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5th March 2024
Population-level immunogenetic variation is a factor underlying lung cancer risk in current and former smokers, a large study has found.
Researchers used genetic and clinical data from two large-scale population cohorts – UK Biobank and FinnGen – together with multi-modal genomic analyses of non-malignant and lung tumour samples to evaluate the effect of human leukocyte antigen (HLA) heterozygosity on lung cancer risk.
The analysis found heterozygosity at the HLA class II (HLA-II) loci was associated with reduced risk of lung cancer over more than a decade of follow-up, study authors wrote in the journal Science
Of note, HLA-II heterozygosity was associated with reduced risk of lung cancer in both current and former smokers, but not never-smokers.
This suggested that smoking-derived antigens might augment the immune response to early neoplastic disease, they wrote.
In contrast, HLA-II homozygosity conferred substantial lifetime risk of disease (13.9% for current smokers in the UK Biobank cohort) and was independent of known clinical and genetic risk factors.
Co-senior author Dr Diego Chowell, assistant professor of oncological sciences, and immunology and immunotherapy at the Icahn School of Medicine at Mount Sinai in New York, which led the study in collaboration with the University of Helsinki and Massachusetts General Hospital, said the findings challenged conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, played a significant role in lung cancer risk, especially among smokers.
Dr Chowell said: ‘Further, when we added polygenic risk scores – which is a measure of genetic predisposition based on multiple genes – to the analysis, it increased the lifetime risk of lung cancer, specifically in smokers who have identical versions of the HLA-II genes.’
HLAs are cell surface molecules that recognise antigenic peptides and present them to T-cells to initiate an immune response.
In lung cancer, genetic variation in the HLA locus was known to be linked to tumour evolution and treatment outcomes, but it was unclear whether HLA polymorphisms reduced lung cancer risk, the researchers explained.
This study was designed to test the heterozygote advantage hypothesis, which is a foundational principle of the evolution of the HLA system and of HLA-mediated protection against disease.
‘According to this hypothesis, individuals heterozygous at HLA are afforded greater protection against disease because they present more antigens for T-cell recognition through their two different HLA allomorphs than do homozygous individuals and consequently clear infected or neoplastic cells more efficiently,’ the researchers wrote.
The data underscored the role of immunosurveillance in protecting against lung cancer, the researchers said.
‘The association of HLA-II heterozygosity with reduced risk of lung cancer implies that genetic variation in immune-surveillance is a feature of cancer susceptibility, together with environmental exposures, hereditary risk and DNA replication errors,’ they said.
The findings broadened the understanding of the role the host immune system played in cancer risk and might motivate the incorporation of immunogenetics into lung cancer screening programmes, the study authors concluded.
‘A greater understanding of immunogenetic determinants of cancer risk, including genetic variation in HLA and other immune genes and pathways commonly associated with autoimmune and infectious diseases, may foster the development of improved strategies for cancer prevention,’ they wrote.
The findings suggested that current or former smokers homozygous at HLA-II could be considered at an earlier age for low-dose computed tomographic (LDCT) screening, which might reduce lung cancer mortality.
Whether the combination of genotype-driven risk assessment and LDCT reduced lung cancer mortality compared with either method alone should be comprehensively investigated in a future prospective clinical trial, they said.
30th August 2023
Young men with a higher level of cardiorespiratory fitness have a significantly lower risk of developing several cancers in later life, according to the findings of a new study published in the British Journal of Sports Medicine.
It is already known that aerobic exercise induces interleukin-6 and suppresses a marker of DNA damage, which may account for a protective role in colon cancer. But whether being fit could reduce the risk of developing cancer in later life is far less clear.
For the recent study, Swedish researchers set out to assess the associations between cardiorespiratory fitness in young men and the incidence of site-specific cancer.
They turned to data held on men who underwent military conscription between 1968 and 2005 and for whom cardiorespiratory function was assessed by maximal aerobic workload cycle test at conscription.
The men’s level of fitness was then categorised as low, moderate or high, and those who received a cancer diagnosis before or within five years after the military conscription were excluded from the analysis.
The team included 1,078,000 men, of whom 6.9% subsequently developed cancer in at least one site during a mean follow-up of 33 years.
A higher cardiorespiratory fitness was linearly associated with a significantly lower risk of developing nine different cancers. This included cancer in the head and neck (Hazard ratio, HR = 0.81), oesophagus (HR = 0.61), stomach (HR = 0.79), pancreas (HR = 0.88) and liver (HR = 0.60).
In contrast, a higher cardiorespiratory fitness significantly increased the risk of being diagnosed with prostate cancer (HR = 1.07) and malignant skin cancer (HR = 1.31).
While it is an observational study and no firm conclusions can be drawn about cause and effect, the researchers suggested that the findings strengthened the incentive for promoting interventions aimed at increasing cardiorespiratory fitness in younger people.
12th June 2023
UVB phototherapy (UVBP) for the treatment of atopic eczema in adults does not increase the risk of cutaneous cancers, according to a retrospective analysis.
Published in the Journal of the American Academy of Dermatology, Taiwanese researchers retrospectively assessed whether UVBP use in adults with atopic eczema elevated the risk of cutaneous cancers.
The team undertook a nationwide, population-based cohort study from 2001-18 to estimate the risk of developing both non-melanoma skin cancer and melanoma. They excluded patients under 20 years of age, those with a prior diagnosis of skin cancer and individuals who had received PUVA therapy. The cohort of patients who had received UVBP were then matched 4:1 to a group of atopic eczema patients who had not received phototherapy.
The researchers calculated the number of UVBP sessions for each patient and adjusted their analysis for a number of covariates including immunosuppressant therapy.
After exclusion, a total of 1,241 patients in the UVBP group were matched to 4,964 patients in the non-UVBP group. For the entire cohort, mean age was 42.4 years and 65.8% were men.
Compared to those not receiving UVBP, there was no overall and significant increased risk of skin cancer in the phototherapy group (adjusted Hazard ratio, aHR = 0.91, 95% CI 0.35 – 2.35). Similarly, there was no increased risk of either non-melanoma skin cancer (aHR = 0.80, 95% CI 0.29 – 2.26) or cutaneous melanoma (aHR = 0.80, 95% CI 0.08 – 7.64).
In addition, the risk of either form of cutaneous cancer was not increased when analysed based on the number of UVBP sessions.
UVBP is a recommended second-line treatment following failure of first-line treatment in patients with atopic eczema. While the existing literature suggests that longer-term use of UVBP does not increase the risk of cancer, this evidence is derived from patients with psoriasis. Consequently, whether this treatment modality is also safe in the longer term among those with atopic eczema remains uncertain.
9th June 2023
SGLT2 inhibitor drug use in patients with diabetes appears to reduce cancer risk, according to a retrospective analysis by Taiwanese researchers.
Epidemiological evidence suggests that diabetes increases the risk of cancer. It is thought the combination of hyper-insulinaemia, chronic inflammation and hyperglycaemia could increase the growth of tumours. Consequently, it may be possible to reduce this risk with anti-diabetic treatment. A recent meta-analysis of randomised clinical trials, suggests that SGLT2 inhibitor drugs could lower cancer risk compared to placebo. However, the extent to which these drugs might reduce the risk of cancer in practice is less clear.
The current study, published in the Journal of Diabetes and its Complications, retrospectively compared cancer development among SGLT2 inhibitor users. The team matched these patients with a group not prescribed these drugs. The primary outcome was cancer development and the analysis adjusted for several potential confounders.
A cohort of 325,990 SGLT2 inhibitor users with mean age of 58.6 years (42.2% female) and 325,989 non-users was identified.
SGLT2 inhibitor users had a significantly lower cancer risk (adjusted hazard ratio, aHR = 0.79, 95% CI 0.76 – 0.83) than non-users. The risk of cancer was also higher among males (aHR = 1.35, 95% CI 1.30 – 1.41) and in patients aged 50-64 and older than 65 years.
Researchers also noticed that this risk reduction was dependent on the duration of SGLT2 inhibitor use. Short-term use (60-140 days) was actually linked to a higher cancer risk (aHR = 1.30, 95% CI 1.21 – 1.39).
In addition, while cancer risk was generally lower, there was a significant increased risk of pancreatic cancer (aHR = 1.51, 95% CI 1.22 – 1.87) which was consistent with the findings of a recent case study.
11th May 2023
Asthmatics have a higher risk of developing cancer, though use of inhaled steroids may have a slight protective effect, according to a US study.
Globally, cancer is the leading cause of mortality, with nearly 10 million recorded deaths in 2020. Data suggests that infection and inflammation contribute to a quarter of all cancers. In fact, the inflammatory milieu within a tumour seems to be an indispensable participant in tumour progression. In asthmatics, the inflammatory nature of their condition increases the risk of lung cancer. Nevertheless, other data either demonstrate a positive association or no association with the risk of other cancers.
In the current study, researchers sought to better understand the relationship between asthma and cancer risk. They analysed electronic health records in a US claims database. The team developed a matching cohort of those with and without asthma which served as the control group. Using regression models, researchers searched for any relationship between asthma and the subsequent development of cancer. The primary outcome was the time to a cancer diagnosis after the date of an asthma diagnosis.
The asthma cohort included 90,021 individuals matched to 270,063 without the disease. In multivariable analysis, asthmatics were more likely to develop cancer (hazard ratio, HR = 1.36, 95% CI 1.29 – 1.44). For example, significantly higher risks were observed for melanoma, blood, kidney and lung cancers. However, in contrast, risks were non-significant for bladder, colorectal and prostate cancers.
In a separate analysis examining the effect of inhaled steroid use, the overall cancer risk was slightly lower among steroid users (HR = 1.60 vs 1.11, inhaled steroid vs no steroid). Taken together, cancer risk was higher for nine of 13 cancers in asthmatics not using inhaled steroids but in only two cancers among steroid users. These findings suggest a possible protective effect of inhaled steroid use on cancer risk that requires further evaluation.
26th April 2023
A heart healthy lifestyle reduces the risk of cancer which suggests that both conditions share risk factors. This relationship appears to be bi-directional such that cancer patients with CVD risk factors have an increased chance of an adverse cardiac event. Some evidence also points to atherosclerotic CVD itself being a risk for the development of cancer. However, whether all forms of CVD increase cancer risk and if there is a relationship with the cancer type remains unclear.
In the current study, researchers sought to investigate the association between both atherosclerotic and non-atherosclerotic cardiovascular disease with the development of cancer. In a retrospective examination of an insurance claims database, the team identified patients initially free from cancer. These individuals were then categorised as having either atherosclerotic cardiovascular disease or non-atherosclerotic disease. This latter group had for instance, valvular heart disease, arrhythmias or congenital heart disease. In their analysis, the researchers made adjustments for age, sex, diabetes, hypertension, chronic kidney disease and hyperlipidaemia.
CVD and cancer risk
There were a total 27,195,088 individuals with data for analysis. Those with CVD had a 12% higher risk of developing cancer than those without the disease. (Hazard ratio, HR = 1.12, 95% CI 1.11 – 1.13). This risk was elevated for both atherosclerotic disease (HR = 1.20) and non-atherosclerotic disease (HR = 1.11).
Both forms of cardiovascular disease also linked to a higher incidence of a number of cancers. For example, atherosclerotic cardiovascular disease increased the risk of lung cancer more than two-fold (HR = 2.78). But this was slightly lower for non-atherosclerotic CVD (HR = 1.73).
Citation
Bell CF et al. Risk of Cancer After Diagnosis of Cardiovascular Disease. J Am Coll Cardiol CardioOnc. 2023
1st February 2023
US and Taiwanese researchers have shown that the use of a single low-dose computed tomography (CT) scan, together with a deep learning algorithm, allows for a prediction of an individual’s risk of lung cancer over the next six years.
The use of low-dose CT screening has been shown to reduce mortality from lung cancer. Such screening allows for the early detection of the disease and hence the potential for better patient outcomes, although it has been suggested that the current screening guidelines might overlook vulnerable populations with a disproportionate lung cancer burden. Nevertheless, the efficiency of lung cancer screening could be improved by individualising the assessment of future cancer risk. The problem is determining how this can achieved. To date, there are some data to support the use of clinical risk assessment models that incorporate various factors compared to simply using age and cumulative smoking exposure. However, there are enormous possibilities created by greater use of artificial intelligence and deep learning models. In fact, it has become possible to utilise low-dose CT scan results and the presence of pulmonary nodules, into a model and to therefore optimise the screening process. But how useful are other pieces of information gathered from a CT scan beyond the presence of nodules, and could this other information be used by a deep learning model to predict future cancer risk.
This was the aim of the current study in which researchers developed a model, which they termed ‘Sybil’ using the entire volumetric low-dose CT data, without clinical and demographic information, to predict an individual’s future cancer risk. Sybil was able to run in the background of a radiology reading station and did not require annotation by a radiologist. The model was validated using information from three independent screening datasets which included individuals who were non-smokers.
In total, data were retrieved from over 27,000 patients held in three separate databases. Sybil achieved an area under the curve (AUC) of 0.92, 0.86 and 0.94, for the 1-year prediction of lung cancer for each of these datasets. In addition, the concordance indices over 6 years were 0.75, 0.81 and 0.80 for the same three data sets.
The authors concluded that Sybil was able to accurately predict individual’s future risk of lung cancer based on a single low-dose CT scan and called for further studies to better understand Sybil’s clinical application.
Citation
Mikheal PG et al. Sybil: a validated Deep learning model to predict future lung cancer risk from a single low-dose chest computed tomography. Clin Oncol 2023
26th January 2023
Regular use of the herbicide glyphosate among farmers is associated with higher urinary levels of oxidative stress biomarkers, a key characteristic of carcinogens, according to US researchers.
Glyphosate appears to be one of the most widely used herbicides across the world. However, in 2015, the International Agency for Research on Cancer, deemed glyphosate as ‘probably carcinogenic to humans’ based on sufficient evidence derived from animal studies. Despite this assertion, the evidence derived from human studies is mixed. For example, a 2016 systemic review was unable to detect a causal relationship between use of the herbicide and lymphohematopoietic cancer. In contrast, a more recent, 2019 meta-analysis concluded that the findings from both experimental and mechanistic studies suggested a compelling link between the use of glyphosate-based herbicides and non-Hodgkin lymphoma. Moreover, while several in vitro studies indicate the the toxicological effects of glyphosate may occur through the induction of oxidative stress, the evidence from actual human studies is limited.
In the present study, the US team matched US farmers who self-reported use of glyphosate with non-farmers, with no history of cancer of exposure to pesticides within the last 10 years. Enrolled participates provided a first morning urine sample and were asked about use of specific pesticides in the last 12 months. Urinary concentrations of glyphosate and three oxidative stress biomarkers, 8-OHdG, 8-isoprostane and MDA were made and regression analysis performed after adjustments for age, lifestyle and medical factors.
Glyphosate and relationship with oxidative stress biomarkers
A total of 268 males with a mean age of 63.4 (100 of whom served as non-farming controls) were included in the analysis.
The highest quartile of glyphosate urinary concentration was significantly associated with the highest levels of 8-OHdG (geometric mean ratio, GMR = 1.15, 95% CI 1.03 – 1.28) and for MDA (GMR = 1.20, 95% CI 1.03 – 1.40) but not for 8-isoprostane.
Among farmers exposed to the herbicide within 1 day (compared to 5 to 7 days) of urine collection, there was also an association with both 8-OHdG (GMR = 1.20, 95% CI 1.01 – 1.42) and MDA (GMR = 1.28).
The authors suggested that since 8-OHdG reflects oxidative stress-induced DNA damage, their findings support the genotoxic potential of the herbicide.
They concluded that these findings may inform evaluations of the carcinogenic potential of the herbicide.
Citation
Chang VC et al. Glyphosate Exposure and Urinary Oxidative Stress Biomarkers in the Agricultural Health Study. J Natl Cancer Inst 2023.
27th October 2022
Patients who take up an invite for screening colonoscopy have a significantly reduced risk of developing colorectal cancer after 10 years according to the findings of a randomised trial by the NordICC study group.
In 2020, the World Health Organisation estimated that globally, there were 1.93 million cases of colorectal cancer and which resulted in 916,000 deaths. There are a variety of tests available for colorectal cancer screening and to date only the guaiac-based faecal occult blood test and sigmoidoscopy have been shown to reduce the incidence of colorectal cancer and its associated mortality in randomised trials. In addition to sigmoidoscopy, another endoscopic method is screening colonoscopy and which is considered to be the gold standard tool with a high sensitivity and specificity. However, to date, there are no large-scale randomised trials comparing the effectiveness of screening colonoscopy compared to no screening, to determine whether this impacts on the incidence of colorectal cancer.
In the present study, researchers created the Northern-European Initiative on Colorectal Cancer (NordICC) trial, which was a randomised trial investigating the effect of colonoscopy on colorectal cancer incidence and mortality. The trial enrolled individuals aged 55 to 64 who had not undergone previous screening and were randomised 1:2 to either an invitation to undergo screening colonoscopy or no invitation. The primary endpoint of the trial were the risks of colorectal cancer and death from the cancer after a 10 to 15 years, whereas the secondary endpoint was death from any cause.
Screening colonoscopy and cancer outcomes
A total of 84,585 individuals with a median age of 59 years (49.8% female) were enrolled, 28,220 of whom were invited for screening and who were followed-up for a median of 10 years. However, only 11,842 (42%) of participants accepted the invite and underwent screening.
The risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.2% in the usual care (i.e., non-invited group), which was associated with an 18% lower risk of cancer (Risk ratio, RR = 0.82, 95% CI 0.70 – 0.93). However, the risk of colorectal cancer-related death was not significantly different between the groups (RR = 0.90, 95% CI 0.64 – 1.16). In addition, during the follow-up period, there was a similar level of death (11%) from any cause, in both groups.
The above data related to those who responded to the invite for screening but when researchers undertook a per-protocol analysis, i.e., assuming that all invitees underwent screening, the results were even more impressive. The risk of colorectal cancer at 10 years was reduced even further (RR = 0.69, 95% CI 0.55 – 0.83) as was the risk of colorectal cancer death (RR – 0.50, 95% CI 0.27 – 0.77).
The authors concluded that inviting patients for screening colonoscopy reduced the 10-year risk of colorectal cancer compared to those who were not screened.
Citation
Bretthauer M et al. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death N Eng J Med 2022
22nd August 2022
A study has identified a higher male cancer risk in 19 out of 21 different cancers at shared anatomical sites which is only partially explained by known risk factors, underscoring the importance of sex-related biological features according to a study by a team of US researchers.
Cancer is a leading worldwide cause of deaths and which, according to the World Health Organisation, in 2020, was responsible for nearly one in six deaths. It is already recognised that there are sex-related differences in both the incidence and mortality from cancer. For example, the cancer incidence rate is 20% higher in men than in women though the male cancer death rate is 40% higher.
Moreover, the reasons behind this disparity remain to be determined although traditional risk factor such as smoking and alcohol intake are clearly important. In fact, one European study found that smoking-related deaths accounted for around 40% to 60% of the gender gap and alcohol-related mortality for 20% to 30% in Eastern Europe and 10% to 20% elsewhere in Europe.
In an attempt to better understand the reasons for these sex-related differences in cancer, the US team estimated the risk for 21 solid tumours at shared anatomical sites and examined whether the higher male cancer incidence could be explained by known risk factors, such as smoking, diet, physical activity and alcohol use.
They used data from the National Institutes of Health Diet and Health Study which began in 1995 and where a baseline questionnaire, asking about a wide range of issues including demographics, health status, co-morbidities and various lifestyle measures e.g. physical activity, levels of smoking, was mailed to over 3.5 million individuals aged 50 – 71 years of age.
For the current study, the US team restricted their analysis to a smaller cohort who had completed both the baseline and follow-up questionnaire between 1996 and 1997. The main aim of the research was to estimate both crude and covariate adjusted male-to-female risk ratios of cancer incidence and to determine the extent to which these covariates and risk factors could account for the sex-related disparity in cancer risk.
Male cancer incidence and cancer disparities
The cohort included a total of 294,100 individuals with a median age of 63.5 years (41.7% female) with a mean of 11.5 person-years follow-up for men and 12.4 person-years for women.
Cancer incidence was recorded for 21 cancers and the biggest difference in the male-female incidence risk ratio (IRR) was for oesophageal adenocarcinoma (IRR = 12.19, 95% CI 8.32 – 17.86) and for gastric cardia cancer (IRR = 4.93, 95% CI 3.59 – 6.77). In fact, only thyroid and gall bladder cancer were more common in women than men.
After adjustment for covariates, oesophageal adenocarcinoma remained more common in men (Hazard ratio, HR = 10.80, 95% CI 7.33 – 15.90) as did gastric cardia cancer (HR = 3.49). Overall and after adjustment, the higher risk for men remained for 11 of the cancers.
When examining the effect of known risk factors, among 7 cancers (lung, colon, rectum, other biliary tract, skin, bladder and oesophageal adenocarcinoma), the distribution of risk factors and covariates explained some of the observed differences, ranging from 11.2% (oesophageal adenocarcinoma) to 49.4% (lung cancer).
After adjusting for alcohol use, smoking status, body mass index and age groups, there was still no significant interaction effect for any of the cancer sites.
The authors concluded that sex-related biological factors appeared to represent major determinants of cancer incidence. The added that further analysis of physiologic, immunologic and genetic or genomic factors are needed across a wider range of cancers to better understand their contribution to the higher male cancer burden.
Citation
Jackson SS et al. Sex disparities in the incidence of 21 cancer types: Quantification of the contribution of risk factors Cancer 2022
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