Malmö Diet And Cancer Study Research Articles

Breast cancer recurrence in relation to mode of detection: implications on personalized surveillance.

The effectiveness of current follow-up guidelines after breast cancer treatment is uncertain. Tailored surveillance based on patient age and tumor characteristics may be more adequate. This study aimed to analyze the frequency of ipsilateral locoregional recurrences (LR) and second primary breast cancers (SP) detected outside of scheduled surveillance and to analyze risk factors associated with these events. Patients with surgically treated early-stage breast cancer from the Malmö Diet and Cancer Study (MDCS), 1991-2014 (n = 1080), and the Västernorrland region, 2009-2018 (n = 1648), were included. Clinical and pathological information on the primary tumor and recurrences was retrieved from medical records. The mode of recurrence detection was defined as detection within (planned) or outside (symptomatic) of scheduled surveillance. The median follow-up was 6.5 years. Overall, 461 patients experienced a recurrence. The most common initial event was distant metastasis (47%), followed by locoregional recurrence (LR) (22%) and second primary (SP) (18%). 56% of LR and 28% of SP were identified outside of scheduled surveillance. Logistic regression analysis revealed that younger age (under 50 years) (OR 2.57, 95% CI 1.04-6.88), lymph node-positive breast cancer (OR 2.10, 95% CI 1.03-4.39) and breast cancer of the HER2 positive subtype (OR 5.24, 95% CI 1.40-25.90) were correlated with higher odds of detecting a recurrence outside of planned surveillance. Most recurrent events were detected outside of scheduled surveillance, particularly for locoregional recurrences. Risk-based surveillance, which takes into account patient and tumor characteristics, might be more suitable for specific patient subsets.

Novel Plasma Biomarkers Associated with Future Peripheral Atherosclerotic Disease and Abdominal Aortic Aneurysm-Insights from Contemporary Prospective Studies from the Malmö Diet and Cancer Study.

The potential utility of inflammatory and hemodynamic plasma biomarkers for the prediction of incident lower extremity arterial disease (LEAD), carotid artery stenosis (CAS), isolated atherosclerotic disease without concomitant abdominal aortic aneurysm (AAA), and isolated AAA without concomitant atherosclerotic disease has not yet been integrated in clinical practice. The main objective of this prospective study was to find predictive plasma biomarkers for cardiovascular disease and to evaluate differences in plasma biomarker profiles between asymptomatic and symptomatic CAS, as well as between isolated atherosclerotic disease and isolated AAA. Blood samples collected at baseline from participants in the prospective Malmö Diet and Cancer study (MDCS) cardiovascular cohort (n = 5550 middle-aged individuals; baseline 1991-1994) were used for plasma biomarker analysis. Validation of each incident cardiovascular diagnosis was performed by random sampling. Cox regression analysis was used to calculate hazard ratios (HRs) per one standard deviation increment of each respective log-transformed plasma biomarker with 95% confidence intervals (CI). Adjusted lipoprotein-associated phospholipase A2 (Lp-PLA2) activity (HR 1.33; CI 1.17-1.52) and mass (HR 1.20; CI 1.05-1.37), C-reactive protein (CRP) (HR 1.55; CI 1.36-1.76), copeptin (HR 1.46; CI 1.19-1.80), N-terminal pro-B-type natriuretic peptide (N-BNP) (HR 1.28; 1.11-1.48), and cystatin C (HR 1.19; 95% 1.10-1.29) were associated with incident symptomatic LEAD. Adjusted N-BNP (HR 1.59; CI 1.20-2.11), mid-regional proadrenomedullin (HR 1.40; CI 1.13-1.73), cystatin C (HR 1.21; CI 1.02-1.43), and CRP (HR 1.53; CI 1.13-1.73) were associated with incident symptomatic but not asymptomatic CAS. Adjusted HR was higher for Lp-PLA2 (mass) for incident isolated AAA compared to for isolated atherosclerotic disease. Plasma biomarker profile data support that subclinical vascular inflammation and cardiovascular stress seem to be relevant for the development of atherosclerotic disease and AAA.

Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk

Prostate cancer, a leading cause of cancer death among men, urgently requires new prevention strategies, which may involve targeting men with an underlying genetic susceptibility. To explore differences in risk of early prostate cancer death among men with higher vs lower genetic risk to inform prevention efforts. This cohort study used a combined analysis of genotyped men without prostate cancer at inclusion and with lifestyle data in 2 prospective cohort studies in Sweden and the US, the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS), followed up from 1991 to 2019. Data were analyzed between April 2023 and April 2024. Men were categorized according to modifiable lifestyle behaviors and genetic risk. A polygenic risk score above the median or a family history of cancer defined men at higher genetic risk (67% of the study population); the remaining men were categorized as being at lower genetic risk. Prostate cancer death analyzed using time-to-event analysis estimating hazard ratios (HR), absolute risks, and preventable deaths by age. Among the 19 607 men included for analysis, the median (IQR) age at inclusion was 59.0 (53.0-64.7) years (MDCS) and 65.1 (58.0-71.8) years (HPFS). During follow-up, 107 early (by age 75 years) and 337 late (after age 75 years) prostate cancer deaths were observed. Compared with men at lower genetic risk, men at higher genetic risk had increased rates of both early (HR, 3.26; 95% CI, 1.82-5.84) and late (HR, 2.26; 95% CI, 1.70-3.01) prostate cancer death, and higher lifetime risks of prostate cancer death (3.1% vs 1.3% [MDCS] and 2.3% vs 0.6% [HPFS]). Men at higher genetic risk accounted for 94 of 107 early prostate cancer deaths (88%), of which 36% (95% CI, 12%-60%) were estimated to be preventable through adherence to behaviors associated with a healthy lifestyle (not smoking, healthy weight, high physical activity, and a healthy diet). In this 20-year follow-up study, men with a genetic predisposition accounted for the vast majority of early prostate cancer deaths, of which one-third were estimated to be preventable. This suggests that men at increased genetic risk should be targeted in prostate cancer prevention strategies.

Metabolite Profiling in a Diet-Induced Obesity Mouse Model and Individuals with Diabetes: A Combined Mass Spectrometry and Proton Nuclear Magnetic Resonance Spectroscopy Study.

Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy techniques have been used extensively for metabolite profiling. Although combining these two analytical modalities has the potential of enhancing metabolite coverage, such studies are sparse. In this study we test the hypothesis that combining the metabolic information obtained using liquid chromatography (LC) MS and 1H NMR spectroscopy improves the discrimination of metabolic disease development. We induced metabolic syndrome in male mice using a high-fat diet (HFD) exposure and performed LC-MS and NMR spectroscopy on plasma samples collected after 1 and 8 weeks of dietary intervention. In an orthogonal projection to latent structures (OPLS) analysis, we observed that combining MS and NMR was stronger than each analytical method alone at determining effects of both HFD feeding and time-on-diet. We then tested our metabolomics approach on plasma from 56 individuals from the Malmö Diet and Cancer Study (MDCS) cohort. All metabolic pathways impacted by HFD feeding in mice were confirmed to be affected by diabetes in the MDCS cohort, and most prominent HFD-induced metabolite concentration changes in mice were also associated with metabolic syndrome parameters in humans. The main drivers of metabolic disease discrimination emanating from the present study included plasma levels of xanthine, hippurate, 2-hydroxyisovalerate, S-adenosylhomocysteine and dimethylguanidino valeric acid. In conclusion, our combined NMR-MS approach provided a snapshot of metabolic imbalances in humans and a mouse model, which was improved over employment of each analytical method alone.

Associations between modifiable and non‐modifiable risk factors and domain‐specific cognitive decline over a 17‐year period

AbstractBackgroundModifiable risk factors account for 40% of worldwide dementias. However, to what extent different risk factors are associated with different types of cognitive decline remains unclear. The aim of this study was to investigate how different risk factors contribute to future decline in memory and attention/executive function, respectively.MethodBaseline examination of individuals without dementia in the prospective Swedish population‐based Malmö Diet and Cancer Study (MDCS) took place in 1991‐1996. In 2007‐2012, a randomly selected subsample was invited to a re‐examination using cognitive assessments (the Mini‐Mental State Examination [MMSE], A Quick Test of cognitive speed (AQT) and, for a sub‐population, The Montreal Cognitive Assessment (MoCA). Participants with complete data on cognitive assessments, body measurements, education and APOE genotype were included in the study (n = 2,881; n = 720 with MoCA). Linear regression models were used to examine the modifiable risk factors (hypertension, body mass index [BMI], long‐term glucose levels [HbA1c], lipid levels, physical activity and alcohol consumption) and non‐modifiable risk factor (APOE‐genotype). Follow‐up outcomes were 1) AQT‐color/form (processing speed and executive function, higher scores indicating worse function), 2) delayed recall and orientation scores from MMSE (memory function), and 3) subscores from MoCA. All models were adjusted for age, sex, education and time between baseline and cognitive assessments.ResultMedian follow‐up time was 17.3 (inter‐quartile range [IQR] 2.2) years. APOE‐e4 and higher HbA1c levels were independently associated with worse future memory function in a multivariable model (Table 1). Mean arterial blood pressure, obesity, lower HDL‐C, and higher HbA1c levels were independently associated with worse future processing speed/executive function (Table 2). Higher alcohol consumption was associated better performance in executive function (Table 2). Similar results were found using corresponding MoCA subscores (delayed recall and orientation subscores; visuospatial/executive and attention subscores).ConclusionIn this prospective, population‐based, 17‐years follow‐up study, cardiovascular risk factors in mid‐life were associated with future decline in processing speed and executive functions, while an APOE‐e4 genotype was associated with worse memory function. Alcohol consumption in mid‐life was associated with better performance in both cognitive domains. These results suggest that targeting cardiovascular risk factors in interventions may have a greater effect on future executive function than memory.

Adherence to dietary guidelines, and the risk of developing rheumatoid arthritis: results from a nested case-control study.

To examine the relationship between adherence to dietary guidelines and the risk of developing RA. Participants in the Malmö Diet and Cancer Study (MDCS) cohort diagnosed with RA were identified through register linkage and validated in a structured review. Four controls per case were selected, matched for sex, year of birth, and year of inclusion in the MDCS. Diet was assessed at baseline (1991-1996) using a validated diet history method. A Diet Quality Index (DQI) based on adherence to the Swedish dietary guidelines including intakes of fibre, vegetables and fruits, fish and shellfish, saturated fat, polyunsaturated fat, and sucrose, was used. The associations between the DQI and its components and the risk of RA were assessed using conditional logistic regression analysis, adjusting for total energy intake, smoking, leisure time physical activity and alcohol consumption. We identified 172 validated cases of incident RA in the cohort. Overall adherence to the dietary guidelines was not associated with the risk of RA. Adherence to recommended fibre intake was associated with decreased risk of RA in crude and multivariable-adjusted analyses, with odds ratios (ORs) 0.60 (95% CI 0.39, 0.93) and 0.51 (95% CI 0.29, 0.90), respectively, compared with subjects with non-adherence. Reaching the recommended intake level of dietary fibre, but not overall diet quality, was independently associated with decreased risk of RA. Further studies are needed to assess the role of different food sources of dietary fibre in relation to risk of RA and the underlying mechanisms.

Abstract PD12-02: PD12-02 Obesity is associated with poor breast cancer prognosis, particularly among women with low socioeconomic position

Abstract Purpose: To examine the association between obesity and breast cancer outcomes and to describe socioeconomic position (SEP) in patients enrolled in the Malmö Diet and Cancer Study (MDCS) according to anthropometric measures. Patients and methods: The MDCS is a prospective cohort study that enrolled 17,035 female individuals in Malmö, Sweden from 1991 to 1996. The primary objective of the MDCS was to investigate associations between dietary patterns and cancer risk. Body mass index (BMI) and waist circumferences were measured upon enrollment, in the MDCS cohort. We identified all female MDCS participants with incident invasive breast cancer diagnosed between 1991 and 2014. The primary endpoint was breast cancer recurrence, defined as the time from breast cancer diagnosis until the earliest occurrence of invasive loco-regional recurrence or distant metastases. Follow-up time began at breast cancer diagnosis and continued until the first of breast cancer recurrence, death, emigration, or end of follow-up (June 8, 2020). BMI and waist circumference were categorized according to the World Health Organization guidelines as healthy weight (18.5-24.9 kg/m2 or waist < 81 cm), overweight (25.0-29.9 kg/m2 or waist 81-85 cm), and obese (≥ 30.0 kg/m2 or waist > 85 cm). Consistent with the Swedish socioeconomic classification, we categorized labor status into two groups—manual labor and non-manual labor. We categorized socioeconomic position (SEP) as low if patients had unskilled manual labor with < 2 years post-high school education, low-middle if skilled manual labor with > 2 years of post-high school education, high-middle if assistant non-manual labor with < 3 years of post-high school education, and high if non-manual labor with > 3 years of post-high school education. We fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI) of breast cancer recurrence as well as all-cause mortality according to BMI and waist circumference. To evaluate effect measure modification, we stratified the Cox models by labor status, SEP, and smoking. Results: Among 1,099 breast cancer patients, 263 breast cancer recurrences were diagnosed over 12,810 person-years with a median follow-up of 11.1 years (interquartile range [IQR] was 6.6-16.2). The cohort consisted of 556 patients with healthy weight, 384 patients with overweight, and 159 patients with obesity. The median age at breast cancer diagnosis was 66.3 years (IQR: 61.2-72.8), and patients with obesity were older than patients with healthy weight (69.2 vs 64.9 years). In multivariable analyses, having obesity according to BMI was associated with increased rate of recurrence (HR= 1.44 [95% CI: 1.00-2.07]) and all-cause mortality (HR= 1.50 [95% CI: 1.13-1.98]) in comparison to having healthy weight. Similarly, having obesity according to waist circumference was associated with higher risk of recurrence (HR= 1.31 [95% CI: 0.98-1.77]) and all-cause mortality (HR= 1.72 [95% CI: 1.39-2.13]) in comparison to having healthy weight. When evaluating effect measure modification, we observed that obesity was associated with breast cancer recurrence in obese non-smoking women (HR= 1.66 [95% CI: 1.01-2.73]), in obese women with manual labor (HR= 2.45 [95% CI: 1.22-4.93]), and obese women with low SEP (HR= 2.55 [95% CI: 1.08-6.02]). We observed little evidence of an association between obesity and breast cancer recurrence among smokers (HR= 1.12 [95% CI: 0.43-2.92]), among patients with non-manual labor (HR= 0.94 [95% CI: 0.44-2.00]), or among patients with high SEP (HR= 1.47 [95% CI: 0.58-3.75]). Conclusion: Obesity defined by pre-diagnostic levels of BMI and waist circumference was associated with an increased risk of recurrence and all-cause mortality among breast cancer patients. The association between obesity and breast cancer recurrence seems dependent on patient characteristics such as labor status, socioeconomic position, and smoking. Citation Format: Sixten Harborg, Maria Feldt, Deirdre Cronin-Fenton, Susanne Dalton, Ann Rosendahl, Signe Borgquist. PD12-02 Obesity is associated with poor breast cancer prognosis, particularly among women with low socioeconomic position [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-02.

Red cell distribution width and its polygenic score in relation to mortality and cardiometabolic outcomes.

Elevated red cell distribution width (RDW) has been associated with a range of health outcomes. This study aims to examine prognostic and etiological roles of RDW levels, both phenotypic and genetic predisposition, in predicting cardiovascular outcomes, diabetes, chronic kidney disease (CKD) and mortality. We studied 27,141 middle-aged adults from the Malmö Diet and Cancer study (MDCS) with a mean follow up of 21 years. RDW was measured with a hematology analyzer on whole blood samples. Polygenic scores for RDW (PGS-RDW) were constructed for each participant using genetic data in MDCS and published summary statistics from genome-wide association study of RDW (n = 408,112). Cox proportional hazards regression was used to assess associations between RDW, PGS-RDW and cardiovascular outcomes, diabetes, CKD and mortality, respectively. PGS-RDW was significantly associated with RDW (Pearson's correlation coefficient = 0.133, p < 0.001). RDW was significantly associated with incidence of stroke (hazard ratio (HR) per 1 standard deviation = 1.06, 95% confidence interval (CI): 1.02-1.10, p = 0.003), atrial fibrillation (HR = 1.09, 95% CI: 1.06-1.12, p < 0.001), heart failure (HR = 1.13, 95% CI: 1.08-1.19, p < 0.001), venous thromboembolism (HR = 1.21, 95% CI: 1.15-1.28, p < 0.001), diabetes (HR = 0.87, 95% CI: 0.84-0.90, p < 0.001), CKD (HR = 1.08, 95% CI: 1.03-1.13, p = 0.004) and all-cause mortality (HR = 1.18, 95% CI: 1.16-1.20, p < 0.001). However, PGS-RDW was significantly associated with incidence of diabetes (HR = 0.96, 95% CI: 0.94-0.99, p = 0.01), but not with any other tested outcomes. RDW is associated with mortality and incidence of cardiovascular diseases, but a significant association between genetically determined RDW and incident cardiovascular diseases were not observed. However, both RDW and PGS-RDW were inversely associated with incidence of diabetes, suggesting a putative causal relationship. The relationship with incidence of diabetes needs to be further studied.

Polygenic scores for low lung function and the future risk of adverse health outcomes

AimsReduced lung function and adverse health outcomes are often observed. This study characterizes genetic susceptibility for reduced lung function and risk of developing a range of adverse health outcomes.MethodsWe studied 27,438 middle-aged adults from the Malmö Diet and Cancer study (MDCS), followed up to 28.8 years. Trait-specific Polygenic scores (PGS) for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were constructed for each participant using MDCS genetic data and summary statistics from the latest GWAS of lung function. Linear regression models and cox proportional hazards regression models were used to assess associations between adverse health outcomes and lung function-PGS.ResultsFEV1-PGS and FVC-PGS were significantly associated with mean sBP at baseline after adjustments (FEV1-PGS Q1 (highest PGS = highest lung function): 140.7mmHg vs. Q4: 141.5mmHg, p-value 0.008). A low FVC-PGS was significantly associated with the risk of future diabetic events after adjustments (Q4 vs. Q1 HR: 1.22 (CI 1.12–1.32), p-trend < 0.001) and had added value to risk prediction models for diabetes. Low FEV1-PGS was significantly associated with future coronary events (Q4 vs. Q1 HR: 1.13 (CI: 1.04–1.22), p-trend 0.008). No significant association was found between PGS and sudden cardiac death, chronic kidney disease or all-cause mortality. Results remained largely unchanged in a subgroup of subjects when further adjusted for apolipoproteins.ConclusionGenetic susceptibility for reduced lung function is associated with higher sBP, increased risk of diabetes and to a lesser extent, future coronary events, suggesting etiological roles of lung function on these outcomes. Using PGS, high-risk groups could be early detected to implement early lifestyle changes to mitigate the risk.

Carpal Tunnel Syndrome and Ulnar Nerve Entrapment at the Elbow Are Not Associated With Plasma Levels of Caspase-3, Caspase-8 or HSP27.

BackgroundNerve compression disorders, such as carpal tunnel syndrome (CTS) and ulnar entrapment at the elbow (UNE), may be associated with apoptosis and neuroprotective mechanisms in the peripheral nerve that may be detected by biomarkers in the blood. The relationships between CTS and UNE and two biomarkers of apoptosis, i.e., caspase-3 and caspase-8, and the neuroprotective factor Heat Shock Protein 27 (HSP27) in plasma were examined in a population-based cohort.MethodThe biomarkers caspase-3, caspase-8 and HSP27 were measured in plasma at inclusion of 4,284 study participants aged 46–68 years in the population-based Malmö Diet and Cancer study (MDCS). End-point retrieval was made from national registers concerning CTS and UNE. Independent t-test was used to examine the association between caspase-3, caspase-8 and HSP27 plasma levels and incidence of CTS and UNE. Cox proportional hazards regression was used to investigate if plasma levels of caspase-3, caspase-8 and HSP27 affected time to diagnosis of CTS or UNE.ResultsDuring the mean follow-up time of 22 years, 189/4,284 (4%) participants were diagnosed with CTS and 42/4,284 (1%) were diagnosed with UNE. No associations were found between incident CTS or UNE and the biomarkers caspase-3, caspase-8 and HSP27 in plasma.ConclusionThe apoptotic biomarkers caspase-3 and caspase-8 and the neuroprotective factor HSP27 in plasma, factors conceivably related to a nerve injury, are not associated with the nerve compression disorders CTS and UNE in a general population.

Abstract P4-07-06: Circulating lipids and breast cancer survival in the Malmö diet and cancer study

Abstract Rationale: Overweight and obesity are associated with inferior prognosis in breast cancer. The explanation is considered multifactorial, and dyslipidemia may be a contributing factor. The purpose of this study was to examine the association between circulating lipids and breast cancer outcomes in patients enrolled in the Malmö Diet and Cancer Study (MDCS). Patients and methods: Circulating lipid levels were measured in the blood sampled upon enrollment in the female MDCS cohort (N=17,035). We identified all MDCS participants with incident invasive breast cancer diagnosed between 1991-2014. The follow-up time began at breast cancer diagnosis and continued until the first event of breast cancer recurrence, death, emigration, or five years of follow-up. We estimated the incidence rates of recurrence at five years and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI) of breast cancer recurrence as well as all-cause mortality according to cohort-specific tertiles of apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B). Results: We enrolled 850 eligible patients. During the five years of follow up, 90 invasive recurrences with over 3,807 person-years occurred. In multivariable analyses, high levels of Apo B were associated with an increased rate of recurrence (tertile 3 vs. 1, HR= 2.30 [95% CI: 1.13-4.68]). However, high levels of Apo B were not associated with all-cause mortality (tertile 3 vs. 1, HR= 1.23 [95%CI: 0.68-2.25]). We observed no associations between levels of Apo A-1 and recurrence (tertile 3 vs. 1, HR= 1.34 [95%CI: 0.70-2.58]) or all-cause mortality (tertile 3 vs. 1, HR=1.12 [95%CI: 0.61-2.05]). Conclusion: High pre-diagnostic levels of Apo B were associated with an increased risk of recurrence among breast cancer patients. Circulating Apo A-1 was not associated with breast cancer outcome. These results warrant further investigation into the importance of lipid-regulation in breast cancer patients. Citation Format: Sixten Harborg, Thomas P Ahern, Maria Feldt, Ann H Rosendahl, Deirdre Cronin-Fenton, Olle Melander, Signe Borgquist. Circulating lipids and breast cancer survival in the Malmö diet and cancer study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-06.

Statin use and patterns of breast cancer recurrence in the Malmö Diet and Cancer Study

BackgroundAccumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear. Patients and methodsWe identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users. ResultsThe final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 [95% CI: 0.82–0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 [95% CI: 0.80–0.94]) but not loco-regional recurrence (HRadj = 0.97 [95% CI: 0.87–1.08]). ConclusionIn the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.

The association between diet in mid‐life and dementia incidence over a 20‐year period

AbstractBackgroundModifiable risk factors account for 40% of worldwide dementias. A potential modifiable risk factor for dementia and cognitive impairment is diet. However, there are conflicting results and methodological weaknesses in previous studies. The aim of this study was to investigate whether midlife diet quality is associated with subsequent risk of developing all‐cause dementia, Alzheimer’s disease (AD) or vascular dementia (VaD). In addition, the association between diet quality and future accumulation of β‐amyloid (Aβ) in cerebrospinal fluid (CSF) was examined.MethodBaseline examination within the Swedish population‐based Malmö Diet and Cancer Study (MDCS) took place between 1991‐1996 on 30,447 middle‐aged individuals. Participants from the MDCS with complete baseline dietary examination were included in this study (n=28,027) and the follow‐up for incident dementia took place until December 31, 2014. Diagnoses were collected from the Swedish National Patient Register and validated by Memory Clinic physicians. CSF Aβ42 was available in a sub‐population (n=777). Information on dietary habits was gathered through a 7‐day food diary, a detailed food frequency questionnaire and a one‐hour interview. A diet quality index was calculated from adherence to nutrition recommendations of intake of dietary fibre, added sugar, fish and shellfish, fruit and vegetables and red and processed meat (0‐5 points, poor to good). Cox proportional hazard models were used to examine associations between diet and risk of developing dementia adjusted for age, sex, education, total caloric intake and season.ResultDuring a median of 19.8 years of follow‐up, 1,943 (6.9%) participants were diagnosed with dementia. Individuals adhering to diet recommendations did not lower the risk of developing all cause dementia (HR 0.98, 95% CI 0.95‐1.02), AD (HR 0.99, 95% CI 0.95‐1.04) or VaD (HR 0.98, 95% CI 0.91‐1.06). No significant association was found between diet score and abnormal Aβ accumulation measured with CSF Aβ42 (OR 1.10, 95% CI 0.66‐1.84),Conclusion: In this long‐term prospective cohort study, adherence to dietary recommendations for fibre, sugar, fish, fruit and vegetables and red and processed meat was not significantly associated with subsequent reduced risk for developing all‐cause dementia, AD or VaD.

Diabetes Mellitus as a Risk Factor for Trigger Finger -a Longitudinal Cohort Study Over More Than 20 Years.

Trigger finger (TF) or stenosing tenosynovitis has been associated with diabetes mellitus (DM), although today's knowledge is mostly based on cross-sectional and case-control studies. Thus, the aim of the present population-based cohort study over more than 20 years was to investigate DM as a risk factor for TF. Data from Malmö Diet and Cancer Study (MDCS), including 30,446 individuals, were analysed with regards to baseline DM and known or potential confounders. Information regarding TF diagnosis until study end date of Dec 31st, 2018, was retrieved from the Swedish National Patient Register (NPR) using ICD-codes. Survival probability was investigated in Kaplan-Meier plots. Cox proportional hazard regression model was used to evaluate DM as risk factor for TF, adjusted for several confounders and presented as Hazard Ratio (HR) with 95% confidence intervals (CI). At baseline, 4.6% (1,393/30,357) participants had DM. In total, 3.2% (974/30,357) participants were diagnosed with TF during the study period. Kaplan-Meier plot showed that the probability for incident TF was significantly higher in participants with baseline DM compared with individuals without baseline DM. Adjusted HR for DM as risk factor for TF was 2.0 (95% CI: 1.5-2.6, p<0.001). This longitudinal study showed that DM is an important risk factor for developing TF. When adjusting for sex, age, BMI, manual work, statin use, smoking and alcohol consumption, DM remained the main risk factor for TF.

“Association of mammographic features with molecular breast tumor profiles”

PurposeMammographic density and tumor appearance are breast cancer prognostic factors. Conceivably, mammographic features are macroscopic reflections of tumor´s molecular composition, but to an unknown extent. Our aim was to study associations of mammographic features with molecular tumor profiles. MethodsInvasive breast cancers (2007-2016) in Malmö Diet and Cancer Study (MDCS) for which there were tumor RNA-sequencing analyses within Sweden Cancerome Analysis Network – Breast (SCAN-B) (n=102) or All Breast Cancer in Malmö (ABIM) (n=50) were identified. Density (fatty vs. dense), tumor appearance (mass vs. spiculation), and intrinsic subtypes were registered. Differences in gene/metagene expression and Microenvironment Cell Population Counter were analyzed with R. Overall survival was used as endpoint. ResultsNo gene expression differences between density groups was observed. In one cohort (but not the other), Luminal A tumors associated with fatty breasts. For spiculation vs. mass, (p<0.01, t-test) 86 genes were differentially expressed; only one gene was differentially expressed comparing density. Gene set enrichment analysis showed genes highly expressed in spiculated tumors were enriched for extracellular matrix-associated genes whereas genes highly expressed with masses were associated with proliferation. A spiculation metagene, based on differentially expressed genes, showed association with estrogen receptor positivity, lower grade, and improved survival, but it was not an independent prognostic factor. ConclusionThere are clear differences in molecular composition between breast tumors with a spiculated appearance vs. a mass as the dominant tumor appearance. However, there are no apparent molecular differences related to the density of the breast in which the tumor has arisen.

Diet and Lifestyle as Risk Factors for Carotid Artery Disease: A Prospective Cohort Study

Background: Stroke is one of the leading causes of death, and out of all stroke cases, 10–15% originate from a previously asymptomatic stenosis in the internal carotid artery. Aims: The aim of the study was to investigate whether dietary and lifestyle habits were associated with future risk of incident carotid artery disease (CAD). Methods: Baseline examinations on middle-aged individuals (n = 30,447) in the Malmö Diet and Cancer study (MDCS), a prospective cohort study, took place between 1991 and 1996 in Malmö, Sweden. Individuals with cardiovascular disease and diabetes mellitus were excluded at baseline, resulting in a total study population of 25,952 patients. Information on dietary intake was gathered through a 7-day food diary, a detailed questionnaire, and a 1-h interview. A diet quality index was calculated from adherence to recommended intake of 6 dietary components (saturated fat, polyunsaturated fat, fish and shellfish, fiber, vegetables and fruit, and sucrose). Individuals with a first registered diagnosis of CAD were identified from the Swedish National Patient register. Results: During a median follow-up of 21.8 years, 469 participants (1.8%) developed CAD. The diagnosis of incident CAD was validated and confirmed in 99% of a random sample of 100 individuals. Higher intake of vegetables and fruit was associated with a trend of decreased risk of CAD in a Cox regression analysis (hazard ratio of 0.76, 95% confidence interval 0.56–1.03; p = 0.080). Conclusions: In conclusion, the present study found a trend toward a protective effect of higher intake of vegetables and fruit against incident CAD. More prospective studies investigating the association between diet and CAD and stroke are needed in order to give firm recommendations.

The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival: the Malmö Diet and Cancer Study.

BackgroundGenetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear.PurposeTo investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS).Material and MethodsA total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991–2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1).ResultsMinor homozygotes of SNPs rs9383589, CCDC170 and rs6557161, ESR1 were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35–59.57; AOR 2.08, 95% CI 1.19–3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HRadj] 6.46, 95% CI 1.95–21.39; HRadj 2.30, 95% CI 1.33–3.96, respectively) compared to major homozygotes. For SNP rs3757318, ESR1, minor homozygotes (HRadj 7.46, 95% CI 2.28–24.45) were associated with poorer survival. We confirmed that rs6557161, ESR1 was significantly associated with both density and survival in the LIBRO-1 study.ConclusionThese findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.

Healthy diet and fiber intake are associated with decreased risk of incident symptomatic peripheral artery disease - A prospective cohort study.

Peripheral artery disease (PAD) is caused by atherosclerosis and associated with an increased risk of leg amputation, cardiovascular disease, and death. A healthy diet has been shown to reduce the risk of cardiovascular events, but relationships between diet, fiber intake, and incidence of PAD are virtually unknown. The aim was to investigate the long-term impact of diet on the development of PAD among 26,010 middle-aged individuals in the prospective Malmö Diet and Cancer study (MDCS). Data on dietary intake were collected through a 7-day food diary combined with a food questionnaire and a 1-hour interview. Adherence to a recommended intake of six dietary components - saturated fat, polyunsaturated fat, fish and shellfish, fiber, fruit and vegetables, and sucrose - was scored (sum 0-6 points) to assess a diet quality index, adjusting for potential confounders. Cox regression analysis was used to estimate associations between diet variables and PAD incidence expressed in hazard ratios (HR) with 95% CI. During a median follow-up of 21.7 years, 1122 participants developed PAD. Diet score was associated with a reduced risk of PAD in multivariable analysis (p = 0.03). When mutually adjusting for all dietary variables, only adherence to recommended levels of fiber intake was associated with a reduced risk of incident PAD (HR 0.84; 95% CI 0.72-0.99). In this prospective, population-based study including 26,010 participants with over 20 years of follow-up, a healthy diet, especially a high intake of fiber, was associated with a reduced risk of PAD. Primary prevention programs directed against PAD should therefore include a fiber recommendation.

Copeptin, B-type natriuretic peptide and cystatin C are associated with incident symptomatic PAD

Purpose: The aim of this study is to evaluate plasma biomarkers as predictors for peripheral arterial disease (PAD).Materials and methods: Prospective longitudinal cohort study of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (MDCS) (n = 5550; 1991–94). Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), mid-regional proadrenomedullin (MR-proADM), and conventional risk factors were measured at baseline. The diagnosis of symptomatic PAD was validated in 97% of the cases.Results: Cumulative incidence of PAD during median follow up of 23.4 years was 4.4% (men 5.9%, women 3.3%). Adjusted for age, sex, smoking, body mass index, hypertension, diabetes mellitus and total cholesterol, copeptin (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.19–1.80), N-BNP (HR 1.28; 95% CI 1.11–1.48), and cystatin C (HR 1.19; 95% CI 1.10–1.29) were independently associated with incident PAD. Subjects with the three biomarkers copeptin, N-BNP, and cystatin C in the highest quartiles, ran a high risk of incident PAD (HR 3.29; 95% CI 1.76–6.17) compared to those with no biomarker in the highest quartile.Conclusion: Copeptin, N-BNP, and cystatin C were associated with incident symptomatic PAD, implying that these biomarkers are sensitive indicators of early subclinical PAD.Clinical significanceFirst prospective longitudinal cohort study evaluating Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) as predictors for peripheral arterial disease (PAD).Copeptin, N-BNP, and Cystatin C where independently associated with incident symptomatic PAD after adjustment for conventional risk factors.Copeptin, N-BNP, and Cystatin C seem to be sensitive indicators of early subclinical PAD.

Probing the Virtual Proteome to Identify Novel Disease Biomarkers.

Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β. We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.