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We asked whether a minimal circulating-protein signature anticipates incident cancer in patients with atheromatous cardiovascular disease (ACVD) exposed to tobacco. Discovery used a nested case\u2013control set drawn from the longitudinal FLEMENGHO cohort (n=156; 38 incident lung cancers). Multi-omic profiling returned a two-step classifier: four proteins, smoking status, personal cancer history. Preprocessing constants, classifiers and both thresholds were fixed before transfer to PREVALUNG (n=397; 58 incident cancers, 26 of them lung). There, low O-GlcNAcase (OGA) with low interleukin-6 (IL-6) defined a very-low-risk stratum holding 1 of 58 cancers (sensitivity 98.3%, negative predictive value 98.8%); low chymotrypsin C (CTRC) with high \u03b2-microseminoprotein (MSMB) defined a high-risk stratum in which 15 of 28 participants developed cancer. No additional omic feature \u2014 metabolomic, immunophenotypic, clonal-haematopoietic or metagenomic \u2014 was retained as a reproducible improvement to the classifier under our selection framework. Discrimination was greater for cancers diagnosed \u226512 months after sampling than for near-term cancers (AUC 0.766, 95% CI 0.671\u20130.857, versus 0.589, 0.485\u20130.692), arguing against performance being driven principally by occult disease. These estimates are conditional on the cancer frequency of this population. They require prospective confirmation before any imaging schedule is changed.<\/jats:p>","DOI":"10.64898\/2026.09.09.750392","type":"posted-content","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:30:53Z","timestamp":1789144253000},"source":"Crossref","is-referenced-by-count":0,"title":["Glycometabolic, inflammatory and exocrine plasma proteins predict cancer in individuals with cardiovascular disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5589-9688","authenticated-orcid":false,"given":"Marine","family":"Fidelle","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Boulate","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, H\u00f4pital-Nord-APHM, Aix-Marseille University, Marseille, 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