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Supplementary Table 1 from Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer

Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes. Cancer Epidemiol Biomarkers Prev; 19(11); 2877–87. ©2010 AACR.

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.

Background Trans fatty acid (TFA) intake persists in much of the world, posing ongoing threats to public health that warrant further elucidation. Published evidence suggests a positive association of self-reported TFA intake with non-Hodgkin lymphoma (NHL) risk. Objectives To confirm those reports, we conducted a prospective study of prediagnosis RBC membrane TFA levels and risk of NHL and common NHL histologic subtypes. Methods We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants with archived RBC specimens and no history of cancer at blood draw (1989-1090 and 1994-1995, respectively). We confirmed 583 incident NHL cases (332 women and 251 men) and individually matched 583 controls on cohort (sex), age, race, and blood draw date/time. We analyzed RBC membrane TFA using GLC (in 2013-2014) and expressed individual TFA levels as a percentage of total fatty acids. We used unconditional logistic regression adjusted for the matching factors to estimate ORs and 95% CIs for overall NHL risk per 1 SD increase in TFA level and assessed histologic subtype-specific associations with multivariable polytomous logistic regression. Results Total and individual TFA levels were not associated with risk of all NHL or most subtypes. We observed a positive association of total TFA levels with diffuse large B cell lymphoma (DLBCL) risk [n = 98 cases; OR (95% CI) per 1 SD increase: 1.30 (1.05, 1.61); P = 0.015], driven by trans 18:1n-9(ω-9)/elaidic acid [OR (95% CI): 1.34 (1.08, 1.66); P = 0.007], trans 18:1n-7/vaccenic acid [OR (95% CI): 1.28 (1.04, 1.58); P = 0.023], and trans 18:2n-6t,t [OR (95% CI): 1.26 (1.01, 1.57); P = 0.037]. Conclusions Our findings extended evidence for TFA intake and DLBCL risk but not for other NHL subtypes. Reduced TFA consumption through dietary choices or health policy measures may support prevention of DLBCL, an aggressive NHL subtype.

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre-diagnosis red blood cell (RBC) specimens in the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T-NHL), B cell NHL (B-NHL) and three individual B-NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B-NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0, and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T-NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B-NHLs other than CLL/SLL and for VLCSFA and MUFA with T-NHL suggest an influence of fatty acid metabolism on lymphomagenesis.

The high prevalence and long latency period of prostate cancer (PCa) provide a unique opportunity to control disease progression with dietary and nutraceutical approaches. We developed ProFine, a standardized composition of luteolin, quercetin, and kaempferol, and investigated its potential as a nutraceutical for PCa in preclinical models. The three ingredients of ProFine demonstrated synergistic in vitro cytotoxicity and effectively induced apoptosis in PCa cells. ProFine markedly affected the transcriptome of PCa cells, suppressed the expression of androgen receptor, and inhibited androgen-regulated genes. Oral administration of ProFine did not exhibit obvious toxicities in mice, and the three ingredients retained their individual pharmacokinetic and bioavailability profiles. Importantly, ProFine significantly retarded the growth of PCa xenografts in athymic nude mice and extended the survival of animals. This study provides preclinical evidence supporting the promise of ProFine as a safe, efficacious, and affordable intervention to control PCa progression and improve clinical outcomes.

Background: Dietary fat intake may contribute to non-Hodgkin lymphoma (NHL) pathogenesis by influencing carcinogen exposure or through immune modulation.Objective: We aimed to evaluate NHL risk associated with total and specific dietary fat intake.Design: We evaluated associations within the Nurses' Health Study (NHS) (n = 88,598) and the Health Professionals Follow-Up Study (HPFS) (n = 47,531) using repeated validated dietary assessments. We confirmed 1802 incident NHL diagnoses through 2010. Using multivariable Cox proportional hazards models, we estimated hazard ratios (HRs) for all NHL and common subtypes associated with a 1-SD increase in cumulative mean intakes of total, animal, saturated, trans, and vegetable fats and marine fatty acids. We pooled sex-specific HRs using random-effects meta-analysis.Results: Over 24-30 y of follow-up, neither total nor specific dietary fats were significantly associated with NHL risk overall. Higher total, animal, and saturated fat intakes were positively associated with the risk of the chronic lymphocytic leukemia/small lymphocytic lymphoma subtype among women only (253 cases; P-trend ≤ 0.05), driven by strong associations during 1980-1994. From baseline through 1994, among women and men combined, total fat intake was borderline-significantly positively associated with NHL overall (pooled HR per SD: 1.13; 95% CI: 0.99, 1.29) and was significantly associated with diffuse large B cell lymphoma (pooled HR per SD: 1.47; 95% CI: 1.06, 2.05), with similar trends for animal and saturated fat intake. For women only, trans fat was significantly positively associated with all NHL. In contrast, during 1994-2010, there was little evidence for associations of dietary fat intake with NHL overall or by subtype.Conclusion: Previous observations of an increased risk of NHL associated with intakes of total, animal, saturated, and trans fat with 14 y of follow-up did not persist with longer follow-up.

PURPOSE: We examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women. METHODS: We conducted a nested case-control study within the Nurses’ Health Study II. From blood samples collected in 1996–1999 and follow-up through 2007, plasma measures were available for 610 cases and 1,207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics. RESULTS: Plasma vitamin B(12) was associated with a 64% higher risk of breast cancer comparing the highest versus lowest quintile (95%CI=1.17–2.29, p-trend=0.02). Plasma folate (comparable RR=1.18, 95%CI=0.84–1.66), pyridoxal 5’-phosphate (RR=1.18, 95%CI=0.85–1.64)(,) homocysteine (RR=0.93, 95%CI=0.67–1.28), cysteine (RR=1.14, 95%CI=0.81–1.62), and cysteinylglycine (RR=0.93, 95%CI=0.66–1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive and estrogen receptor-positive/progesterone receptor-positive breast cancer, and this association was suggestively stronger for bloods collected post-fortification. Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use and MTHFR status (p-interaction

Background Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge. Objectives We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Women's Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline). Design Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors. Results Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90; P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97; P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98; P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97; P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49; P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93; P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained. Conclusions Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Women's Health Study was registered at clinicaltrials.gov as NCT00000479.

Summary Objective To describe the characteristics of real‐world patients potentially eligible for adjunctive pharmacotherapy for weight loss. Methods Patients from the GE Centricity electronic medical record database were selected if they had body mass index (BMI) ≥30 or ≥27 to

Bone metastasis is a major cause of prostate cancer (PCa) morbidity and mortality. Despite some success in transiently controlling clinical symptoms with docetaxel-based therapy, PCa patients become docetaxel-resistant and inevitably progress with no cure. We synthesized an acyl-tyrosine bisphosphonate amide derivative, BKM1644, with the intent of targeting bone metastatic PCa and enhancing docetaxel's efficacy. BKM1644 exhibits potent anti-cancer activity in the NCI-60 panel and effectively inhibits the proliferation of metastatic, castration-resistant PCa (mCRPC) cells, with IC50 ranging between 2.1 μM and 6.3 μM. Significantly, BKM1644 sensitizes mCRPC cells to docetaxel treatment. Mice with pre-established C4-2 tumors in the tibia show a marked decrease in serum prostate-specific antigen (control: 173.72 ± 37.52 ng/ml, combined treatment: 64.45 ± 22.19 ng/ml; p < 0.0001) and much improved bone architecture after treatment with the combined regimen. Mechanistic studies found that docetaxel temporarily but significantly increases survivin, an anti-apoptotic protein whose overexpression has been correlated with PCa bone metastasis and therapeutic resistance. Intriguingly, BKM1644 effectively inhibits survivin expression, which may antagonize docetaxel-induced survivin in bone metastatic PCa cells. Signal transducer and activator of transcription 3 (Stat3) may be involved in the suppression of survivin transcription by BKM1644, as confirmed by a survivin reporter assay. Collectively, these data indicate that BKM1644 could be a promising small-molecule agent to improve docetaxel efficacy and retard the bone metastatic growth of PCa.

Prior epidemiologic findings for plasma folate and B-vitamins and breast cancer risk are inconsistent and have not assessed the influence of folic acid fortification. Therefore, we examined the associations of plasma folate, B(12), pyridoxal 5′-phosphate (PLP), homocysteine, cysteine and cysteinylglycine with breast cancer risk, before and after fortification. We conducted a nested case–control study within the prospective Nurses’ Health Study. In 1989–1990 (pre-fortification), 32,826 women donated a blood sample and 18,743 donated an additional blood sample in 2000–2001 (post-fortification). Between the first blood collection and 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two were 1:1 matched to controls. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for breast cancer risk factors. Overall, higher plasma folate, B(12), PLP, homocysteine, cysteine and cysteinylglycine levels were not associated with breast cancer risk. Associations did not vary by in situ/invasive, hormone receptor status, or tumor molecular subtype. Additionally, associations were null before and after fortification. For example, the RR (95% CI) for the highest versus lowest tertile of 1990 (pre-fortification) plasma folate with 1990–2000 follow-up was 0.93 (0.75–1.16) and for the 2000 plasma folate (post-fortification) with 2000–2006 follow-up the RR (95% CI) was 1.17 (0.79–1.74). Plasma folate, B(12), PLP, homocysteine, cysteine and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific tumor molecular subtypes. However, long term associations (>8 years) after the implementation of fortification could not be examined.

Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients' survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.

Purpose: Prior epidemiologic cohort studies have generally found no associations of folate and other B-vitamins with breast cancer overall, but differences by menopause status have been suggested. However, prior studies have been limited by small numbers to examine the relationship between different plasma measures and related polymorphisms and breast cancer risk among younger women. Therefore, we examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women. Methods: We conducted a nested case-control study within the Nurses’ Health Study II. From blood samples collected in 1996-1999 and follow-up through 2007, plasma measures were available for 610 cases and 1,207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics. Results: Plasma vitamin B12 was associated with a 71% increase in risk of breast cancer comparing the highest versus lowest quintile (95%CI=1.22-2.39, p-trend=0.02). Plasma folate (comparable RR=1.20, 95%CI=0.85-1.68), pyridoxal 5’-phosphate (RR=1.19, 95%CI=0.85-1.65), cysteine (RR=1.15, 95%CI=0.81-1.63), homocysteine (RR=0.90, 95%CI=0.65-1.25), and cysteinylglycine (RR=0.92, 95%CI=0.65-1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive (RR highest tertile vs. lowest=1.48, 95%CI=1.09-2.01) and estrogen receptor-positive/progesterone receptor-positive breast cancer (RR T3 vs. T1= 1.59, 95%CI= 1.12-2.27) and the invasive association was suggestively stronger for bloods collected post-fortification (p-heterogeneity=0.19). Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use and MTHFR status (p-interaction Conclusions: Overall, plasma B-vitamins and metabolites were not consistently associated with lower breast cancer risk. For increasing plasma folate and B12 levels higher risk of invasive breast cancer was observed. Additionally, there may be associations in subgroups defined by related genetic variants, breast cancer risk factors, and tumor factors. Future studies in younger women are needed to confirm findings. Citation Format: Serena C. Houghton, A Heather Eliassen, Shumin Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson. Folate and other B-vitamins and the risk of breast cancer in younger women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5042.

To confirm previous reports of increased non-Hodgkin lymphoma (NHL) risk with higher intake of dietary trans fatty acids (TFA), we conducted the first prospective study of pre-diagnosis red blood cell (RBC) TFA levels and risk of NHL and common NHL histologic subtypes (diffuse large-B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic lymphoma/small lymphocytic leukemia, other B-cell NHL, T-cell NHL). Methods: We conducted a nested case-control study in Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) participants with archived RBC specimens and no history of cancer at sample collection (NHS: 1989–90; HPFS: 1994–5). We confirmed 583 NHL cases (332 women in NHS, 251 men in HPFS) and matched 583 controls by cohort (sex), age, race/ethnicity and blood draw date/time. We analyzed RBC TFAs using gas-liquid chromatography; individual TFA levels were expressed as a percentage of total fatty acids. We used unconditional logistic regression, adjusted for the matching factors, to estimate odds ratios (OR) and 95% confidence intervals (CI) for overall NHL risk per 1 standard deviation (SD) unit increase in TFA level. We fitted multivariate polytomous logistic regression models to assess associations for the specific subtypes listed above. Results: Total and individual RBC TFAs were not associated with overall NHL risk or risk of most histologic subtypes. However, we observed a positive association of total RBC TFA with DLBCL risk (n = 86 cases; OR [95% CI] per 1 SD: 1.29 [1.02, 1.64]), driven primarily by 18:1 TFAs (1.35 [1.07, 1.72]). Among 18:1 TFA isomers, we found a positive association for trans 18:1 n-9 (elaidic acid; 1.33 [1.05, 1.68]) but not for other isomers. Conclusions: We observed significant positive associations for RBC TFA levels with DLBCL risk. These findings are consistent with published studies of self-reported TFA intake; further, previous studies have shown that TFA levels – particularly trans 18:1n-9, which is industrially-derived – are positively correlated with biomarkers of inflammation and immune activation, supporting the biologic plausibility of our findings. Food industry and public health measures to diminish TFA intake may help to reduce risk of NHL, and particularly of DLBCL.

Background Several molecularly-targeted agents are being evaluated in gastric cancer cell lines. In this study we evaluated the synergistic potential of MK-2206, an oral potent allosteric Akt inhibitor, in combination with chemotherapeutic agents in human gastric cancer cell lines. Materials and Methods We evaluated effects of MK-2206 on cell growth and cell signaling using a panel of gastric cancer cell lines AGS, SNU-1 and SNU 16. The analysis of drug combinations was conducted by using CellTiter-Blue™ Cell Viability Assay which yielded the combination index (CI). MK-2206 and representative chemotherapy agent were further evaluated regarding their effects on Akt inhibition and downstream targets using western blots probed with the appropriate antibodies. We assessed the combination of MK-2206 and chemotherapy in three different treatment sequences. Results We demonstrated in vitro synergistic efficacy of MK-2206 when combined with carboplatinum and paclitaxel in the three cell lines examined. Efficacy was dose dependent. We assessed the combination of MK-2206 and carboplatinum/paclitaxel in three different treatment sequences; 24 h of exposure to combination chemotherapy followed by a 48 h exposure to MK-2206 resulted in the highest synergistic antiproliferative effect in all cell lines. On the other hand, the reverse sequence (MK-2206 followed by chemotherapy) and the concurrent treatment schedule were slightly synergistic or additive as well. The effects of MK-2206 on p-Akt and other downstream targets was reported. Conclusions Our findings suggest that Akt inhibition augments the efficacy of existing gastric cancer therapeutics (carboplatinum and paclitaxel); thus, MK-2206 is a promising agent to treat gastric cancer patients who receive these cytotoxic agents. The magnitude of synergy depended on the treatment sequence; a schedule of MK-2206 dosed before or concurrently with chemotherapy was not as effective as being dosed after chemotherapy. Further experiments addressing MK-2206’s mechanism of action in combination with chemotherapy are needed.

The etiology of non-Hodgkin lymphoma (NHL) is poorly understood. Obesity is associated with inflammation, a cytokine milieu conducive to lymphocyte proliferation, and has been associated with NHL risk in some epidemiologic studies. To prospectively examine NHL risk in relation to adult and earlier life obesity, we documented 635 incident NHL diagnoses among 46,390 men in the Health Professionals Follow-up Study and 1,254 diagnoses among 116,794 women in the Nurses' Health Study over 22 to 32 years of follow-up. Using multivariable Cox proportional hazards models, we estimated cohort-specific incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of NHL and major histologic subtypes associated with cumulative average middle and young adult (ages, 18–21 years) body mass index (BMI) and adolescent and childhood somatotype. NHL risk was modestly increased in men (but not women) with a cumulative average middle adult BMI ≥ 30 kg/m2 (vs. 15–22.9 kg/m2; RR, 1.28; 95% CI, 0.92–1.77; Ptrend = 0.05). In meta-analyses across cohorts, higher young adult BMI was associated with increased risk of all NHL (pooled RR per 5 kg/m2, 1.19; 95% CI, 1.05–1.37), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (all Ptrend ≤ 0.02). Adolescent somatotype was also positively associated with all NHL, DLBCL, and follicular lymphoma in pooled analyses (all Ptrend ≤ 0.03), whereas childhood somatotype was positively associated with NHL overall among women only (Ptrend < 0.01). These findings in two large prospective cohorts provide novel evidence that larger body size in childhood, adolescence, and young adulthood predicts increased risk of NHL, and particularly of DLBCL and follicular lymphoma. Cancer Prev Res; 6(8); 864–73. ©2013 AACR.

Estrogen receptor-negative (ER(-)) breast cancer has few known or modifiable risk factors. Because ER(-) tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER(-) breast cancer.Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER(+)) and 4821 ER(-) breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided.Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER(-) breast cancer but not with risk of breast cancer overall or of ER(+) tumors. The inverse association for ER(-) tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER(-) breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER(+) breast cancer (P (common-effects) by ER status.001). Total fruit consumption was non-statistically significantly associated with risk of ER(-) breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04).We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER(-) breast cancer in our large pooled analyses.

Background: Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods: To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10-4) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results: We confirmed the association of 14 SNPs with breast cancer risk (Ptrend = 2.57 × 1023 -3.96 × 10 219). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P heterogeneity = .0016 for FGFR2-rs2981582 and P heterogeneity = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P heterogeneity = .0028). Conclusion: This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer. © Oxford University Press 2011.

Background Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts. Methods During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model. Results Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing ≥ 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER- breast cancer (Ptrend ≤ 0.001; Pcommon-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake (Pinteraction ≥ 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status. Conclusions Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk.

Results The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B6, or vitamin B12. Conclusion Our results indicate no statistically significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma among women at high risk for cardiovascular disease. J Natl Cancer Inst 2012;104:1562–1575 Folate, vitamin B6, and vitamin B12 are essential cofactors that play important roles in one-carbon metabolism, which is required for the maintenance of intracellular DNA synthesis and methylation. Data from both in vitro and animal studies have suggested a protective effect of B vitamins against colorectal carcinogenesis (1,2), although the results have been somewhat mixed and the complex mechanisms have not yet been fully elucidated. Observational evidence, though not entirely consistent, has suggested that blood levels of folate or vitamin B6 are inversely related to the risk of colorectal neoplasia. Some, but not all prospective studies have suggested a 20%–40% reduction in the risk of colorectal cancer or adenoma in those with the highest intake of folate compared with those with the lowest intake (1–3). A recent meta-analysis of nine prospective studies showed a 10% reduction in colorectal cancer in individuals with the highest vitamin B6 intake compared with those

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle–related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (Pheterogeneity = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46–0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76–2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A. Cancer Res; 72(12); 3020–8. ©2012 AACR.

Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). SCLC cell lines were exposed to increasing concentrations of single-agent HDAC inhibitors and topoisomerase inhibitors, in various combinations, to assess for cell viability, additivity or synergy, and apoptosis. We found that MGCD0103 and vorinostat decreased cell viability by at least 60% and 80%, respectively. In the majority of cell lines, the strongest synergism was seen when vorinostat was followed by either etoposide or topotecan; concurrent therapy led to antagonism in most cell lines. Synergistic effects were seen when MGCD0103 was given concurrently or sequentially with both amrubicin and epirubicin. Enhanced additive effects leading to caspase activation were noted for the combination of MGCD0103 or vorinostat with a topoisomerase inhibitor vs. either agent alone. Thus, the combination of HDAC inhibitors and topoisomerase inhibitors showed enhanced cytotoxic effects in SCLC cell lines. Further evaluation in a clinical setting may be warranted.

Background: Epidemiologic studies examining associations between carotenoid intakes and risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR) status are limited. Objective: We investigated these associations in a pooled analysis of 18 cohort studies. Design: Of 1,028,438 participants followed for a maximum follow-up of 26 y across studies, 33,380 incident invasive breast cancers were identified. Study-specific RRs and 95% CIs were estimated by using Cox proportional hazards regression and then pooled by using a random-effects model. Results: α-Carotene, β-carotene, and lutein/zeaxanthin intakes were inversely associated with the risk of ER-negative (ER−) breast cancer (pooled multivariable RRs of the comparison between the highest and lowest quintiles): α-carotene (0.87; 95% CI: 0.78, 0.97), β-carotene (0.84; 95% CI: 0.77, 0.93), and lutein/zeaxanthin (0.87; 95% CI: 0.79, 0.95). These variables were not inversely associated with the risk of ER-positive (ER+) breast cancer (pooled multivariable RRs for the same comparison): α-carotene (1.04; 95% CI: 0.99, 1.09), β-carotene (1.04; 95% CI: 0.98, 1.10), and lutein/zeaxanthin (1.00; 95% CI: 0.93, 1.07). Although the pooled RRs for quintile 5 for β-cryptoxanthin were not significant, inverse trends were observed for ER− and ER+ breast cancer (P-trend ≤ 0.05). Nonsignificant associations were observed for lycopene intake. The associations were largely not appreciably modified by several breast cancer risk factors. Nonsignificant associations were observed for PR-positive and PR-negative breast cancer. Conclusions: Intakes of α-carotene, β-carotene, and lutein/zeaxanthin were inversely associated with risk of ER−, but not ER+, breast cancer. However, the results need to be interpreted with caution because it is unclear whether the observed association is real or due to other constituents in the same food sources.

Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2 x 2 factorial trial of vitamin D (in the form of vitamin D(3) [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurrence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; and rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.

Purpose: To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias. Experimental Design: In a “3 + 3” design, patients received escalating doses of tipifarnib (days 1–14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMC) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-κB activity. Results: The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-κB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and additional 5 patients had stable disease. Conclusions: Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance. Clin Cancer Res; 17(5); 1140–6. ©2011 AACR.

Background: It is somewhat controversial whether caffeine consumption is associated with an increased risk of developing atrial fibrillation (AF). Objective: We prospectively assessed the relation between caffeine intake and incident AF. Design: A total of 33,638 initially healthy women who participated in the Womenrsquos Health Study and who were gt 45 y of age and free of cardiovascular disease and AF at baseline were prospectively followed for incident AF from 1993 to 2 March 2009. All women provided information on caffeine intake via food-frequency questionnaires at baseline and in 2004. Results: During a median follow-up of 14.4 y (interquartile range: 13.8–14.8 y), 945 AF events occurred. Median caffeine intakes across increasing quintiles of caffeine intake were 22, 135, 285, 402, and 656 mg/d, respectively. Age-adjusted incidence rates of AF across increasing quintiles of caffeine intake were 2.15, 1.89, 2.01, 2.24, and 2.04 events, respectively, per 1000 person-years of follow-up. In Cox proportional hazards models updated in 2004 by using time-varying covariates, the corresponding multivariable-adjusted hazard ratios (95% CI) were 1.0, 0.88 (0.72, 1.06), 0.78 (0.64, 0.95), 0.96 (0.79, 1.16), and 0.89 (0.73, 1.09) (P for linear trend: 0.45). None of the individual components of caffeine intake (coffee, tea, cola, and chocolate) were significantly associated with incident AF. Conclusions: In this large cohort of initially healthy women, elevated caffeine consumption was not associated with an increased risk of incident AF. Therefore, our data suggest that elevated caffeine consumption does not contribute to the increasing burden of AF in the population. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00000479","term_id":"NCT00000479"}}NCT00000479.

Background: Prior epidemiologic findings for plasma folate and B-vitamins and breast cancer risk are inconsistent and have not assessed the possible influence of folic acid fortification mandated in 1998. Excess folate, through the one-carbon cycle, might promote neoplastic lesions through DNA synthesis and methylation and inactivation of tumor suppressor genes. However, deficiencies in folate and other B-vitamins may also stimulate carcinogenesis through this same cycle. With concern for carcinogenesis at both low and high folate levels, folic acid fortification has been controversial. Therefore, we examined the associations between plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine and breast cancer risk, before and after fortification. Methods: We conducted a nested case-control study within the prospective Nurses' Health Study. In 1989-1990 (pre-fortification), 32,826 women donated a first blood sample and 18,743 donated an additional blood sample in 2000-2001 (post-fortification). From 1989 to 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two blood samples were matched 1:1 to controls on age, date/ time of blood draw, fasting status, postmenopausal hormones use, and menopausal status. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for age at menarche, parity/age at first birth, age at menopause, family history of breast cancer, history of benign breast disease, height, body mass index at 18, weight change since 18, and alcohol intake. Additionally to assess the effect of fortification, we cross-classified plasma levels at the median for women with two bloods and used unconditional logistic regression adjusting for breast cancer risk factors using low ( Results: Overall, higher plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine levels were not associated with breast cancer risk. For example, comparing women in the highest versus lowest quintile of 1990 plasma folate, adjusted RR (95% CI) was 0.95 (0.77-1.17) for breast cancer. Associations did not vary by in situ /invasive, hormone receptor status, or molecular subtype of the tumor. Additionally, associations did not vary before/after fortification. For example, compared to those with consistently low plasma folate levels, RRs (95% CI) were 0.90 (0.58-1.40) among those that were low 1990/ high 2000, 0.93 (0.59-1.45) among those high 1990/ low 2000, and 1.10 (0.75-1.63) among those that were consistently high. Conclusion: Plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific molecular subtypes. These results do not support concerns about folic acid fortification and breast cancer risk. Citation Format: Serena C. Houghton, A. Heather Eliassen, Shumin M. Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson. Plasma B-vitamin and one-carbon metabolites and risk of breast cancer before and after folic acid fortification in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3221.

Objectives Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. Methods We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. Results Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82–3.49), IL-6 (HR = 2.78, 95% CI: 2.03–3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46–2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83–3.50), compared to those in the bottom quartile (P-trend

Homocysteine and cysteine are associated with oxidative damage and metabolic disorders, which may lead to carcinogenesis. Observational studies assessing the association between circulating homocysteine or cysteine and breast cancer are very limited, and findings have been inconsistent. We prospectively evaluated plasma levels of homocysteine and cysteine in relation to breast cancer risk among 812 incident cases of invasive breast cancer and 812 individually matched control subjects from 28,345 women in the Women's Health Study; these women were ≥45 years old, provided blood samples, and had no history of cancer and cardiovascular disease at baseline. Logistic regression controlling for matching factors and risk factors for breast cancer was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. Homocysteine levels were not associated with overall risk for breast cancer. However, we observed a positive association between cysteine levels and breast cancer risk; the multivariate RR for the highest quintile group relative to the lowest quintile was 1.65 (95% CI, 1.04–2.61; P for trend = 0.04). In addition, women with higher levels of homocysteine and cysteine were at a greater risk for developing breast cancer when their folate levels were low (P for interaction = 0.04 and 0.002, respectively). Although our study offers little support for an association between circulating homocysteine and overall breast cancer risk, higher homocysteine levels may be associated with an increased risk for breast cancer among women with low folate status. The increased risk of breast cancer associated with high cysteine levels warrants further investigation. Cancer Res; 70(6); 2397–405

Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2).We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs).There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correctionor =0.25). There was also no association with any of the haplotypes examined (por = 0.15) and no evidence of joint effects of variants in the 5 genes (por = 0.51).Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1, and HSD17B2 and risk for developing colorectal cancer.

Fruit and vegetable consumption has been hypothesized to reduce the risk of renal cell cancer. We conducted a pooled analysis of 13 prospective studies, including 1,478 incident cases of renal cell cancer (709 women and 769 men) among 530,469 women and 244,483 men followed for up to 7 to 20 years. Participants completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RR) were calculated using the Cox proportional hazards model and then pooled using a random effects model. We found that fruit and vegetable consumption was associated with a reduced risk of renal cell cancer. Compared with

Background: Flavonoids may protect against cancer development through several biological mechanisms. However, epidemiologic studies on dietary flavonoids and cancer risk have yielded inconsistent results. Objective: We prospectively investigated the association between the intake of selected flavonoids and flavonoid-rich foods and risk of cancers in the Women’s Health Study. Design: A total of 3234 incident cancer cases were identified during 11.5 y of follow-up among 38,408 women aged � 45 y. Intake of individual flavonols (quercetin, kaempferol, and myricetin) and flavones (apigenin and luteolin) was assessed from food-frequency questionnaires. Cox regression models were used to estimate the relative risk (RR) of total and site-specific cancer across increasing intakes of total and individual selected flavonoids and flavonoid-rich foods (tea, apple, broccoli, onion, and tofu). Results: The multivariate RRs of total cancer across increasing quintiles of total quantified flavonoid intake were 1.00, 1.00, 0.93, 0.94, and 0.97 (P for trend ¼ 0.72). For site-specific cancers, the multivariate RRs in the highest quintile of total quantified flavonoid intake compared with the lowest quintile were 1.03 for breast cancer, 1.01 for colorectal cancer, 1.03 for lung cancer, 1.15 for endometrial cancer, and 1.09 for ovarian cancer (all P . 0.05). The associations for the individual flavonoid intakes were similar to those for the total intake. There was also no significant association between intake of flavonoid-rich foods and the incidence of total and site-specific cancers. Conclusion: Our results do not support a major role of 5 common flavonols and flavones or selected flavonoid-rich foods in cancer prevention. Am J Clin Nutr 2009;89:905‐12.

Cysteinylglycine, a prooxidant generated during the catabolism of glutathione, has been suggested to induce oxidative stress and lipid peroxidation, leading to the development of human cancers. Observational data relating cysteinylglycine status to breast cancer risk are lacking. We prospectively evaluated plasma cysteinylglycine levels and invasive breast cancer risk among 812 case-control pairs nested in the Women's Health Study, a completed randomized trial evaluating low-dose aspirin and vitamin E in middle-aged and older women. We additionally evaluated the effect modification by risk factors for oxidative stress, such as vitamin E assignment, alcohol consumption, obesity, and postmenopausal hormone use. Logistic regression controlling for matching factors, as well as other risk factors for breast cancer, was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. We observed no overall association between plasma cysteinylglycine and invasive breast cancer risk. However, higher cysteinylglycine levels were marginally associated with an increased risk of breast cancer in the high oxidative stress groups. Women in the highest quintile group of cysteinylglycine relative to the lowest group had multivariate RRs (95% CIs) of 1.64 (1.01–2.66; Ptrend = 0.04) in the vitamin E placebo group, 2.51 (1.01–6.24; Ptrend = 0.07) in the high alcohol intake group (≥9 g/day), and 1.66 (0.97–2.84; Ptrend = 0.03) in the overweight and obese group. Our findings suggest that women who are susceptible to experiencing oxidative stress may be at a greater risk for developing breast cancer. [Cancer Res 2007;67(23):11123–7]

Specific beverage intake may be associated with the risk of renal cell cancer through a diluting effect of carcinogens, alterations of hormone levels, or other changes in the renal tubular environment, but few prospective studies have examined these associations. We evaluated the associations between coffee, tea, milk, soda and fruit and vegetable juice intakes and renal cell cancer risk in a pooled analysis of 13 prospective studies (530,469 women and 244,483 men). Participants completed a validated food-frequency questionnaire at baseline. Using the primary data, the study-specific relative risks (RRs) were calculated and then pooled using a random effects model. A total of 1,478 incident renal cell cancer cases were identified during a follow-up of 7-20 years across studies. Coffee consumption was associated with a modestly lower risk of renal cell cancer (pooled multivariate RR for 3 or more 8 oz (237 ml) cups/day versus less than one 8 oz (237 ml) cup/day = 0.84; 95% CI = 0.67-1.05; p value, test for trend = 0.22). Tea consumption was also inversely associated with renal cell cancer risk (pooled multivariate RR for 1 or more 8 oz (237 ml) cups/day versus nondrinkers = 0.85; 95% CI = 0.71-1.02; pvalue, test for trend = 0.04). No clear associations were observed for milk, soda or juice. Our findings provide strong evidence that neither coffee nor tea consumption increases renal cell cancer risk. Instead, greater consumption of coffee and tea may be associated with a lower risk of renal cell cancer. (c) 2007 Wiley-Liss, Inc. AD - Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

The authors assessed the association between moderate alcohol consumption and breast cancer risk in the Women's Health Study (United States, 1992-2004). During an average of 10 years of follow-up, 1,484 cases of total breast cancer (1,190 invasive and 294 in situ) were documented among 38,454 women who, at baseline, were free of cancer and cardiovascular disease and provided detailed dietary information, including alcohol consumption, for the preceding 12 months. Higher alcohol consumption was associated with a modest increase in breast cancer risk; the multivariable relative risks for > or =30 g/day of alcohol vs. none were 1.32 (95% confidence interval (CI): 0.96, 1.82) for total breast cancer and 1.43 (95% CI: 1.02, 2.02) for invasive breast cancer. An increased risk was limited to estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors; the multivariable relative risks for an increment of 10 g/day of alcohol were 1.11 (95% CI: 1.03, 1.20) for ER+PR+ tumors (804 cases), 1.00 (95% CI: 0.81, 1.24) for ER+PR- tumors (125 cases), and 0.99 (95% CI: 0.82, 1.20) for ER-PR- tumors (167 cases). The association also seemed strongest among those taking postmenopausal hormones currently, but the test for interaction was not significant. The findings from this prospective study suggest that moderate alcohol consumption increases breast cancer risk.

Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case–control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25–0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17–0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women. Cancer Prev Res; 8(8); 675–82. ©2015 AACR. See related commentary by Demetrius Albanes, p. 657

Dietary flavonoids can inhibit cancer development by protecting tissues against free oxygen radicals and inhibiting cell proliferation, but observational studies of flavonoid intake and colorectal cancer incidence are sparse. The authors prospectively evaluated the association between intake of flavonoids and colorectal cancer incidence in 71,976 women from the Nurses' Health Study and 35,425 men from the Health Professionals Follow-Up Study. Dietary intake was assessed in 1990, 1994, and 1998 by means of a food frequency questionnaire. The authors used Cox proportional hazards models with time-varying variables to estimate relative risks of colorectal cancer. Between 1990 and 2000, the authors documented 878 incident cases of colorectal cancer (498 in women and 380 in men). Total flavonoid intake was not inversely associated with colorectal cancer risk among women and men combined. The combined relative risk for the highest quintile of total flavonoid intake compared with the lowest was 1.19 (95% confidence interval: 0.94, 1.49; p for trend = 0.15). Higher intakes of individual flavonols, including quercetin, myricetin, and kaempferol, were also not related to a lower risk of colorectal cancer. These data provide little support for the hypothesis of an association between flavonoid intake and colorectal cancer risk, at least within the ranges of intakes consumed in the populations studied.

Carotenoids, found in fruits and vegetables, have the potential to protect against cancer because of their properties, including their functions as precursors to vitamin A and as antioxidants. We examined the associations between intakes of α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin and lycopene and the risk of invasive epithelial ovarian cancer. The primary data from 10 prospective cohort studies in North America and Europe were analyzed and then pooled. Carotenoid intakes were estimated from a validated food frequency questionnaire administered at baseline in each study. Study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Among 521,911 women, 2,012 cases of ovarian cancer occurred during a follow-up of 7-22 years across studies. The major carotenoids were not significantly associated with the risk of ovarian cancer. The pooled multivariate RRs (95% confidence intervals) were 1.00 (0.95-1.05) for a 600 μg/day increase in α-carotene intake, 0.96 (0.93-1.03) for a 2,500 μg/day increase in β-carotene intake, 0.99 (0.97-1.02) for a 100 μg/day increase in β-cryptoxanthin intake, 0.98 (0.94-1.03) for a 2,500 μg/day increase in lutein/zeaxanthin intake and 1.01 (0.97-1.05) for a 4,000 μg/day increase in lycopene intake. These associations did not appreciably differ by study (p-values, tests for between-studies heterogeneity >0.17). Also, the observed associations did not vary substantially by subgroups of the population or by histological type of ovarian cancer. These results suggest that consumption of the major carotenoids during adulthood does not play a major role in the incidence of ovarian cancer. © 2006 Wiley-Liss, Inc.

With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined.

Parkinson's disease (PD) patients have higher mortality than individuals without PD. However, most of the previous studies were based on prevalent cases and few examined the potential effects of duration and smoking on the survival of PD patients. We compared the survival experience of 288 men with incident PD diagnosed between 1986 and 2000 with that of 51,012 men free of PD in the Health Professionals Follow-up Study. As of January 2002, 92 deaths occurred among PD cases and 8,485 among men without PD. After controlling for age, men with PD had 60% higher mortality than those without PD (95% CI: 1.3-2.0). PD mortality was strongly related to disease duration: compared with men without PD, the age-adjusted relative risk for PD patients was 1.1 during the first 5 years from diagnosis, 2.3 from 5 to 10 years, and 3.5 after 10 years (P 30 pack-years vs. never smokers, relative risk, 2.0; P < 0.0001 for trend), but this association was not observed among PD patients (RR: 1.0; P = 0.95 for trend). This study confirms that PD patients have a higher mortality than individuals without PD and that the excess mortality increases with disease duration. However, smoking seems to impose little additional risk among PD patients in this large cohort of health professionals.

Background: Dairy foods and their constituents (lactose and calcium) have been hypothesized to promote ovarian carcinogenesis. Although case-control studies have reported conflicting results for dairy foods and lactose, several cohort studies have shown positive associations between skim milk, lactose, and ovarian cancer. Methods: A pooled analysis of the primary data from 12 prospective cohort studies was conducted. The study population consisted of 553,217 women among whom 2,132 epithelial ovarian cases were identified. Study-specific relative risks and 95% confidence intervals were calculated by Cox proportional hazards models and then pooled by a random-effects model. Results: No statistically significant associations were observed between intakes of milk, cheese, yogurt, ice cream, and dietary and total calcium intake and risk of ovarian cancer. Higher lactose intakes comparing ≥30 versus Discussion: Overall, no associations were observed for intakes of specific dairy foods or calcium and ovarian cancer risk. A modest elevation in the risk of ovarian cancer was seen for lactose intake at the level that was equivalent to three or more servings of milk per day. Because a new dietary guideline recommends two to three servings of dairy products per day, the relation between dairy product consumption and ovarian cancer risk at these consumption levels deserves further examination. (Cancer Epidemiol Biomarkers Prev 2006;15(2):364–72)

KEYWORDS - CLASSIFICATION: adverse effects;analysis;Boston;cancer epidemiology;Cholesterol;Cohort Studies;dietary modulation of cancer & cancer biomarkers;Dietary Fats;epidemiology;etiology;Eggs;Female;Food Habits;Humans;North America;Ovarian Neoplasms;Public Health;Research;Risk. Fat and cholesterol are theorized to promote ovarian carcinogenesis by increasing circulating estrogen levels. Although case-control studies have reported positive associations between total and saturated fat intake and ovarian cancer risk, two cohort studies have observed null associations. Dietary cholesterol and eggs have been positively associated with ovarian cancer risk. A pooled analysis was conducted on 12 cohort studies. Among 523,217 women, 2,132 incident epithelial ovarian cancer cases were identified. Study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Total fat intake was not associated with ovarian cancer risk (pooled multivariate RR = 1.08, 95% CI 0.86-1.34 comparing > or =45 to 30

The authors evaluated associations between intakes of folate and vitamin B(6) and colorectal cancer risk among women enrolled in a randomized trial on aspirin and vitamin E in disease prevention. At baseline (1992-1995), 37,916 US women aged >or=45 years who were free of cancer and cardiovascular disease provided dietary information. During an average of 10.1 years of follow-up (through February 20, 2004), 220 colorectal adenocarcinoma cases were documented. Total folate and vitamin B(6) intakes were not significantly associated with the risk of colorectal cancer. However, dietary intakes of folate and vitamin B(6) were significantly inversely associated with colorectal cancer risk among women who were not taking supplements containing folate and vitamin B(6). Multivariable relative risks among women in the highest quintiles of intake versus the lowest were 1.16 (95% confidence interval (CI): 0.76, 1.79) for total folate, 1.14 (95% CI: 0.77, 1.69) for total vitamin B(6), 0.46 (95% CI: 0.26, 0.81) for dietary folate, and 0.69 (95% CI: 0.41, 1.15) for dietary vitamin B(6). The use of multivitamin supplements was not related to colorectal cancer risk. These findings suggest that higher dietary intakes of folate and vitamin B(6) may reduce the risk of colorectal cancer in women. An alternative explanation is that other factors related to dietary intakes of folate and vitamin B(6) account for the inverse associations.

The use of complementary and alternative medicines-including a variety of herbal therapies-by patients undergoing cancer chemotherapy has been well documented. Despite such widespread use, however, the benefits and potential mechanisms of such herbal medicines remain largely anecdotal. In this study we examined the effects of a Chinese herbal formula, Bing De Ling, when administered as an adjunct to chemotherapeutic agent 5-fluorouracil (5-FU) in the CT26 mouse colon cancer model. 5-FU and Bing De Ling were administered to both nave and CT26 mouse colon cancer-bearing BALB/c mice. Our results indicate that although the herbal formula alone did not result in antitumor effects under experimental conditions, it significantly enhanced 5-FU-induced tumor growth inhibition. Oral administration of Bing De Ling also increased survival rates of both tumor-bearing and tumor-free mice treated with 5-FU. Furthermore, oral administration of Bing De Ling reduced weight loss in tumor-free mice receiving 5-FU when compared to tumor-free mice that received 5-FU alone. Our data further show that 5-FU upregulates serum levels of IL-6, known to contribute to weight loss, in tumor-free mice, and that this increase in IL-6 is significantly less in mice that received Bing De Ling in addition to 5-FU. These data show Bing De Ling both enhances the antitumor responses of 5-FU and ameliorates side effects.

In vivo and in vitro studies have suggested a protective role of calcium and vitamin D in the development of colorectal cancer. However, epidemiologic data have been inconclusive. The authors prospectively assessed intakes of calcium and vitamin D in relation to risk of colorectal cancer in a large, prospective, female cohort from the US Women's Health Study. In 1993, 39,876 women aged > or = 45 years and free of cardiovascular disease and cancer were enrolled in the study. During an average follow-up of 10 years, 223 of 36,976 women eligible for the present study developed colorectal cancer. Intakes of calcium and vitamin D from dietary sources and supplements were assessed with a baseline food frequency questionnaire. Cox proportional hazards regression was used to estimate relative risks and 95% confidence intervals. Intakes of total calcium and vitamin D were not associated with risk of colorectal cancer; multivariate relative risks comparing the highest with the lowest quintile were 1.20 (95% confidence interval: 0.79, 1.85; p for trend = 0.21) for total calcium and 1.34 (95% confidence interval: 0.84, 2.13; p for trend = 0.08) for total vitamin D. Intakes of both nutrients from specific types of sources, including diet and supplements, were also not significantly associated with colorectal cancer risk. Data provide little support for an association of calcium and vitamin D intake with colorectal cancer risk.

Objective: Although animal studies suggest an inverse association between consumption of plant foods and risk of colorectal cancer, many observational data have failed to support such an association. We prospectively examined the association between dietary intakes of fruit, vegetables, and fiber and colorectal cancer risk in a large female cohort from the Women’s Health Study. Methods: Among 39,876 healthy women aged ≥45 years at baseline, 36,976 with baseline self-reported information on dietary intakes and other risk factors for colorectal cancer were included in the analyses. During an average follow-up of 10 years, 223 women were diagnosed with colorectal cancer. Intakes of fruit, vegetables, and fiber were assessed by a baseline food-frequency questionnaire. The analyses were carried out using the Cox proportional hazards regression and all tests were two-sided. Results: Intakes of fruit, vegetables, and the specific subgroups were not found to be associated with colorectal cancer risk. Multivariate relative risks (RRs) comparing the highest with lowest quintile were 0.79 (95% CI = 0.49–1.27,pfor trend = 0.30) for fruit intake, and 0.88 (95% CI=0.56–1.38,pfor trend=0.30) for vegetables intake. Similarly, intake of total fiber was not associated with colorectal cancer risk; the RR for the highest relative to lowest quintile was 0.75 (95% CI=0.48–1.17,pfor trend=0.12). However, higher intake of legume fiber was associated with a lower risk of colorectal cancer; the RR for the highestversuslowest quintile was 0.60 (95% CI=0.40–0.91,pfor trend=0.02). Conclusions: Our data offer little support for associations between intakes of fruit, vegetables, and fiber, and colorectal cancer risk. However, our data suggest that legume fiber and/or other related sources may reduce risk of colorectal cancer.