BMI, Metabolic Syndrome, And Pancreatic Cancer

Here is study linking higher BMI, and higher fasting insulin levels (metabolic syndrome, insulin resistance), with an increased risk for pancreatic cancer.  The burden of morbidity and mortality caused by overweight/obesity is staggering, something to keep in mind when reading all the popular stories on the Internet that attempt to normalize obesity and rant about “fat shaming” and “body shaming.”  Being overweight is literally killing people, why normalize it?  Abstract:

BACKGROUND:

Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.

METHODS:

We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses.

RESULTS:

Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias.

CONCLUSIONS:

Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

More On Neoantigens

Neoantigens – aberrant proteins produced by mutated genes (e.g., in cancer) – are associated with long-term survivors of pancreatic cancer, possibly because the neoantigens are stimulating anti-tumor immune responses.  Neoantigen production is also associated with response to anti-cancer immunotherapy.  Abstract:

Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-treated patients with lung cancer. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens.

Non-Invasive Blood Test For Pancreatic Cancer: Early Study

One reason pancreatic cancer is so deadly is that it is usually diagnosed late, giving few or no symptoms in its early stages. Development of a non-invasive test – such as a blood test – for this cancer is therefore imperative.  Some developments are shown in this study.  A sensitivity of 64% is obviously not perfect and can stand improvement, but is certainly better than having no test at all and it is a solid starting point for further improvement.  The 99.5% specificity (demonstrating a very low probability of false positives) is excellent.  Abstract:

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Red Meat and Pancreatic Cancer

Consistent with previous concerns about red meat and cancer, a new study suggests consuming heme iron from red meat increases the risk for pancreatic cancer:
 

Several studies on pancreatic cancer have reported significant positive associations for intake of red meat but null associations for heme iron. We assessed total, red, white, and processed meat intake, meat cooking methods and doneness, and heme iron and mutagen intake in relation to pancreatic cancer...Pancreatic cancer risk significantly increased with intake of total meat (Q5 vs. Q1 HR=1.20, 95% CI 1.02-1.42, p-trend=0.03), red meat (HR=1.22, 95% CI 1.01-1.48, p-trend=0.02), high-temperature cooked meat (HR=1.21, 95% CI 1.00-1.45, p-trend=0.02), grilled/barbequed meat (HR=1.24, 95% CI 1.03-1.50, p-trend=0.007), well/very well done meat (HR=1.32, 95% CI 1.10-1.58, p-trend = 0.005), and heme iron from red meat (Q4 vs. Q1 HR=1.21, 95% CI 1.01-1.45, p-trend=0.04)...Additional studies should confirm our findings that consuming heme iron from red meat increases pancreatic cancer risk. 

Once again, we see evidence that reducing red meat consumption is likely helpful for cancer prevention.