Statin Use After Diagnosis of Colon Cancer and Patient Survival.

BACKGROUND & AIMS: Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer. Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein (BMP) signaling pathway in colorectal cancer cells. We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer, and whether their effects were associated with changes in KRAS or the BMP signaling pathways. METHODS: Data were derived from the PHARMO database network (Netherlands) and linked to patients diagnosed with colon cancer from 2002 through 2007, listed in the Eindhoven Cancer Registry. We obtained information on causes of death from statistics Netherlands. We constructed a tissue microarray of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008. Survival was analyzed with statin user status after diagnosis as a time-dependent covariate. Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival. Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4, BMPR1A, BMPR1B, and BMPR2 proteins. Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A, BMPR1B, or BMPR2. DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS. The primary outcome measures were overall mortality and cancer-specific mortality. RESULTS: In this cohort, 21.0% of the patients (210/999) were defined as statin users after diagnosis of colon cancer. Statin use after diagnosis was significantly associated with reduced risk of death from any cause (adjusted relative risk [RR], 0.67; 95% confidence interval [CI], 0.51-0.87; P = .003) and death from cancer (adjusted RR, 0.66; 95% CI, 0.49-0.89; P = .007). Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling (adjusted RR, 0.39; 95% CI, 0.22-0.68; P = .001), but not for patients whose tumors did not have BMP signaling (adjusted RR, 0.81; 95% CI, 0.55-1.21; P = .106; P < .0001 for the interaction). Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations (adjusted RR, 0.81; 95% CI, 0.56-1.18; P = .273) or whose tumors did have KRAS mutations (adjusted RR, 0.59; 95% CI 0.35-1.03; P = .062; P = .90 for the interaction). CONCLUSIONS: In an analysis of 999 patients with a diagnosis of colon cancer, we associated statin with reduced risk of death from any cause or from cancer. The benefit of statin use is greater for patients whose tumors have intact BMP signaling, independent of KRAS mutation status. Randomized controlled trials are required to confirm these results.

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes.

AIMS/HYPOTHESIS: Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis. METHODS: All new users of GLDs between 1998 and 2011 who lived in the Eindhoven Cancer Registry-PHARMO Database Network catchment area were selected. Those with a primary cancer diagnosis during follow-up were considered cases and matched with eligible controls without cancer during follow-up. Medication possession ratio (MPR) was used as indicator for medication adherence. Segmented linear auto-regression analysis with interrupted time series was used to assess changes in MPR for cases compared with controls (i.e. overall trend) due to (any) cancer diagnosis and specific cancer types. RESULTS: From the 52,228 GLD users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study. In our analyses, before cancer diagnosis the MPR increased by 0.10% per month (95% CI 0.10, 0.10). Besides a significant drop in MPR at the time of cancer diagnosis of -6.3% (95% CI -6.5, -6.0), there was an ongoing, yet lower, monthly decline in MPR (-0.20%; 95% CI -0.21, -0.20) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11-15%, were seen among patients with stage IV disease and gastrointestinal or pulmonary cancers. CONCLUSIONS/INTERPRETATION: Our findings indicate a clear decline in adherence to GLD treatment regimens following a cancer diagnosis. The reason for the decline in MPR needs to be further elucidated.

No association between metformin use and survival in patients with pancreatic cancer: An observational cohort study.

Several studies have suggested an association between use of metformin and an increased overall survival in patients diagnosed with pancreatic cancer, however with several important methodological limitations. The aim of the study was to assess the association between overall survival, pancreatic cancer, and metformin use.A retrospective cohort study of 1111 patients with pancreatic cancer was conducted using data from The Netherlands Comprehensive Cancer Organization (1998-2011). Data were linked to the PHARMO Database Network containing drug-dispensing records from community pharmacies. Patients were classified as metformin user or sulfonylurea derivatives user from the moment of first dispensing until the end of follow up. The difference in overall survival between metformin users and nonusers was assessed, and additionally between metformin users and sulfonylurea derivatives users. Univariable and multivariable parametric survival models were used and use of metformin and sulfonylurea derivatives was included as time-varying covariates.Of the 1111 patients, 91 patients were excluded because of differences in morphology, 48 patients because of using merely metformin before diagnosis, and 57 metformin-users ever used contemporary sulfonylurea derivatives and were therefore excluded. Lastly, 8 patients with a survival of zero months were excluded. This resulted in 907 patients for the analysis. Overall, 77 users of metformin, 43 users of sulfonylurea derivatives, and 787 nonusers were identified. The adjusted rate ratio for overall survival for metformin users versus nonusers was 0.86 (95% CI: 0.66-1.11; P = 0.25). The difference in overall survival between metformin users and sulfonylurea derivatives users showed an adjusted rate ratio of 0.90 (95% CI: 0.59-1.40; P = 0.67).No association was found between overall survival, pancreatic cancer, and metformin use. This was in concordance with 2 recently published randomized controlled trials. Future research should focus on the use of adjuvant metformin in other cancer types and the development or repurposing of other drugs for pancreatic cancer.

Impact of cancer diagnosis and treatment on glycaemic control among individuals with colorectal cancer using glucose-lowering drugs.

AIMS: This study aims to evaluate the impact of cancer and its treatment on HbA1c values among individuals with colorectal cancer (CRC) using glucose-lowering drugs (GLDs). METHODS: Patients with primary CRC (1998-2011) were selected from the Eindhoven Cancer Registry and linked to the PHARMO Database Network including outpatient pharmacy and clinical laboratory data. Patients with more than 2 years of GLDs use prior to cancer diagnosis were included. Linear mixed-effects models were conducted to evaluate changes in HbA1c for colon cancer (CC) and rectal cancer (RC) patients in the 4 years around CRC diagnosis. RESULTS: Of all CRC patients (n = 4714), 294 (6 %) GLDs users with CC and 144 (3 %) with RC were selected. In the crude model, mean HbA1c at cancer diagnosis was 6.9 % (51.6 mmol/mol) among CC patients and 7.1 % (53.5 mmol/mol) among RC patients. Among CC patients, HbA1c decreased with 0.12 % per year (p = 0.0002) before cancer diagnosis in the adjusted model, and after diagnosis, it increased with 0.12 % per year (p = 0.02). In subgroup analyses, effects on HbA1c were more pronounced in users of anti-anaemic preparations. Among RC patients, HbA1c decreased before diagnosis with 0.18 % per year (p = 0.0006), whereas after diagnosis it changed non-significantly. CONCLUSIONS: Among users of GLDs, HbA1c decreased with 0.12-0.18 % (1-2 mmol/mol) per year before CRC diagnosis. Only among CC patients, HbA1c increased after diagnosis (0.12 % per year; 1.3 mmol/mol). Modest changes in HbA1c before CRC diagnosis may reflect the effects of an undiagnosed cancer, such as weight loss, anaemia, or the use of anti-anaemic preparations.

Effect of diabetes on endometrial cancer recurrence and survival.

OBJECTIVE: The purpose of this study was to investigate the influence of diabetes mellitus (DM) on cancer stage at diagnosis, cancer recurrence, and survival of endometrial cancer (EC) patients and the influence of the treatment of EC on glycaemic control, treatment, and complications of DM. METHODS: In this retrospective cohort study all 1644 patients with EC newly diagnosed in 2000-2008 and recorded in the population-based Eindhoven Cancer Registry (ECR) were included. In addition, from this total cohort a subcohort was selected for additional data collection and analyses, including 193 EC patients with DM and an age-matched sample of 195 EC patients without DM. Patients with FIGO stage IV as well as non-endometrioid histology were excluded. RESULTS: In the total cohort EC patients with DM had a significantly higher age (69 years vs. 64 years), higher FIGO stages and more additional comorbidities compared to EC patients without DM. The 5-year overall survival rate for EC patients with DM was significantly lower than for EC patients without DM (68% vs. 84%). After adjusting for age, stage, period of diagnosis, cardiovascular disease, and treatment, this significant effect of DM on overall mortality persisted (HR 1.4, 95% CI: 1.0-1.8). Subcohort analyses showed that EC patients with DM were diagnosed more often with a higher body mass index (BMI) (34 kg/m(2) vs. 30 kg/m(2)) and EC was not significantly associated with changes in DM characteristics over time. Although the 5-year overall survival rate for EC patients with DM was significantly lower in the subcohort, for EC-specific mortality (n=388) no statistically significant effect of DM was observed after adjustment for FIGO stage (HR=1.7, 95% CI: 0.7-3.9). CONCLUSIONS: EC patients with DM compared to those without had worse patient characteristics, a higher FIGO stage, similar recurrence rates and worse overall survival.