Are colon cancer subtypes linked to a greater risk of recurrence – and could diet be relevant?

A particular colon cancer subtype, imCMS4, was linked to the highest risk of recurrence, and a more ‘pro-inflammatory’ diet was associated with greater recurrence risk in this same subgroup.

Cancer is an extremely complex disease, with over 200 different types. Even tumours belonging to the same cancer type can have important biological differences. Tumour heterogeneity refers to the differences observed between tumours of the same type in different patients.

For example, colon cancers are not all biologically the same. They can be grouped into molecular subtypes that may behave differently and respond differently to their surroundings.

Research funded by Wereld Kanker Onderzoek Fonds (WKOF) – the Netherlands-based charity within the World Cancer Research Fund network of charities – explored whether colon cancer recurrence differed between tumour subtypes and whether diet and other lifestyle factors at diagnosis were associated with recurrence.

The new study, published recently in the journal Cancer Epidemiology, suggests that people with a particular tumour subtype – the imCMS4 subtype – had a significantly higher risk of cancer recurrence.

The results also found that, among people with imCMS4 tumours, a more pro-inflammatory diet around the time of diagnosis was associated with a higher rate of recurrence. However, this association was not seen in other subtypes.

Dr Evertine Wesselink, based at the Netherlands Cancer Institute and lead author of the research, said:

“When we talk about lifestyle habits, such as diet, physical activity, and body weight, and cancer, we often look at the big picture. But tumours are incredibly diverse. We wanted to explore whether a person’s diet is associated with their risk of cancer recurrence differently depending on the specific ‘molecular personality’ of their tumour”.

Colorectal cancer subtypes

To capture some of the biological variation seen between colon cancer tumours, researchers classify colorectal tumours (meaning both colon and rectal tumours) according to their molecular, cellular and surrounding tissue characteristics. One widely used framework is the four Consensus Molecular Subtypes, or CMS.

 For this research, tumours were grouped into four main subtypes:

• CMS1: These tumours show strong immune-system activity and often contain many immune cells. They commonly have defects in the system that usually repairs DNA which can lead to the accumulation of genetic changes.
• CMS2: This is the most common subtype. These tumours are mainly driven by well-known cancer growth pathways and tend to have less immune activity around them.
• CMS3: These tumours have distinctive changes in how cancer cells process energy and nutrients and have relatively little immune activity.
• CMS4: These tumours have a strong supporting tissue and display inflammation-related and immune-suppressive characteristics. They also tend to have a greater potential to spread and are generally associated with poorer outcomes.

Previous studies have highlighted the value of CMS as a prognostic marker in colorectal cancer, but the association between CMS and cancer recurrence, and whether the inflammatory potential of diet and lifestyle relates to recurrence differently across colon cancer subtypes, is not well understood.

Looking at tumours under the microscope

The researchers studied people with stage I–III colon cancer from two large Dutch patient cohorts. They compared 167 people whose cancer recurred with 668 people whose cancer had not returned by the same point in follow-up.

They used artificial intelligence to analyse routine microscope images of tumour tissue from 532 patients and assign each tumour to an image-based molecular subtype, known as imCMS1, imCMS2, imCMS3 or imCMS4.

Dr Evertine Wesselink said:

“The subtype was identified from standard tumour slides using artificial intelligence. Because these slides are already widely collected in hospitals, this approach could eventually offer a relatively quick and scalable way to classify tumours.”

Participants also completed questionnaires about their diet, physical activity, smoking, alcohol use and body weight in the month preceding their diagnosis. These were used to generate:

• A dietary inflammation score, where a higher score meant a more pro-inflammatory diet.
• A lifestyle inflammation score (which took into account physical activity, smoking status, BMI and alcohol consumption), where a higher score meant a more pro-inflammatory lifestyle.

Next, the research team examined whether tumour subtype, diet and lifestyle were associated with the risk of recurrence.

What did the results show?

Their analysis found that people with an imCMS4 tumour had more than twice the risk of recurrence compared with those with the most common subtype, imCMS2.

Across all patients combined, the inflammatory potential of the diet was not clearly associated with recurrence. However, the picture changed when the researchers looked separately at each tumour subtype. Among people with imCMS4 tumours, each one-unit increase in the dietary inflammation score was associated with a 39% higher risk of recurrence, but no clear association was seen in the other subtypes.

Within the imCMS4 group, higher intakes of tomatoes, apples and berries, fish and nuts were each associated with a lower risk of recurrence. However, the research team stress that these findings were exploratory, based on a relatively small subgroup, and do not prove that these foods themselves prevented recurrence.

A more pro-inflammatory lifestyle showed a possible association with higher recurrence risk overall, but this finding was not statistically clear. The researchers found no clear association between the lifestyle inflammation score and risk of recurrence across different tumour subgroups.

World Cancer Research Fund International Assistant Director of Research and Policy , Dr Helen Croker, said:

“The study suggests that the biological subtype of a colon tumour may help identify people at greater risk of recurrence and that diet may play a role.

“It is wonderful to see early-career researchers produce such interesting results as part of our INSPIRE research challenge. These findings raise the possibility that diet could be especially important for certain patients, particularly those with imCMS4 tumours.”

Dr Evertine Wesselink added:

“As our study was observational, relied on self-reported diet and lifestyle, and included relatively small numbers once patients were divided into subgroups, the results should be repeated in other populations and tested in studies that follow dietary changes after diagnosis.”