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.

Skeletal muscle metastasis from extrahepatic cholangiocarcinoma: A case report and literature review.

Background: Cholangiocarcinoma (CCA) is a type of malignant tumor that arises from the epithelium of the bile ducts. According to anatomical location, CCA can be classified as intrahepatic (ICC), perihilar (PCC), or extrahepatic (ECC). CCA can invade and metastasize to other tissues in various ways, but distal skeletal muscle metastasis (SMM) is extremely rare. There are several reports on SMM from ICC or PCC, but SMM from ECC has not yet been reported. Case presentation: A 71-year-old woman was diagnosed with ECC, for which she underwent pancreatoduodenectomy and partial hepatectomy. Nine months after surgery, she was re-admitted to the hospital complaining of a rapidly growing mass on her right thigh with progressive lower extremity edema. Magnetic resonance imaging of the right thigh showed two masses with iso-signal intensity on T1-weighted images and hyper-intensity on T2-weighted images compared with the surrounding muscles. Pathological examination of the fine-needle biopsy specimen revealed that it was similar to the previously detected ECC, and the diagnosis was metastasis of ECC. The patient was treated with opioid analgesics and died of systemic failure three months later. Conclusion: SMM should be considered during the follow-up period despite its low incidence, and perineural invasion may be an essential pathway of distant metastasis in CCA.

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.

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

PURPOSE: Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. EXPERIMENTAL DESIGN: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors (n = 438, n = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes. RESULTS: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures. CONCLUSIONS: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically "cold" tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.

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.

Plasma levels of polychlorinated biphenyls (PCBs) and breast cancer mortality: The Carolina Breast Cancer Study.

BACKGROUND: It is unknown whether carcinogenic and endocrine disrupting polychlorinated biphenyls (PCBs) influence mortality following breast cancer. We examined plasma levels of 17 PCB congeners in association with mortality among women with breast cancer. METHODS: Participants included 456 white and 292 black women in North Carolina who were diagnosed with primary invasive breast cancer from 1993 to 1996, and who had PCB and lipid measurements from blood samples obtained an average of 4.1 months after diagnosis. Over a median follow-up of 20.6 years, there were 392 deaths (210 from breast cancer). We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific 5-year mortality, and 20-year mortality (conditional on 5-year survival) in association with tertiles and continuous ln-transformed lipid-adjusted PCB levels. RESULTS: The highest (vs. lowest) tertiles of PCB74, PCB99, and PCB118 were associated with 5-year breast cancer-specific mortality HRs of 1.46 (95%CI = 0.86-2.47), 1.57 (95%CI = 0.90-2.73), and 1.86 (95%CI = 1.07-3.23), respectively. Additionally, one-ln unit increases in PCB74, PCB99, PCB118, and total PCBs were each associated with 33-40% increases in 5-year breast cancer-specific mortality rates. The PCBs were not, however, associated with longer-term breast cancer-specific mortality. For all-cause mortality, one-ln unit increases in PCB118, PCB146, PCB153, PCB182, PCB187, and total PCBs were associated with 20-37% increases in 20-year all-cause mortality rates among women who survived at least 5 years. CONCLUSION: PCBs may increase the risk of short-term breast cancer-specific mortality and long-term all-cause mortality among women with breast cancer.

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.

Borderline Estrogen Receptor-Positive Breast Cancers in Black and White Women.

BACKGROUND: Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. METHODS: Using the Carolina Breast Cancer Study (phase I: 1993-1996; 2: 1996-2001; 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided. RESULTS: ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%). CONCLUSIONS: ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.

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.

Plasma levels of dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyltrichloroethane (DDT) and survival following breast cancer in the Carolina Breast Cancer Study.

OBJECTIVES: To examine plasma levels of dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyltrichloroethane (DDT) in association with survival among women with breast cancer who participated in a population-based case-control study. METHODS: Participants included 456 white and 292 black women from the Carolina Breast Cancer Study Phase I who were diagnosed with primary invasive breast cancer from 1993 to 1996, and who had available DDE/DDT and lipid measurements from blood samples obtained on average 4.1 months after diagnosis. Using the National Death Index, we identified 392 deaths (210 from breast cancer) over a median follow-up of 20.6 years. We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific 5-year mortality, and 20-year mortality conditional on 5-year survival, for lipid-standardized DDE and DDT levels. Associations stratified by race and estrogen receptor (ER) status were also examined. RESULTS: The highest versus lowest DDE tertile and the highest vs non-detectable DDT quantile were associated with HRs of 1.95 (95% CI = 1.31-2.92) and 1.64 (95% CI = 1.10-2.44), respectively, for 20-year conditional all-cause mortality. DDE levels above versus below the median were associated with a HR of 1.69 (95% CI = 1.06-2.68) for 20-year conditional breast cancer-specific mortality among women overall, and HRs were 2.36 (95% CI = 1.03-5.42) among black women and 1.57 (95% CI = 0.86-2.89) among white women (PInteraction = 0.42), and 3.24 (95% CI = 1.38-7.58) among women with ER- tumors and 1.29 (95% CI = 0.73-2.28) among women with ER+ tumors (PInteraction = 0.03). CONCLUSION: Exposure to DDE/DDT may adversely impact overall and breast cancer-specific survival. DDE exposure may contribute to the racial disparities in breast cancer survival.

BMI, Physical Inactivity, and Pap Test Use in Asian Women in the U.S.

INTRODUCTION: In the U.S., limited epidemiologic studies have investigated associations between BMI and physical inactivity and Pap test use among Asian women. The aim was to disentangle associations using data from the Behavioral Risk Factor Surveillance System between 2014 and 2016. METHODS: In the Behavioral Risk Factor Surveillance System, BMI was categorized into four levels (<18.5, 18.5 to <25, 25 to <30, and ≥30) and inactivity was defined as having no physical activity in addition to the individual's regular job during the past month. Analyses were conducted in June 2018. Weighted percentages of covariates were used to descriptively summarize the data. Multivariable logistic regression corrected for sampling weight was used to estimate associations between BMI and inactivity and Pap test use. Subgroup analysis was conducted by income and education. RESULTS: The analysis included 9,424 women and 59.6% of them had their last Pap test within 3 years. OR in the mutually adjusted model suggested underweight (BMI <18.5 compared with normal weight) was inversely associated with Pap test use within the last 3 years (OR=0.56, 95% CI=0.36, 0.88). Inactivity (compared with activity) was not associated with Pap test use within the last 3 years (OR=0.80, 95% CI=0.60, 1.06). Different association patterns of BMI and inactivity were observed by education. CONCLUSIONS: This study suggests that being underweight, rather than overweight or obesity, is associated with a lower rate of Pap test use in U.S. Asian women. Health interventions to facilitate Pap test use in Asian women should explore other potential targets, not aiming to just prevent obesity or change physical inactivity.

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.

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.

Intra-individual Gene Expression Variability of Histologically Normal Breast Tissue.

Several studies have sought to identify novel transcriptional biomarkers in normal breast or breast microenvironment to predict tumor risk and prognosis. However, systematic efforts to evaluate intra-individual variability of gene expression within normal breast have not been reported. This study analyzed the microarray gene expression data of 288 samples from 170 women in the Normal Breast Study (NBS), wherein multiple histologically normal breast samples were collected from different block regions and different sections at a given region. Intra-individual differences in global gene expression and selected gene expression signatures were quantified and evaluated in association with other patient-level factors. We found that intra-individual reliability was relatively high in global gene expression, but differed by signatures, with composition-related signatures (i.e., stroma) having higher intra-individual variability and tumorigenesis-related signatures (i.e., proliferation) having lower intra-individual variability. Histological stroma composition was the only factor significantly associated with heterogeneous breast tissue (defined as > median intra-individual variation; high nuclear density, odds ratio [OR] = 3.42, 95% confidence interval [CI] = 1.15-10.15; low area, OR = 0.29, 95% CI = 0.10-0.86). Other factors suggestively influencing the variability included age, BMI, and adipose nuclear density. Our results underscore the importance of considering intra-individual variability in tissue-based biomarker development, and have important implications for normal breast research.

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases.

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008-2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

PAM50 and Risk of Recurrence Scores for Interval Breast Cancers.

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327-36. ©2018 AACR.