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The World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure-cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a "hypothesis-free" approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness-IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure-cancer associations. On the basis of our experience, we provide recommendations for future users. [ABSTRACT FROM AUTHOR]

The article discusses the case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Topics discussed include evaluation of C-reactive protein (CRP), IL6 (interleukin 6), and EOC risk by tumor characteristics, evidences of no linkage of CRP and IL6 with EOC risk, and association of CRP with increased risk of EOC.

The article presents study on dietary intake of acrylamide and epithelial ovarian cancer (EOC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort study. It mentions the use of multivariate Cox proportional hazards models for assessment of association between acrylamide intake and EOC risk. It reveals that no dose-response were observed for the same.

Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER+/PR+ disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER-/PR- breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association. [ABSTRACT FROM AUTHOR]

The article focuses on a study which investigated the association between insulin-like growth factor (IGF)-I in pregnancy and the maternal risk of breast cancer. The study was nested within the Finnish Maternity Cohort (FMC). The study found no association between serum concentrations of IGF-I and maternal risk of breast cancer during early pregnancy.

The article examines the results of a study on the association between circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer (NEOC). The researchers selected their study subjects among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. The case subjects were 41 women with sex cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). The study indicates that elevated androgens could play a role in the pathogenesis of SCST.

Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02-1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03-1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60-0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC. [ABSTRACT FROM AUTHOR]

Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status ( P het = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01-1.63); P trend = 0.20], but not ER- disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER-PR- disease [5th vs. 1st quintile RR = 0.60 (0.31-1.14); P trend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk. Cancer Prev Res; 10(9); 525-34. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, OR Q4 vs. Q1 , 1.10; 95% CI, 0.64-1.89; ≥15 years, OR Q4 vs. Q1 , 1.36; 95% CI, 0.86-2.13; p heterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. Cancer Res; 77(1); 134-41. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.