Plasma serine and glycine in relation to clinical outcomes following neoadjuvant radiotherapy for rectal cancer.

Introduction: There is substantial variation in radiotherapy response among patients with rectal cancer. The amino acids serine and glycine have been proposed as radiosensitizers in preclinical studies. Here, we explored associations between plasma serine, glycine, and their ratio and clinical outcomes following neoadjuvant treatment for rectal cancer, including tumour downstaging and cancer recurrence. Methods: Based on a prospective cohort study, 288 patients with stage I-III rectal cancer were included. Blood was collected around diagnosis and plasma levels of serine and glycine were measured using GC-MS/MS. Tumour downstaging was defined as T-classification downstaging (pT < cT) after neoadjuvant treatment and recurrence included locoregional recurrences and distant metastases occurring in the 5-years after surgery. Regression models were used to calculate relative risks (RR) and hazard ratios (HR) and their 95% confidence intervals (CI) for tumour downstaging and recurrence, respectively. Results: Tumour downstaging was observed in 41% (n = 117) of the patients and the 5-year recurrence rate was 23% (n = 67). Serine, glycine, and their ratio were not associated with tumour downstaging. A higher serine/glycine ratio was associated with a lower risk of cancer recurrence (HR Conclusion: This is the first study demonstrating a potential association between the serine/glycine ratio, an indicator of SHMT enzyme activity, and rectal cancer recurrence. Further studies are warranted to confirm these findings, as well as investigate underlying biological mechanisms and potentially explore strategies to target SHMT enzyme activity in the context of cancer treatment.