Association of tumor markers CA 15-3, CEA, and CA 125 with [18F]NaF PET findings in breast cancer patients

Arvin Naeimi; Sara Harsini; Vilma Derbekyan; Gad Abikhzer; Marc Hickeson; Shawn Karls; Farzad Abbaspour

doi:10.3389/fonc.2025.1673504

Association of tumor markers CA 15-3, CEA, and CA 125 with [¹⁸F]NaF PET findings in breast cancer patients

Front Oncol. 2025 Nov 21:15:1673504. doi: 10.3389/fonc.2025.1673504. eCollection 2025.

Authors

Arvin Naeimi^{1

2}, Sara Harsini^{3

4}, Vilma Derbekyan⁵, Gad Abikhzer⁶, Marc Hickeson⁵, Shawn Karls⁵, Farzad Abbaspour^{5

7}

Affiliations

¹ Department of Radiology, McGill University Health Center, McGill University, Montreal, QC, Canada.
² Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
³ Department of Molecular Imaging and Therapy, BC Cancer, Vancouver, BC, Canada.
⁴ Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
⁵ Department of Medical Imaging, Division of Nuclear Medicine, McGill University Health Center, McGill University, Montreal, QC, Canada.
⁶ Department of Medical Imaging, Division of Nuclear Medicine, Jewish General Hospital, McGill University, Montreal, QC, Canada.
⁷ Division of Nuclear Medicine, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada.

Abstract

Introduction: Breast cancer often metastasizes to bone, and [¹⁸F]NaF PET is commonly used to detect skeletal involvement. This study examines the association of serum CA 15-3, CEA, and CA 125 with [¹⁸F]NaF PET findings in breast cancer to guide clinical decision-making.

Methods: This retrospective study included 360 breast cancer patients who underwent [¹⁸F]NaF PET. Associations between serum tumor markers (CA 15-3, CEA, CA 125) and [¹⁸F]NaF PET findings and lesion count were analyzed. Optimal cut-off values for predicting [¹⁸F]NaF PET positivity were determined using ROC analysis. Multivariable logistic regression identified independent predictors.

Results: Among 360 patients (mean age 61.1 ± 13.9 years), median serum CA 15-3, CEA, and CA 125 levels were significantly elevated in patients with positive versus negative PET scans (all p<0.001). Marker levels revealed a dose-response relationship, rising with increasing numbers of skeletal lesions. In multivariable analysis, CA 15-3 (OR 1.053, p=0.002) and CEA (OR 1.264, p=0.001) independently predicted PET positivity, whereas CA 125 showed a marginal trend (p=0.081). ROC analysis identified optimal cut-offs of 19.25 U/mL for CA 15-3 (sensitivity 70.1%, specificity 90.4%, AUC 0.837) and 3.15 ng/mL for CEA (sensitivity 65.6%, specificity 85.2%, AUC 0.821). Combined model incorporating all three markers (probability cut-off 0.29) improved diagnostic performance (AUC 0.863; sensitivity 79.7%, specificity 92.3%). Invasive lobular histology and restaging indication were significant predictors of PET positivity.

Conclusion: Elevated CA 15-3 and CEA independently predict [¹⁸F]NaF PET positivity in breast cancer. Optimal cut-offs were 19.25 U/mL for CA 15-3 (sensitivity 70.1%, specificity 90.4%, LR + 7.38, AUC 0.837) and 3.15 ng/mL for CEA (sensitivity 65.6%, specificity 85.2%, LR + 4.43, AUC 0.821). The clinical utility of CA 15-3 and CEA lies in rule-in and risk-stratification strategies. Patients above these thresholds, particularly those with invasive lobular carcinoma undergoing restaging, may benefit from prioritized [¹⁸F]NaF PET evaluation or improved interpretation of equivocal PET findings. CA 15-3 threshold, lower than routine laboratory reference, may guide aggressive screening and prioritized [¹⁸F]NaF PET in patients with high clinical suspicion. Multivariable model combining CA 15-3, CEA, and CA 125 (probability cut-off 0.29) improved diagnostic performance (sensitivity 79.7%, specificity 92.3%, AUC 0.863). Integrating CA 15-3 and CEA into clinical decision-making may enable a nuanced, risk-adapted approach, optimizing metastasis detection and resource allocation.

Keywords: 18F-NaF; CA 125; CA 15-3; CEA; PET; bone metastases; breast cancer; tumor marker.