Lactate Dehydrogenase in Patients with Metastatic Colorectal Cancer: Retrospective Study to Explore a Target Subgroup for Utilization as a Tumor Marker

Well-established predictive and prognostic biomarkers, such as rat sarcoma (RAS) and B-Raf proto-oncogene (BRAF) mutations and microsatellite instability (MSI), are already incorporated into routine clinical practice for the treatment of mCRC. 2 However, mCRC is a clinically and molecularly heterogeneous disease, and novel treatment options, such as immunotherapy, are under investigation. 2 Therefore, there is a need for additional biomarkers and for further characterization ABSTRACT Aim: Serum lactate dehydrogenase (LDH) may be a prognostic marker in metastatic colorectal cancer (mCRC).However, mCRC is a heterogeneous disease, and data on LDH-related subgroups are limited.This study aimed to investigate clinical and molecular features associated with LDH in mCRC.Method: Demographic, clinical, treatment response, and survival data from a retrospective cohort of patients diagnosed with synchronous mCRC between 2019 and 2023 were analyzed according to serum LDH levels.Lactate dehydrogenase A (LDHA) gene expression and molecular features were assessed in an independent cohort. Results:The clinical cohort included 135 patients.The median LDH level was 231 U/L (range: 106-5,655), and 55.1% (n=75) of patients had high LDH.The presence of liver metastases (p=0.037), the number of liver metastases (5 vs. <5, p=0.035), carcinoembryonic antigen (p=0.000),carbohydrate antigen 19-9 (p=0.042), and C-reactive protein (p=0.002)levels were significantly associated with high LDH.Among patients with liveronly metastases, high LDH was significantly associated with worse overall survival (OS) (19.7 months [95% confidence interval (CI): 13.8-28.1]vs. 39.0 months (95% CI: 19.8-59.2),p=0.017).Non-responders to 5-fluorouracil, leucovorin, and oxaliplatin had higher LDH levels (p=0.016) and worse OS [11.4 months (95% CI: 6.2-12.7)vs. not reached, p=0.002].Among 84 patients in the independent mCRC cohort, 16.7% (n=14) had high LDHA expression in tumor tissue.High LDHA expression was associated with lower microsatellite instability scores (p=0.048) and higher hypoxia scores (p for Buffa=0.001,Winter=0.003),but not with tumor mutational burden or aneuploidy score.Expression of metabolic-epithelial-mesenchymal transition pathway genes was correlated with LDHA expression. Conclusion:LDH may be a potential marker in microsatellite-stable (MSS), nonimmunogenic, liver-dominant mCRC.Whether LDH could serve as a biomarker for immunotherapy studies in MSS colorectal cancer warrants investigation in future studies.