High tumour monocyte content linked to improved survival in oesophageal cancer

12th July 2023

A high pre-treatment tumour monocyte content prior to immunochemotherapy in patients with inoperable oesophageal cancer is associated with greater overall survival, according to a recent study.

Writing in the journal Cell Cancer, the researchers from the Ludwig Institute for Cancer Research, University of Oxford together with international colleagues, sought to identify which patients would best respond to an initial four week course of immune checkpoint inhibitors followed by immunochemotherapy.

As part of their analysis, the researchers performed comprehensive biomarker profiling, as well as multi-timepoint transcriptomic profiling during the initial four-week course of an immune checkpoint inhibitor. The analysis revealed how a novel T-cell inflammation signature, which they termed INCITE, was up-regulated and correlated with immune checkpoint inhibitor induced tumour shrinkage.

As such, they determined that a high tumour monocyte content in patients receiving immunochemotherapy, was predictive of greater overall survival.

High monocyte tumour burden and clinical response

The study included 35 patients with inoperable oesophageal cancer. While four weeks of immune checkpoint inhibitors was enough to induce tumour shrinkage in some patients, overall, around 40% achieved a clinical benefit (defined as 12 months of progression-free survival) from the immunochemotherapy. The factors responsible for this clinical benefit were unclear.

Using deconvolution of pre-treatment gastroesophageal cancer transcriptomes, it was found that a cluster of patients had tumours with a high monocyte content pre-treatment. In Cox regression on the pre-treatment level of each cell type, the tumour monocyte count was significantly associated with improved overall survival (hazard ratio, HR = 0.38, 95% CI 0.22 – 0.67, p = 0.0008).

When researchers stratified the monocyte content as either high or low, the median overall survival was 24.3 months for the high content group but only 8.6 months for the lower level group.

Commenting on these findings, the researchers suggested that the pre-treatment tumour monocyte count could be a particularly useful marker of durable benefit for those prescribed immunochemotherapy.

The researchers observed a drop in monocyte levels following immune checkpoint inhibitor therapy, yet patients still went on to achieve a clinical benefit.

They therefore suggested that the use of immune checkpoint inhibitors may drive differentiation of intra-tumoural monocytes into pro-inflammatory myeloid effectors and that this was a more likely explanation for the improved outcomes.

Oesophageal cancer risk related to higher genetically predicted coffee consumption

1st September 2022

Oesophageal cancer risk is causally associated with genetically-predicted coffee consumption and this effect might be temperature-related

Oesophageal cancer risk is associated with genetically predicted coffee consumption even after adjustment for factors such as body mass index (BMI), smoking initiation and alcohol intake according to the findings of a Mendelian randomisation study by UK and Swedish researchers.

Coffee drinking has been found to have a wide range of health benefits including a reduced risk of cardiovascular disease and cancer.

Coffee contains a wide range of compounds, some of which including kahweol that has been reported to exert anti-cancer properties. Moreover, coffee has been associated with a significant decrease in the risk of colorectal cancer and colon cancer with a higher intake of the beverage also linked to a lower risk of prostate cancer.

Nevertheless, much of the data has been derived from epidemiological studies which can be subject to confounding and reverse causality, i.e., where the direction of causality between to factors is the opposite of what might be expected.

A Mendelian randomisation (MR) study is designed to avoid the problems due to confounding and reverse causality and assesses whether the genetically-predicted levels of a risk factor, for instance, coffee consumption, and a disease outcome, such as oesophageal cancer are associated.

Since genetic variants are present at birth, MR studies reduce the potential for reverse causality and confounding and are therefore more likely to generate a causal interpretation.

In the present study, researchers investigated the association of genetically-predicted coffee consumption and the risk of 22 different cancers which, for example, included those affecting the ovary, thyroid and bladder.

There were a total of 15 single nucleotide polymorphisms (SNPs) identified to be associated with coffee consumption although only 12 of these were used in the analysis. Most of the SNPs were in gene regions (one for example was near a locus linked to the smell/test perception of coffee) that were likely to affect coffee drinking behaviour or behaviour indirectly by altering the metabolism of caffeine.

The researchers tested the association using data from the UK Biobank and also tested these for replication in the FinnGen consortium. The results were then adjusted for differences in genetically-predicted body mass index, smoking and alcohol consumption.

The effect sizes of the associations between genetically-predicted coffee consumption and cancer risk were scaled to a 50% increase in coffee consumption.

Oesophageal cancer risk and coffee consumption

Using a sample of 367,561 European participants, 59,647 had one of the 22 site-specific cancers. However, genetically-predicted coffee consumption was not associated with the risk of any cancer in the main analysis (odds ratio, OR = 1.05, 95% CI 0.98 – 1.14, p = 0.183) even after adjustment for BMI, smoking and alcohol intake.

But when the team looked at digestive system cancers overall, there was an increased risk (OR = 1.28, 95% CI 1.09 – 1.51, P = 0.003) and which remained significant after adjustment for BMI, smoking initiation and alcohol consumption.

This higher risk was largely driven by oesophageal cancer (OR = 2.79, 95% CI 1.73 – 4.50) in the Biobank and remained after adjustment for the effect of BMI, smoking and alcohol intake. In the FinnGen consortium, genetically predicted coffee consumption was associated with a non-significant increase in oesophageal cancer (OR = 2.01, 95% CI 0.57 – 7.05, p = 0.27) and which was attenuated after adjustment for BMI.

Coffee consumption was also associated with an increased risk of multiple myeloma in the Biobank data (OR = 2.25) even after adjustment and a reduced risk of ovarian cancer.

Interestingly, when the researchers looked at coffee consumption and individual’s preferences for drinking, they found that a preference for drinking warm (OR = 2.74) and hot (OR = 5.45) coffee was also significantly associated with a higher risk of oesophageal cancer but, surprisingly, not for very hot.

In a further subgroup analysis based on self-reported coffee intake, the risk of oesophageal cancer was similar among those drinking 1 – 3 cups/day compared with those who did not drink coffee and which the authors suggested might be due to consumption of tea.

The authors concluded that their study found evidence that coffee consumption was causally associated with a risk of oesophageal cancer and that there was some evidence that this was related to a temperature effect.

Citation
Carter P et al. Coffee consumption and cancer risk: a Mendelian randomisation study Clin. Nutr 2022

Study finds that oesophageal adenocarcinoma cases tripled in younger people over past 30 years

5th October 2021

Oesophageal cancer cases have tripled in under 50s over the past 30 years, a study presented at UEG Week Virtual 2021 has found.

The research, conducted in the Netherlands on almost 60,000 patients, found new cases of oesophageal adenocarcinoma had risen from 0.34 to 0.92 per 100,000 population between 1989 and 2018. There was an average increase of 1.5% in males and 3% in females. The dramatic increases were seen in patients under the age of 50 years old with oesophageal adenocarcinoma.

Experts believe that the rise in cases of oesophageal adenocarcinoma reflect changes in lifestyle-related risk factors for the disease, with increases in unhealthy habits including smoking, poor diet and reduced physical exercise.

Ali Al-Kaabi, from Radboud University Medical Centre in Nijmegen, Netherlands, and lead author of the study, explained, “The incidence of oesophageal adenocarcinoma is increasing in young adults. We know the disease is associated with Barrett’s oesophagus, which is a premalignant condition in the lower end of the oesophagus. Gastro-oesophageal reflux (acid reflux), obesity and smoking are also important risk factors for oesophageal adenocarcinoma. We also know that rates of these risk factors have all increased in young adults over the past 30 years.”

Oesophageal cancer is the seventh most common cancer worldwide and it is a highly fatal disease, accounting for 500,000 deaths each year. There are two main subtypes: oesophageal adenocarcinoma, which is linked to obesity and gastro-oesophageal reflux disease, and oesophageal squamous cell carcinoma, which is linked to alcohol and tobacco consumption.

Although patients under the age of 50 were more likely to be diagnosed at an incurable stage compared to those aged 50-74 and over 74 years (47%, 40% and 29% respectively), younger patients were more likely to undergo multimodality treatments and relative survival for the younger age group rose accordingly in comparison to older patients.

Over the study period, the highest survival rates were seen in under 50s with early-stage diseases, with their five-year survival increasing to 99% (+52%). Those who were classed as ‘potentially curable’ had a five-year survival rate of 46% (+22%), whilst incurable or palliative patients had an one-year survival rate of 32% (+11%).

“Relative survival has markedly improved in the younger age group, with a widening survival gap in comparison to older adults”, commented Ali Al-Kaabi. “These differences may reflect the fact that younger patients are more likely to be treated more aggressively with multiple treatments, including chemoradiotherapy followed by surgery, helping either to provide a cure or prolong patient life.

There are many symptoms for oesophageal cancer, but they can often be difficult to spot and confused with other gastrointestinal symptoms. These include having problems swallowing, feeling or being sick, heartburn and indigestion.

“Based on these study findings, it is important that adults under 50 are aware of these oesophageal cancer symptoms to enable earlier diagnosis and a higher chance of survival”, furthered Ali Al-Kaabi. “This is especially important in high-risk groups, including those that smoke, those with obesity, or those that have high levels of alcohol consumption.”