# Serum metabolite levels identify incipient metastatic progression of rectal cancer

## TL;DR

Blood metabolite levels at diagnosis can predict which rectal cancer patients are more likely to develop metastases later.

## Contribution

Identified specific serum metabolites (alanine, lactate, pyruvate, citrate) linked to metastatic risk in rectal cancer patients at diagnosis.

## Key findings

- Patients with metastatic progression had elevated serum levels of alanine, lactate, pyruvate, and citrate.
- High citrate levels (above 0.24 mmol/L) were strongly associated with poorer progression-free survival.
- The findings suggest a distinct serum metabolite profile that can identify patients at risk of metastasis.

## Abstract

The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression.

One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification.

Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test).

We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.

Cancer cells need energy and building blocks, such as amino acids and lipids, when growing. This is particularly important when the cancer cells are spreading to other organs in the body, named metastasis. Metastatic spread is a common cause of death from bowel cancer. We analysed metabolites (energy and building block proteins) in the blood from 123 patients with bowel cancer and found that patients who later developed metastasis had other levels of blood metabolites than patients who never were diagnosed with metastasis. In particular, we found higher levels of four specific metabolites: lactate, pyruvate, alanine and citrate. These findings may enable more precise diagnosis of bowel cancer at risk of spread to other organs and may help us better understand why metastasis occurs.

Bakke, Bousquet et al. identify serum metabolite biomarkers at the time of primary tumour diagnosis in rectal cancer participants prone to metastatic progression. These individuals show higher serum metabolites of alanine, lactate, pyruvate, and citrate compared to those without metastatic progression.