• Willemijn de Klaver, Pieter H A Wisse, Francine van Wifferen, BoschLinda J WLJWNetherlands Cancer Institute, Amsterdam, the Netherlands (L.J.B., R.J.F., B.C., M.d.W., G.A.M.)., Connie R Jimenez, van der HulstRené W MRWMSpaarne Gasthuis, Haarlem, the Netherlands (R.W.H.)., FijnemanRemond J ARJA0000-0003-2076-5521Netherlands Cancer Institute, Amsterdam, the Netherlands (L.J.B., R.J.F., B.C., M.d.W., G.A.M.)., Ernst J Kuipers, Marjolein J E Greuter, Beatriz Carvalho, SpaanderManon C WMCW0000-0002-9103-9757Erasmus MC University Medical Center, Rotterdam, the Netherlands (E.J.K., M.C.S.)., Evelien Dekker, CoupéVeerle M HVMH0000-0002-9553-9791Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, the Netherlands (F.V., C.R.J., M.J.G., V.M.H.C.)., Meike de Wit, and Gerrit A Meijer.
• Netherlands Cancer Institute and Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands (W.d.K.).
• Ann. Intern. Med. 2021 Sep 1; 174 (9): 1224-1231.

BackgroundThe fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, yet it leaves room for improvement.ObjectiveTo develop a multitarget FIT (mtFIT) with better diagnostic performance than FIT.DesignDiagnostic test accuracy study.SettingColonoscopy-controlled series.ParticipantsPersons (n = 1284) from a screening (n = 1038) and referral (n = 246) population were classified by their most advanced lesion (CRC [n = 47], advanced adenoma [n = 135], advanced serrated polyp [n = 30], nonadvanced adenoma [n = 250], and nonadvanced serrated polyp [n = 53]), along with control participants (n = 769).MeasurementsAntibody-based assays were developed and applied to leftover FIT material. Classification and regression tree (CART) analysis was applied to biomarker concentrations to identify the optimal combination for detecting advanced neoplasia. Performance of this combination, the mtFIT, was cross-validated using a leave-one-out approach and compared with FIT at equal specificity.ResultsThe CART analysis showed a combination of hemoglobin, calprotectin, and serpin family F member 2-the mtFIT-to have a cross-validated sensitivity for advanced neoplasia of 42.9% (95% CI, 36.2% to 49.9%) versus 37.3% (CI, 30.7% to 44.2%) for FIT (P = 0.025), with equal specificity of 96.6%. In particular, cross-validated sensitivity for advanced adenomas increased from 28.1% (CI, 20.8% to 36.5%) to 37.8% (CI, 29.6% to 46.5%) (P = 0.006). On the basis of these results, early health technology assessment indicated that mtFIT-based screening could be cost-effective compared with FIT.LimitationStudy population is enriched with persons from a referral population.ConclusionCompared with FIT, the mtFIT showed better diagnostic accuracy in detecting advanced neoplasia because of an increased detection of advanced adenomas. Moreover, early health technology assessment indicated that these results provide a sound basis to pursue further development of mtFIT as a future test for population-based CRC screening. A prospective screening trial is in preparation.Primary Funding SourceStand Up to Cancer/Dutch Cancer Society, Dutch Digestive Foundation, and HealthHolland.

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