Effect of Estradiol as a Continuous Variable on Breast Cancer Survival by Menopausal Status: a Cohort Study in China

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR=1.79, 95% CI: 1.17-2.75, P=0.008) and OS in post-menopausal women (HR=1.35, 95% CI: 1.04-1.74, P=0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation (“L-shaped” and “U-shaped”, respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a “U-shaped” relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

Assessing Lifespan and Aging Phenotypes Resulting From FOXO3 Induction Using Mouse Models

Environmental signals, including caloric restriction and oxidative stress, trigger FoxO3 to upregulate genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis that may help mitigate age-related diseases. Activation of FoxO3 has been shown to have a profound life-extending effect on model organisms. Protective SNPs in FOXO3 are strongly associated with exceptional longevity in humans. The objective of this study is test the relation between FoxO3 and longevity using mouse models. We generated a mouse line containing an extra copy of FoxO3 that can be induced at any age. In our model, FoxO3 remains driven by its natural promoter to avoid mis-expression in inappropriate cells and to maintain the gene’s ability to respond to signals such as stress. We are utilizing this new model to assess survival endpoints and test a panel of aging phenotypes reflecting healthspan throughout the mouse lifespan and compare these to similar human phenotypes.

Conditional copula models for correlated survival endpoints: Individual patient data meta-analysis of randomized controlled trials

Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox ( https://CRAN.R-project.org/package=joint.Cox ). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm ( p-value<0.001), whereas disease-free survival remains a valid surrogate at individual level for overall survival in these trials.

602Prevalence of cancer history and association with risk factors in a healthy older population

Background The ASPirin in Reducing Events in the Elderly (ASPREE) study randomised healthy older individuals to 100mg aspirin or placebo, with clinical outcomes and disability-free survival endpoints. Detailed baseline data provides a rare opportunity to explore cancer burden and association with known cancer risk factors in this population. Methods At enrolment (2010-2014), self-reported personal cancer history, cancer type and cancer risk factor data were sought from 19,114 participants (Australia, n = 16,703; U.S., n = 2,411). Participants were healthy and expected to survive 5 years. Results Of those reporting a prior cancer diagnosis (18% women, 22% men), women were diagnosed younger (16% vs 6% of diagnoses &lt;50 years). Cancer prevalence increased with age. Prostate and breast cancer history were higher in U.S. participants; melanoma and colorectal cancer were higher in Australian participants. Cancer history prevalence was not associated with any common risk factors, but was associated with poor health ratings in men. Blood and breast cancer history was more common with past aspirin use. Conclusions Personal cancer history in healthy older ASPREE participants was as expected for the most common cancer types in the respective populations. The lack of alignment with known risk factors is attributable to survivor bias, driven by entry criteria, and to possible molecular differences in cancer between elderly and younger people. Key messages As the prevalence of cancer increases with age, the lack of alignment with known risk factors implies other factors play a significant role.

MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study

Background In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. Methods We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). Results In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. Conclusions Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

Impact of unequal censoring and insufficient follow-up on comparing survival outcomes: Applications to clinical studies

Clinical trials with survival endpoints are typically designed to enroll patients for a specified number of years, (usually 2–3 years) with another specified duration of follow-up (usually 2–3 years). Under this scheme, patients who are alive or free of the event of interest at the termination of the study are censored. Consequently, a patient may be censored due to insufficient follow-up duration or due to being lost to follow-up. Potentially, this process could lead to unequal censoring in the treatment arms and lead to inaccurate and adverse conclusions about treatment effects. In this article, using extensive simulation studies, we assess the impact of such censorings on statistical procedures (the generalized logrank tests) for comparing two survival distributions and illustrate our observations by revisiting Mukherjee et al.’s 1 findings of cardiovascular events in patients who took Rofecoxib (Vioxx).