Abstract
BackgroundWe investigated the efficacy of circulating biomarkers together with histological grade and age to predict deep myometrial invasion (dMI) in endometrial cancer patients.MethodsHE4ren was developed adjusting HE4 serum levels towards decreased glomerular filtration rate as quantified by the eGFR-EPI formula. Preoperative HE4, HE4ren, CA125, age, and grade were evaluated in the context of perioperative depth of myometrial invasion in endometrial cancer (EC) patients. Continuous and categorized models were developed by binary logistic regression for any-grade and for G1-or-G2 patients based on single-institution data from 120 EC patients and validated against multicentric data from 379 EC patients.ResultsIn non-cancer individuals, serum HE4 levels increase log-linearly with reduced glomerular filtration of eGFR ≤ 90 ml/min/1.73 m2. HE4ren, adjusting HE4 serum levels to decreased eGFR, was calculated as follows: HE4ren = exp[ln(HE4) + 2.182 × (eGFR-90) × 10-2]. Serum HE4 but not HE4ren is correlated with age. Model with continuous HE4ren, age, and grade predicted dMI in G1-or-G2 EC patients with AUC = 0.833 and AUC = 0.715, respectively, in two validation sets. In a simplified categorical model for G1-or-G2 patients, risk factors were determined as grade 2, HE4ren ≥ 45 pmol/l, CA125 ≥ 35 U/ml, and age ≥ 60. Cumulation of weighted risk factors enabled classification of EC patients to low-risk or high-risk for dMI.ConclusionsWe have introduced the HE4ren formula, adjusting serum HE4 levels to reduced eGFR that enables quantification of time-dependent changes in HE4 production and elimination irrespective of age and renal function in women. Utilizing HE4ren improves performance of biomarker-based models for prediction of dMI in endometrial cancer patients.
Highlights
Endometrial cancer (EC) is a malignant tumor of endometrial epithelial origin, accounting for 20% to 30% of malignant diseases of the female reproductive system [1]
To adjust Human epididymis protein 4 (HE4) serum levels to decreased estimated glomerular filtration rates (eGFR), a HE4 level adjusted to glomerular filtration rate (HE4ren) was calculated as follows: HE4ren = exp[ln(HE4) + 2.182 × × 10-2] for the range eGFR ≤ 90 ml/ min/1.73 m2 ; HE4ren is equal to HE4 for the range eGFR > 90 ml/min/1.73 m2 (Figure 1 right)
While HE4 is falsely elevated in individuals with impaired glomerular functions, the 95th percentile of the HE4ren distribution in the chronic kidney disease (CKD)-positive control cohort corresponded to 46.6 pmol/l (Supplementary Figure 1)
Summary
Endometrial cancer (EC) is a malignant tumor of endometrial epithelial origin, accounting for 20% to 30% of malignant diseases of the female reproductive system [1]. Owing to potential morbidity associated with lymphadenectomy leading to symptomatic lymphocysts, lymphedema, deep vein thrombosis, neurologic injury, vein injury, and need for blood transfusion, the decision regarding lymph node dissection should be based on quantification of risk factors for nodal metastasis, such as histology of tumor, grade, and myometrial invasion ≥ 50% (deep MI, dMI) [4]. The inclusion of preoperative levels of peripheral blood-derived biomarkers is potentially informative when assessing dMI and is highly relevant for the risk prediction and decision making process for the upfront assessment of the extent of endometrial cancer surgery [11, 12]. We investigated the efficacy of circulating biomarkers together with histological grade and age to predict deep myometrial invasion (dMI) in endometrial cancer patients
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