Bio­mark­er-Based Mod­els for Pre­op­er­a­tive Assess­ment of Adnex­al Mass: A Mul­ti­cen­ter Val­i­da­tion Study

Authors

MustRafał Watrows­ki,^1,2,† Eva Ober­mayr,^2,† Chris­tine Wal­lisch,³ Ste­fanie Aust,² Nicole Concin,⁴ Ele­na Ioana Braicu,⁵ Toon Van Gorp,⁶ Annette Hasen­burg,^7,8 Jalid Sehouli,⁵ Ignace Ver­gote,⁶ and Robert Zeillinger^2,*

Sim­ple Summary

Ovar­i­an can­cer (OC) is the dead­liest gen­i­tal tumor in women. In this mul­ti­cen­ter study, we devel­oped three new diag­nos­tic mod­els based on serum pro­teins and patient age. All mod­els were then val­i­dat­ed using data from cen­ters oth­er than those used for the mod­el devel­op­ment. We also com­pared the per­for­mance of these mod­els with com­mon sin­gu­lar mark­ers (CA125, HE4) and algo­rithms (ROMA-50 and the Copen­hagen Index). We used mod­ern tech­nol­o­gy (Luminex^®, Austin, TX, USA) that enables the simul­ta­ne­ous deter­mi­na­tion of sev­er­al bio­mark­ers in a small amount of blood. A com­bi­na­tion of patient age with four to six mark­ers per­formed best: CA125, osteo­pon­tin, pro­lactin, macrophage migra­tion inhibito­ry fac­tor, and, even­tu­al­ly, HE4 and lep­tin. Our mod­els were bet­ter than the ROMA-50 index but did not out­per­form the Copen­hagen Index. In post­menopausal patients, all the new­ly devel­oped mod­els per­formed excel­lent­ly. Unfor­tu­nate­ly, none of the mod­els test­ed improved the diag­no­sis in pre­menopausal patients and those missed due to nor­mal CA125 levels.

Abstract

Ovar­i­an can­cer (OC) is the most lethal gen­i­tal malig­nan­cy in women. We aimed to devel­op and val­i­date new pro­teom­ic-based mod­els for non-inva­sive diag­no­sis of OC. We also com­pared them to the mod­i­fied Risk of Ovar­i­an Malig­nan­cy Algo­rithm (ROMA-50), the Copen­hagen Index (CPH‑I) and our ear­li­er Pro­teom­ic Mod­el 2017. Bio­mark­ers were assessed using bead-based mul­ti­plex tech­nol­o­gy (Luminex^®) in 356 women (250 with malig­nant and 106 with benign ovar­i­an tumors) from five Euro­pean cen­ters. The train­ing cohort includ­ed 279 women from three cen­ters, and the val­i­da­tion cohort 77 women from two oth­er cen­ters. Of six pre­vi­ous­ly stud­ied serum pro­teins (CA125, HE4, osteo­pon­tin [OPN], pro­lactin, lep­tin, and macrophage migra­tion inhibito­ry fac­tor [MIF]), four con­tributed sig­nif­i­cant­ly to the Pro­teom­ic Mod­el 2021 (CA125, OPN, pro­lactin, MIF), while lep­tin and HE4 were omit­ted by the algo­rithm. The Pro­teom­ic Mod­el 2021 revealed a c‑index of 0.98 (95% CI 0.96, 0.99) in the train­ing cohort; how­ev­er, in the val­i­da­tion cohort it only achieved a c‑index of 0.82 (95% CI 0.72, 0.91). Adding patient age to the Pro­teom­ic Mod­el 2021 con­sti­tut­ed the Com­bined Mod­el 2021, with a c‑index of 0.99 (95% CI 0.97, 1) in the train­ing cohort and a c‑index of 0.86 (95% CI 0.78, 0.95) in the val­i­da­tion cohort. The Full Com­bined Mod­el 2021 (all six pro­teins with age) yield­ed a c‑index of 0.98 (95% CI 0.97, 0.99) in the train­ing cohort and a c‑index of 0.89 (95% CI 0.81, 0.97) in the val­i­da­tion cohort. The val­i­da­tion of our pre­vi­ous Pro­teom­ic Mod­el 2017, as well as the ROMA-50 and CPH‑I revealed a c‑index of 0.9 (95% CI 0.82, 0.97), 0.54 (95% CI 0.38, 0.69) and 0.92 (95% CI 0.85, 0.98), respec­tive­ly. In post­menopausal women, the three new­ly devel­oped mod­els all achieved a speci­fici­ty of 1.00, a pos­i­tive pre­dic­tive val­ue (PPV) of 1.00, and a sen­si­tiv­i­ty of >0.9. Per­for­mance in women under 50 years of age (c‑index below 0.6) or with nor­mal CA125 (c‑index close to 0.5) was poor. CA125 and OPN had the best dis­crim­i­nat­ing pow­er as sin­gle mark­ers. In sum­ma­ry, the CPH‑I, the two com­bined 2021 Mod­els, and the Pro­teom­ic Mod­el 2017 showed sat­is­fac­to­ry diag­nos­tic accu­ra­cies, with no clear supe­ri­or­i­ty of either mod­el. Notably, although com­bin­ing val­ues of only four pro­teins with age, the Com­bined Mod­el 2021 per­formed com­pa­ra­bly to the Full Com­bined Mod­el 2021. The mod­els con­firmed their excep­tion­al diag­nos­tic per­for­mance in women aged ≥50. All mod­els out­per­formed the ROMA-50.

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