Endogenous sex hormones and colorectal cancer survival among men and women

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, p_trend = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41–1.29, p_trend = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, p_trend = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01–3.84, p_trend = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.     

Association between post-treatment circulating biomarkers of inflammation and survival among stage II–III colorectal cancer patients

Background Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival.Methods We included 306 eligible incident stage II–III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models.Results Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10–2.59), 2.72 (2.07–3.56), 1.97 (1.18–3.28) and 1.71 (1.14–2.58), respectively. IL-6 and adiponectin had a dose–response effect (P_trend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2–2.56), IL-6 (HR = 5.02, 95% CI: 2.92–8.59), MCP-1 (HR = 3.78, 95% CI: 1.41–10.08), and adiponectin (HR = 3.16, 95% CI: 1.27–7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29–0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years.Conclusion Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II–III CRC patients.Subject terms: Prognostic markers, Colorectal cancer, Epidemiology     

Sugar-sweetened beverage,artificially sweetened beverage and sugar intake and colorectal cancer survival

Background The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.Methods Among 1463 stage I–III CRC patients from the Nurses’ Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.Results Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26–0.75 and 0.70, 95% CI: 0.55–0.89, respectively).Conclusions Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination.Subject terms: Epidemiology, Cancer epidemiology, Colorectal cancer, Nutrition     

Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study

Background Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality.Methods We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure.Results Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32–1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0−I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40–1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24–1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality.Conclusion PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.Subject terms: Gastrointestinal cancer, Epidemiology     

Association between the dietary inflammatory index and all-cause mortality in colorectal cancer long-term survivors

Pro-inflammatory dietary factors have been shown to be associated with the incidence of a range of cancers. However, there are many fewer studies on the association between the inflammatory potential of diet and survival after cancer diagnosis. We examined the association between post-diagnosis dietary inflammatory index (DII®) scores and all-cause mortality in long-term survivors of colorectal cancer (CRC). DII scores were calculated from dietary data of 1,404 CRC survivors collected at a median of 6 years after CRC diagnosis. Using multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association of DII scores, modeled continuous and in quartiles, with all-cause mortality. After a median follow-up time of 7 years (after dietary assessment), 204 study participants had died. Overall, in the fully adjusted model there was a suggestion of a positive association between DII score and all-cause mortality (HR_{DIIquartile4vs1}: 1.36; 95% CI: 0.88–2.09 and HR_{DIIcontinuous}: 1.08; 95% CI: 0.97–1.20). However, in subgroup analyses, we found significant differences in individuals with metastatic disease (HR_{DIIcontinuous}: 1.34; 95% CI: 1.07–1.67) and the absence of stoma (HR_{DIIcontinuous}: 1.15; 95% CI: 1.02–1.29). Overall, the post-diagnosis DII was not statistically significantly associated with all-cause mortality in CRC long-term survivors; however, there was suggestive evidence of an association in select subgroups.     

Impact of prediagnostic smoking and smoking cessation on colorectal cancer prognosis: a meta-analysis of individual patient data from cohorts within the CHANCES consortium

BackgroundSmoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited.Patients and methodsFor this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology.ResultsA total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04–1.20] and current smoking (HR = 1.29; 95% CI = 1.04–1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR_{<10 years} = 0.78; 95% CI = 0.69–0.88; HR_{≥10 years} = 0.78; 95% CI = 0.63–0.97) and CRC-specific survival (HR_{≥10 years} = 0.76; 95% CI = 0.67–0.85).ConclusionIn this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.     

One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study

Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B₁₂ and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B₂ (riboflavin), B₃ (niacin), B₆ and B₁₂. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B₃ intake was associated with a lower HCC risk (HR_{Q5 vs Q1} = 0.60; 95% CI = 0.42-0.85; P_trend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HR_{Q5 vs Q1} = 0.32; 95% CI = 0.18-0.55; P_trend < .0001). Among participants with >3 years of follow-up, higher total vitamin B₃ intake was again associated with lower risk (HR_{Q5 vs Q1} = 0.37; 95% CI = 0.20-0.68; P_trend = .001), whereas higher total vitamin B₆ intake was associated with higher risk (HR_{Q5 vs Q1} = 2.04; 95% CI = 1.02-4.07; P_trend = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B₃ intake and HCC risk, and dose-response positive association between total vitamin B₆ intake and HCC risk. The study suggests that higher vitamin B₃ intake is associated with lower HCC risk, whereas higher vitamin B₆ intake is associated with increased risk.     

Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common,inherited vitamin D-binding protein isoforms

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)—considered the best marker of total vitamin D exposure—is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (P_interaction = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P_interaction = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.     

Erythrocyte membrane fatty acids and breast cancer risk: a prospective analysis in the nurses' health study II

The roles of specific fatty acids in breast cancer etiology are unclear, particularly among premenopausal women. We examined 34 individual fatty acids, measured in blood erythrocytes collected between 1996 and 1999, and breast cancer risk in a nested case‐control study of primarily premenopausal women in the Nurses' Health Study II. Breast cancer cases diagnosed after blood collection and before June 2010 (n = 794) were matched to controls and conditional logistic regression was used to estimate OR's (95% CI's) for associations of fatty acids with breast cancer; unconditional logistic regression was used for stratified analyses. Fatty acids were not significantly associated with breast cancer risk overall; however, heterogeneity by body mass index (BMI) was observed. Among overweight/obese women (BMI ≥ 25), several odd‐chain saturated (SFA, e.g. 17:0, OR_Q4vsQ1(95% CI) =1.85 (1.18 – 2.88), p_trend=0.006 p_int<0.001), trans (TFA, e.g. 18:1, OR_Q4vsQ1(95% CI) =2.33 (1.45 – 3.77), p_trend<0.001, p_int=0.007) and dairy‐derived fatty acids (SFA 15:0 + 17:0 + TFA 16:1n‐7t; OR_Q4vsQ1(95% CI) =1.83(1.16 – 2.89), p_trend=0.005, p_int<0.001) were positively associated, and n‐3 polyunsaturated fatty acids (n‐3 PUFA, e.g. alpha‐linolenic acid; OR_Q4vsQ1(95% CI) =0.57 (0.36 – 0.89), p_trend=0.017, p_int=0.03) were inversely associated with breast cancer. Total SFA were inversely associated with breast cancer among women with BMI < 25 (OR_Q4vsQ1(95% CI) =0.68 (0.46 – 0.98), p_trend=0.05, p_int=0.01). Thus, while specific fatty acids were not associated with breast cancer overall, our findings suggest positive associations of several SFA, TFA and dairy‐derived fatty acids and inverse associations of n‐3 PUFA with breast cancer among overweight/obese women. Given these fatty acids are influenced by diet, and therefore are potentially modifiable, further investigation of these associations among overweight/obese women is warranted.     

Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC)

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; P_trend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; P_trend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; P_trend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; P_trend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, P_trend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, P_trend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; P_trend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; P_trend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.     

Family history of breast cancer in first-degree relatives and triple-negative breast cancer risk

Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER−/PR−/HER2+, N = 308) breast cancer among women aged 40–84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43–2.09, HR = 1.62, 95% CI: 1.54–1.70, and HR = 1.56, 95% CI: 1.15–2.13, for triple-negative, ER+, and ER−/PR−/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR_{triple-negative} = 2.66, 95% CI: 1.66–4.27, HR_ER+ = 2.05, 95% CI: 1.79–2.36, HR_ER−_/PR−_/HER2+ = 2.25, 95% CI: 0.99–5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER−/PR−/HER2+ breast cancer.     

Central adiposity after breast cancer diagnosis is related to mortality in the Health,Eating, Activity,and Lifestyle study

We examined whether waist circumference (WC) and waist-to-hip ratio (WHR) after breast cancer diagnosis are associated with all-cause or breast cancer-specific mortality and explored potential biological pathways mediating these relationships. Our analysis included 621 women diagnosed with local or regional breast cancer who participated in the Health, Eating, Activity, and Lifestyle study. At 30 (±4) months postdiagnosis, trained staff measured participants’ waist and hip circumferences and obtained fasting serum samples for biomarker assays for assays of insulin, glucose, C-peptide, insulin growth factor-1 and binding protein-3, C-reactive protein (CRP), and adiponectin. We estimated multivariate hazard ratios (HR) and 95 % confidence intervals (CI) for death over ~9.5 years of follow-up. After adjustment for measured body mass index, treatment, comorbidities, race/ethnicity, diet quality, and postdiagnosis physical activity, WC was positively associated with all-cause mortality (HR_q4:q1: 2.99, 95 % CI 1.14, 7.86) but its positive association with breast cancer-specific mortality was not statistically significant (HR_q4:q1: 2.69, 95 % CI 0.69, 12.01). WHR was positively associated with all-cause mortality (HR_q4:q1: 2.10, 95 % CI 1.08, 4.05) and breast cancer-specific mortality (HR_q4:q1: 4.02, 95 % CI 1.31, 12.31). After adjustment for homeostatic model assessment (HOMA) score and C-reactive protein, risk estimates were attenuated and not statistically significant. In this diverse breast cancer survivor cohort, postdiagnosis WC and WHR were associated with all-cause mortality. Insulin resistance and inflammation may mediate the effects of central adiposity on mortality among breast cancer patients.     

Ingested nitrate and nitrite,disinfection by‐products,and pancreatic cancer risk in postmenopausal women

Nitrate and nitrite are precursors of N‐nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by‐products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986–2011). We used historical monitoring and treatment data to estimate levels of long‐term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one‐half the maximum contaminant level (>½ MCL; 5 mg/L nitrate‐nitrogen, 40 µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HR_{p95 vs. Q1} = 1.16, 95% CI: 0.51–2.64). Associations with average TTHM levels were also null (HR_{Q4 vs. Q1} = 0.70, 95% CI:0.42–1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HR_{p95 vs. Q1} = 1.66, 95% CI 1.00–2.75;p_trend = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer.     

The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus

Metformin use has been associated with decreased cancer risk and mortality. However, the effects of metformin on clinical outcomes of colorectal cancer (CRC) are not defined. This study aimed to evaluate the association between metformin use and mortality of CRC in diabetic patients. We identified 595 patients who were diagnosed both CRC and diabetes mellitus. Patients were compared by two groups; 258 diabetic patients taking metformin and 337 diabetic patients not taking metformin. Patient's demographics, clinical characteristics, overall mortality and CRC-specific mortality were analyzed. After a median follow-up of 41 months, there were 71 total deaths (27.5%) and 55 CRC-specific deaths (21.3%) among 258 patients who used metformin, compared with 136 total deaths (40.4%) and 104 CRC-specific deaths (30.9%) among 337 patients who did not use metformin. Metformin use was associated with decreased overall mortality (p = 0.018) and CRC-specific mortality (p = 0.042) by univariate analysis. After adjustment for clinically relevant factors, metformin use showed lower risk of overall mortality (HR, 0.66; 95% CI 0.476-0.923; p = 0.015) and CRC-specific mortality (HR, 0.66; 95% CI 0.45-0.975; p = 0.037) in CRC patients with diabetes. Metformin use in CRC patients with diabetes is associated with lower risk of CRC-specific and overall mortality.     

Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells – Associations with histopathology and patients outcome

AimTo elucidate cellular features accountable for colorectal cancers’ (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC.MethodsImmunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II–IV and subsequently treated with adjuvant 5-fluorouracil.ResultsExpression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR = 1.0; 95% CI: 0.6–1.8; P = 0.9) or overall survival (OS) (HR = 0.9; 95% CI: 0.5–1.6; P = 0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR = 1.3; 95% CI: 0.9–1.8; P = 0.08) and OS (HR = 1.5; 95% CI: 1.1–2.1; P = 0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR = 0.7; 95% CI: 0.6–0.9; P = 0.02) and OS (HR = 0.7; 95% CI: 0.6–1.0; P = 0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P = 0.02) but not with RFS (HR = 0.9; 95% CI: 0.7–1.1; P = 0.2) or OS (HR = 0.8; 95% CI: 0.7–1.0; P = 0.07).ConclusionTIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host–cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC.     

Ultra-processed food consumption and the risk of pancreatic cancer in the Prostate,Lung, Colorectal and Ovarian Cancer Screening Trial

Whether ultra-processed food consumption is associated with the risk of pancreatic cancer has not been determined. We performed a prospective study to fill this gap. A population-based cohort of 98 265 American adults was identified from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer incidence. Subgroup analysis was performed to identify the potential effect modifiers. During a mean follow-up of 8.86 years, 387 pancreatic cancer cases occurred. High consumption of ultra-processed foods was found to be associated with an increased risk of pancreatic cancer (fully adjusted HR_{quartile 4 vs 1}:1.49; 95% confidence interval [CI]: 1.07-2.07; P_trend = .021) in a linear dose-response manner (P_nonlinearity = .075). Subgroup analysis further found that the positive association of ultra-processed food consumption with the risk of pancreatic cancer was more pronounced in subjects aged <65 years (HR_{quartile 4 vs 1}:2.17; 95% CI: 1.14-4.15) than in those aged ≥65 years (HR_{quartile 4 vs 1}:1.32; 95% CI: 0.88-1.94), though the interaction test failed to achieve the statistical significance (P_interaction = .061). These findings suggest that reducing ultra-processed food consumption may be beneficial in decreasing pancreatic cancer incidence.     

Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis

Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986–2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (P _Trend = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73–1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43–1.14). The trend did not extend to mixed ductal–lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.     

Mortality is persistently increased in Hodgkin’s lymphoma survivors

BackgroundNegative health outcomes of chronic fatigue (CF) in disease-free cancer survivors are mainly unexplored. Aims of this study were to examine mortality and causes of death in Hodgkin’s lymphoma survivors (HLSs) compared to controls from the general population, and to explore if CF was associated with increased mortality.MethodsHLSs (n = 557) invited to participate in a survey on late effects in 1994 were divided into three groups: participants without CF (n = 329), participants with CF (n = 113), non-participants (n = 98). Controls matched for gender and age were drawn from the general population (five per HLSs, n = 2785). Observation time was calculated from 1st January 1994 until date of death or cut-off at 1st January 2007. Kaplan–Meier plots were used for univariate analyses and Cox models for multiple covariates.ResultsCompared to controls HLSs had nearly five times higher mortality (HR = 4.93; 95% confidence interval [CI]: 3.91–6.21) and the mortality rate of HLSs was higher than the rate of their controls for the entire observation period. Mortality was increased in all groups: participants with CF: HR = 4.85 (95% CI: 3.02–7.77), participants without CF: HR = 4.35 (95% CI: 3.16–6.00), non-participants: HR = 9.45 (95% CI: 5.44–16.41).Compared to the controls HLSs had over six times increased mortality of cancer (HR: 6.6, 95% CI: 4.7–9.2) and almost five times increased mortality of cardiovascular diseases (HR: 4.9, 95% CI: 3.1–7.9).ConclusionsHLSs had almost five-time increased mortality compared to controls. CF was not associated with increased mortality rate. The high mortality among the non-participating HLSs indicates that serious health problems are underestimated in this group. This has implications for the interpretation of surveys in cancer survivors.     

Association between sleep disorders and the presence of breast cancer metastases in gynecological practices in Germany: a case–control study of 11,412 women

Purpose

ALDH1A1, one of the main isotopes of aldehyde dehydrogenase-1 is involved in the differentiation and protection of normal hematopoietic stem cells and functions in alcohol sensitivity and dependence. We evaluated the associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white (NHW) breast cancer (BC) cases from the Breast Cancer Health Disparities Study.

Methods

Nine SNPs in ALDH1A1 were evaluated in 920 Hispanic and 1372 NHW women diagnosed with incident invasive BC. Adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were stratified by Native American (NA) ancestry and alcohol consumption.

Results

A total of 443 deaths occurred over a median follow-up time of 11 years. After adjusting all results for multiple comparisons, rs7027604 was significantly associated with all-cause mortality (HR_AA = 1.40; 95% CI 1.13–1.73, P _adj = 0.018). The rs1424482 CC genotype (HR_CC = 1.69; 95% CI 1.20–2.37, P _adj = 0.027) and the rs7027604 AA genotype (HR_AA = 1.65; 95% CI 1.21–2.26, P _adj = 0.018) were positively associated with non-BC mortality. Among long-term light drinkers, rs1888202 was associated with decreased all-cause mortality (HR_CG/GG = 0.36; 95% CI 0.20–0.64), while associations were not significant among non-drinkers or moderate/heavy drinkers (P _interation = 0.218). The increased risk of all-cause mortality associated with rs63319 was limited to women with low NA ancestry (HR_AA = 1.53; 95% CI 1.19–1.97).

Conclusions

Multiple SNPs in ALDH1A1 were associated with increased risk of mortality after BC. Future BC studies examining the relationship between ALDH1A1 and mortality should consider the modifying effects of alcohol consumption and NA ancestry.