Will bowel cancer come back after liver surgery? What protein biomarkers could show

Why is recurrence after liver surgery so hard to predict?

Bowel cancer is the third most common cancer worldwide and the second leading cause of cancer death. The liver is its most common site of spread because blood from the bowel drains straight to the liver through the portal vein, and liver metastases are present in about 20% of people at diagnosis.

Liver resection can cure selected patients, with about one in five free of cancer ten years later. Even so, about 75% develop recurrence, mostly within two years. The clinical and pathology factors used to estimate risk, such as tumour number and size, are inconsistent and lose their predictive power within a few years of surgery. Early recurrence is the single most useful sign of how the disease will behave, and there is currently no reliable way to predict it.

Why study proteins when we can sequence tumour genes?

Genetic sequencing has transformed understanding of how bowel cancer develops, and tests such as RAS and BRAF already guide treatment. A gene mutation, though, does not always change the protein it codes for, and proteins are modified after they are made in ways that change how they work. Proteins carry out the tumour's behaviour, and most cancer drugs target proteins.

Mass spectrometry can now identify and measure thousands of proteins in a small tissue sample. Studies combining genetic and protein data show that a bowel cancer and its liver metastasis are very similar genetically and clearly different at the protein level, which helps explain why gene tests alone predict behaviour imperfectly.

What research did the review cover?

The authors identified 17 protein-profiling studies and 5 combined gene and protein studies of human liver metastasis tissue published from 2011 to 2021. Together they included 301 patients, with 1 to 44 patients in each study. Sixteen used fresh frozen tissue and six used formalin-fixed tissue of the kind routinely stored by pathology labs.

Which protein signals look most promising?

Several patterns recur across the studies. The scaffolding around tumour cells, called the extracellular matrix, changes markedly in liver metastases, with altered collagen types and chemical modifications that distinguish metastasis from normal liver.

• Early recurrence: patients whose cancer returned within six months of liver surgery had higher levels of MMP7 and DPEP1 and lower LOXL1 than those whose cancer returned at 6 to 12 months.
• Citrullination: the enzyme PAD4 was 11 times more abundant in the matrix of liver metastases than normal liver, and blocking it reduced metastasis growth in mice.
• Thrombospondin-1: higher levels were linked with liver spread and poorer prognosis, and depleting it slowed cancer cell invasion in the laboratory.
• Tumour zones: the centre, rim and surrounding tissue of a liver metastasis each show distinct protein activity, including drug metabolism at the rim.
• Subtypes: protein profiling has defined bowel cancer subtypes with different prognoses, which could refine risk estimates.

How could protein biomarkers help patients in future?

The review sets out six ways these discoveries could reach the clinic. They include estimating the risk of liver spread after bowel cancer surgery, tailoring scan schedules after liver surgery to each person's risk, finding metastases that disappear on scans after chemotherapy, monitoring the disease with blood or urine tests, predicting which treatment will work, and selecting patients for trials of targeted drugs.

Better risk prediction would also help with decisions such as the length of chemotherapy. In stage III bowel cancer, six months of chemotherapy improves three-year disease-free survival by only 0.9 percentage points over three months while adding side effects, the kind of trade-off a biomarker could help individualise.

Why are protein biomarkers not yet used in clinical care?

After more than a decade of research, no protein biomarker for liver metastases has reached clinical use. Studies have been small, which inflates chance findings, and most candidate markers were never tested again in a second group of patients. Different laboratories use different platforms, so their data are hard to combine.

The authors call for large collaborative studies built around clinically meaningful endpoints, such as recurrence within six months of liver surgery compared with patients who are recurrence-free at ten years. Professor Hugh's unit holds exactly this kind of long-term data, reported in its 20-year liver metastases study.

How is recurrence monitored after liver surgery today?

Until biomarkers are validated, follow-up after liver resection relies on regular imaging and blood tests reviewed by the multidisciplinary team. Finding recurrence early matters because further treatment, including repeat liver surgery, remains possible for many patients. In the unit's 20-year series, 32 patients had another liver resection with curative intent for recurrent disease.