A New Test for Endometrial Cancer?
—The WID-qEC endometrial cancer test is a 3-marker molecular test that uses self-collected samples, allowing healthy patients to avoid invasive screening methods.
Standard tests for suspected endometrial cancer (EC) are expensive, invasive, and require referral to a specialist.1 Chiara Herzog, PhD, and Martin Widschwendter, MD, both with the European Translational Oncology Prevention and Screening (EUTOPS) Institute, Tirol, Austria, along with their colleagues, set out to develop and validate a simple, noninvasive screening and triage tool in EC detection called the Women’s cancer risk IDentification-quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC). Through their study, published in a recent issue of the Journal of Clinical Oncology, the researchers found that the WID-qEC identified 100% of EC cases, with a specificity of 89%, in a group of women presenting with postmenopausal bleeding.1
“The WID-qEC may enable rapid, noninvasive screening and triage for symptomatic women at greatest risk, avoiding invasive investigations in healthy women,” the authors suggested in their report.1
Traditional diagnostic methods
The current method for diagnosing EC is transvaginal ultrasound (TVUS), followed by hysteroscopy and biopsy of the endometrium.1,2 Access to a specialist to perform these tests, however, may be limited in certain circumstances, for example, in rural settings, during crises like the COVID-19 pandemic, or due to long referral times. Additionally, TVUS can only be used to estimate endometrial thickness in postmenopausal women. Although the sensitivity of this procedure is 96.2% for the cutoff in thickness of ≥ 5 mm, the specificity is only 51.5%. There are also racial disparities, with a sensitivity of only 43.7% in Black women.1 Because of these drawbacks, other methods of screening using molecular testing have been investigated, although research has been limited.1
In a ڴŮ interview about the WID-qEC study, Dr. Widschwendter stated, “It was critical to us that this research addressed all of the issues associated with current detection methods for womb cancer.”
How was the test developed and validated?
The investigators developed the WID-qEC by identifying the most informative areas in an epigenome-wide screen of 726 cervicovaginal specimens obtained from women with and without EC (FORECEE Pilot). Accordingly, the test was based on quantitative, methylation-specific polymerase chain reaction targeting of one ZSCAN12 gene region and two GYPC gene regions.1 They then validated the test using samples from 562 women in five clinically relevant diagnostic or predictive settings:
- the FORECEE group (cervicovaginal liquid-based cytology samples from symptomatic women with ECs, gynecology patients without EC, and healthy volunteers)
- the Barcelona group (cervicovaginal self-collected samples from patients with EC, patients at the hospital with benign conditions, and women at the hospital for nongynecological reasons)
- the postmenopausal bleeding (PMB) group (vaginal swabs from patients with PMB at University College London Hospital)
- the Lynch group (cervicovaginal liquid-based cytology samples from women presenting with Lynch syndrome at University College London Hospital)
- the Karolinska group (cervicovaginal liquid-based cytology samples from a Swedish cervical sample cohort-based bio-bank from women diagnosed with EC up to 3 years after sample collection and women who did not develop EC by the end of the study period)
The reference standards for all patients with EC were confirmed by histology from a biopsy or hysterectomy. There were no confirmations, however, for some patients in the control groups.1
Validation results by clinical setting
In the Barcelona group (self-collected samples), the WID-qEC had a 90.1% sensitivity and an 86.7% specificity, with a PPV of 40.1% and NPV of 98.9%. This was true for all ages, stages, grades, histologies, and menopausal status. Some of the patients with EC had a DNA mismatch repair (MMR) status available; in this subset, the performance of WID-qEC was comparable in detecting MMR-proficient and MMR-deficient ECs.1
The data from the Barcelona group were also used to compare ultrasound results and DNA mutation analyses with the WID-qEC. The sensitivities of the WID-qEC and ultrasound were similar, but the specificity of the WID-qEC was significantly higher, the authors noted. Additionally, the WID-qEC had a similar specificity to that of the DNA mutation analysis, but a significantly improved sensitivity, the researchers added. From these comparisons, the authors concluded that the WID-qEC was more accurate than the DNA mutation analysis and at least as accurate as ultrasound.1
The women with PMB were evaluated to examine the WID-qEC in a real-life setting. The findings demonstrated that the WID-qEC had a 100% sensitivity and 89.1% specificity for women who were eventually diagnosed with EC.1
Data for two cohorts were assessed to explore the predictive accuracy of the WID-qEC. In the Lynch syndrome cohort with a genetic predisposition to EC, the WID-qEC was negative in all patients who had no signs of EC when the sample was collected. There was only one patient with a positive WID-qEC; she had a biopsy that showed stage 1, grade 1 EC. The sensitivity in this cohort was 33.3%, with a specificity of 100%.1 Future risk was evaluated in the Karolinska cohort, in which sensitivity was 68.8% and specificity was 98.1%. In that group, 69% of ECs were identified up to 3 years before diagnosis. The sensitivity collected < 1 year before diagnosis or follow-up (90.9% sensitivity, 100% specificity) was much better than those collected ≥ 1 year before last follow-up (20% sensitivity, 97.4% specificity).1
Benefits and future studies
Discussing the advantages of the WID-qEC test, Dr. Widschwendter explained, “Post-menopausal women with abnormal bleeding have a 1 in 10 chance of having womb cancer; for pre-menopausal women, the chance is much lower (as low as 1 in 200). For these women,” he commented, “the simplicity and accuracy of the WID-qEC test offer real advantages for detecting womb cancer early. Most importantly, using our test, far fewer women with abnormal bleeding will have to undergo invasive diagnostic procedures. Our test,” he added, “does not depend on the operator and results can be returned quickly, reducing anxiety.”
When asked about future studies that should be done, Dr. Widschwendter told ڴŮ, “We are well aware that transvaginal ultrasound, which is currently used for womb cancer detection, is less reliable in Black women, who have much higher rates of benign womb conditions, such as fibroids, which cause a thickened womb lining. New studies are already planned to validate the effectiveness of the WID-qEC test in this specific patient group.”
The investigators suggested in their report that “…the WID-qEC could represent a patient-friendly test for the screening and triage of women with symptoms suggestive of EC or those at risk of EC. Because of its suitability for use in self-collected samples,” they continued, “the WID-qEC may be a suitable tool for managing women with abnormal bleeding, particularly when access to specialist care is restricted.”1
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