Risk of first recurrence after treatment in a population-based cohort of young women with breast cancer.

PURPOSE: Breast cancer (BC) in women under 45 is rare yet often aggressive. We aim to analyze loco-regional recurrences (LR), distant recurrences (DR), second breast cancers, and mortality in young BC patients. METHODS: We enrolled 776 women with non-metastatic BC ≤45 years diagnosed from 1970 to 2012. Variables included age, family history, tumor stage/grade, and treatment. We used multivariate Cox regression and competing risk models. RESULTS: Among the participants, 37.0% were diagnosed before the age of 40. Most had stage I or II, grade II, ER- and PR-positive, HER2-negative tumors. Over a median follow-up of 8.7 years, 10.1% experienced LR, 13.7% developed DR, and 10.8% died, primarily due to BC. The majority of recurrences occurred within the first five years. Older age (>40) significantly reduced the risk of LR and DR. Advanced disease stage, certain surgical strategies, and positive margins increased DR risk. In the cohort diagnosed between 2001 and 2012, recent diagnosis, triple-negative cancer, and hormonal therapy were associated with reduced LR risk. Breast-conserving surgery appeared to offer protective effects against DR. CONCLUSION: This study highlights that BC in young women carries a significant risk of early recurrence, with age, tumor characteristics, and treatment modalities influencing outcomes. The findings emphasize the need for tailored treatment strategies for young BC patients, focusing on surgical precision and aggressive adjuvant therapy for high-risk cases. This research contributes valuable insights into managing BC in younger patients, aiding in improving long-term outcomes.

Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors.

BACKGROUND: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. OBJECTIVE: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions. INTERVENTION: Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial-derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model. RESULTS AND LIMITATIONS: Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant. CONCLUSIONS: This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation. PATIENT SUMMARY: We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.

Cohort profile: COBLAnCE: a French prospective cohort to study prognostic and predictive factors in bladder cancer and to generate real-world data on treatment patterns, resource use and quality of life.

PURPOSE: Bladder cancer is a complex disease with a wide range of outcomes. Clinicopathological factors only partially explain the variability between patients in prognosis and treatment response. There is a need for large cohorts collecting extensive data and biological samples to: (1) investigate gene-environment interactions, pathological/molecular classification and biomarker discovery; and (2) describe treatment patterns, outcomes, resource use and quality of life in a real-world setting. PARTICIPANTS: COBLAnCE (COhort to study BLAdder CancEr) is a French national prospective cohort of patients with bladder cancer recruited between 2012 and 2018 and followed for 6 years. Data on patient and tumour characteristics, treatments, outcomes and biological samples are collected at enrolment and during the follow-up. FINDINGS TO DATE: We describe the cohort at enrolment according to baseline surgery and tumour type. In total, 1800 patients were included: 1114 patients with non-muscle-invasive bladder cancer (NMIBC) and 76 patients with muscle-invasive bladder cancer (MIBC) had transurethral resection of a bladder tumour without cystectomy, and 610 patients with NMIBC or MIBC underwent cystectomy. Most patients had a solitary lesion (56.3%) without basement membrane invasion (71.7% of Ta and/or Tis). Half of the patients with cystectomy were stage ≤T2 and 60% had non-continent diversion. Surgery included local (n=298) or super-extended lymph node dissections (n=11) and prostate removal (n=492). Among women, 16.5% underwent cystectomy and 81.4% anterior pelvectomy. FUTURE PLANS: COBLAnCE will be used for long-term studies of bladder cancer with focus on clinicopathological factors and molecular markers. It will lead to a much-needed improvement in the understanding of the disease. The cohort provides valuable real-world data, enabling researchers to study various research questions, assess routine medical practices and guide medical decision-making.

A Case-Only Genome-Wide Interaction Study of Smoking and Bladder Cancer Risk: Results from the COBLAnCE Cohort.

Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies.

Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.

BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.

Cohort profile: population-based cohorts of patients with colorectal cancer and of their relatives in Geneva, Switzerland.

PURPOSE: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Variability between patients in prognosis and treatment response is partially explained by traditional clinicopathological factors. We established a large population-based cohort of patients with CRC and their first-degree and second-degree relatives registered in the Canton of Geneva, to evaluate the role of family history and tumour biomarkers on patient outcomes. PARTICIPANTS: The cohort includes all patients with CRC diagnosed between 1985 and 2013. Detailed information on patient and tumour characteristics, treatment and outcomes were extracted from the Geneva Cancer Registry database, completed by medical records review and linkage with administrative and oncogenetics databases. Next-generation tissue microarrays were constructed from tissue samples of the primary tumour. A prospective follow-up of the cohort is realised annually to collect data on outcomes. First-degree and second-degree relatives of patients are identified through linkage with the Cantonal Population Office database and information about cancer among relatives is retrieved from the Geneva Cancer Registry database. The cohort of relatives is updated annually. FINDINGS TO DATE: The cohort includes 5499 patients (4244 patients with colon cancer and 1255 patients with rectal cancer). The great majority of patients were diagnosed because of occurrence of symptoms and almost half of the cases were diagnosed with an advanced disease. At the end of 2019, 337 local recurrences, 1143 distant recurrences and 4035 deaths were reported. At the same date, the cohort of first-degree relatives included 344 fathers, 538 mothers, 3485 children and 375 siblings. Among them, we identified 28 fathers, 31 mothers, 18 siblings and 53 children who had a diagnosis of CRC. FUTURE PLANS: The cohort will be used for long-term studies of CRC epidemiology with focus on clinicopathological factors and molecular markers. These data will be correlated with the most up-to-date follow-up data.

Occupational socioeconomic risk associations for head and neck cancer in Europe and South America: individual participant data analysis of pooled case-control studies within the INHANCE Consortium.

BACKGROUND: The association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures. METHODS: Pooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige-Treiman's Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position-International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs. RESULTS: For the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94). CONCLUSIONS: These findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.

Concordance of tumour characteristics and survival clustering among pairs of first-degree relatives with breast cancer.

BACKGROUND: Family history is a known risk factor for breast cancer, but its prognostic value and the prognostic value of tumour characteristics in relation to family history has not been clearly established. In addition, studies of intra-familial tumour characteristics and prognosis in population-based settings are very rare. Two previous studies have suggested that breast cancer prognosis clusters within families. However, both studies lack information on HER2 expression status, which is a strong prognostic factor and could contribute to the observed results. METHODS: We conducted a population-based study on 145 mother-daughter and sister-sister affected pairs using data extracted from the Geneva Cancer Registry. Histopathological characteristics were determined in archived tumour blocks by immunochemistry techniques. Breast cancer survival among family members was studied according to patient and tumour characteristics. RESULTS: No significant intra-familial agreement of pathological characteristic features was observed. We found that relatives of breast cancer patients experienced a much higher risk of breast cancer death compared to the general population. However, we did not find significant concordance in good and poor breast cancer-specific survival between pairs. The small number of family pairs and deaths from breast cancer may partly explain our results. CONCLUSIONS: Large-scale studies with accurate data on strong prognosticators are still needed to confirm the possibility of familial inheritance of breast cancer prognosis.  .

A data mining approach to investigate food groups related to incidence of bladder cancer in the BLadder cancer Epidemiology and Nutritional Determinants International Study.

At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case-control and one nested case-cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.

Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Analysis of Case-Control Studies.

Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.

Diesel Engine Exhaust Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Exposure-Response Analysis of 14 Case-Control Studies.

Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 µg/m3 were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

BACKGROUND: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk. METHODS: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models. RESULTS: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR<10 years vs. ≥30 years: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR<10 years vs. ≥30 years: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed. CONCLUSIONS: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.

A population-based cohort of young women diagnosed with breast cancer in Geneva, Switzerland.

PURPOSE: Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the fact that breast cancer is more frequent after fifty years of age, breast cancer among young women has recently drawn particular attention due to an increase in incidence in several western countries. With the exception of individuals with a high genetic risk, breast cancer occurring in younger women remains poorly understood. This project aims at investigating the patient, tumour and treatment characteristics as well as the long-term health outcomes of these women by evaluating numerous variables that were collected from their pathology and medical files, including the social environment, family history, fertility and pregnancy. PARTICIPANTS: We constituted a population-based cohort from the Geneva Cancer Registry of 1586 patients with breast cancer who were aged less than 46 years at the time of diagnosis. FINDINGS TO DATE: Breast cancer was diagnosed before the age of 35 years in 225 women (14.2%), between 35 and 39 years of age in 368 women (23.2%) and between 40 and 45 years of age in 993 women (62.6%). Most of the patients were diagnosed with luminal A or luminal B molecular subtypes (32.8 and 37.5%, respectively), stage I or II tumours (75.2%), and estrogen (74.8%) and progesterone (67.5%) positive receptors. During the study period, 16.7% of these women developed loco-regional recurrences and 25.4% developed distant metastases; the majority (66.3%) did not have a recurrence. Regarding mortality, 474 (29.9%) women died during the study period, 347 (73.2%) from breast cancer. FUTURE PLANS: The results of this study will help filling the knowledge gap about treatment of young breast cancer patients and having a child after breast cancer, and will provide clinicians and public health professionals' with additional information to improve quality of care and decrease the impact of breast cancer in young women.

Sex specific associations in genome wide association analysis of renal cell carcinoma.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

The association between coffee consumption and bladder cancer in the bladder cancer epidemiology and nutritional determinants (BLEND) international pooled study.

BACKGROUND: Inconsistent results for coffee consumption and bladder cancer (BC) risk have been shown in epidemiological studies. This research aims to increase the understanding of the association between coffee consumption and BC risk by bringing together worldwide case-control studies on this topic. METHODS: Data were collected from 13 case-control comprising of 5,911 cases and 16,172 controls. Pooled multivariate odds ratios (ORs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel logistic regression models. Furthermore, linear dose-response relationships were examined using fractional polynomial models. RESULTS: No association of BC risk was observed with coffee consumption among smokers. However, after adjustment for age, gender, and smoking, the risk was significantly increased for never smokers (ever vs. never coffee consumers: ORmodel2 1.30, 95% CI 1.06-1.59; heavy (> 4 cups/day) coffee consumers vs. never coffee consumers: ORmodel2 1.52, 95% CI 1.18-1.97, p trend = 0.23). In addition, dose-response analyses, in both the overall population and among never smokers, also showed a significant increased BC risk for coffee consumption of more than four cups per day. Among smokers, a significant increased BC risk was shown only after consumption of more than six cups per day. CONCLUSION: This research suggests that positive associations between coffee consumption and BC among never smokers but not smokers.

Multiple recurrences and risk of disease progression in patients with primary low-grade (TaG1) non-muscle-invasive bladder cancer and with low and intermediate EORTC-risk score.

AIM: To assess the prognostic value of multiple recurrences on the risk of progression in a large cohort of TaG1 bladder cancer of low and intermediate risk based on the EORTC score and to evaluate prognostic factors of multiple recurrences. MATERIALS AND METHODS: We retrospectively analyzed a French cohort of 470 patients with primary TaG1 bladder cancer diagnosed between 1986 and 2010 and followed until 2012. They were classified at low and intermediate risk using the EORTC risk score. Associations between the number of recurrences and the risk of progression to high grade Ta/T1 bladder cancer and progression to muscle-invasive disease were assessed. The characteristics of recurrences, as occurrence time or localization, and risk of other recurrences were evaluated. RESULTS: Out of 470 patients, 251 had recurrence, 34 progressed to high grade Ta/T1 and 17 to muscle-invasive disease, including 4 who had non muscle-invasive progression first. The median follow-up was 7.2 years (interquartile range: 4.2-10.9). In half the progressions, no previous recurrence was observed. No association between the number of recurrences and the risk of progression was detected. Even after 5 years free of event, patients had a 15% risk of recurrence. History of two or more recurrences increased by 4.5 the risk of subsequent recurrence. Time between two recurrences inferior to six months and multifocal localization increased the risk of recurrence. CONCLUSION: Surveillance of patients with TaG1 should be continued beyond 5 years of follow-up. However, cystoscopy exams could be spaced after 5 years. Multiple TaG1 recurrences did not appear to be prognostic for disease progression, but increased significantly the risk of subsequent recurrences. Short time between two recurrences and multifocal localization may serve to adapt monitoring of patients with TaG1 Bladder cancer.

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Impact of experience in breast cancer surgery on survival: the role of quality of care in a registry-based cohort.

AIMS OF THE STUDY: Previous studies have suggested that the surgeon's experience in breast cancer surgery may affect patient survival. In this registry-based retrospective cohort study, we examined whether quality of care could partly explain this association. METHODS: All invasive breast cancers operated on in the private sector between 2000 and 2009 were identified in the Geneva Cancer Registry and followed up for 5 years. Surgeons were classified according to their experience into three categories: ≤5, 6-10, >10 breast cancer operations performed per year. We extracted patient and tumour characteristics. Quality of care was scored as the proportion of 11 quality indicators correctly fulfilled for each patient. Breast cancer-specific mortality was examined with a Cox model adjusted for variables known to affect survival, surgeon experience, and quality of care. RESULTS: A total of 1489 patients were operated on by 88 surgeons; 50 patients (3.4%) died from breast cancer during the 5 years of follow-up. Socioeconomic status and country of birth of the patients, as well as period of diagnosis, differed according to the surgeons' experience. Quality of care provided improved with surgeons' experience. Surgeons performing >10 operations/year more frequently assessed histology before surgery, excised sentinel lymph nodes, removed ≥10 lymph nodes, and prescribed adjuvant radiotherapy when indicated. Crude breast cancer-specific mortality was lower in patients treated by surgeons performing >10 compared with ≤5 operations/year (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.17-0.67; p = 0.002). The strength of the association decreased after adjustment for patient and tumour characteristics (HR 0.45, 95% CI 0.21-0.94; p = 0.034) and decreased further after adjustment for quality of care (HR 0.51, 95% CI 0.24-1.08, p = 0.078). CONCLUSIONS: The association between surgeon's experience and 5-year breast cancer survival is at least partly explained by quality of care, patient and tumour characteristics. Further investigations on the impact of other quality indicators such as multidisciplinary networks are needed.

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.