Incident Renal Cell Carcinoma Research Articles

Renal cell carcinoma and risk of second primary cancer: A Danish nationwide cohort study.

To examine the risk of second primary cancer in patients with incident renal cell carcinoma (RCC). We identified all patients diagnosed with incident RCC during 1995-2019, using population-based Danish medical registries. Patients were followed from the date of RCC diagnosis until any second primary cancer diagnosis, death, emigration, or December 31, 2019, whichever came first. We computed the absolute risk, standardized incidence ratio (SIR), and excess absolute risk of second primary cancer, with 95% confidence intervals (CIs), among patients with RCC compared to the general population. The absolute 1- and 20-year risks of any second primary cancer were 2.8% and 17.8%, respectively. Within 1 year after RCC diagnosis, we detected 20 excess cancer cases per 1000 person-years (PY) (SIR, 2.3; 95% CI: 2.1-2.6). Moreover, we detected an additional four excess cancer cases per 1000 PY during 1 to <5 years of follow-up (SIR, 1.3; 95% CI: 1.2-1.4), and 6 per 1000 PY beyond 5 years of follow-up (SIR, 1.4; 95% CI: 1.3-1.5). The sustained elevated cancer risk beyond 1 year of follow-up was mainly attributed to excess risk of lung and bladder cancer. The risk of second primary cancer was higher in 2006-2019 than in 1995-2005, but only during the first year of follow-up. Patients with incident RCC have a sustained 40% elevated long-term risk of second primary cancer, compared with the general population. This increased risk is mainly attributed to lung and bladder cancer.

Decreased risk of renal cell carcinoma in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors.

Patients with type 2 diabetes (T2D) are at a higher risk of developing renal cell carcinoma (RCC) than the general population. Invitro and invivo investigations of the effects of sodium glucose cotransporter-2 inhibitors (SGLT2I) have shown a significantly reduced risk of RCC. However, the impact of these drugs on the incidence of RCC in the human population is unclear. This study aimed to examine the association between SGLT2I use and RCC risk in patients with T2D. We undertook a nationwide retrospective cohort study using the Health and Welfare Data Science Center database (2016-2020). The primary outcome was the risk of incident RCC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression modeling was applied to analyze the association between SGLT2I use and RCC risk in patients with T2D. In a cohort of 241,772 patients with T2D who were using SGLT2Is and 483,544 participants who were not, 220 and 609 RCC cases, respectively, were recorded. The mean follow-up period of the study subjects was 2 years. There was a decreased risk of RCC for SGLT2I users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.68; 95% CI, 0.58-0.81). The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.67; 95% CI, 0.55-0.81). The subgroup analysis revealed consistent results for sex, age (<70 years), and comorbidity with chronic kidney disease. The present study indicates that SGLT2I therapy significantly decreases RCC risk in patients with T2D. This finding was also consistent among the sensitivity test and subgroup analysis for those with or without chronic kidney disease/hypertension.

Risk of incident renal cell carcinoma in patients with type 2 diabetes on sodium-glucose co-transporter-2 inhibitor users: a population-based cohort study

Abstract Background and aims Patients with type 2 diabetes (T2D) are at substantially higher risk for developing renal cell carcinoma (RCC) than the general population. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 inhibitor (SGLT-2I) use on the development of incident RCC in patients with T2D, but the findings are inconsistent. This study aimed to examine the association between SGLT-2I use and incident RCC risk in patients with T2D. Methods We conducted a nationwide retrospective cohort study using the Taiwan Health Insurance Review and Assessment Service database (2009–2019). The primary outcome was the risk of incident RCC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Therefore, multiple Cox regression modeling was conducted to analyze the association between SGLT-2I use and incident RCC risk in patients with T2D. Results In a cohort of 241,772 patients with T2D using SGLT-2I and 483,544 participants not using SGLT-2Is, 220 and 609 incident RCCs were recorded, respectively. There was a decreased risk of incident RCC for SGLT-2I users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.68, 95% CI 0.58–0.81) compared with non-SGLT-2I users. The sensitivity test for the propensity score 1:1-matched analyses showed similar result (adjusted HR 0.67, 95% CI 0.56–0.81). Conclusions SGLT-2I therapy may effectively decrease RCC risk in patients with T2D. More studies are needed to credibly evaluate the effects of SGLT-2I therapy on RCC prevention in patients with T2D.

Abstract 5893: Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies

Abstract Background: Analgesics are the most commonly consumed over-the-counter drugs worldwide. Considerable evidence suggests a beneficial effect of analgesics, and especially aspirin, on cardiovascular disease and colorectal cancer risk. Studies examining whether widely used analgesics - aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen - play a role in renal cell carcinoma (RCC) have yielded mixed results. Methods: We examined associations between pre-diagnostic analgesic use and incidence of total and fatal RCC in the Health Professionals Follow-up Study (HPFS; 1986-2016), Nurses’ Health Study (NHS; 1980-2016 for aspirin; 1990-2016 for non-aspirin NSAIDs and acetaminophen), and Nurses’ Health Study 2 (NHS2; 1989-2015; total RCC only). Information on use of aspirin, non-aspirin NSAIDs, and acetaminophen was collected longitudinally on biennial questionnaires. We used Cox proportional hazards models to estimate cohort-specific, multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) according to current use (updated in each questionnaire period) and, separately, duration of use (since study baseline) of each analgesic. Results across cohorts were combined using random-effects meta-analyses. We also used Cox regression to evaluate post-diagnostic analgesic use with respect to RCC-specific mortality among RCC cases in the pooled HPFS and NHS cohorts. Results: Among 259,545 participants, 796 incident RCC cases were diagnosed. Neither current nor duration of pre-diagnostic use of any of the analgesics was associated with the risk of total RCC in meta-analyses of the three study cohorts. For fatal RCC (n=175 cases), however, meta-analyses of the HPFS and NHS suggested covariate-adjusted positive associations with current (HR: 1.37, 95% CI: 0.96-1.96, p-heterogeneity: 0.80) and duration of (HR&amp;gt;10yrs vs. Never: 2.62, 95% CI: 1.23-5.58, p-trend: 0.006, p-heterogeneity: 0.30) pre-diagnostic non-aspirin NSAID use. In addition, in the HPFS only, current (HR: 2.35, 95% CI: 1.33-4.17) and duration of (HR&amp;gt;10yrs vs. Never: 1.83, 95% CI: 0.42-7.93, p-trend: 0.07) pre-diagnostic acetaminophen use indicated positive associations with fatal RCC. Analyses of RCC-specific mortality among participants diagnosed with RCC demonstrated an inverse association with current post-diagnostic aspirin use (HR: 0.68, 95% CI: 0.48-0.97), but not duration of post-diagnostic aspirin use (HR&amp;gt;10yrs vs. Never: 0.89, 95% CI: 0.53-1.51, p-trend: 0.98). Analgesics were not otherwise associated with RCC survival. Conclusions: Our findings support a potential positive association between non-aspirin NSAID use and incident fatal RCC. It remains possible that analgesics may operate differently in the setting of RCC from the context of other chronic diseases. Citation Format: Rebecca E. Graff, Alejandro Sanchez, Toni K. Choueiri, Meir J. Stampfer, Edward L. Giovannucci, Lorelei A. Mucci, Eunyoung Cho, Mark A. Preston. Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5893.

The relationship between blood pressure and risk of renal cell carcinoma.

BackgroundThe relation between blood pressure and kidney cancer risk is well established but complex and different study designs have reported discrepant findings on the relative importance of diastolic blood pressure (DBP) and systolic blood pressure (SBP). In this study, we sought to describe the temporal relation between diastolic and SBP with renal cell carcinoma (RCC) risk in detail.MethodsOur study involved two prospective cohorts: the European Prospective Investigation into Cancer and Nutrition study and UK Biobank, including >700 000 participants and 1692 incident RCC cases. Risk analyses were conducted using flexible parametric survival models for DBP and SBP both separately as well as with mutuality adjustment and then adjustment for extended risk factors. We also carried out univariable and multivariable Mendelian randomization (MR) analyses (DBP: ninstruments = 251, SBP: ninstruments = 213) to complement the analyses of measured DBP and SBP.ResultsIn the univariable analysis, we observed clear positive associations with RCC risk for both diastolic and SBP when measured ≥5 years before diagnosis and suggestive evidence for a stronger risk association in the year leading up to diagnosis. In mutually adjusted analysis, the long-term risk association of DBP remained, with a hazard ratio (HR) per standard deviation increment 10 years before diagnosis (HR10y) of 1.20 (95% CI: 1.10–1.30), whereas the association of SBP was attenuated (HR10y: 1.00, 95% CI: 0.91–1.10). In the complementary multivariable MR analysis, we observed an odds ratio for a 1-SD increment (ORsd) of 1.34 (95% CI: 1.08–1.67) for genetically predicted DBP and 0.70 (95% CI: 0.56–0.88) for genetically predicted SBP.ConclusionThe results of this observational and MR study are consistent with an important role of DBP in RCC aetiology. The relation between SBP and RCC risk was less clear but does not appear to be independent of DBP.

751Investigation of the obesity paradox in kidney cancer: mystifying association or myth?

Abstract Background An “obesity paradox” has been reported in kidney cancer, whereby obesity is a risk factor, yet appears to be associated with better survival. To evaluate this paradox, we investigated the association between pre-diagnostic adiposity and renal cell carcinoma (RCC) incidence and mortality. Methods Using data from 363,521 men and women in the European Prospective Investigation into Cancer and Nutrition (EPIC), Cox regression models yielded confounder-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence and mortality in relation to BMI modelled continuously and using restricted cubic splines. RCC-specific and all-cause mortality were evaluated among cases. Results During a mean follow-up of 14.9 years, 936 incident RCC cases were identified, 383 of whom died (278 due to RCC). Each 5 kg/m2 increment in BMI was associated with 27% and 46% higher RCC incidence and mortality (HRs=1.27, 95% CI 1.18-1.37 and 1.46, 95% CI 1.28-1.66, respectively). Comparing a BMI of 35 with 22 kg/m2, HRs for RCC incidence and mortality were 1.88 (95% CI 1.54-2.30) and 2.37 (95% CI 1.68-3.35), respectively. Among RCC cases, HRs per 5 kg/m2 increment in BMI were 1.22 (95% CI 1.07-1.41) for RCC-specific mortality and 1.18 (95% CI 1.04-1.34) for all-cause mortality. Similar, positive linear associations were evident for waist circumference and waist-to-hip ratio. Conclusions Obesity was associated with increased RCC incidence and mortality, and worse prognosis among cases. Key messages The kidney cancer-obesity paradox does not appear to be real. Higher adiposity is associated with an increased risk of incident and fatal RCC.

985Sex differences in the incidence of renal cell carcinoma: results from the EPIC cohort study

Abstract Background Incidence of renal cell carcinoma (RCC) is two-fold higher in men compared with women. This ratio has been remarkably stable, both geographically and over time. We investigated whether established risk factors for RCC can explain the higher incidence in men. Methods 230,399 participants in the EPIC cohort study with complete data for BMI, history of hypertension, and smoking variables were included. Cox regression models with age as the time-scale were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for sex. Results We identified 690 incident RCC cases. The marginal HR [95% CI] for men versus women was 2.30 [1.98, 2.69]. There was no strong evidence for interactions between hypertension, BMI, or smoking status and sex. Adjusting for BMI, hypertension and smoking variables did not materially affect the estimate (HR: 2.18 [1.85, 2.56]), accounting for only 10% of the observed excess risk. In contrast, smoking factors alone could account for 88% of the observed excess risk of lung cancer for men (marginal HR: 2.19 [2.02, 2.38]; adjusted HR: 1.14 [1.04, 1.25]) Conclusions The two-fold higher incidence of RCC in men compared with women cannot be explained by established risk factors. Key messages Whilst obesity, hypertension, and smoking are established risk factors for RCC, they cannot account for the greater incidence among men compared with women. This indicates the presence of as yet unknown factors to which men are more susceptible than women.

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively). Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.

Hysterectomy, Oophorectomy, and Risk of Renal Cell Carcinoma.

Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy, and risk of RCC and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy. Postmenopausal women (n = 144,599) ages 50-79 years at enrollment (1993-1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders. A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR, 1.28; 95% CI, 1.03-1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR, 1.34; 95% CI, 1.01-1.80) or older than 55 years (HR, 1.52; 95% CI, 1.01-2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC. In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use. If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.

Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.

Background:Agricultural work and occupational pesticide use have been associated with increased risk of renal cell carcinoma (RCC), the most common form of kidney cancer. However, few prospective studies have investigated links to specific pesticides.Objective:We evaluated the lifetime use of individual pesticides and the incidence of RCC.Methods:We evaluated the associations between intensity-weighted lifetime days (IWDs) of 38 pesticides and incident RCC in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Among 55,873 applicators, 308 cases were diagnosed between enrollment (1993–1997) and the end of follow-up (2014–2015). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounding factors, with lagged and unlagged pesticide exposures.Results:There was a statistically significant increased risk of RCC among the highest users of 2,4,5-T compared with never users [unlagged (95% CI: 1.65, 5.17; )], with similar risk estimates for lagged exposure [20-y lag (95% CI: 1.83, 6.22; )]. In 20-y lagged analyses, we also found exposure–response associations with chlorpyrifos [ (95% CI: 1.05, 2.70; )], chlordane [ (95% CI: 1.10, 3.87; )], atrazine [ (95% CI: 1.00, 2.03; )], cyanazine [ (95% CI: 1.03, 2.50; )], and paraquat [ (95% CI: 1.03, 3.70; )].Conclusions:This is, to our knowledge, the first prospective study to evaluate RCC risk in relation to various pesticides. We found evidence of associations with RCC for four herbicides (2,4,5-T, atrazine, cyanazine, and paraquat) and two insecticides (chlorpyrifos and chlordane). Our findings provide insights into specific chemicals that may influence RCC risk among pesticide applicators. Confirmation of these findings and investigations of the biologic plausibility and potential mechanisms underlying the observed associations are warranted. https://doi.org/10.1289/EHP6334

Dietary Patterns in Italy and the Risk of Renal Cell Carcinoma.

Background: Conclusive evidence on foods, nutrients, or dietary patterns and the risk of renal cell carcinoma (RCC) is lacking in the literature. Methods: We considered data from an Italian hospital-based case–control study (1992–2004) on 767 incident RCC cases and 1534 controls. A posteriori dietary patterns were identified by applying principal component factor analysis on 28 nutrients derived from a 78-item food-frequency questionnaire. We estimated the odds ratios (ORs) of RCC and corresponding 95% confidence intervals (CIs) for each quartile category (compared to the lowest one) using conditional multiple logistic regression models providing adjustment for major confounding factors. Results: We identified four dietary patterns, named “Animal products”, “Starch-rich”, “Vitamins and fiber”, and “Cooking oils and dressings”. Higher intakes of the “Starch-rich” pattern were positively associated with RCC risk (OR = 1.38, 95% CI: 1.04–1.82 for the highest quartile, p = 0.018). The association was inverse with the “Cooking oils and dressings” pattern (OR = 0.61, 95% CI: 0.47–0.80, p < 0.001), whereas no association was found with “Animal products” and “Vitamins and fiber” patterns. Conclusions: Higher intakes of starch-related foods may increase RCC risk, whereas consumption of olive and seed oils may favorably influence RCC risk.

Elevated neutrophil-lymphocyte ratio combined with hyponatremia indicate poor prognosis in renal cell carcinoma

Background: Elevated neutrophil-lymphocyte ratio (NLR) and hyponatremia each predict poor prognosis in renal cell carcinoma (RCC). Since no previous studies have looked at the combined effect of these two prognostic markers, we examined how NLR and hyponatremia combined associates with mortality and hypothesized that elevated NLR and hyponatremia at RCC diagnosis and at RCC recurrence indicate poorer prognosis.Material and methods: Using Danish medical registries 1999–2015, we included 970 patients from two regions with incident RCC and a measurement of NLR and sodium. NLR was categorized as ≤3.0 and >3.0 and sodium as < lower limit of normal (LLN) and ≥ LLN. Outcomes were survival after RCC diagnosis and first recurrence, respectively. We estimated absolute survival and hazard ratios (HR) using multivariate Cox regression.Results: At RCC diagnosis, 559 (57.6%) had NLR >3.0 and 240 (24.7%) had hyponatremia, the 5 year-survival rate was 35.2% in NLR > 3.0 vs. 69.2% in NLR ≤3.0, adjusted HR 1.8 (95% confidence intervals (CI), 1.4; 2.2). In patients with NLR >3.0 and concomitant hyponatremia vs. NLR ≤3.0 and normal sodium the 5-year survival rate was 21.7% vs. 73.2%, adjusted HR 2.8 (95% CI, 2.1; 3.8). At RCC recurrence, patients with NLR >3.0 and hyponatremia similarly had poorest survival, adjusted HR 3.6 (95% CI, 1.0; 12.8).Conclusion: Elevated NLR alone and in combination with hyponatremia at time of initial RCC diagnosis and at time of RCC recurrence are associated with poor prognosis. Combining these two prognostic markers yield a stronger association than NLR considered alone. This may impact prognostic prediction and its related therapeutic strategy.

A higher circulating concentration of 25-hydroxyvitamin-D decreases the risk of renal cell carcinoma: a case-control study

ABSTRACTObjective:To investigate the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25 (OH) D], and renal cell carcinoma (RCC) risk in a case-control study, because the association between the two is unclear in China.Materials and Methods:A total of 135 incident RCC cases were matched with 135 controls by age and sex. The blood samples were collected on the first day of hospitalization before surgery to measure plasma 25 (OH) D. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) with adjustment for several confounders (e.g. age, gender, smoking and season of blood draw). Furthermore, the association of RCC with 25 (OH) D in units of 10 ng / mL as a continuous variable were also examined.Results:The average plasma 25 (OH) D concentrations in RCC were significantly lower compared with those of the controls (21.5 ± 7.4 ng / mL vs. 24.1 ± 6.6 ng / mL, respectively; P = 0.003). In the adjusted model, inverse associations were observed between circulating 25 (OH) D levels and RCC risk for 25 (OH) D insufficiency (20-30 ng / mL) with OR of 0.50 (95% CI: 0.29-0.88; P = 0.015) and a normal 25 (OH) D level (≥ 30 ng / mL) with OR of 0.30 (95% CI: 0.13-0.72; P = 0.007), compared with 25 (OH) D deficiency (< 20 ng / mL). Furthermore, results with 25 (OH) D as a linear variable indicated that each 10 ng / mL increment of plasma 25 (OH) D corresponded to a 12% decrease in RCC risk.Conclusions:This case-control study on a Chinese Han population supports the protective effect of a higher circulating concentration of 25 (OH) against RCC, whether the confounding factors are adjusted or not.

Coffee consumption and risk of renal cell carcinoma.

Studies have suggested an inverse association between coffee consumption and risk of renal cell carcinoma (RCC); however, data regarding decaffeinated coffee are limited. We conducted a case-control study of 669 incident RCC cases and 1,001 frequency-matched controls. Participants completed identical risk factor questionnaires that solicited information about usual coffee consumption habits. The study participants were categorized as non-coffee, caffeinated coffee, decaffeinated coffee, or both caffeinated and decaffeinated coffee drinkers. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for multiple risk factors for RCC. Compared with no coffee consumption, we found an inverse association between caffeinated coffee consumption and RCC risk (OR 0.74; 95% CI 0.57-0.99), whereas we observed a trend toward increased risk of RCC for consumption of decaffeinated coffee (OR 1.47; 95% CI 0.98-2.19). Decaffeinated coffee consumption was associated also with increased risk of the clear cell RCC (ccRCC) subtype, particularly the aggressive form of ccRCC (OR 1.80; 95% CI 1.01-3.22). Consumption of caffeinated coffee is associated with reduced risk of RCC, while decaffeinated coffee consumption is associated with an increase in risk of aggressive ccRCC. Further inquiry is warranted in large prospective studies and should include assessment of dose-response associations.

Metformin and the risk of renal cell carcinoma: a case-control analysis.

Metformin use has been associated previously with a decreased risk of cancer, but its association with renal cell carcinoma has not yet been investigated in observational studies. We aimed to explore the association between the use of metformin and other antidiabetic drugs and the risk of renal cell carcinoma (RCC). We carried out a case-control analysis in the UK-based Clinical Practice Research Datalink. We included individuals with an incident RCC between January 1995 and December 2013 younger than the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the Clinical Practice Research Datalink before the index date. We included BMI, smoking, alcohol consumption, hypertension, and diabetes mellitus as potential confounders in a multivariate model using conditional logistic regression to calculate odds ratios with 95% confidence intervals, and we carried out a sensitivity analysis restricted only to diabetic cases and controls. Long-term use of metformin was not associated with an altered relative risk of RCC (≥30 prescriptions, adjusted odds ratio 1.18, 95% confidence interval 0.88-1.58), nor was use of other antidiabetic drugs. Results in the sensitivity analysis including only diabetic cases and controls were largely the same. Use of metformin or other antidiabetic drugs was not associated with a materially altered risk of RCC. Further studies are warranted.

Better survival of renal cell carcinoma in patients with inflammatory bowel disease.

Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population. A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991-2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes. 180 IBD patients with RCC were identified. Pancolitis (OR 1.8-2.5), penetrating Crohn's disease (OR 2.8), IBD related surgery (OR 3.7-4.5), male gender (OR 3.2-5.0) and older age at IBD onset (OR 1.0-1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression. IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

Abstract A45: The association between type 2 diabetes mellitus and incidence of renal cell carcinoma (RCC) and fatal RCC in two prospective cohorts

Abstract Introduction: Current epidemiologic evidence suggests that type 2 diabetes (T2D) is associated with an increased risk of renal cell carcinoma (RCC), but no prospective studies have explored the association in both men and women. Postulated mechanisms include hyperinsulinemia, increases in circulating growth factors, increased endogenous estrogens, and changes in glucose availability. Given the increasing incidence of T2D it is imperative to further evaluate its role in RCC incidence. Methods: We investigated the association between T2D and RCC using prospective cohorts of 117,616 women from the Nurses' Health Study (NHS) and 48,818 men from the Health Professionals Follow-up Study. Self-reports of physician-diagnosed diabetes were collected at baseline, updated biennially, and confirmed via supplemental questionnaires. We used multivariable Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of both total and fatal pathology-confirmed RCC. Models were adjusted for BMI, hypertension, smoking, alcohol intake, NSAID use, and physical activity. Additional adjustment for race, fruit, and vegetable intake did not affect results. Results: During 34 years of follow-up in the NHS we confirmed 309 cases of RCC, including 60 fatal cases. During 24 years of follow-up in the HPFS we confirmed 214 total cases, including 34 fatal cases. In women, T2D was associated with a significantly increased risk of incident RCC (multivariable HR 1.55; 95%CI 1.08 – 2.19), but not fatal RCC (multivariable HR 0.74; 95%CI 0.22 – 2.48). In men, T2D was not associated with an increased risk of incident RCC (multivariable HR 1.10; 95%CI 0.65 – 1.86), but men with T2D were at a non-significantly higher risk of fatal RCC (multivariable HR 2.89; 95%CI 0.93 – 9.02). Compared to non-diabetic women, the association between T2D and RCC was non-significantly stronger in women with a shorter duration of T2D (multivariable HR for ≤ 5 years: HR 2.11; 95%CI 1.31 – 3.38; for &amp;gt; 5 years: HR 1.23; 95%CI 0.77 – 1.95; pdiff: 0.58). In men, duration of T2D was not associated with an increased risk of incident RCC. Conclusions: Our results support previous findings of an association between T2D and incidence of RCC in women; however, we found no significant association in men. T2D may be associated with an increased risk of fatal RCC in men, though power for this analysis in men and women was low. Citation Format: Rebecca E. Graff, Alejandro Sanchez, Jed-Sian Cheng, Dayron Rodriguez, Adam S. Feldman, Glen Barrisford, Seth Bechis, Michael L. Blute, Meir Stampfer, Mark A. Preston, Kathryn M. Wilson, Eunyoung Cho. The association between type 2 diabetes mellitus and incidence of renal cell carcinoma (RCC) and fatal RCC in two prospective cohorts. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A45.

Association of hypertension and obesity with renal cell carcinoma risk: a report from the Shanghai Men's and Women's Health Studies.

Consistently reported associations between hypertension and obesity and renal cell carcinoma (RCC) risk have largely come from studies in Western populations. These associations were examined in a case-control study nested in the Shanghai Women's Health Study (SWHS, 1996-2000) and Shanghai Men's Health Study (SMHS, 2001-2006). Overall, 271 incident RCC cases (124 women, 147 men) were identified through 31 December 2011, and 2,693 controls were individually matched by sex, age, and calendar time at cohort enrollment, and menopausal status (for women). Participants completed a structured questionnaire by in-person interview at baseline, and conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Self-reported hypertension was associated with a significant 40% increased risk of RCC among women and men (95% CI 1.1, 1.9). Body mass index (BMI), modeled continuously, was associated with an elevated risk of RCC among men, with an OR of 1.5 (95% CI 1.1, 2.0) per 5kg/m(2) increase in BMI, but not among women. Hypertension is independently associated with risk of RCC among both women and men in Shanghai, while overweight and obesity appear to be associated with risk of RCC in Chinese men only.

Abstract 1262: Established genetic variants and dietary patterns jointly impact risk of renal cell carcinoma in non-Hispanic whites

Abstract Background: Several emerging renal cell carcinoma (RCC) risk factors related to diet and energy balance have been identified; however, the etiology of RCC and potential mechanisms remain poorly described. Utilizing data collected in an ongoing case-control study, we identified dietary patterns associated with RCC risk. We further assessed whether these associations varied by known and suspected RCC risk factors, such as obesity, tobacco use, physical inactivity and hypertensive status, as well as established genetic variants identified through GWAS. Methods: Diet was assessed among 703 incident RCC cases recruited from the University of Texas MD Anderson Cancer Center in Houston, Texas and 746 healthy controls recruited via random digit dialing. We derived three primary dietary patterns: “fruits and vegetables”, an “American/Western” and a “Tex-Mex” pattern using factor analysis. We examined associations between dietary pattern scores and RCC risk and effect modification by obesity, smoking status, physical activity, history of hypertension and genetic variants. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using multivariate logistic regression adjusted for age, gender, total energy intake, and other RCC risk factors. Results: Greater adherence to the fruits and vegetables dietary pattern was inversely related to RCC risk [OR and 95% CI across tertiles: 1.00 (ref), 0.68 (0.51-0.86) and 0.55 (0.41-0.74), respectively; P-trend &amp;lt;0.001], while the American/Western dietary pattern was directly associated with RCC risk [1.00 (ref), 1.60 (95% CI: 1.19-2.15) and 1.96 (95% CI: 1.47-2.61); P-trend&amp;lt;0.001]. Results were consistent across various stratified analyses. We observed evidence of a significant synergistic interaction between the American/Western pattern and hypertensive status [highest vs. lowest tertile OR = 1.82 95% CI: 1.20-2.74 among individuals with no history of hypertension and highest vs. lowest tertile OR =2.14 95% CI: 1.42-3.23 among those with history of hypertension; additive Pinteraction= 0.01]. Variants in genes ITPR2, ZEB2, PDZD2 and CEP85L were also found to significantly interact with dietary patterns in relation to RCC risk. The strongest interaction was observed between rs718314 (ITPR2) and the American/Western dietary pattern (multiplicative Pinteraction =0.04; additive Pinteraction= 0.02). ITPR2 has previously been shown to be related to nutrient metabolism and central obesity. Conclusion: Dietary patterns, genetic variants, and host characteristics may individually and jointly influence susceptibility to RCC. Citation Format: Melkonian Stephanie, Carrie R. Daniel, Michelle Hildebrandt, Nizar Tannir, Yuanqing Ye, Wong-Ho Chow, Christopher Wood, Xifeng Wu. Established genetic variants and dietary patterns jointly impact risk of renal cell carcinoma in non-Hispanic whites. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1262. doi:10.1158/1538-7445.AM2014-1262