Colorectal cancer (CRC) is the third most common cancer worldwide, and the second commonest cause of cancer deaths worldwide [1]. From 1990 to 2019, the global incidence of CRC rose from 842,098 to 2.17 million, and an increase in CRC-related deaths from 518,126 to 1.09 million [2]. Concurrently there has been an increase in cases of “early-onset” CRC, defined as patients being diagnosed less than 50 years old. These cases are also associated with a more advanced stage of disease, which is in turn associated with poorer survival outcomes [3]. Five year survival of patients is 92% at stage 1 CRC, but drops to 10% for stage 4 CRC [4]. It can be argued that diagnosing CRC at an early stage of disease is the most important factor influencing disease prognosis, above grade of disease or patient characteristics [5]. Most CRC patients are diagnosed once symptomatic - with change in bowel habit, rectal bleeding, or anaemia, but multiple studies show that once these symptoms are present it most commonly signifies late-stage disease with poor prognosis [[6], [7], [8]] (see Fig. 1, Fig. 2)

By contrast screening of asymptomatic patients by colonoscopy has been shown to pick up early-stage CRC and reduce CRC-related mortality, but this is limited by monetary constraints (especially in public health systems) and patient attitudes and uptake [9]. Therefore more efforts could be focused on the asymptomatic patient population with a view to early diagnosis of CRC and also of high-risk adenomas, which are thought to be a precursor to invasive CRC [10].

Biomarkers are molecules or compounds that can serve as signals of pathological processes and disease activity. In relation to CRC biomarkers can help in three main ways – 1) for early diagnosis, 2) to inform prognosis and treatment options, 3) and finally in post-treatment surveillance by looking for disease recurrence [11].

In the last twenty years there have been advances in prognostic biomarkers – especially genetic and epigenetic biomarkers from tumour tissues such as KRAS and BRAF mutations – allowing tailoring of individual patient oncological therapies [12].

By contrast clinical use of biomarkers for early diagnosis has been severely limited up until recently - predominantly due to lack of biomarkers with sufficient sensitivity and specificity for the disease. However since 2020, many countries have seen increased adoption of the faecal immunochemical test (FIT) to guide screening programmes and risk stratify patients for investigation [13].

FIT is still imperfect, with more false positives and false negatives than colonoscopy, and thus there is still an unmet need for further non-invasive biomarkers to be clinically validated so we can increase early CRC diagnostic rates [14]. Fortunately we are in an exciting period of time where research is being carried out on several potential biomarkers apart from FIT to try and deliver enhanced diagnostic capabilities.

In this article we will review the current diagnostic biomarkers with promise for the future, and the evidence supporting them at this juncture. Specifically, we will review their diagnostic accuracy and their sampling methods which will influence acceptability and potential patient compliance rates.

Although this is not the main focus of this review, it will be useful to touch upon FIT as a reference standard for biomarkers. FIT has now become the pre-eminent biomarker for CRC. A study of 9800 patients in 2021 showed a sensitivity of 97% (95% CI 94.5–98.5%) for CRC at the limit of detection, and a negative predictive value of 99.8% (95% CI 99.7–99.9%) at the same threshold [15]. It is now incorporated into national guidelines for screening of asymptomatic patients and diagnosis of symptomatic patients in the United Kingdom [16]. It is also being adopted in North America, much of Europe such as Germany, the Netherlands, Belgium and Italy, and in Australia as part of screening.

However it is not perfect – in the above study – its specificity at the limit of threshold was only 64.9% (95% CI 63.9–65.8%) and its positive predictive value was 8.7% (95% CI 7.8–9.7%).

Despite its benefits and the progress that has been made – there is still an urgent need to look further afield for other reliable biomarkers and potentially combinations of tests to rival the gold standard of colonoscopy.