Rudolf Kaaks

Background: Fatigue is a common symptom in cancer patients associated with impaired quality of life (QoL). Little is known about long-term fatigue trajectories in prostate cancer (PCa) patients. Methods: Using the European Organisation for Research and Treatment of Cancer Quality of Life Group Core Questionnaire (EORTC QLQ-C30), 1758 men treated with radiotherapy (2014–2016) for non-metastatic PCa prospectively reported fatigue up to five years later. Associations between pre-radiotherapy characteristics and clinically important fatigue (Score: ≥39/100) two years post-radiotherapy were investigated using logistic regression. Fatigue trajectories were explored using latent class growth analysis and multinomial regression. Results: About 35% (608/1758) of patients experienced clinically important fatigue at least once from the start of radiotherapy up to five years later. Two years post-radiotherapy, 14% of patients reported fatigue, which was associated with pre-radiotherapy fatigue level (OR: 8.67), self-reported diabetes (OR: 1.94), BMI (OR: 1.07), and age (OR: 1.03). Long-term fatigue was strongly linked to pain, insomnia, pelvic symptoms, functional impairments, and reduced QoL. Four fatigue trajectories were identified, characterised by low (45%), moderate (42%), elevated and decreasing (8%), and (6%) increasing mean fatigue levels. Diabetes was associated with a 6 percentage point increase in the probability of experiencing an increasing fatigue trajectory. Conclusions: The findings emphasise the need for early identification of PCa patients susceptible to long-term fatigue. PCa patients with elevated pre-radiotherapy fatigue levels and diabetes may require closer monitoring in risk-stratified aftercare programmes.

Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study. We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.

The immune system is a major driver in pancreatic cancer development. Several prospective cohort studies have found associations for single immune system‐derived proteins such as IL6 or CRP, but results are inconclusive, and Omics‐based research is scarce. Hence, we aimed to investigate associations of a comprehensive protein panel with the risk of pancreatic cancer. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 92 immune proteins were measured in baseline blood samples of 406 incident pancreatic cancer cases and 406 sex‐ and age‐matched controls, using the Olink Immuno‐Oncology panel. Multivariable adjusted conditional logistic regression was used to estimate odds ratios (OR, 95% CI) for protein levels in association with pancreatic cancer risk. Eight biomarkers were associated with pancreatic cancer risk (MMP12, LAMP3, CD28, IL‐6, IL‐12, FASLG, PD‐L2, and PDCD1) but only MMP12 was significantly associated after multivariable adjustments for confounders and the seven proteins, with OR = 1.56 (95% CI: 1.20–2.03) for a doubling in protein concentration. After correction for multiple testing, none of the proteins were associated with risk. Restricting analyses to cases diagnosed within the first 4 years and 4–8 years after recruitment resulted in OR of 1.89 (95% CI: 1.28–2.80) and 1.37 (95% CI: 1.01–1.86) for MMP12, respectively. Higher levels of MMP12 were associated with pancreatic cancer risk specifically in those diagnosed shortly after recruitment, while other immune‐related factors were not associated with risk. Further cohort studies are needed to confirm our initial findings.

Background:Although there is evidence that Fusobacterium spp. in colon tissue is associated with prognosis, less is known about the association between antibody response to antigens expressed by fusobacteria and colorectal cancer–specific mortality.Methods:Antibody responses to 11 Fusobacterium nucleatum (ATCC 25586) antigens were measured in prediagnostic blood for 471 incident colorectal cancer cases (median time to diagnosis = 3.4 years), among whom 188 colorectal cancer–specific deaths and 250 total deaths were confirmed over a median follow-up of 9.2 years in the European Prospective Investigation into Cancer and Nutrition cohort. Cox models were conducted to examine associations between antigen seropositivity and colorectal cancer–specific mortality.Results:Seropositivity to fusobacterial antigens was not associated with overall or colorectal cancer–specific mortality, individually or combined. Similar results were observed when restricting to patients who donated blood <3 years prior to cancer diagnosis. When restricting to individuals diagnosed at an earlier age of onset (<55 years; N = 74), we observed positive associations for seropositivity to three fusobacteria antigens reflecting different putative autotransporter adhesins. The strongest association was for Fn1893 antigen seropositivity (HR, 6.95; 95% confidence interval, 1.78–27.2, compared with none) and colorectal cancer–specific mortality, but confidence intervals were wide.Conclusions:Although null overall, this is the first study to observe an association between antibody response to fusobacteria and colorectal cancer–specific mortality among individuals with earlier-onset colorectal cancer. Future studies are needed to confirm these findings and understand the role of systemic antibody responses to fusobacteria in cancer.Impact:Specific antigens expressed by fusobacteria may play a role in mortality from earlier-onset colorectal cancers.

Pre-diagnostic antibody responses to 11 F. nucleatum nucleatum (ATCC 25586) proteins and CRC-specific mortality among cases with blood draw <3 years prior to cancer diagnosis, in the EPIC cohort.

F. nucleatum (strain ATCC25586) antigens and antigen-specific cut-off values (MFI)

Background: Eligibility criteria for lung cancer (LC) screening aim to identify long-term smokers who have exceeded a minimum-risk threshold of having LC, while still having sufficiently long remaining life expectancy. For individuals who have once met eligibility criteria (i.e., reached sufficiently high LC risk), a question is whether longer-term smoking cessation and corresponding improvement in other-cause mortality risk could justify a higher maximum screening age for former smokers than for continuing smokers. Methods: We performed time-varying Cox models in the EPIC-Heidelberg cohort (N = 24,715), using 3-yearly questionnaire data collected between 1994 and 2014 to estimate hazard ratios (HRs) and incidence rates for death by LC or other causes, in relation to age-specific smoking status and eligibility by German LC screening criteria (LCSC). Results: Depending on age, models showed up to 3-fold higher risk of other-cause mortality for recent and LCSC-eligible smokers, relative to never smokers. Among former smokers, those who quit before age 30 or 40 showed no significant difference in other-cause mortality compared with never-smokers, in men and women, respectively. However, at higher quitting ages HRs increased up to about 1.9 for men who stopped at age ≥60, or 1.5 in women who stopped at age 50-10 years (thereby losing formal screening eligibility), showed HRs of about 1.5–3.0 for other-cause mortality in men and 1.3–1.9 in women. In both sexes, the absolute incidence rate for other-cause mortality amongst past-eligible smokers age 75-<80 was similar to that for current-eligible smokers of the younger, 70-10 years the risk of other-causes mortality remains elevated, but less so than for continuing smokers, which may argue for a moderate extension of the maximum age limit for LC screening. Larger studies will be needed to obtain more precise risk estimates.

Fatigue is a common symptom of cancer patients, which can impair quality of life even years after treatment. Little is known about genetic determinants of fatigue, especially in prostate cancer (PCa). This study aims to identify SNPs associated with long-term fatigue in a prospective cohort of PCa patients. A genome-wide association study was conducted in non-metastatic PCa patients treated with radiotherapy in 7 European countries and the USA. A total of 1,381 men recorded fatigue using the EORTC QLQ-C30 and 877 men additionally completed the Multidimensional Fatigue Inventory (MFI) up to two years post-radiotherapy. Clinically important fatigue is defined for the EORTC QLQ-C30 based on the proposed threshold as scores ≥39 and for the MFI as scores ≥75 ^th percentile in the general German male population aged ≥60 years. Regression models adjusted for demographic, disease- and treatment-specific characteristics examine SNPs associated with clinically important fatigue. Differential gene expressions are explored using expression quantitative trait analysis. rs142212041 located in the ACTR3/CBWD2 gene region is significantly associated ( P = 3×10 ^-8 ) with long-term physical fatigue in 643 men without physical fatigue pre-radiotherapy. Several potential risk loci ( P < 5×10 ^-6 ) are identified for distinct fatigue phenotypes. Gene expression differences are observed for ACTR3 and CBWD2 , although not significant after correction for multiple testing. The results emphasise the multidimensionality of fatigue and suggest a plausible biological mechanism in fatigue pathophysiology, previously discussed for myalgic encephalomyelitis/chronic fatigue syndrome, which might be a potential intervention target.