The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies.

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research.

Clinical and pathological features of undifferentiated pancreatic carcinoma with osteoclastic giant cells: a rare case.

INTRODUCTION: undifferentiated pancreatic carcinoma with osteoclastic giant cells (UOC) is a rare pancreatic malignancy composed of three unique cell types. Currently, the histopathologic origin of UOCs remains unclear. Some studies considered that it was differentiated from epithelial tissues, while others favored a mesenchymal derivation. METHODS: we present the case of a 59-year-old UOC patient with a tumor (3.0 cm × 3.0 cm × 2.5 cm) in the pancreatic neck. He underwent an en bloc resection of the distal pancreas associated with the spleen. RESULTS: light microscopic examination revealed two typical types of UOC cells, with one type absent. The immunohistochemical staining was positive for pancytokeratin, epithelial membrane antigen, vimentin and cluster of differentiation 68, which indicated different derivations for these two kinds of cells. DISCUSSION: UOC is a rare condition with unique imaging and pathological features. Endoscopic ultrasonography and fine needle aspiration are dispensable preoperatively. Radical resection should be tried for UOC treatments. In our opinion, osteoclastic giant cells are reactive cells derived from histocytes. The case presented here will be of interest to the whole UOC cohort.

Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m2 ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors.

A Congener-specific and Mixture Analysis of Plasma Polychlorinated Biphenyl Levels and Incident Breast Cancer.

BACKGROUND: Polychlorinated biphenyls (PCBs), a diverse class of chemicals, are hypothesized mammary carcinogens. We examined plasma levels of 17 PCBs as individual congeners and as a mixture in association with breast cancer using a novel approach based on quantile g-computation. METHODS: This study included 845 White and 562 Black women who participated in the population-based, case-control Carolina Breast Cancer Study Phase I. Cases (n = 748) were women with a first diagnosis of histologically confirmed, invasive breast cancer residing in 24 counties in central and eastern North Carolina; controls (n = 659) were women without breast cancer from the same counties. PCBs were measured in plasma samples obtained during the study interview. We estimated associations [covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs)] between individual PCB congeners and breast cancer using multivariable logistic regression. We assessed PCB mixtures using quantile g-computation and examined effect measure modification by race. RESULTS: Comparing highest and lowest tertiles of PCBs resulted in ORs of 1.3 (95% CI = 0.95, 1.8) for congener 74, 1.4 (95% CI = 1.0, 1.9) for 99, 1.3 (95% CI = 0.91, 1.8) for 194, and 1.2 (95% CI = 0.90, 1.7) for 201. Among all women, we estimated a joint effect of the PCB mixture with an OR of 1.3 (95% CI = 0.98, 1.6) per tertile change. In race-stratified analyses, associations for tertiles of PCB mixtures were stronger among Black women (OR = 1.5; 95% CI = 1.0, 2.3) than among White women (OR = 1.1; 95% CI = 0.81, 1.6). CONCLUSION: Our results are consistent with the hypothesis that exposure to PCB mixtures increase the risk of breast cancer, but studies of populations with different exposure profiles are needed.

Fruit and vegetable consumptions in relation to frequent mental distress in breast cancer survivors.

PURPOSE: Evidence suggests that fruit and vegetable consumptions may improve mental health among general population. However, their associations among breast cancer survivors are unclear. We planned to investigate this association via a nationwide survey in the USA. METHODS: We identified 7988 breast cancer survivors from 2009 Behavioral Risk Factor Surveillance System (BRFSS). Fruit juice, fruit, and vegetable consumptions were categorized as ordinal variables to approximate tertiles. Survivors who were mentally unhealthy for at least 14 days in the past 30 days were defined as having frequent mental distress (FMD). Multivariable logistic regression treating FMD as the outcome was used to calculate adjusted odd ratios (aORs) and 95% confidence intervals (CIs) for exposures. Quadratic model was used to depict the dose-response pattern in primary analysis. Subgroup analyses by adverse lifestyle behaviors were conducted; Wald tests were used to examine if there were interactions between these factors and exposures in relation to FMD. RESULTS: Overall, 825 (10.3%) survivors had FMD. Mean age was 67.2 years, and 89.7% of survivors were white. Juice showed non-significant associations with FMD. Moderate (aOR = 0.81, 95% CI = 0.68-0.98) and high (aOR = 0.79, 95% CI = 0.63-0.98) fruit consumptions, as well as moderate vegetable consumption (aOR = 0.78, 95% CI = 0.64-0.94), were significantly and inversely associated with FMD. The dose-response curves were consistent with results in primary analysis. No interaction was identified for adverse lifestyle behaviors. CONCLUSION: Fruit and vegetable, but not fruit juice, show potential preventive effects against FMD among breast cancer survivors. The conclusion should be verified by studies with clear temporality in future.

Bimodal age distribution at diagnosis in breast cancer persists across molecular and genomic classifications.

PURPOSE: Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosis, interpretable as two main etiologic subtypes or groupings of tumors with shared risk factors. While RNA-based methods including PAM50 have identified well-established clinical subtypes, age distribution patterns at diagnosis as a proxy for etiologic subtype are not established for molecular and genomic tumor classifications. METHODS: We evaluated smoothed age frequency distributions at diagnosis for Carolina Breast Cancer Study cases within immunohistochemistry-based and RNA-based expression categories. Akaike information criterion (AIC) values compared the fit of single density versus two-component mixture models. Two-component mixture models estimated the proportion of early-onset and late-onset categories by immunohistochemistry-based ER (n = 2860), and by RNA-based ESR1 and PAM50 subtype (n = 1965). PAM50 findings were validated using pooled publicly available data (n = 8103). RESULTS: Breast cancers were best characterized by bimodal age distribution at diagnosis with incidence peaks near 45 and 65 years, regardless of molecular characteristics. However, proportional composition of early-onset and late-onset age distributions varied by molecular and genomic characteristics. Higher ER-protein and ESR1-RNA categories showed a greater proportion of late age-at-onset. Similarly, PAM50 subtypes showed a shifting age-at-onset distribution, with most pronounced early-onset and late-onset peaks found in Basal-like and Luminal A, respectively. CONCLUSIONS: Bimodal age distribution at diagnosis was detected in the Carolina Breast Cancer Study, similar to national cancer registry data. Our data support two fundamental age-defined etiologic breast cancer subtypes that persist across molecular and genomic characteristics. Better criteria to distinguish etiologic subtypes could improve understanding of breast cancer etiology and contribute to prevention efforts.

Immune gene expression profiling reveals heterogeneity in luminal breast tumors.

BACKGROUND: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features. METHODS: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets. RESULTS: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations. CONCLUSION: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

Healthy dietary patterns and risk and survival of breast cancer: a meta-analysis of cohort studies.

PURPOSES: Dietary patterns have been found to be associated with the overall cancer risk and survival. However, the associations of healthy dietary patterns and breast cancer remain unclear. We aimed to conduct a meta-analysis of prospective cohort studies to estimate the pooled results of the association of healthy dietary patterns with breast cancer risk and survival. METHODS: PubMed, EMBASE, and Web of Science were searched for literature published until June 24th, 2018 that examined the associations between healthy dietary patterns and breast cancer risk and survival. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by using a random-effects model for meta-analysis. RESULTS: There were 32 articles retrieved for the meta-analysis, with 27 for breast cancer risk and five for breast cancer survival. There was a statistically significant lower risk of breast cancer associated with healthy dietary patterns (RR = 0.93, 95% CI: 0.88, 0.98). Subgroup analysis results suggested that there was an inverse association between breast cancer risk and posterori-derived healthy patterns, but no statistically significant associations were found in other stratified subgroups (a priori-derived diet, study region, menopausal status, or breast cancer subtypes). Healthy dietary patterns were associated inversely with all-cause mortality (RR = 0.76, 95% CI: 0.63, 0.92); however, no association was found for breast cancer-specific mortality. CONCLUSIONS: The results suggested that healthy dietary patterns might be associated with a reduced risk of breast cancer and all-cause mortality among breast cancer patients. It could be clinically relevant to promote healthy dietary patterns for breast cancer prevention and improve survival among breast cancer patients.

Lifestyle Patterns and Survival Following Breast Cancer in the Carolina Breast Cancer Study.

BACKGROUND: Few studies have examined the impact of lifestyle patterns on survival following breast cancer. We aimed to identify distinct lifestyle patterns based on five behavior/dietary exposures among a population-based sample of women diagnosed with breast cancer and to examine their association with subsequent survival. METHODS: In the Carolina Breast Cancer Study Phases I/II, we interviewed 1,808 women 20-74 years of age following diagnosis of invasive breast cancer. We determined vital status using the National Death Index (717 deaths, 427 from breast cancer; median follow-up 13.56 years). We assessed lifestyle patterns using a latent class analysis based on five behavioral and dietary exposures: current versus never/former smokers; low versus high vegetable and fruit intake; high and low/moderate, versus no alcohol consumption; and no and low/moderate, versus high regular physical activity. We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality, and cause-specific and subdistribution HRs for breast cancer-specific mortality within 5 years and 13 years postdiagnosis conditional on 5-year survival. RESULTS: We identified three distinct lifestyle patterns: healthy behavior and diet (n = 916); healthy behavior and unhealthy diet (n = 624); and unhealthy behavior and diet (n = 268). The unhealthy (vs. healthy) behavior and diet pattern was associated with a 13-year conditional all-cause mortality HR of 1.4 (95% CI = 1.1, 1.9) and with 13-year conditional breast cancer-specific and subdistribution HRs of 1.2 (95% CI = 0.79, 1.9) and 1.2 (95% CI = 0.77, 1.8), respectively. CONCLUSIONS: Behavioral and dietary patterns can be used to identify lifestyle patterns that influence survival patterns following breast cancer diagnosis.

Frequency of breast cancer subtypes among African American women in the AMBER consortium.

BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis.

OBJECTIVE: The definition of drug-resistant epilepsy (DRE) affects case identification and treatment, and impacts prevalence or incidence estimates and health burden estimation in epidemiology. The objective of this systematic review is to evaluate the consistency between definitions of DRE in the literature and the official definition in the International League Against Epilepsy (ILAE) guidelines, and to estimate the incidence, prevalence, and risk factors for DRE. METHODS: MEDLINE and EMBASE were searched for observational studies of DRE published between January 1980 and July 2015. The definitions of DRE in these studies were compared with the definition in the ILAE guidelines. Random-effect model meta-analyses were used to generate pooled estimates of prevalence or incidence and pooled odds ratios of the association with risk factors. RESULTS: Thirty-five studies met inclusion criteria, including 13 080 epilepsy patients and 3941 patients with DRE. The definition of DRE varied widely across studies, with only 12% meeting the requirements of the ILAE definition. The pooled prevalence proportion of DRE among epilepsy patients was 0.30 (95% confidence interval [CI] 0.19-0.42), and the pooled incidence proportion was 0.15 (95% CI 0.11-0.19). Age at onset, symptomatic epilepsy, abnormal neuroimaging findings, abnormal electroencephalography results, history of mental retardation, neuropsychiatric disorders, febrile seizure, and status epilepticus increased risk for DRE. SIGNIFICANCE: There are limited high-quality data available on DRE. Lack of consistency in definitions limits the ability to obtain robust estimates on the burden of DRE. More data based on the ILAE definition from well-designed epidemiologic studies are needed to generate accurate and reliable results.

Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study.

BACKGROUND: We examined racial differences in the expression of eight genes and their associations with risk of recurrence among 478 white and 495 black women who participated in the Carolina Breast Cancer Study Phase 3. METHODS: Breast tumor samples were analyzed for PAM50 subtype and for eight genes previously found to be differentially expressed by race and associated with breast cancer survival: ACOX2, MUC1, FAM177A1, GSTT2, PSPH, PSPHL, SQLE, and TYMS. The expression of these genes according to race was assessed using linear regression and each gene was evaluated in association with recurrence using Cox regression. RESULTS: Compared to white women, black women had lower expression of MUC1, a suspected good prognosis gene, and higher expression of GSTT2, PSPHL, SQLE, and TYMS, suspected poor prognosis genes, after adjustment for age and PAM50 subtype. High expression (greater than median versus less than or equal to median) of FAM177A1 and PSPH was associated with a 63% increase (hazard ratio (HR) = 1.63, 95% confidence interval (CI) = 1.09-2.46) and 76% increase (HR = 1.76, 95% CI = 1.15-2.68), respectively, in risk of recurrence after adjustment for age, race, PAM50 subtype, and ROR-PT score. Log2-transformed SQLE expression was associated with a 20% increase (HR = 1.20, 95% CI = 1.03-1.41) in recurrence risk after adjustment. A continuous multi-gene score comprised of eight genes was also associated with increased risk of recurrence among all women (HR = 1.11, 95% CI = 1.04-1.19) and among white (HR = 1.14, 95% CI = 1.03-1.27) and black (HR = 1.11, 95% CI = 1.02-1.20) women. CONCLUSIONS: Racial differences in gene expression may contribute to the survival disparity observed between black and white women diagnosed with breast cancer.

Age at diagnosis, obesity, smoking, and molecular subtypes in muscle-invasive bladder cancer.

BACKGROUND: Heterogeneity of muscle-invasive bladder cancer (MIBC) has been characterized using whole-genome mRNA expression data, showing distinct molecular and clinicopathological characteristics by subtypes. However, associations between risk factors and molecular subtypes have not been reported. METHODS: Four previously published schemes were used to categorize molecular subtypes in 372 MIBC patients from the Cancer Genome Atlas (TCGA). Data on gene expression (RNA-seq), demographic, and clinicopathological characteristics were retrieved through TCGA data portal. Polytomous logistic regression was used to estimate the associations of subtypes by different schemes with age at diagnosis, obesity, and smoking. RESULTS: While some quantitative variation was evident, distinct molecular subtype schemes showed considerable consistency in the association with the risk factors. Generally, compared to patients with luminal-like tumors, patients with basal-like subtypes were more likely to be older (OR75 + yrs vs. <60 years range = 1.32-2.89), obese (ORobese vs. normal range = 1.30-3.05), and to start smoking at early age (OR<18 years vs. 25+ years range = 1.11-4.57). CONCLUSIONS: Different molecular subtypes of MIBC may have distinct risk profiles. Large population-based studies with detailed information on bladder cancer risk factors are needed to further define etiologic heterogeneity for bladder cancer.

Active smoking and survival following breast cancer among African American and non-African American women in the Carolina Breast Cancer Study.

PURPOSE: To examine racial differences in smoking rates at the time of breast cancer diagnosis and subsequent survival among African American and non-African American women in the Carolina Breast Cancer Study (Phases I/II), a large population-based North Carolina study. METHODS: We interviewed 788 African American and 1,020 Caucasian/non-African American women diagnosed with invasive breast cancer from 1993 to 2000, to assess smoking history. After a median follow-up of 13.56 years, we identified 717 deaths using the National Death Index; 427 were breast cancer-related. We used Cox regression to examine associations between self-reported measures of smoking and breast cancer-specific survival within 5 years and up to 18 years after diagnosis conditional on 5-year survival. We examined race and estrogen receptor status as potential modifiers. RESULTS: Current (vs never) smoking was not associated with 5-year survival; however, risk of 13 year conditional breast cancer-specific mortality was elevated among women who were current smokers at diagnosis (HR 1.54, 95% CI 1.06-2.25), compared to never smokers. Although smoking rates were similar among African American (22.0%) and non-African American (22.1%) women, risk of breast cancer-specific mortality was elevated among African American (HR 1.69, 95% CI 1.00-2.85), but only weakly elevated among non-African American (HR 1.22, 95% CI 0.70-2.14) current (vs. never) smokers (P Interaction = 0.30). Risk of breast cancer-specific mortality was also elevated among current (vs never) smokers diagnosed with ER- (HR 2.58, 95% CI 1.35-4.93), but not ER+ (HR 1.11, 95% CI 0.69-1.78) tumors (P Interaction = 0.17). CONCLUSIONS: Smoking may negatively impact long-term survival following breast cancer. Racial differences in long-term survival, as related to smoking, may be driven by ER status, rather than by differences in smoking patterns.

BMI, reproductive factors, and breast cancer molecular subtypes: A case-control study and meta-analysis.

BACKGROUND: The effects of body mass index (BMI) and reproductive factors may vary among breast cancer molecular subtypes, evidence of which is lacking in East Asia. METHODS: From 2002 to 2010, 1256 breast cancer patients and 1416 healthy women were recruited. Anthropometric and reproductive factors were collected from medical charts. Breast cancer subtype was defined by ER, PR, and HER2 status. Polytomous logistic regression was used to evaluate associations between risk factors and breast cancer subtypes, with subgroup analysis by menopausal status. A meta-analysis of relevant published studies in East Asia was also performed. RESULTS: In our case-control study, late menarche was negatively associated with luminal tumor risk (Ptrend = 0.03). Higher BMI was associated with risk of both luminal and triple-negative tumors (Ptrend<0.001). Late age at first live birth was associated with a 1.41- to 2.08-fold increased risk of all subtypes, while late menopause increased risk by 2.62-5.56 times. Heterogeneity of these associations was not detected for different menopausal statuses. The meta-analysis revealed a positive dose-response relationship between BMI and risk of both luminal and ER-PR- subtypes (Ptrend<0.05). Early menarche and nulliparity increased luminal tumor risk by 1.39 and 1.26 times, respectively. Non-breastfeeding also increased the risk of all subtypes. CONCLUSIONS: For East Asian women, overweight, late menopause, and lack of breastfeeding appear to increase risk of both luminal and ER-PR- tumors. Early menarche and nulliparity mainly impacted luminal tumor risk. These associations were not impacted by menopausal status.

Intratumoral heterogeneity as a source of discordance in breast cancer biomarker classification.

BACKGROUND: Spatial heterogeneity in biomarker expression may impact breast cancer classification. The aims of this study were to estimate the frequency of spatial heterogeneity in biomarker expression within tumors, to identify technical and biological factors contributing to spatial heterogeneity, and to examine the impact of discordant biomarker status within tumors on clinical record agreement. METHODS: Tissue microarrays (TMAs) were constructed using two to four cores (1.0 mm) for each of 1085 invasive breast cancers from the Carolina Breast Cancer Study, which is part of the AMBER Consortium. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was quantified using automated digital imaging analysis. The biomarker status for each core and for each case was assigned using clinical thresholds. Cases with core-to-core biomarker discordance were manually reviewed to distinguish intratumoral biomarker heterogeneity from misclassification of biomarker status by the automated algorithm. The impact of core-to-core biomarker discordance on case-level agreement between TMAs and the clinical record was evaluated. RESULTS: On the basis of automated analysis, discordant biomarker status between TMA cores occurred in 9 %, 16 %, and 18 % of cases for ER, PR, and HER2, respectively. Misclassification of benign epithelium and/or ductal carcinoma in situ as invasive carcinoma by the automated algorithm was implicated in discordance among cores. However, manual review of discordant cases confirmed spatial heterogeneity as a source of discordant biomarker status between cores in 2 %, 7 %, and 8 % of cases for ER, PR, and HER2, respectively. Overall, agreement between TMA and clinical record was high for ER (94 %), PR (89 %), and HER2 (88 %), but it was reduced in cases with core-to-core discordance (agreement 70 % for ER, 61 % for PR, and 57 % for HER2). CONCLUSIONS: Intratumoral biomarker heterogeneity may impact breast cancer classification accuracy, with implications for clinical management. Both manually confirmed biomarker heterogeneity and misclassification of biomarker status by automated image analysis contribute to discordant biomarker status between TMA cores. Given that manually confirmed heterogeneity is uncommon (<10 % of cases), large studies are needed to study the impact of heterogeneous biomarker expression on breast cancer classification and outcomes.

Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype.

PURPOSE: Adiposity has been linked with increased breast cancer risk and mortality. It is established that etiologic associations for adiposity vary by tumor subtype, but the influence of adiposity on subtype-specific survival is unknown. METHODS: Study participants were 1,109 invasive breast cancer participants in the population-based Carolina Breast Cancer Study, diagnosed between 1993 and 2001, and with tissue blocks available for immunohistochemical subtyping. General and central adiposities were assessed by body mass index (BMI) and waist-to-hip ratio (WHR), respectively, based on in-person measurements after diagnosis. Vital status as of 2011 was determined using the National Death Index (median follow-up = 13.5 years). Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer (BC)-specific and all-cause mortalities. RESULTS: Among all patients, high WHR (≥0.84), but not BMI, was associated with all-cause mortality (adjusted HR 1.50, 95% CI 1.11-2.05, <0.77 as reference). No significant association between adiposity and BC-specific mortality was detected, although there was a suggestion of increased mortality risk among high-BMI (≥30 kg/m(2)) patients with basal-like tumors (adjusted HR 2.44, 95% CI 0.97-6.12, <25 kg/m(2) as reference). Quantitative differences in all-cause mortality were observed by subtype, with BMI associated with basal-like mortality and WHR associated with luminal mortality. The associations were attenuated by tumor characteristics. CONCLUSIONS: Our study confirms the association of adiposity and unfavorable overall survival in breast cancer patients and suggests that this association may vary by intrinsic subtype and adiposity measure.

Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status.

INTRODUCTION: Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor-positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk. METHODS: We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status. RESULTS: We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors. CONCLUSIONS: Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors.

A non-iterative implementation of Tango's score confidence interval for a paired difference of proportions.

For matched-pair binary data, a variety of approaches have been proposed for the construction of a confidence interval (CI) for the difference of marginal probabilities between two procedures. The score-based approximate CI has been shown to outperform other asymptotic CIs. Tango's method provides a score CI by inverting a score test statistic using an iterative procedure. In this paper, we propose an efficient non-iterative method with closed-form expression to calculate Tango's CIs. Examples illustrate the practical application of the new approach.