Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1  = 1.53, 95% CI: 1.04-2.25, Ptrend  = .002) and all-cause (HRQ5 vs Q1  = 1.62, 95% CI: 1.16-2.26, Ptrend  < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon  = 1.02, 95% CI: 0.74-1.42; HRdistal colon  = 1.51, 95% CI: 1.20-1.91; Peffect modification  = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

Smoking and pancreatic cancer: a sex-specific analysis in the Multiethnic Cohort study.

PURPOSE: To examine whether the detrimental smoking-related association with pancreatic cancer (PC) is the same for women as for men. METHODS: We analyzed data from 192,035 participants aged 45-75 years, enrolled in the Multiethnic Cohort study (MEC) in 1993-1996. We identified PC cases via linkage to the Hawaii and California Surveillance, Epidemiology, and End Results Program cancer registries through December 2017. RESULTS: During a mean follow-up of 19.2 years, we identified 1,936 incident PC cases. Women smokers smoked on average less than men smokers. In multivariate Cox regression models, as compared with sex-specific never smokers, current smokers had a similar elevated risk of PC for women, hazard ratio (HR) 1.49 (95% CI 1.24, 1.79) and as for men, HR 1.48 (95% CI 1.22, 1.79) (pheterogeneity: 0.79). Former smokers showed a decrease in risk of PC for men within 5 years, HR 0.74 (95% CI 0.57, 0.97) and for women within 10 years after quitting, HR 0.70 (95% CI 0.50, 0.96), compared with their sex-specific current smokers. Both sexes showed a consistent, strong, positive dose-response association with PC for the four measures (age at initiation, duration, number of cigarettes per day, number of pack-years) of smoking exposure among current smokers and an inverse association for years of quitting and age at smoking cessation among former smokers (all ptrend's < 0.001). CONCLUSION: Although MEC women smoke on average less than their men counterparts, the smoking-related increase in PC risk and the benefits of cessation seem to be of similar magnitudes for women as for men.

Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer.

BACKGROUND: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer. RESULTS: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9-18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone. CONCLUSION: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0-9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125.

Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort.

BACKGROUND: Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status. METHODS: Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration. RESULTS: Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)]. CONCLUSIONS: Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.

Prospective analysis of circulating metabolites and endometrial cancer risk.

BACKGROUND: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. RESULTS: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. CONCLUSION: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.

Inflammatory potential of the diet and risk of breast cancer in the European Investigation into Cancer and Nutrition (EPIC) study.

The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01-1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04-1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01-1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.

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 (Pinteraction = .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 (Pinteraction = .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.

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.

Smoking-Related Risks of Colorectal Cancer by Anatomical Subsite and Sex.

The purpose of this study was to examine whether the increased risk of colorectal cancer due to cigarette smoking differed by anatomical subsite or sex. We analyzed data from 188,052 participants aged 45-75 years (45% men) who were enrolled in the Multiethnic Cohort Study in 1993-1996. During a mean follow-up period of 16.7 years, we identified 4,879 incident cases of invasive colorectal adenocarcinoma. In multivariate Cox regression models, as compared with never smokers of the same sex, male ever smokers had a 39% higher risk (hazard ratio (HR) = 1.39, 95% confidence interval (CI): 1.16, 1.67) of cancer of the left (distal or descending) colon but not of the right (proximal or ascending) colon (HR = 1.03, 95% CI: 0.89, 1.18), while female ever smokers had a 20% higher risk (HR = 1.20, 95% CI: 1.06, 1.36) of cancer of the right colon but not of the left colon (HR = 0.96, 95% CI: 0.80, 1.15). Compared with male smokers, female smokers had a greater increase in risk of rectal cancer with number of pack-years of smoking (P for heterogeneity = 0.03). Our results suggest that male smokers are at increased risk of left colon cancer and female smokers are at increased risk of right colon cancer. Our study also suggests that females who smoke may have a higher risk of rectal cancer due to smoking than their male counterparts.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65-1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk.

Tumor-associated autoantibodies as early detection markers for ovarian cancer? A prospective evaluation.

Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.

Sex Differences in Risk of Smoking-Associated Lung Cancer: Results From a Cohort of 600,000 Norwegians.

Whether women are more susceptible than men to smoking-related lung cancer has been a topic of controversy. To address this question, we compared risks of lung cancer associated with smoking by sex. Altogether, 585,583 participants from 3 Norwegian cohorts (Norwegian Counties Study, 40 Years Study, and Cohort of Norway (CONOR) Study) were followed until December 31, 2013, through linkage of data to national registries. We used Cox proportional hazards models and 95% confidence intervals to estimate risks. During nearly 12 million person-years of follow-up, 6,534 participants (43% women) were diagnosed with lung cancer. More men than women were heavier smokers. Compared with never smokers, male and female current smokers with ≥16 pack-years of smoking had hazard ratios for lung cancer of 27.24 (95% confidence interval (CI): 22.42, 33.09) and 23.90 (95% CI: 20.57, 27.76), respectively (P for heterogeneity = 0.30). In contrast, for current smokers, in a model with pack-years measured continuously, men had a hazard ratio of 1.43 (95% CI: 1.39, 1.48) and women a hazard ratio of 1.64 (95% CI: 1.57, 1.71) for each 10-pack-year increment of smoking (P for heterogeneity < 0.01). Our results suggest that women have an increased susceptibility to lung cancer compared with men, given the same lifetime smoking exposure.

Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort.

Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination.

The fraction of breast cancer attributable to smoking: The Norwegian women and cancer study 1991-2012.

BACKGROUND: Results from several recent cohort studies on smoking and breast cancer incidence and mortality suggest that the burden of smoking on society is underestimated. We estimated the fraction of breast cancer attributable to smoking in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study. METHODS: We followed 130 053 women, aged 34-70 years, who completed a baseline questionnaire between 1991 and 2007, through linkages to national registries through December 2012. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), while adjusting for confounders. Never smokers, excluding passive smokers, were used as the reference group in all main analyses. We estimated attributable fractions (AFs) % in smokers and in the population (PAFs) % with 95% CIs. RESULTS: Altogether, 4293 women developed invasive breast cancer, confirmed by histology. Compared with never active, never passive smokers, ever (former and current) smokers had an overall risk of breast cancer that was 21% higher (HR=1.21; 95% CI=1.08-1.34). For ever smokers, the AF was 17.3% (95% CI =7.4-25.4) and for the population the PAF of breast cancer was 11.9% (95% CI=5.3-18.1). For passive smokers, the PAF of breast cancer was 3.2% (95% CI=1.0-5.4). When we applied PAF estimates for ever smoking on the 2907 new breast cancer cases among Norwegian women aged 35+ at diagnosis in 2012, this yielded 345 (95% CI=154-526) breast cancer cases that could have been avoided in the absence of active smoking that year. CONCLUSIONS: In smokers, one in six and in the population, one in nine breast cancer cases could have been avoided in the absence of active smoking. Our findings support the notion that the global cancer burden due to smoking is substantially underestimated.

An epidemiological model for prediction of endometrial cancer risk in Europe.

Endometrial cancer (EC) is the fourth most frequent cancer in women in Europe, and as its incidence is increasing, prevention strategies gain further pertinence. Risk prediction models can be a useful tool for identifying women likely to benefit from targeted prevention measures. On the basis of data from 201,811 women (mostly aged 30-65 years) including 855 incident EC cases from eight countries in the European Prospective Investigation into Cancer and Nutrition cohort, a model to predict EC was developed. A step-wise model selection process was used to select confirmed predictive epidemiologic risk factors. Piece-wise constant hazard rates in 5-year age-intervals were estimated in a cause-specific competing risks model, five-fold-cross-validation was applied for internal validation. Risk factors included in the risk prediction model were body-mass index (BMI), menopausal status, age at menarche and at menopause, oral contraceptive use, overall and by different BMI categories and overall duration of use, parity, age at first full-term pregnancy, duration of menopausal hormone therapy and smoking status (specific for pre, peri- and post-menopausal women). These variables improved the discriminating capacity to predict risk over 5 years from 71% for a model based on age alone to 77% (overall C statistic), and the model was well-calibrated (ratio of expected to observed cases = 0.99). Our model could be used for the identification of women at increased risk of EC in Western Europe. To achieve an EC-risk model with general validity, a large-scale cohort-consortium approach would be needed to assess and adjust for population variation.

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition.

The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2 = 0.79, 95% confidence interval [CI] = [0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2 = 1.99 [0.98-4.06]; high grade: ORlog2 = 0.75 [0.61-0.93], phet ≤ 0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed.