Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:
Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.
METHODS:
A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.
RESULTS:
Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.
CONCLUSIONS:
In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis.

The relationship between adipokines and the onset of type 2 diabetes in middle-aged men: The PRIME study

Aims: Epidemiological evidence suggests that adipokines may be associated with the onset of type 2 diabetes, but the evidence to date is limited and inconclusive. This study examined the association between adiponectin and leptin and the subsequent diagnosis of type 2 diabetes in a UK population based cohort of non-diabetic middle-aged men.
Methods: Baseline serum levels of leptin and adiponectin were measured in 1839 nondiabetic men aged 50–60 years who were participating in the prospective populationbased PRIME study. Over a mean follow-up of 14.7 years, new cases of type 2 diabetes were determined from self-reported clinical information with subsequent validation by general practitioners.
Results: 151 Participants developed type 2 diabetes during follow-up. In Cox regression models adjusted for age, men in the top third of the leptin distribution were at increased risk (hazard ratio (HR) 4.27, 95% CI 2.67–6.83) and men in the top third of the adiponectin
distribution at reduced risk (HR 0.24, 95% CI 0.14–0.42) relative to men in the bottom third. However, significance was lost for leptin after additional adjustment for BMI, waist to hip ratio, lifestyle factors and biological risk factors, including C-reactive protein (CRP). Further adjustment for HOMA-IR also resulted in loss of significance for adiponectin.
Conclusions: This study provides evidence that adipokines are associated with men’s future type 2 diabetes risk but not independently of other risk factors.

Statin use and breast cancer survival: a nationwide cohort study in Scotland

Background: Preclinical evidence suggests that statins could delay cancer progression. Previous epidemiological findings have been inconsistent and some have been limited by small sample sizes, as well as certain time-related biases. This study aimed to investigate whether breast cancer patients who were exposed to statins had reduced breast cancer-specific mortality. Methods: We conducted a retrospective cohort study of 15,140 newly diagnosed invasive breast cancer patients diagnosed from 2009 to 2012 within the Scottish Cancer Registry. Dispensed medication usage was obtained from linkages to the Scottish Prescribing Information System and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Using time-dependent Cox regression models, hazard ratios (HR) and 95 % confidence intervals (CI) were calculated for the association between post-diagnostic exposure to statins (including simvastatin) and breast cancer-specific mortality. Adjustments were made for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of aspirin. Results: A total of 1,190 breast cancer-specific deaths occurred up to January 2015. Overall, after adjustment for potential confounders, there was no evidence of an association between statin use and breast cancer-specific death (adjusted HR 0.93, 95 % CI 0.77, 1.12). No significant associations were observed in dose–response analyses or in analysis of all-cause mortality. For simvastatin use specifically, a weak non-significant reduction in breast cancer-specific mortality was observed compared to non-users (adjusted HR 0.89, 95 % CI 0.73, 1.08). Statin use before diagnosis was weakly associated with a reduction in breast cancer-specific mortality (adjusted HR 0.85, 95 % CI 0.74, 0.98). Conclusion: Overall, we found little evidence of a protective association between post-diagnostic statin use and cancer-specific mortality in a large nation-wide cohort of breast cancer patients. These findings will help inform the decision whether to conduct randomised controlled trials of statins as an adjuvant treatment in breast cancer.

Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial.

Background: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods: We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion: This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

FcγRIIa and FcγRIIIa polymorphisms and cetuximab benefit in the microscopic disease

Purpose: FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX ± cetuximab in high-risk, locally advanced rectal cancer.

Experimental Design: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.

Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation from the Hardy–Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcγRIIa-131R (HR, 0.38; P = 0.058) and FcγRIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003).

Conclusion: This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.

In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P <.05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis

BACKGROUND: The aim of this study was to investigate the association between statin use and survival in a population-based colorectal cancer (CRC) cohort and perform an updated meta-analysis to quantify the magnitude of any association.

METHODS: A cohort of 8391 patients with newly diagnosed Dukes' A-C CRC (2009-2012) was identified from the Scottish Cancer Registry. This cohort was linked to the Prescribing Information System and the National Records of Scotland Death Records (until January 2015) to identify 1064 colorectal cancer-specific deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use were calculated using time dependent Cox regression models. The systematic review included relevant studies published before January 2016. Meta-analysis techniques were used to derive combined HRs for associations between statin use and cancer-specific and overall mortality.

RESULTS: In the Scottish cohort, statin use before diagnosis (HR=0.84, 95% CI 0.75-0.94), but not after (HR=0.90, 95% CI 0.77-1.05), was associated with significantly improved cancer-specific mortality. The systematic review identified 15 relevant studies. In the meta-analysis, there was consistent (I(2)=0%,heterogeneity P=0.57) evidence of a reduction in cancer-specific mortality with statin use before diagnosis in 6 studies (n=86,622, pooled HR=0.82, 95% CI 0.79-0.86) but this association was less apparent and more heterogeneous (I(2)=67%,heterogeneity P=0.03) with statin use after diagnosis in 4 studies (n=19,152, pooled HR=0.84, 95% CI 0.68-1.04).

CONCLUSION: In a Scottish CRC cohort and updated meta-analysis there was some evidence that statin use was associated with improved survival. However, these associations were weak in magnitude and, particularly for post-diagnosis use, varied markedly between studies.