Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non‐small‐cell lung cancer patients with EGFR mutations

This study was designed to examine the prediction of pretreatment circulating bilirubin and cholesterol for overall survival in 459 advanced non‐small‐cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Circulating total bilirubin, direct bilirubin (DB), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) levels were measured at baseline. The mean age (standard deviation) of all study patients was 58.7 (10.5) years, and 42.9% of them was males. Ever smokers accounted for 27.0% and lung adenocarcinoma for 90.4%. The median follow‐up time and survival time were 29.5 and 34.9 months, respectively. Patients with higher DB had a 1.68‐fold increased risk of death compared with patients with lower DB (hazard ratio [HR] = 1.68, 95% confidence interval [CI]: 1.22–2.30, p = 0.001), while patients with higher TC were at a 63% reduced risk of death compared with patients with lower TC (HR = 0.37, 95% CI: 0.20–0.67, p = 0.001). As for HDL‐C, patients with higher levels had the risk of death reduced by 46% (HR = 0.54, 95% CI: 0.29–1.00, p = 0.049) compared with patients with lower levels. After the Bonferroni correction, only DB and TC were significantly associated with NSCLC survival. Our findings demonstrate for the first time that pretreatment DB was identified as a significant risk factor, yet TC as a protective factor, for overall survival in NSCLC patients with EGFR mutations.     

Consumption of meat,traditional and modern processed meat and colorectal cancer risk among the Moroccan population: A large-scale case–control study

The current study aimed to investigate the relationship between red and white meat subtypes, processed meat (divided into traditional “Khlii, Kaddid” and industrially processed meat) and colorectal cancer (CRC) risk, considering CRC subsites, in Moroccan adults. A case–control study was conducted including 2,906 matched case–control pairs recruited from the five largest university hospitals in Morocco. Dietary data were collected through a validated Food Frequency Questionnaire (FFQ). Multivariable odds ratios (OR) and 95% confidence intervals (CI), for the association of CRC risk with meat consumption (high vs. low intake), were estimated using conditional logistic regression models, adjusted for relevant confounding variables. Overall, consumption of red meat was positively associated with colon cancer and CRC risk (OR = 1.23, 95% CI = 1.05–1.44; OR = 1.14, 95% CI = 1.02–1.27), respectively. In contrast, no significant association was observed between the consumption of red meat and rectal cancer risk (OR = 1.05, 95% = 0.90–1.23). Interestingly, while processed meat from industrial processes was positively associated with colon cancer, rectal cancer and CRC (OR = 1.61, 95% CI = 1.27–2.04; OR = 1.73, 95% CI = 1.34–2.23; OR = 1.67, 95% CI = 1.41–1.98), processed meat prepared using traditional methods was inversely associated with colon cancer and CRC risk (OR = 0.74, 95% CI = 0.57–0.98; OR = 0.77, 95% CI = 0.64–0.93), respectively. Furthermore, positive associations were observed between poultry intake and colon cancer risk among men (OR = 1.27, 95% CI = 1.01–1.59). Our study showed similar associations between the consumption of red meat and CRC risk in Morocco as in developed countries, while inverse associations were found for traditionally processed meat products. This is the first study to investigate the differential effects of traditional vs. westernized processed meat products in a developing country. Other studies are needed to confirm these findings and to understand the physiological pathways underlying these associations.     

Adipokines and inflammation markers and risk of differentiated thyroid carcinoma: The EPIC study

Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C‐reactive protein, interleukin (IL)‐6, IL‐10 and tumor necrosis factor (TNF)‐α and the risk of TC. A case‐control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer‐free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (OR_T3vs.T1 = 0.69, 95% CI: 0.49–0.98, P_trend = 0.04) but not among men (OR_T3vs.T1 = 1.36, 95% CI: 0.67–2.76, P_trend = 0.37). Increasing levels of IL‐10 were positively associated with TC risk in both genders and significantly so in women (OR_T3vs.T1 = 1.59, 95% CI: 1.13–2.25, P_trend = 0.01) but not in men (OR_T3vs.T1 = 1.78, 95% CI: 0.80–3.98, P_trend = 0.17). Leptin, CRP, IL‐6 and TNF‐α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL‐10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight.     

Baseline serum C‐reactive protein and death from colorectal cancer in the NHANES III cohort

Several prospective studies suggest that C‐reactive protein (CRP), a nonspecific serologic marker of inflammation, might be linked to risk of colorectal cancer (CRC), whereas others have reported null or protective effects. We analyzed data from 7,072 participants (50–85 years) in the U.S. National Health and Nutrition Examination Survey III (1988–1994), a nationally representative cohort (n = 33,994; 2 months–85 years) with vital status follow‐up to 2000. Hazard ratios (HRs) for mortality associated with baseline clinically raised (≥1.00 mg/dL) and intermediate (≥0.22–0.99 mg/dL) CRP levels were estimated using Cox proportional hazards regression controlling for CRC risk factors. There were 59 deaths from CRC, 106 from other obesity‐related cancers (other‐ORCs) and 1,130 from cardiovascular disease (CVD). Participants with clinically raised CRP at baseline were found to have a statistically significant greater risk of CRC death (HRs = 2.36–2.47) in comparison to persons with undetected levels. HRs were lower for death from other‐ORC and CVD (1.82, 95% CI 1.05–3.15; 1.53, 95% CI 1.29–1.81, respectively). Intermediate CRP level was associated with a nonsignificant 10–21% increased risk for CRC death. HR for CRC death was higher among persons with a normal BMI (2.16, 95% 0.96–4.87, p = 0.06) compared to those who were overweight (1.22, 95% CI 0.53–2.78) or obese (1.23, 95% CI, 0.37–4.08). A similar pattern was observed for waist circumference. This effect modification suggests that the impact of chronic inflammation may be independent of excess body fat. Future research is recommended to confirm emerging data that elevated serologic CRP might reflect underlying colonic inflammation.     

Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use

BACKGROUND:

Statins and nonsteroidal anti‐inflammatory drugs (NSAIDs) are associated with reduced risk of colorectal cancer (CRC) in some studies. The objective of this study was to quantify the relative risk of inflammatory bowel disease (IBD) as a risk factor for CRC and to estimate whether this risk may be modified by long‐term use of NSAIDs or statins.

METHODS:

The Molecular Epidemiology of Colorectal Cancer study is a population‐based, case‐control study of incident colorectal cancer in northern Israel and controls matched by age, sex, clinic, and ethnicity. Personal histories of IBD and medication use were measured by structured, in‐person interview. The relative risk of IBD and effect modification by statins and NSAIDs were quantified by conditional and unconditional logistic regression.

RESULTS:

Among 1921 matched pairs of CRC cases and controls, a self‐reported history of IBD was associated with a 1.9‐fold increased risk of CRC (95% confidence interval [CI], 1.12‐3.26). Long‐term statin use was associated with a reduced risk of both IBD‐associated CRC (odds ratio [OR] = 0.07; 95% CI, 0.01‐0.78) and non‐IBD CRC (OR = 0.49; 95% CI, 0.39‐0.62). Stratified analysis suggested that statins may be more protective among those with IBD (ratio of OR = 0.14; 95% CI, 0.01‐1.31; P = .51), although not statistically significant. NSAID use in patients with a history of IBD was suggestive of reduced risk of CRC but did not reach statistical significance (OR = 0.47; 95% CI, 0.12‐1.86).

CONCLUSIONS:

The risk of CRC was elevated 1.9‐fold in patients with IBD. Long‐term statin use was associated with reduced risk of CRC in patients with IBD. Cancer 2011. © 2010 American Cancer Society.     

The association between −1304T>G polymorphism in the promoter of MKK4 gene and the risk of sporadic colorectal cancer in southern Chinese population

MKK4 (mitogen‐activated protein kinase kinase 4, NM_003010.2), which belongs to the mitogen‐activated protein kinase pathways, possesses functions in tumorigenesis. We hypothesized the genetic variants in MKK4 gene may alter its functions and thus cancer risk. In current hospital‐based case‐control study of 706 patients with sporadic colorectal cancer (CRC) and 723 sex‐age–frequency‐matched control subjects in a southern Chinese population, we genotyped two polymorphisms of MKK4 promoter (i.e., ?1304T>G, rs3826392 and ?1044A>T, rs3809728) and assessed their associations with the risk of sporadic CRC. Compared with ?1304TT genotypes, ?1304TG had a significantly decreased risk of CRC (adjusted odds ratios [OR] = 0.56; 95% CI = 0.44–0.72; p = 3.53 × 10^?6), the ?1304GG carriers had a further decreased risk of CRC (OR = 0.40; 95% CI = 0.23–0.70; p = 1.32 × 10^?3), and there was a significant trend for an allele dose effect on risk of CRC (p_trend = 2.64 × 10^?7). The decreased risk associated with ?1304G variant genotypes (i.e., TG+GG) was more pronounced in the subjects older than 60 years (adjusted OR = 0.41; 95% CI = 0.29–0.57; p = 2.25 × 10^?7), in ever drinkers (adjusted OR = 0.41; 95% CI = 0.28–0.59; p = 2.42 × 10^?6). The age and alcohol drinking status interacted with ?1304G variant genotypes on reducing cancer risk (p values for interaction were 0.015 and 0.043, respectively). Western blotting analysis showed that the levels of Mkk4 protein in sporadic CRC neoplastic tissues were significantly higher in the carriers of ?1304G variant genotypes than that in those with ?1304TT genotypes. However, no significant association was observed between ?1044A>T polymorphism and risk of CRC. To the best of our knowledge, this is the first study of genetic variants in MKK4 and cancer susceptibility. Larger studies are needed to validate our findings. © 2009 UICC     

A copy number variation in PKD1L2 is associated with colorectal cancer predisposition in korean population

Recently reported genome‐wide association studies have identified more than 20 common low‐penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR = 1.44, 95% CI = 1.04–1.98, p = 0.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR = 2.14, 95% CI 1.39–3.30, p = 5.8 × 10^?4). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR = 2.29, 95% CI 1.29–4.05, p = 0.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR = 5.24, 95% CI 2.36–11.64, p = 4.8 × 10^?5). Moreover, we found that PKD1L2 variation in obese patients (BMI ≥ 25) was associated with poor survival rate (p = 0.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival.     

Preoperative metabolic syndrome and prognosis after radical resection for colorectal cancer: The Fujian prospective investigation of cancer (FIESTA) study

This prospective study sought to investigate the prediction of preoperative metabolic syndrome and its components for the risk of colorectal cancer (CRC) mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. In total, 1,318 CRC patients who received radical resection were consecutively enrolled between January 2000 and December 2008. The median follow‐up time was 58.6 months, with 412 deaths from CRC. The CRC patients with metabolic syndrome had significantly shorter median survival time (MST) than those without (50.9 vs. 170.3 months, p < 0.001). Among four components of metabolic syndrome, hyperglycemia was the strongest predictor and its presence was associated with shorter MST than its absence (44.4 vs. 170.3 months, p < 0.001). Moreover, the complication of metabolic syndrome in CRC patients was associated with a 2.98‐fold increased risk of CRC mortality (hazard ratio [HR] = 2.98, 95% confidence interval [CI]: 2.40–3.69, p < 0.001) after adjusting for confounding factors. The magnitude of this association was especially potentiated in CRC patients with tumor‐node‐metastasis stage I/II (HR = 3.94, 95% CI: 2.65–5.85, p < 0.001), invasion depth T1/T2 (HR = 5.41, 95% CI: 2.54–11.50, p < 0.001), regional lymph node metastasis N0 (HR = 4.06, 95% CI: 2.85‐5.80, p < 0.001) and negative distant metastasis (HR = 3.23, 95% CI: 2.53–4.12, p < 0.001). Further survival tree analysis reinforced the prognostic capability of fasting blood glucose in CRC survival. Our findings convincingly demonstrated that preoperative metabolic syndrome, especially hyperglycemia, was a robust predictor for CRC mortality, and the protection was more obvious in patients with Stage I/II.     

Association between adult weight gain and colorectal cancer: A dose–response meta‐analysis of observational studies

This study investigated the association between adult weight gain and risk of colorectal cancer (CRC). Using terms related to weight gain and CRC, we searched PubMed, Embase and Web of Science for relevant studies published before June 2014. Two evaluators independently selected studies according to the selection criteria, and eight studies were included (three case–control and five cohort studies). Summary estimates were obtained using fixed‐ or random‐effects models. The relative risk (RR) of the association between adult weight gain and CRC was 1.25 (95% confidence interval [CI], 1.10–1.43); the RR was 1.30 (95% CI, 1.14–1.49) for colon cancer (CC) and 1.27 (95% CI, 1.02–1.58) for rectal cancer (RC) for the highest versus lowest category. For every 5‐kg increase in adult weight, the risk increased by 5% (RR, 1.05; 95% CI, 1.02–1.09) for CRC, 6% (RR, 1.06; 95% CI, 1.02–1.11) for CC and 6% (RR, 1.06; 95% CI, 1.03–1.08) for RC. The subgroup analyses showed a positive association between adult weight gain and risk of CRC only in men, and the RR was 1.65 (95% CI, 1.42–1.92) for the highest versus lowest category of adult weight gain and 1.10 (95% CI, 1.06–1.15) for a 5‐kg increase in adult weight. In conclusion, there is evidence that adult weight gain is associated with an increased risk of CRC. However, the positive association between adult weight gain and risk of CRC is stronger among men than among women.     

Mismatch repair status and synchronous metastases in colorectal cancer: A nationwide cohort study

The causality between the metastatic potential, mismatch repair status (MMR) and survival in colorectal cancer (CRC) is complex. This study aimed to investigate the impact of MMR in CRC on the occurrence of synchronous metastases (SCCM) and survival in patients with SCCM on a national basis. A nationwide cohort study of 6,692 patients diagnosed with CRC between 2010 and 2012 was conducted. Data were prospectively entered into the Danish Colorectal Cancer Group's database and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable and multinomial logistic‐ and Cox‐regression and proportional excess hazards analyses were used for confounder adjustment and to adjust for the general population mortality. In total, 983 of 6,692 patients (14.7%) had dMMR and 935 (14.0%) had SCCM. dMMR was associated with a decreased risk of SCCM, adjusted Odds Ratio (aOR) = 0.54 (95% confidence interval (CI):0.40–0.70, p < 0.001). The association only applied to confined hepatic metastases (aOR = 0.30, 95%CI: 0.18–0.49, p < 0.001), whereas the presence of confined pulmonary metastases (aOR = 0.71, 95% CI: 0.39–1.29, p = 0.258) or synchronous hepatic and pulmonary metastases (aOR = 0.69, 95% CI:0.26–1.29, p = 0.436) were unaffected by MMR. MMR in patients with SCCM had no impact on survival (Cox: adjusted Hazard Ratio (aHR) = 0.76, 95% CI: 0.54–1.06, p = 0.101; Proportional excess hazards: aHR = 0.73, 95% CI: 0.50–1.07, p = 0.111) when adjusting for other prognostic factors. The metastatic pattern varied according to MMR status. MMR had no impact on survival in patients with UICC Stage IV CRC. These findings may be important for the understanding of the metastatic processes and thus for optimizing staging and treatment in CRC patients.     

The fecal hemoglobin concentration,age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f‐Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi‐square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02–1.05), male sex: 1.6 (95% CI: 1.1–2.3) and f‐Hb (0–<20 µg Hb/g feces): 2.0 (95% CI: 0.7–5.5), (20‐<200 µg Hb/g): 16.8 (95% CI: 6.6–42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3–164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85–0.90) in the derivation and 0.91 (95% CI: 0.90–093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value—PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.     

Coffee consumption and the risk of colorectal cancer by anatomical subsite in Japan: Results from the HERPACC studies

Consumption of coffee, a popular beverage worldwide, has been associated with lower colorectal cancer (CRC) risk. Although CRC exhibits different biological characteristics by anatomical subsite, the possibly heterogeneous impact of coffee on CRC by anatomical subsite has remained unclear. Here, we conducted two case‐control studies to examine the association between coffee consumption and CRC risk as well as risk by anatomic subsite among Japanese using data from the Hospital‐based Epidemiological Research Program at Aichi Cancer Center I and II (HERPACC‐I and II). Subjects were enrolled in HERPACC‐I between 1988 and 2000 and in HERPACC‐II between 2001 and 2005. Coffee consumption was measured with a self‐administered questionnaire. A conditional logistic regression model was used to calculate odds ratios (ORs) of CRC with coffee consumption, adjusted for potential confounders of age, smoking, alcohol drinking, red meat intake, BMI, exercise, family history of CRC, and diabetes mellitus history. We estimated summary ORs by pooling study‐specific ORs with a fixed effects model. In total, 2,696 CRC cases and 13,480 non‐cancer outpatients as controls were included. Overall, compared to non‐drinkers, ORs of less than 1 cup/day, 1–2 cups/day and 3 or more cups/day for CRC were 0.88 (95% CI: 0.77–1.00), 0.90 (95% CI: 0.80–1.01) and 0.78 (95% CI: 0.65–0.92), respectively (trend‐p = 0.009). Subsite‐specific analysis revealed a significant inverse linear trend between coffee consumption and distal colon cancer (p‐trend = 0.048), and a tendency toward a lower risk of rectal cancer (p‐trend = 0.068). These findings suggest that coffee consumption might impact the prevention of CRC, especially distal colon cancer.     

Consumption of fruits,vegetables and fruit juices and differentiated thyroid carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Fruit and vegetable (F&V) intake is considered as probably protective against overall cancer risk, but results in previous studies are not consistent for thyroid cancer (TC). The purpose of this study is to examine the association between the consumption of fruits, vegetables, fruit juices and differentiated thyroid cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The EPIC study is a cohort including over half a million participants, recruited between 1991 and 2000. During a mean follow‐up of 14 years, 748 incident first primary differentiated TC cases were identified. F&V and fruit juice intakes were assessed through validated country‐specific dietary questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors. Comparing the highest versus lowest quartile of intake, differentiated TC risk was not associated with intakes of total F&V (HR: 0.89; 95% CI: 0.68–1.15; p‐trend = 0.44), vegetables (HR: 0.89; 95% CI: 0.69–1.14; p‐trend = 0.56), or fruit (HR: 1.00; 95% CI: 0.79–1.26; p‐trend = 0.64). No significant association was observed with any individual type of vegetable or fruit. However, there was a positive borderline trend with fruit juice intake (HR: 1.23; 95% CI: 0.98–1.53; p‐trend = 0.06). This study did not find any significant association between F&V intakes and differentiated TC risk; however a positive trend with fruit juice intake was observed, possibly related to its high sugar content.     

Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Genome‐wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome‐wide association study in 1,701 CRC cases and 14,082 cancer‐free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single‐nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10⁻⁴; OR, 1.14; 95% CI, 1.06–1.23), and it was genome‐wide significant in combined analysis (p = 1.50 × 10⁻⁹; OR, 1.12; 95% CI, 1.08–1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.     

Calcium intake and colorectal cancer risk: Dose–response meta‐analysis of prospective observational studies

Mechanistic and epidemiologic studies provide considerable evidence for a protective association between calcium intake and incident colorectal cancer (CRC). While the relationship has not been substantiated by short‐duration randomized controlled trials (RCTs) of CRC, trials do show a benefit on adenomas, a precursor to CRC. To address some of this inconsistency, we conducted dose–response meta‐analyses by sources of calcium intake, based on prospective observational studies published up to December 2013 identified from PubMed, Embase, and BIOSIS. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random‐effects model. For total calcium intake, each 300 mg/day increase was associated with an approximately 8% reduced risk of CRC (summary RR = 0.92, 95% CI = 0.89–0.95, I² = 47%, 15 studies with 12,305 cases, intake = 250–1,900 mg/day, follow‐up = 3.3–16 years). While the risk decreased less steeply in higher range of total calcium intake (P_{non‐linearity} = 0.04), the degree of curvature was mild and statistical significance of non‐linearity was sensitive to one study. For supplementary calcium, each 300 mg/day increase was associated with an approximately 9% reduced risk of CRC (summary RR = 0.91, 95% CI = 0.86–0.98, I² = 67%, six studies with 8,839 cases, intake = 0–1,150 mg/day, follow‐up = 5–10 years). The test for non‐linearity was not statistically significant (P_{non‐linearity} = 0.11). In conclusion, both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1,000 mg/day. Calcium supplements and non‐dairy products fortified with calcium may serve as additional targets in the prevention of CRC. RCTs of calcium supplements with at least 10 years of follow‐up are warranted to confirm a benefit of calcium supplements on CRC risk.     

Breast cancer risk in relation to history of preeclampsia and hyperemesis gravidarum: Prospective analysis in the Generations Study

Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow‐up of 82,053 parous women, 1,969 were diagnosed with invasive or in situ breast cancer. Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49–0.90) and of HER2‐enriched tumours (HR = 0.33, 95% CI: 0.12–0.91), but there was no association with overall (HR = 0.90, 95% CI: 0.80–1.02) or postmenopausal (HR = 0.97, 95% CI: 0.85–1.12) breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2‐enriched tumours (HR = 1.76, 95% CI: 1.07–2.87), but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2‐enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2‐enriched tumours.     

Association of Streptococcus gallolyticus subspecies gallolyticus with colorectal cancer: Serological evidence

The colonic opportunist Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC). Large‐scale seroepidemiological data for SGG antibodies and their possible association with CRC is currently missing. Associations between CRC and antibody responses to SGG were examined in 576 CRC cases and 576 controls matched by sex, age and province from a population‐based multicase–control project (MCC‐Spain). MCC‐Spain was conducted between 2008 and 2013 in 12 Spanish provinces. Antibody responses to recombinant affinity‐purified SGG pilus proteins Gallo1569, 2039, 2178 and 2179 were analysed by multiplex serology. Polyomavirus (PyV) JC VP1 and PyV 6 VP1 proteins served as disease‐specificity controls. In the control population, antibody responses to pilus proteins were mostly weak. Antibody responses to individual pilus proteins Gallo2039 (OR: 1.58, 95% CI: 1.09–2.28), Gallo2178 (OR: 1.58, 95% CI: 1.09–2.30) and Gallo2179 (OR: 1.45, 95% CI: 1.00–2.11) were significantly associated with CRC risk. The association was stronger for positivity to two or more pilus proteins of Gallo1569, Gallo2178 and Gallo2179 (OR:1.93, 95% CI: 1.04–3.56) and for double‐positivity to Gallo2178 and Gallo2179 (OR: 3.54, 95% CI: 1.49–8.44). The association between SGG infection and CRC risk was stronger among individuals younger than 65 years. For the first time we demonstrated a statistically significant association of exposure to SGG antigens and CRC in a large seroepidemiological study. These results should stimulate further studies on the role of SGG in CRC pathogenesis.     

Type 2 diabetes and colorectal cancer survival: The multiethnic cohort

This analysis examined type 2 diabetes (T2D) as a predictor of colorectal cancer (CRC) survival within the Multiethnic Cohort Study. Registry linkages in Hawaii and California identified 5,284 incident CRC cases. After exclusion of cases with pre‐existing cancer diagnosis within 1 year and systemic disease, the analytic dataset had 3,913 cases with 1,800 all‐cause and 678 CRC‐specific deaths after a mean follow‐up of 9.3 ± 5.2 years. Among CRC cases, 707 were diagnosed with T2D 8.9 ± 5.3 years before CRC. Cox regression with age as time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for T2D status as predictor of CRC‐specific and all‐cause survival while adjusting for known confounders. Overall, CRC‐specific survival was not associated with pre‐existing T2D (HR = 0.84; 95% CI = 0.67–1.07). However, a significant interaction was seen for comorbidity (p_interaction = 0.03) with better survival among those without pre‐existing conditions (HR = 0.49; 95% CI = 0.25–0.96) while no association was seen in patients with comorbid conditions. All‐cause mortality was also not related to pre‐existing T2D (HR = 1.11; 95% CI = 0.98–1.27), but significantly elevated for individuals with T2D reporting comorbid conditions (HR = 1.36; 95% CI = 1.19–1.56). Stratification by T2D duration suggested higher CRC‐specific and all‐cause mortality among participants with a T2D history of ≥10 than <10 years. The findings were consistent across sex and ethnic subgroups. In contrast to previous reports, pre‐existing T2D had no influence on disease‐specific and all‐cause survival among CRC patients. Only participants with additional comorbidity and possibly those with long T2D duration experienced higher mortality related to T2D.     

Interactions between cigarette smoking and selected polymorphisms in xenobiotic metabolizing enzymes in risk for colorectal cancer: A case-only analysis

The metabolism of xenobiotics is complex and involves multiple steps and multiple enzymes. Genetic variation in the genes encoding these enzymes as well as the level of exposure to the substrates of these enzymes could alter metabolism and clearance of potential carcinogens and thus alter cancer susceptibility. This study examined interaction effect between smoking and two single nucleotide polymorphisms (SNPs)—CYP1A1 c.1384A>G (p.Ile462Val) and EPHX1 c.337T>C (p.Tyr113His)—in modulating colorectal cancer (CRC) risk. The SNPs were selected a priori based on functional significance. In a case‐only analysis, unconditional logistic regression was used to examine the associations between smoking and each SNP and between the two SNPs in 786 patients with nonfamilial CRC. There was significant multiplicative interaction for CRC risk between smoking and EPHX1 c.337T>C (odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.03–1.81, P = 0.03), particularly among smokers with a history of greater than 20 pack‐years of smoking (OR = 1.52, 95% CI = 1.07–2.16, P = 0.02). In addition, there was gene–gene interaction between EPHX1 c.337T>C and CYP1A1 c.1384A>G (OR = 1.61, 95% CI = 1.02–2.55, P = 0.04). Smokers with any variant allele of EPHX1 were at increased risk for CRC, as were individuals with any variant allele of CYP1A1 together with any variant allele of EPHX1. Thus, the study of gene–environment and gene–gene interactions may help to identify high‐risk subgroups that can be targeted for intensive smoking cessation and CRC screening interventions. © 2010 Wiley‐Liss, Inc.     

The effect of medications which cause inflammation of the gastro‐oesophageal tract on cancer risk: a nested case–control study of routine Scottish data

Bisphosphonate, tetracycline and spironolactone use has been shown to increase gastro‐oesophageal inflammation, an accepted risk factor for cancer. However, evidence of the effect of these medications on gastro‐oesophageal cancer risk are mixed or missing entirely. Therefore, we conducted a nested case–control study using the Primary Care Clinical Information Unit Research (PCCIUR) database from Scotland. Cases with oesophageal or gastric cancer between 1999 and 2011 were matched to up to five controls based on age, gender, year of diagnosis and general practice. Medication use was ascertained using electronic prescribing records. Conditional logistic regression was used to calculate odds ratios (ORs) for the association between medication use and cancer risk after adjustment for comorbidities and other medication use. A similar proportion of gastro‐oesophageal cancer cases received bisphosphonates (3.9% vs. 3.5%), tetracycline (6.0% vs. 6.0%) and spironolactone (1.4% vs. 1.1%) compared with the controls. The adjusted ORs for the association between gastro‐oesophageal cancer and bisphosphonates, tetracycline and spironolactone were 1.05 (95% CI: 0.85, 1.31), 0.99 (95% CI: 0.84, 1.17) and 1.04 (95% CI: 0.73, 1.49). Further analysis revealed bisphosphonates were associated with increased oesophageal cancer risk (1.34, 95% CI: 1.03, 1.74) but reduced gastric cancer risk (0.71, 95% CI: 0.49, 1.03), although there was no obvious dose–response relationship. Overall, there is little evidence that the use of bisphosphonate, tetracycline or spironolactone is associated with increased risk of gastro‐oesophageal cancer. Our findings should reassure GPs and patients that these widely‐used medications are safe with respect to gastro‐oesophageal cancer risk.