Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial

Abstract

Aim: To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer.

Methods: We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data.

Results: In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11-1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42-2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters.

Conclusion: CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position.

Trial registration: ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

Keywords: CA 19-9; CEA; Resectable gastric cancer; Tumor markers; ctDNA.

Conflict of interest statement

N.C.T. van Grieken reported receiving grants from the Dutch Cancer Society and The Netherlands Organisation for Health Research and Development, and serving on an advisory board for Bristol-Myers Squibb and Merck Sharp and Dohme. H.W.M. van Laarhoven reported receiving grants/medication support from Bayer, BMS, Celgene, Janssen, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier, and serving on an advisory board for BMS, Lilly, MSD, Nordic Pharma, Novartis, Servier E.P.M. Jansen, A. Cats and M. Verheij reported receiving grants from the Dutch Cancer Society, the Dutch Colorectal Cancer Group and Hoffmann La Roche.

© 2021. The Author(s).

Figures

Fig. 1

Overview of CRITICS study design including time-points of blood samples. ctDNA circulating tumor DNA, ECC epirubicin/cisplatin/capecitabine, EOC epirubicin/oxaliplatin/capecitabine, lab laboratory parameters (neutrophil count, hemoglobin, alkaline phosphatase and lactate dehydrogenase), TM tumor markers (CEA and CA 19-9). *Every month until 3 months after surgery, every 3 months until 1 year after surgery, 6 months until 5 years after surgery

Fig. 2

Overall survival curves for patients subdivided by pretreatment tumor markers. Figure 1a CEA (p = 0.002); Fig. 1b CA 19-9 (p < 0.001); Fig. 1c combination CEA and CA 19-9 (p < 0.001)

Fig. 3

Overall survival curves for patients subdivided by change between pretreatment tumor markers and tumor markers prior to cycle 3 (p < 0.001)

Fig. 4

Number of patients with and without detectable ctDNA subdivided by levels of tumor markers (CEA and CA 19-9 within ULN, CEA or CA 19-9 > ULN, or both > ULN)