCs, the ROCA detected 86.4%, whereas using annual serum CA-125 fixed cutoffs of more than 35, more than 30, and more than 22 U/mL would have identified only 41.3%, 48.4%, and 66.5%, respectively.”
The study's authors reported encouraging sensitivity and specificity figures (85.8% and 99.8%, respectively) for their test. “These show that use of an early detection strategy based on an individual's CA125 profile significantly improved cancer detection compared to what we've seen in previous screening trials,” said Usha Menon, Ph.D., the trial's co-principal investigator and coordinator at the University College London.
“The numbers of unnecessary operations and complications were within acceptable limits and we were able to safely and effectively deliver screening for over a decade across 13 NHS Trusts,” Dr. Menon continued. “While this is a significant achievement, we need to wait until later this year when the final analysis of the trial is completed to know whether the cancers detected through screening were caught early enough to save lives.”
The study's authors noted that screening, a key component of the early detection and control of cancer, could be advanced by the development of minimally invasive tests, such as the evaluation of circulating biomarkers. However, the authors also cautioned that reliance on predefined single-threshold rules may result in biomarkers of value being discarded.
“CA125 as a biological marker for ovarian cancer has been called into question. Our findings indicate that this can be an accurate and sensitive screening tool, when used in the context of a woman's pattern of CA125 over time,” commented Professor Ian Jacobs, co-inventor of ROCA and currently President of The University of New South Wales, Australia. “What's normal for one woman may not be so for another. It is the change in levels of this protein that's important. My hope is that when the results of [the trial] are available, this approach will prove capable of detecting ovarian cancer early enough to save lives.”