Biomedical subjects

Bingshu E Chen

Publications and source records attributed to Bingshu E Chen.

12 recordsLinked to original sources

PubMed2026

Association of cancer antigen 15-3 with distant recurrence in immunohistochemically defined breast cancer subtypes in Canadian Cancer Trials Group MA.32.

BACKGROUND: Circulating levels of cancer antigen (CA) 15-3 have been associated with distant breast cancer recurrence; data on breast cancer subtypes are sparse. We examined associations of CA 15-3 with outcomes across immunohistochemically defined breast cancer subtypes in MA.32. METHODS: A total of 3649 participants with T1-3, N0-1, M0 breast cancer were randomly assigned; 2740 (75.1%) provided blood at entry (mean = 278 days postdiagnosis) and 6 months later. Prognostic associations of baseline and 6-month change in CA 15-3 with distant recurrence-free survival (RFS) were examined in luminal (estrogen receptor-positive and/or progesterone receptor-positive, HER2-negative), triple-negative (estrogen receptor, progesterone receptor, HER2 negative) and HER2-positive (any estrogen receptor, progesterone receptor) breast cancer using Cox proportional hazards models. RESULTS: Mean age was 52 years. Breast cancer was luminal in 1589 (58.7%), triple negative in 655 (24.2%), and HER2 positive in 464 (17.1%) participants. Median follow-up was 96 months. CA 15-3 at study entry was not associated with outcome in any subtype. Rising CA 15-3 at 6 months was associated with poor distant RFS in luminal and triple-negative breast cancer (hazard ratio [HR] per 25% increase = 1.41, P < .0001, and HR = 1.35, P < .0001, respectively). New elevations in CA 15-3 at 6 months were adversely associated with distant RFS in those with luminal or triple-negative breast cancer (HR = 4.14, 95% CI = 2.69 to 6.38; P < .001; and HR = 3.57, 95% CI = 1.59 to 7.99; P = .002, respectively). In HER2-positive breast cancer, CA15-3 was not associated with distant RFS. CONCLUSION: Rising CA 15-3 was associated with reduced distant RFS in luminal and triple-negative breast cancer but not in HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01101438.

Humans↗

PubMed2026

Exploration of body mass index and circulating metabolic factors as predictors of metformin benefit in the Canadian Cancer Trials Group MA.32.

BACKGROUND: In the MA.32 randomized adjuvant breast cancer trial, metformin (vs placebo) did not impact invasive disease-free survival or overall survival in estrogen and/or progesterone receptor-positive or -negative breast cancer; exploratory analyses suggested a benefit in HER2-positive breast cancer. We investigated whether body mass index (BMI) and obesity-associated blood variables predicted metformin benefit in immunohistochemically defined breast cancer subtypes (luminal [estrogen/progesterone receptor positive, HER2 negative], triple-negative breast cancer [estrogen receptor, progesterone receptor, HER2 negative], HER2 positive). METHODS: A total of 3649 nondiabetic patients with high risk T1-3, N0-3, M0 breast cancer were randomly assigned. Baseline fasting plasma was assayed for insulin, glucose, leptin, and C-reactive protein; Homeostasis Model Assessment was calculated. For each breast cancer subtype and each outcome (distant recurrence free survival, overall survival, invasive disease-free survival), Cox models examined interactions of BMI and blood variables with metformin vs placebo outcomes. RESULTS: Mean age was 51.1-53.0 years; mean BMI was 27.3-27.5 kg/m2. Most cancers were T2, N0, or N1 and grade 2-3; 2104 (57.7%) were luminal, 925 (25.3%) TN, and 620 (17.0%) HER2 positive. Median follow-up was 95.9 months. In luminal breast cancer, statistically significant interactions were identified for leptin, insulin, and Homeostasis Model Assessment on distant recurrence-free survival, and in triple-negative breast cancer, a statistically significant interaction was identified for glucose on distant recurrence-free survival, with potential adverse effects of metformin at lower levels of each variable. In those with HER2-positive breast cancer, there was no variable that predicted metformin benefit. CONCLUSIONS: Body mass index and blood variables did not identify subgroups with luminal or triple-negative breast cancer who benefited from metformin or those with HER2-positive breast cancer who did not benefit. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01101438: 2010-04-09.

Female↗

PubMed2007

Leukemia following breast cancer: an international population-based study of 376,825 women.

PURPOSE: To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year. PATIENTS AND METHODS: We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943-2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model. RESULTS: A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5-10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3-2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2-1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9-6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively. CONCLUSIONS: Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.

Adult↗

PubMed2007

Estimating age-specific breast cancer risks: a descriptive tool to identify age interactions.

OBJECTIVE: Clarifying age-specific female breast cancer risks and interactions may provide important etiologic clues. METHOD: Using a population-based case-control study in Poland (2000-2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25-74 years, we estimated age-specific breast cancer incidence rates according to risk factors. RESULTS: Breast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA). Notwithstanding overall risks, we observed statistically significant quantitative (non-crossover) and qualitative (crossover) age interactions for all risk factors except for FH and PA. For example, nulliparity compared to parity reduced breast cancer risk among women ages 25-39 years then rates crossed or reversed, after which nulliparity increased relative risks among women ages 40-74 years. CONCLUSION: Though quantitative age interactions could be expected, qualitative interactions were somewhat counterintuitive. If confirmed in other populations, qualitative interactions for a continuous covariate such as age will be difficult to reconcile in a sequential (multistep or monolithic) 'stochastic' breast cancer model. Alternatively, the reversal of relative risks among younger and older women suggests subgroup heterogeneity with different etiologic mechanisms for early-onset and late-onset breast cancer types.

Adult↗

PubMed2006

Suicide after breast cancer: an international population-based study of 723,810 women.

Few studies have examined long-term suicide risk among breast cancer survivors, and there are no data for women in the United States. We quantified suicide risk through 2002 among 723,810 1-year breast cancer survivors diagnosed between January 1, 1953, and December 31, 2001, and reported to 16 population-based cancer registries in the United States and Scandinavia. Among breast cancer survivors, we calculated standardized mortality ratios (SMRs) and excess absolute risks (EARs) compared with the general population, and the probability of suicide. We used Poisson regression likelihood ratio tests to assess heterogeneity in SMRs; all statistical tests were two-sided, with a .05 cutoff for statistical significance. In total 836 breast cancer patients committed suicide (SMR = 1.37, 95% confidence interval [CI] = 1.28 to 1.47; EAR = 4.1 per 100,000 person-years). Although SMRs ranged from 1.25 to 1.53 among registries, with 245 deaths among the sample of US women (SMR = 1.49, 95% CI = 1.32 to 1.70), differences among registries were not statistically significant (P for heterogeneity = .19). Risk was elevated throughout follow-up, including for 25 or more years after diagnosis (SMR = 1.35, 95% CI = 0.82 to 2.12), and was highest among black women (SMR = 2.88, 95% CI = 1.44 to 5.17) (P for heterogeneity = .06). Risk increased with increasing stage of breast cancer (P for heterogeneity = .08) and remained elevated among women diagnosed between 1990 and 2001 (SMR = 1.36, 95% CI = 1.18 to 1.57). The cumulative probability of suicide was 0.20% 30 years after breast cancer diagnosis.

Adult↗

PubMed2006

Multiple hypothesis testing strategies for genetic case-control association studies.

The genetic case-control association study of unrelated subjects is a leading method to identify single nucleotide polymorphisms (SNPs) and SNP haplotypes that modulate the risk of complex diseases. Association studies often genotype several SNPs in a number of candidate genes; we propose a two-stage approach to address the inherent statistical multiple comparisons problem. In the first stage, each gene's association with disease is summarized by a single p-value that controls a familywise error rate. In the second stage, summary p-values are adjusted for multiplicity using a false discovery rate (FDR) controlling procedure. For the first stage, we consider marginal and joint tests of SNPs and haplotypes within genes, and we construct an omnibus test that combines SNP and haplotype analysis. Simulation studies show that when disease susceptibility is conferred by a SNP, and all common SNPs in a gene are genotyped, marginal analysis of SNPs using the Simes test has similar or higher power than marginal or joint haplotype analysis. Conversely, haplotype analysis can be more powerful when disease susceptibility is conferred by a haplotype. The omnibus test tracks the more powerful of the two approaches, which is generally unknown. Multiple testing balances the desire for statistical power against the implicit costs of false positive results, which up to now appear to be common in the literature.

Case-Control Studies↗

PubMed2006

Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer.

BACKGROUND: Breast cancer incidence rates vary according to estrogen receptor expression (ER) and histopathology. We hypothesized that annual mortality rates from breast cancer after initial diagnosis (hazard rates) might also vary by ER and histopathology. METHODS: We accessioned the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER, 1992-2002) program to estimate hazard rates according to ER (positive and negative) and histopathology (duct, tubular, lobular, medullary, inflammatory, papillary, and mucinous types). We used spline functions to model hazard rates free of strongly parametric assumptions for ER negative and positive cases overall and by histopathology. RESULTS: Hazard rates for ER negative and ER positive cases were distinct and non-proportional. At 17 months, ER negative hazard rates peaked at 7.5% per year (95% CI, 7.3-7.8% per year) then declined, whereas ER positive hazard rates lacked a sharp early peak and were comparatively constant at 1.5-2% per year. Falling ER negative and constant ER positive hazard rates crossed at 7 years; after which, prognosis was better for ER negative cases. Among ER positive and negative cases, there were proportional and non-proportional hazards according to histopathologic type, but the two basic ER-associated patterns were maintained. CONCLUSIONS: Hazard rates differed quantitatively and qualitatively according to ER and histopathology. These large-scale population-based results seem consistent with genomic studies, demonstrating two main classes of breast cancers with distinct prognoses according to ER expression.

Adenocarcinoma↗

PubMed2006

Resampling-based multiple hypothesis testing procedures for genetic case-control association studies.

In case-control studies of unrelated subjects, gene-based hypothesis tests consider whether any tested feature in a candidate gene--single nucleotide polymorphisms (SNPs), haplotypes, or both--are associated with disease. Standard statistical tests are available that control the false-positive rate at the nominal level over all polymorphisms considered. However, more powerful tests can be constructed that use permutation resampling to account for correlations between polymorphisms and test statistics. A key question is whether the gain in power is large enough to justify the computational burden. We compared the computationally simple Simes Global Test to the min P test, which considers the permutation distribution of the minimum p-value from marginal tests of each SNP. In simulation studies incorporating empirical haplotype structures in 15 genes, the min P test controlled the type I error, and was modestly more powerful than the Simes test, by 2.1 percentage points on average. When disease susceptibility was conferred by a haplotype, the min P test sometimes, but not always, under-performed haplotype analysis. A resampling-based omnibus test combining the min P and haplotype frequency test controlled the type I error, and closely tracked the more powerful of the two component tests. This test achieved consistent gains in power (5.7 percentage points on average), compared to a simple Bonferroni test of Simes and haplotype analysis. Using data from the Shanghai Biliary Tract Cancer Study, the advantages of the newly proposed omnibus test were apparent in a population-based study of bile duct cancer and polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) gene.

Algorithms↗

PubMed2005

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China.

There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.

Age Factors↗

PubMed2005

Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers.

PURPOSE: Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates. METHODS: Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy. RESULTS: Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers. CONCLUSION: Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.

Adult↗

PubMed2005

Statistical methods for multivariate interval-censored recurrent events.

Multi-type recurrent event data arise when two or more different kinds of events may occur repeatedly over a period of observation. The scientific objectives in such settings are often to describe features of the marginal processes and to study the association between the different types of events. Interval-censored multi-type recurrent event data arise when the precise event times are unobserved, but intervals are available during which the events are known to have occurred. This type of data is common in studies of patients with advanced cancer, for example, where the events may represent the development of different types of metastatic lesions which are only detectable by conducting bone scans of the entire skeleton. In this setting it is of interest to characterize the incidence of the various types of bone lesions, to estimate the impact of treatment and other covariate effects on the development of new lesions, and to understand the relationship between the processes generating the bone lesions. We develop joint models for multi-type interval-censored recurrent events which accommodate dependencies between different types of events and enable one to examine the covariate effects via regression. However, since the marginal likelihood resulting from the multivariate random effect model is intractable, we describe a Gibbs sampling algorithm to facilitate model fitting and inference. We use generalized estimating equations for estimation and inference based on marginal models. The finite sample properties of the marginal approach are studied via simulation. The estimates of both the regression coefficients and the variance-covariance parameters are shown to have negligible bias and 95 per cent confidence intervals based on the asymptotic variance formula are shown to have excellent empirical coverage probabilities in all of the settings considered. The application of these methods to data from a trial of women with advanced breast cancer provides insight into the clinical course of bone metastases in this population.

Bayes Theorem↗

PubMedDate not supplied

Epidemiology of inflammatory breast cancer (IBC).

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with unknown etiology and generally poor outcome. It is characterized by diffuse edema (peau d'orange) and redness (erythema), although either the disease itself or case definitions have varied over time and place, confounding temporal trends and geographic variations. In this review, we discuss case definitions for IBC and its clinical characteristics; describe its geographic variation, age and racial distribution, incidence and survival patterns, and summarize the very limited information on its epidemiologic risk factors. We also incorporate emerging data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.

Adenocarcinoma↗