CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC)

Abstract

Background: We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics.

Methods: Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle.

Results: A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001).

Conclusions: CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC.

Trial registration number: NCT01212510.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Fig. 1. Flow diagram illustrating all the biomarkers of the Coca Colon cohort study.

*Patients for which the results of circulating markers and 12-week evaluation were available. CA19-9 carbohydrate antigen 19-9, CEA carcinoembryonic antigen, cfDNA cell-free DNA, CTC circulating tumour cells, ctDNA circulating tumour DNA, WT wild type. †Kinetics were estimated for living non-progressive patients having a positive baseline value and two or three further measures at fourth cycle. ‡Only CTC baseline-positive patients underwent kinetic analysis.

Fig. 2. Result of biomarkers for prediction of progression at 12-weeks evaluation.

Prediction of progression according to (a) 0.05 threshold CEA kinetics value previously identified (primary endpoint), (b) baseline circulating marker median value and (c) kinetics circulating marker median value. CA19-9, carbohydrate antigen 19-9; CEA, Carcinoembryonic antigen; cfDNA, cell-free DNA; CTC, circulating tumour cells; ctDNA, circulating tumour DNA; L-, likelihood negative ratio; L+, likelihood positive ratio; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value; Se, sensitivity; Sp, specificity.

Fig. 3. Survival according to the circulating markers.

Kaplan–Meier curves of a progression-free survival (PFS) and c overall survival (OS) by the CEA kinetics dichotomised at the previously identified threshold (i.e. 0.05). Kaplan–Meier curves of b PFS and d OS by the circulating scoring system (CSS) dichotomised at the 2 value (i.e. <2 and ≥2). B-spline estimates of the hazard ratio for the CEA kinetics (baseline adjusted) (e) and CSS (f). Progression-free survival and overall survival spline curves are represented by the blue and yellow lines, respectively. CEA carcinoembryonic antigen, HR hazard ratio, PFS progression-free survival, OS overall survival.

Fig. 4. Forest plot of hazard ratios for patient’s survival.

Forest plot of hazard ratios for (a) progression-free survival and (b) overall survival. The hazard ratio (HR) of each variable was calculated separately and was adjusted for clinical and histological covariates using a prognosis score of well-known prognostic variables, i.e., WHO performance status, tumour location, surgery of the primary tumour, synchronous/metachronous metastasis, number of metastases sites, chemotherapy line, use of targeted therapies, and mutational status (KRAS/NRAS/BRAF mutations or no mutation). CA 19-9, carbohydrate antigen 19-9; CEA, Carcinoembryonic antigen; cfDNA, cell-free DNA; CI, confidence interval; ctDNA, circulating tumour DNA; CTC, circulating tumour cells; HR, hazard ratio; No, total number of patients; PFS, progression-free survival; OS, overall survival.