Sensitive and specific blood biomarkers for detection of cancer are highly warranted. To discover such biomarkers, we measured plasma levels of 165 proteins and 244 metabolites in 818 patients with colorectal, lung or ovarian carcinoma at diagnosis, 119 patients with non-malignant conditions of the corresponding organs, and 1,129 healthy individuals. We performed exhaustive search over all cut-off values of the ROC statistic and identified composite biomarkers with diagnostic performance significantly superior to benchmark FDA approved blood tests in clinical use for detection of cancer. We found biomarkers composed of 2-4 proteins separating cases of each tumor type from healthy controls with ROC AUC in the range 0.89 to 0.98. These biomarkers also separated cases of each tumor type from the other two (ROC AUC 0.82-0.88). For lung and ovarian cancers, we identified biomarkers distinguishing cases with intermediate and high from those with low tumor stages. These biomarkers for cancer detection and stage can find use in early detection, staging and differential diagnosis of common tumor types.

The authors have declared no competing interest.

The study was funded by grants to T.S. from the Swedish Cancer Society (CAN 2018/772, 21 1719 Pj, 2024 3831 Pj), the flagship project grant from Sjöberg Foundation (2024-11-06: 18,2) and Lena Wäppling foundation, and from the Swedish Cancer Society to J.Å.Ö. (CAN 21-0430-PT) and B.G. (190382PJ01H). We thank U-CAN for access to blood samples collected through Uppsala Biobank, Uppsala University Hospital and Uppsala University with support from the Swedish Government (SRA grant CancerUU), and EpiHealth for blood samples collected with support from the Swedish Government through the Swedish Research Council.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the Swedish Ethical Review Authority (EPM dnr 2019-00222). The research was in line with informed consents obtained from patients included in U-CAN24 (EPN Uppsala 2010-198) and research participants in EpiHealth.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes