The Performance of HE4 Alone and in Combination with CA125 for the Detection of Ovarian Cancer in an Enriched Primary Care Population

SIMPLE SUMMARY: Ovarian cancer is the most common cause of death from gynaecological cancer in the UK. Survival is better when the disease is diagnosed early. However, identifying ovarian cancer is challenging because symptoms are non-specific. Simple, accurate tests are needed to help identify ovarian cancer in symptomatic women. HE4, a relatively new blood biomarker, has shown promise in the hospital setting. This study aimed to assess whether HE4 would improve ovarian cancer diagnosis in women with symptoms in primary care. We found combining HE4 levels with the currently used test (CA125) within an algorithm (Risk of Ovarian Malignancy Algorithm) improved the detection of ovarian cancer in primary care, particularly in women under 50 years of age, where diagnosis is more challenging. However, our results require validation in a larger sample. This study advances our knowledge of HE4 as an ovarian cancer biomarker in the primary care setting. ABSTRACT: Human epididymis 4 (HE4) is a promising ovarian cancer biomarker, but it has not been evaluated in primary care. In this prospective observational study, we investigated the diagnostic accuracy of HE4 alone and in combination with CA125 for the detection of ovarian cancer in symptomatic women attending primary care. General practitioner (GP)-requested CA125 samples were tested for HE4 at a large teaching hospital in Manchester, and cancer outcomes were tracked for 12 months. We found a low incidence of ovarian cancer in primary care; thus, the cohort was enriched with pre-surgical samples from 81 ovarian cancer patients. The Risk of Ovarian Malignancy Algorithm (ROMA) was calculated using age (</>51) as a surrogate for menopause. Conventional diagnostic accuracy metrics were determined. A total of 1229 patients were included; 82 had ovarian cancer. Overall, ROMA performed best (AUC-0.96 (95%CI: 0.94–0.98, p = <0.001)). In women under 50 years, the combination of CA125 and HE4 (either marker positive) was superior (sensitivity: 100% (95%CI: 81.5–100.0), specificity: 80.1% (95%CI 76.7–83.1)). In women over 50, ROMA performed best (sensitivity: 84.4% (95%CI: 73.1–92.2), specificity: 87.2% (95%CI 84.1–90)). HE4 and ROMA may improve ovarian cancer detection in primary care, particularly for women under 50 years, in whom diagnosis is challenging. Validation in a larger primary care cohort is required.