bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Stem Cell Factor HMGA2 Is Expressed in Non-HPV–Associated Head and Neck Squamous Cell Carcinoma and Predicts Patient Survival of Distinct Subsites
Authors: Günther Kathrin , Foraita Ronja , Friemel Juliane , Günther Frauke , Bullerdiek Jörn , Nimzyk Rolf , Markowski Dominique Nadine , Behrens Thomas , Ahrens Wolfgang
Published: April 2023

Abstract
Background: The transcription factor high-mobility AT-hook 2 (HMGA2) is involved in stem cell renewal and is expressed in many tumor tissues. Head and neck squamous cell carcinomas (HNSCC) comprise tumors of the upper aerodigestive tract and are characterized by high recurrence rates that represent a challenge to patient management. The study addresses the potential of HMGA2 as a molecular biomarker for HNSCC patient survival.

Methods: Patients with HNSCC of the larynx, pharynx, tonsils, or oral cavity were recruited in a hospital-based case–control study (n = 202). Quantitative expression of HMGA2 in tumor tissues was measured by RT-PCR. In a 6- to 10-year follow-up, secondary cancers, vital status, and cause of death were ascertained. The HR and 95% confidence intervals (CI) for overall, tumor-specific, and progression-free survival were estimated by Cox proportional hazards with HMGA2 expression level as the independent variable.

Results: High HMGA2 expression in tumor tissues of HNSCC patients was significantly correlated with negative HPV status (P = 0.01), and associated with shorter overall survival time. In Cox regression modeling, HMGA2 expression yielded a risk increase for overall and tumor-specific death in subsets of HNSCC patients, that is, laryngeal cancer patients (overall survival: HR = 4.00; 95% CI, 1.18–13.62) and in oral cancer patients (tumor-specific survival: HR = 2.88; 95% CI, 1.06–7.84), but not in patients with pharyngeal and tonsillar HNSCC.

Conclusions: HMGA2 expression is associated with a risk increase for adverse outcomes in patients with HNSCC of the larynx and oral cavity.

Impact: The understanding of stem cell signaling in HNSCC may offer new strategies for cancer treatment. Cancer Epidemiol Biomarkers Prev; 26(2); 197–205. ©2016 AACR.
Data from Antibody Response to Merkel Cell Polyomavirus Associated with Incident Lymphoma in the Epilymph Case–Control Study in Spain
Authors: Robles Claudia , Poloczek Andre , Casabonne Delphine , Gonzalez-Barca Eva , Bosch Ramon , Benavente Yolanda , Viscidi Raphael P. , de Sanjosé Silvia
Published: April 2023

Abstract
Background: Merkel cell polyomavirus (MCV) has been identified as the cause of Merkel cell carcinoma. The increased incidence of chronic lymphocytic leukemia in Merkel cell cancer cohorts and the lymphotropic properties of the virus suggest a possible viral association with lymphomagenesis. To investigate this potential role, we explored seroreactivity against MCV VP1 capsids within the Epilymph case–control study in Spain.

Methods: Serum samples from 468 incident lymphomas, categorized into up to 11 entities, and 522 controls frequency matched by age, sex, and recruitment center were tested for MCV antibodies by enzyme immunoassay using Virus-Like-Particles. Adjusted multinomial logistic regression was used to estimate the OR and 95% confidence interval (CI) associated to MCV seroprevalence. Immunosuppressed subjects were excluded.

Results: MCV seroprevalence was 82% in controls and 85% in lymphoma cases. Among 11 lymphoma categories, MCV seropositivity was significantly higher in diffuse large B-cell lymphomas (DLBCL; 96.4%; OR = 6.1, 95%CI = 1.9–19.8), as compared with controls. MCV prevalences were also higher in follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, and mature T-cell lymphoma but differences did not reach statistical significance. Lower prevalences were observed for multiple myeloma and other B-cell lymphoma. Exclusion of samples collected after start of treatment did not change the results. In a subset analysis, no significant association was observed between BKV and JCV seroprevalence and DLBCL.

Conclusion: The association observed between serologic evidence of MCV exposure and DLBCL warrants further research.

Impact: MCV might be involved in the pathway of DLBCL and other lymphomas. Cancer Epidemiol Biomarkers Prev; 21(9); 1592–8. ©2012 AACR.
Data from Weight Change in Breast Cancer Survivors Compared to Cancer-Free Women: A Prospective Study in Women at Familial Risk of Breast Cancer
Authors: Gross Amy L. , May Betty J. , Axilbund Jennifer E. , Armstrong Deborah K. , Roden Richard B.S. , Visvanathan Kala
Published: April 2023

Abstract
Background: This study prospectively examines weight gain in breast cancer survivors compared with cancer-free women from a familial risk cohort.

Methods: Absolute and percent weight change over 4 years was compared among 303 breast cancer survivors and 307 cancer-free women matched on age and menopausal status, from the same familial risk cohort. Linear and logistic regression was used to estimate the association between survivor status and weight gain.

Results: Overall, breast cancer survivors gained significantly more weight [β = 3.06 pounds; 95% confidence intervals (CI), 0.94–5.17] than cancer-free women. Significant weight gain was observed in survivors diagnosed less than 5 years prior to baseline (β = 3.81 pounds; 95% CI, 1.22–6.29) and women with estrogen receptor (ER)-negative tumors (β = 7.26 pounds; 95% CI, 2.23–12.30). Furthermore, survivors treated with chemotherapy were 2.1 times more likely to gain at least 11 pounds during follow-up compared with cancer-free women (OR, 2.10; 95% CI, 1.21–3.63). Weight gain was even greater among survivors who took statins while undergoing chemotherapy treatment (Pinteraction = 0.01).

Conclusion: This is the first study to demonstrate that weight gain is an important issue in breast cancer survivors with a familial risk. In the first five years posttreatment, breast cancer survivors gain weight at a faster rate than cancer-free women, particularly after chemotherapy and statin use but not after hormone therapy alone.

Impact: Our findings provide support for the development of weight gain interventions for young breast cancer survivors with a familial risk. Cancer Epidemiol Biomarkers Prev; 24(8); 1262–9. ©2015 AACR.
Data from Genetic Variation of Genes Involved in Dihydrotestosterone Metabolism and the Risk of Prostate Cancer
Authors: Setlur Sunita R. , Chen Chen X. , Hossain Ruhella R. , Ha Jung Sook , Van Doren Vanessa E. , Stenzel Birgit , Steiner Eberhard , Oldridge Derek , Kitabayashi Naoki , Banerjee Samprit , Chen Jin Yun , Schäfer Georg , Horninger Wolfgang , Lee Charles , Rubin Mark A. , Klocker Helmut , Demichelis Francesca
Published: April 2023

Abstract
Purpose: Dihydrotestosterone (DHT) is an important factor in prostate cancer (PCA) genesis and disease progression. Given PCA's strong genetic component, we evaluated the possibility that variation in genes involved in DHT metabolism influence PCA risk.

Experimental Design: We investigated copy number variants (CNV) and single nucleotide polymorphisms (SNP). We explored associations between CNV of uridine diphospho-glucuronosyltransferase (UGT) genes from the 2B subclass, given their prostate specificity and/or involvement in steroid metabolism and PCA risk. We also investigated associations between SNPs in genes (HSD3B1, SRD5A1/2, and AKR1C2) involved in the conversion of testosterone to DHT, and in DHT metabolism and PCA risk. The population consisted of 426 men (205 controls and 221 cases) who underwent prostate-specific antigen screening as part of a PCA early detection program in Tyrol, Austria.

Results: No association between CNV in UGT2B17 and UGT2B28 and PCA risk was identified. Men carrying the AA genotype at SNP rs6428830 (HSD3B1) had an odds ratio (OR) of 2.0 [95% confidence intervals (95% CI), 1.1-4.1] compared with men with GG, and men with AG or GG versus AA in rs1691053 (SRD5A1) had an OR of 1.8 (95% CI, 1.04-3.13). Individuals carrying both risk alleles had an OR of 3.1 (95% CI, 1.4-6.7) when compared with men carrying neither (P = 0.005). Controls with the AA genotype on rs7594951 (SRD5A2) tended toward higher serum DHT levels (P = 0.03).

Conclusions: This is the first study to implicate the 5α-reductase isoform 1 (SRD5A1) and PCA risk, supporting the rationale of blocking enzymatic activity of both isoforms of 5α-reductase for PCA chemoprevention. Cancer Epidemiol Biomarkers Prev; 19(1); 229–39
Data from A Randomized Double-Blind Placebo-Controlled Trial of the Effect of Vitamin D3 Supplementation on Breast Density in Premenopausal Women
Authors: Brisson Jacques , Bérubé Sylvie , Diorio Caroline , Mâsse Benoît , Lemieux Julie , Duchesne Thierry , Delvin Edgar , Vieth Reinhold , Yaffe Martin J. , Chiquette Jocelyne
Published: April 2023

Abstract
Background: This double-blind, placebo-controlled parallel group trial assessed whether oral supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 over one year reduces percent mammographic breast density in premenopausal women.

Methods: The trial was conducted between October 2012 and June 2015, among premenopausal female volunteers from Quebec City (Quebec, Canada). Women were randomized with ratio 1:1:1:1 to one of four study arms (1,000, 2,000, or 3,000 IU/day vitamin D3 or placebo). The primary outcome was mean change in percent mammographic breast density. Participants and research team were blinded to study arm assignment.

Results: Participants (n = 405) were randomized to receive 1,000 (n = 101), 2,000 (n = 104), or 3,000 IU/day (n = 101) vitamin D3, or a placebo (n = 99). The primary analysis included 391 participants (96, 99, 100, and 96, respectively). After the one-year intervention, mean ± SE change in percent breast density in the arms 1,000 IU/day (–5.5% ± 0.5%) and 2,000 IU/day (–5.9% ± 0.5%) vitamin D3 was similar to that in the placebo arm (−5.7% ± 0.5%) (P values = 1.0). In the 3,000 IU/day vitamin D3 arm, percent breast density also declined but slightly less (–3.8% ± 0.5%) compared with placebo arm (P = 0.03). Adherence to intervention was excellent (92.8%), and reporting of health problems was comparable among study arms (P ≥ 0.95). All participants had normal serum calcium.

Conclusions: In premenopausal women, one-year supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 resulted in a reduction of percent breast density no greater than that seen with the placebo.

Impact: At doses of 1,000–3,000 IU/day, vitamin D supplementation will not reduce breast cancer risk through changes in breast density. Cancer Epidemiol Biomarkers Prev; 26(8); 1233–41. ©2017 AACR.
Data from Body Mass Index Is Associated with Gene Methylation in Estrogen Receptor–Positive Breast Tumors
Authors: Hair Brionna Y. , Troester Melissa A. , Edmiston Sharon N. , Parrish Eloise A. , Robinson Whitney R. , Wu Michael C. , Olshan Andrew F. , Swift-Scanlan Theresa , Conway Kathleen
Published: April 2023

Abstract
Background: Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors.

Methods: Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from phase I of the Carolina Breast Cancer Study, a population-based case–control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor (ER) status was also conducted.

Results: In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with differential methylation (FDR q < 0.05) in just two gene loci in breast tumor tissue overall and in 21 loci among ER-positive tumors. Obesity was associated with methylation of genes that function in immune response, cell growth, and DNA repair.

Conclusions: Obesity is associated with altered methylation overall, and with hypermethylation among ER-positive tumors in particular, suggesting that obesity may influence the methylation of genes with known relevance to cancer. Some of these differences in methylation by obese status may influence levels of gene expression within breast cells.

Impact: If our results are validated, obesity-associated methylation sites could serve as targets for prevention and treatment research. Cancer Epidemiol Biomarkers Prev; 24(3); 580–6. ©2015 AACR.
Data from Statin Use and Breast Cancer Risk in the Nurses' Health Study
Authors: Borgquist Signe , Tamimi Rulla M. , Chen Wendy Y. , Garber Judy E. , Eliassen A. Heather , Ahern Thomas P.
Published: April 2023

Abstract
Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82–1.1; current users: HRadj, 1.1; 95% CI, 0.92–1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. Cancer Epidemiol Biomarkers Prev; 25(1); 201–6. ©2016 AACR.
Data from Nicotine Metabolite Ratio (3-Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation
Authors: Tanner Julie-Anne , Novalen Maria , Jatlow Peter , Huestis Marilyn A. , Murphy Sharon E. , Kaprio Jaakko , Kankaanpää Aino , Galanti Laurence , Stefan Cristiana , George Tony P. , Benowitz Neal L. , Lerman Caryn , Tyndale Rachel F.
Published: April 2023

Abstract
Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.

Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland–Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.

Results: Measures of plasma NMR were in strong agreement between methods according to Bland–Altman analysis (ratios, 0.82–1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.

Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.

Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Cancer Epidemiol Biomarkers Prev; 24(8); 1239–46. ©2015 AACR.
Data from Outcomes of Breast Cancer in Brazil Related to Health Care Coverage: A Retrospective Cohort Study
Authors: Liedke Pedro E.R. , Finkelstein Dianne M. , Szymonifka Jackie , Barrios Carlos H. , Chavarri-Guerra Yanin , Bines José , Vasconcelos Cláudia , Simon Sérgio D. , Goss Paul E.
Published: April 2023

Abstract
Background: Breast cancer is the most common malignancy in women in Brazil. Differences between patients with public versus private healthcare coverage about general characteristics, disease presentation, treatment of primary tumors, and clinical outcomes have not been fully investigated.

Methods: A national, retrospective cohort of 3,142 patients drawn from a representative sample of Brazilian medical centers was selected. Clinical and demographic data and type of healthcare coverage were retrieved by chart review. Groups were compared using the χ2 test. The log-rank test was used for comparison of disease-free survival (DFS), postrelapse, and overall survival (OS). Multivariate Cox regression modeling with adjustment for patient characteristics and stage at diagnosis was performed. All P values are two sided.

Results: Patients with public health coverage presented with more advanced disease at diagnosis (P < 0.001). DFS and OS for patients presenting with stage 0–II disease did not differ according to the type of healthcare coverage, whereas a significant difference in outcomes was seen for stage III–IV patients (P = 0.002 and P = 0.008, respectively). In a Cox multivariate analysis, no association was found for the type of health coverage with either DFS or OS, but there was an association for postrelapse survival (P < 0.001).

Conclusion: In Brazil, patients with breast cancer with public health coverage present with more advanced disease, and this possibly explains worse DFS and OS when compared with those with private coverage.

Impact: Earlier diagnosis and treatment of breast cancer could improve outcomes of women with public health coverage in Brazil. Cancer Epidemiol Biomarkers Prev; 23(1); 126–33. ©2013 AACR.
Data from Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake
Authors: Han Summer S. , Sue Laura Y. , Berndt Sonja I. , Selhub Jacob , Burdette Laurie A. , Rosenberg Philip S. , Ziegler Regina G.
Published: April 2023

Abstract
Background: Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer.

Methods: We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels.

Results: Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10−5]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10−5).

Conclusions and Impact: Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev; 21(3); 417–27. ©2012 AACR.
Data from Body Mass Index, Physical Activity, and Serum Markers of Inflammation, Immunity, and Insulin Resistance
Authors: Kitahara Cari M. , Trabert Britton , Katki Hormuzd A. , Chaturvedi Anil K. , Kemp Troy J. , Pinto Ligia A. , Moore Steven C. , Purdue Mark P. , Wentzensen Nicolas , Hildesheim Allan , Shiels Meredith S.
Published: April 2023

Abstract
Background: Epidemiologic studies examining circulating levels of inflammatory markers in relation to obesity and physical inactivity may aid in our understanding of the role of inflammation in obesity-related cancers. However, previous studies on this topic have focused on a limited set of markers.

Methods: We evaluated associations between body mass index (BMI) and vigorous physical activity level, based on self-report, and serum levels of 78 inflammation-related markers. Markers were measured using a bead-based multiplex method among 1,703 men and women, ages 55–74 years, and with no prior history of cancer at blood draw, and selected for case–control studies nested within the Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial. Analyses were adjusted for age, sex, smoking, case–control study, physical activity, and BMI.

Results: Twelve markers were positively associated with BMI after FDR correction. ORs and 95% confidence interval (CI) for highest versus lowest levels of CCL2/MCP-1, CXCL5/ENA-78, sTNFRII, CXCL10/IP-10, CXCL6/GCP2, CCL13/MCP-4, amylin, CRP, C-peptide, CCL19/MIP-3b, insulin, and leptin were: 1.50 (1.14–1.98), 1.52 (1.12–2.05), 1.61 (1.17–2.20), 1.69 (1.25–2.28), 1.74 (1.24–2.44), 1.75 (1.22–2.50), 1.91 (1.31–2.78), 2.41 (1.36–4.25), 2.78 (1.83–4.24), 3.30 (2.28–4.78), 4.05 (2.51–6.55), and 50.03 (19.87–125.99) per 5 kg/m2, respectively. Only CXCL12/SDF-1a was associated with physical activity (≥3 vs. <1 h/wk; OR, 3.28; 95% CI, 1.55–6.94) after FDR correction.

Conclusions: BMI was associated with a wide range of circulating markers involved in the inflammatory response.

Impact: This cross-sectional analysis identified serum markers could be considered in future studies aimed at understanding the underlying mechanisms linking inflammation with obesity and obesity-related cancers. Cancer Epidemiol Biomarkers Prev; 23(12); 2840–9. ©2014 AACR.
Data from Traditional Breast Cancer Risk Factors in Filipina Americans Compared with Chinese and Japanese Americans in Los Angeles County
Authors: Wu Anna H. , Vigen Cheryl , Lee Eunjung , Tseng Chiu-Chen , Butler Lesley M.
Published: April 2023

Abstract
Background: Filipina Americans have one of the highest breast cancer incidence rates among Asian Americans for poorly understood reasons.

Methods: Breast cancer risk factors were investigated in a population-based study of Filipina (790 cases, 587 controls), Japanese (543 cases, 510 controls), and Chinese (913 cases, 904 controls) Americans. Cases were identified by the Los Angeles County Cancer Surveillance Program, and controls were matched to cases on age, ethnicity, and neighborhood. Multivariable conditional logistic regression was performed by Asian ethnicity.

Results: In Filipina, Chinese, and Japanese Americans, breast cancer risk decreased significantly with increasing parity (all Ptrend < 0.0001). Breast cancer risk increased with increasing quartiles of cumulative menstrual months in premenopausal (Ptrend = 0.019) and postmenopausal Filipina (Ptrend = 0.008), in premenopausal (Ptrend = 0.0003) but not postmenopausal Chinese (Ptrend = 0.79), and in neither premenopausal (Ptrend = 0.092) nor postmenopausal (Ptrend = 0.75) Japanese Americans. For postmenopausal Filipina and Japanese, greater weight gain since age 18 (Ptrend = 0.019 and 0.053, respectively), high current body mass index (both Ptrend < 0.01), and greater waist circumferences (both Ptrend < 0.04) were statistically significant; these associations were weaker for postmenopausal Chinese women.

Conclusions: Cumulative menstrual months and body size factors were statistically significant risk factors for Filipina. Total menstrual months were associated with breast cancer among Chinese but not for Japanese, while body size factors were significantly associated with risk among Japanese but not among Chinese.

Impact: Characterization of breast cancer risk factors in Filipina will help to generate hypotheses for their high breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 25(12); 1572–86. ©2016 AACR.
Data from Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma
Authors: Jary Marine , Vernerey Dewi , Lecomte Thierry , Dobi Erion , Ghiringhelli François , Monnien Franck , Godet Yann , Kim Stefano , Bouché Olivier , Fratte Serge , Gonçalves Anthony , Leger Julie , Queiroz Lise , Adotevi Olivier , Bonnetain Franck , Borg Christophe
Published: April 2023

Abstract
Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metastatic colorectal cancer (mCRC) are lacking. Angiopoietin-2 (Ang-2) is proposed as a potential biomarker in several cancers. We therefore decided to establish the additional prognostic value of Ang-2 for overall survival (OS) in patients with first-line mCRC.

Methods: We enrolled 177 patients treated with a bevacizumab containing chemotherapy in two prospective phase II clinical trials. Patient plasma samples were collected at baseline. ELISAs were used to measure Ang-2.

Results: The multivariable Cox model identified increased lactate dehydrogenase [HR, 1.60; 95% confidence interval (CI), 1.04–2.45; P = 0.03] and Ang-2 log-transformation level (HR, 1.59; 95% CI, 1.14–2.21; P = 0.0065) as two significant independent OS prognostic factors. It exhibited good calibration (P = 0.8) and discrimination (C-index: 0.64; 95% CI, 0.58–0.68). Ang-2 parameter inclusion in the GERCOR reference model significantly and strongly improved its discriminative ability because the C-statistic increased significantly from 0.61 to 0.63 (bootstrap mean difference = 0.07; 95% CI, 0.069–0.077). Interestingly, the addition of Ang-2 binary information with a 5 ng/mL cutoff value to the GERCOR model allowed the reclassification of intermediate-risk profile patients (41%) into two subsets of low and high risks.

Conclusions: Our study provides robust evidence in favor of baseline Ang-2 prognostic value for OS adding to the conventional factors. Its assessment appears to be useful for the improvement in risk stratification for patients with intermediate-risk profile.

Impact: Ang-2 ability to predict OS at diagnosis could be of interest in the selection of patients eligible for intermittent or sequential therapeutic strategies dedicated to the optimization of patients' quality of life and chemotherapy cost-effectiveness. Cancer Epidemiol Biomarkers Prev; 24(3); 603–12. ©2015 AACR.
Data from Opportunities and Challenges for the Use of Large-Scale Surveys in Public Health Research: A Comparison of the Assessment of Cancer Screening Behaviors
Authors: Hamilton Jada G. , Breen Nancy , Klabunde Carrie N. , Moser Richard P. , Leyva Bryan , Breslau Erica S. , Kobrin Sarah C.
Published: April 2023

Abstract
Large-scale surveys that assess cancer prevention and control behaviors are a readily available, rich resource for public health researchers. Although these data are used by a subset of researchers who are familiar with them, their potential is not fully realized by the research community for reasons including lack of awareness of the data and limited understanding of their content, methodology, and utility. Until now, no comprehensive resource existed to describe and facilitate use of these data. To address this gap and maximize use of these data, we catalogued the characteristics and content of four surveys that assessed cancer screening behaviors in 2005, the most recent year with concurrent periods of data collection: the National Health Interview Survey, Health Information National Trends Survey, Behavioral Risk Factor Surveillance System, and California Health Interview Survey. We documented each survey's characteristics, measures of cancer screening, and relevant correlates; examined how published studies (n = 78) have used the surveys' cancer screening data; and reviewed new cancer screening constructs measured in recent years. This information can guide researchers in deciding how to capitalize on the opportunities presented by these data resources. Cancer Epidemiol Biomarkers Prev; 24(1); 3–14. ©2014 AACR.
Data from Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population
Authors: Ahern Thomas P. , Sprague Brian L. , Bissell Michael C.S. , Miglioretti Diana L. , Buist Diana S.M. , Braithwaite Dejana , Kerlikowske Karla
Published: April 2023

Abstract
Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density.

Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1st-degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density.

Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0–2.1 at age 40; RR, 1.5; 95% CI, 1.3–1.7 at age 50; RR, 1.4; 95% CI, 1.2–1.6 at age 60; RR, 1.3; 95% CI, 1.1–1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1–3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88–1.5 at age 70). Associations did not change substantially when adjusted for breast density.

Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history.

Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938–44. ©2017 AACR.
Data from Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans
Authors: Batai Ken , Shah Ebony , Murphy Adam B. , Newsome Jennifer , Ruden Maria , Ahaghotu Chiledum , Kittles Rick A.
Published: April 2023

Abstract
Background: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer.

Methods: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry.

Results: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10−8). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes.

Conclusion: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs.

Impact: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs. Cancer Epidemiol Biomarkers Prev; 21(11); 2059–68. ©2012 AACR.
Data from Age-Group Differences in Human Papillomavirus Types and Cofactors for Cervical Intraepithelial Neoplasia 3 among Women Referred to Colposcopy
Authors: Gargano Julia W. , Nisenbaum Rosane , Lee Daisy R. , Ruffin IV Mack T. , Steinau Martin , Horowitz Ira R. , Flowers Lisa C. , Tadros Talaat S. , Birdsong George , Unger Elizabeth R.
Published: April 2023

Abstract
Background: Recommendations for high-risk human papillomavirus (HR-HPV) testing as an adjunct to cytology for cervical cancer screening differ by age group, because HR-HPV tests lack adequate specificity in women aged <30. Here, we assess age-group differences in HPV types and other risk factors for cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) versus CIN0–2 in women from four colposcopy clinics.

Methods: Women ages 18 to 69 (n = 1,658) were enrolled and completed structured interviews to elicit data on behavioral risk factors prior to their examinations. HPV genotyping was done on exfoliated cervical cell samples. We estimated relative risks (RR) for HPV types and cofactors for CIN3+, overall and stratified by age group.

Results: After 2 years of follow-up, we identified 178 CIN3+, 1,305 CIN0–2, and 175 indeterminate outcomes. Nonvaccine HR-HPV types were only associated with CIN3+ among women ≥30 (RR = 2.3, 95% CI: 1.5–3.4; <30: RR = 0.9). Among all HR-HPV–positive women, adjusting for age, significant cofactors for CIN3+ included current smoking (RR = 1.5), former smoking (RR = 1.8), regular Pap screening (RR = 0.7), current regular condom use (RR = 0.5), and parity ≥5 (RR = 1.6, Ptrend for increasing parity = 0.07). However, the parity association differed by age group (≥30: RR = 1.8, Ptrend = 0.008; <30: RR = 0.9; Ptrend =.55).

Conclusion: Subgroup variation by age in the risk of CIN3+ points to the importance of the timing of exposures in relation to CIN3+ detection.

Impact: Future screening strategies need to consider natural history and secular trends in cofactor prevalence in the pursuit of appropriately sensitive and specific screening tools applied to appropriate age groups. Cancer Epidemiol Biomarkers Prev; 21(1); 111–21. ©2011 AACR.
Data from A Prospective Study of Leukocyte Telomere Length and Risk of Renal Cell Carcinoma
Authors: Hofmann Jonathan N. , Lan Qing , Cawthon Richard , Hosgood H. Dean , Shuch Brian , Moore Lee E. , Rothman Nathaniel , Chow Wong-Ho , Purdue Mark P.
Published: April 2023

Abstract
Background: It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case–control studies suggesting that short leukocyte telomere length may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively.

Methods: We conducted a nested case–control study (209 cases, 410 controls) of RCC risk in relation to prediagnostic leukocyte telomere length in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. ORs and 95% confidence intervals (CI) were estimated using conditional logistic regression.

Results: Leukocyte telomere length was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR, 0.8; 95% CI, 0.5–1.5; Ptrend = 0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null.

Conclusions: The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between prediagnostic leukocyte telomere length and risk of RCC.

Impact: In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of RCC. Cancer Epidemiol Biomarkers Prev; 22(5); 997–1000. ©2013 AACR.
Data from Dairy Consumption in Adolescence and Early Adulthood and Risk of Breast Cancer
Authors: Farvid Maryam S. , Eliassen A. Heather , Cho Eunyoung , Chen Wendy Y. , Willett Walter C.
Published: April 2023

Abstract
Background: Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses' Health Study II cohort.

Methods: For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women ages 27 to 44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991 to 2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998 to 2013; 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression.

Results: Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR = 1.02, 95% CI, 0.97–1.07; for early adulthood total dairy HR = 1.01, 95% CI, 0.97–1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00–1.24; high-fat dairy HR = 1.17, 95% CI, 1.04–1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR = 0.91, 95% CI, 0.86–0.97).

Conclusions: Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors.

Impact: Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 27(5); 575–84. ©2018 AACR.
Data from Cervical Precancer and Cancer Risk by Human Papillomavirus Status and Cytologic Interpretation: Implications for Risk-Based Management
Authors: Castle Philip E. , Aslam Shagufta , Behrens Catherine
Published: April 2023

Abstract
Background: Cervical cancer risks, estimated by using cervical intraepithelial neoplasia grade 3 (CIN3) or more severe diagnoses (≥CIN3) endpoints, have not been quantified for different combinations of results from currently approved screening methods. Understanding these risks will guide optimal patient management.

Methods: Women aged ≥25 years (n = 7,823) underwent high-risk human papillomavirus (hrHPV) and liquid-based cytology (LBC) testing. Women with hrHPV-positive results and/or abnormal LBC, plus a random subset of hrHPV and LBC negatives, underwent colposcopy; those without ≥CIN2 at baseline were screened annually by LBC and referred to colposcopy for an abnormal LBC (n = 7,392). One- and 3-year ≥CIN3 risks with 95% confidence intervals (95% CI) were calculated for paired hrHPV and LBC (hrHPV/LBC) results.

Results: One-year ≥CIN3 risks ranged from 81.27% (95% CI, 66.02%–90.65%) for HPV16 positive/high-grade to 0.33% (95% CI, 0.18%–0.62%) for hrHPV negative/negative for intraepithelial lesion or malignancy (NILM). One-year ≥CIN3 risk for HPV16/NILM (13.95%; 95% CI, 10.98%–17.58%) was greater than low-grade squamous intraepithelial lesion (LSIL; 7.90%; 95% CI, 5.99%–10.37%; P = 0.002) and similar to hrHPV-positive/LSIL (11.45%; 95% CI, 8.61%–15.07%; P = 0.3). Three-year ≥CIN3 risks for HPV16 positive/LSIL and HPV16/atypical squamous cells of undetermined significance was 24.79% (95% CI, 16.44%–35.58%) and 24.36% (95% CI, 15.86%–35.50%), respectively, and 0.72% (95% CI, 0.45%–1.14%) for hrHPV negative/NILM.

Conclusions: hrHPV and LBC results stratify cervical cancer risk by more than two orders of magnitude. HPV16-positive women, regardless of the LBC result, warrant immediate colposcopy. Women with concurrent HPV16 and high-grade LBC might consider treatment without a confirmatory biopsy with informed decision-making with their provider.

Impact: These results provide relevant benchmarks for risk-based cervical cancer screening and management. Cancer Epidemiol Biomarkers Prev; 25(12); 1595–9. ©2016 AACR.
Data from Demand for Colonoscopy in Colorectal Cancer Screening Using a Quantitative Fecal Immunochemical Test and Age/Sex-Specific Thresholds for Test Positivity
Authors: Chen Sam Li-Sheng , Hsu Chen-Yang , Yen Amy Ming-Fang , Young Graeme P. , Chiu Sherry Yueh-Hsia , Fann Jean Ching-Yuan , Lee Yi-Chia , Chiu Han-Mo , Chiou Shu-Ti , Chen Hsiu-Hsi
Published: April 2023

Abstract
Background: Despite age and sex differences in fecal hemoglobin (f-Hb) concentrations, most fecal immunochemical test (FIT) screening programs use population-average cut-points for test positivity. The impact of age/sex-specific threshold on FIT accuracy and colonoscopy demand for colorectal cancer screening are unknown.

Methods: Using data from 723,113 participants enrolled in a Taiwanese population-based colorectal cancer screening with single FIT between 2004 and 2009, sensitivity and specificity were estimated for various f-Hb thresholds for test positivity. This included estimates based on a “universal” threshold, receiver-operating-characteristic curve–derived threshold, targeted sensitivity, targeted false-positive rate, and a colonoscopy-capacity-adjusted method integrating colonoscopy workload with and without age/sex adjustments.

Results: Optimal age/sex-specific thresholds were found to be equal to or lower than the universal 20 μg Hb/g threshold. For older males, a higher threshold (24 μg Hb/g) was identified using a 5% false-positive rate. Importantly, a nonlinear relationship was observed between sensitivity and colonoscopy workload with workload rising disproportionately to sensitivity at 16 μg Hb/g. At this “colonoscopy-capacity-adjusted” threshold, the test positivity (colonoscopy workload) was 4.67% and sensitivity was 79.5%, compared with a lower 4.0% workload and a lower 78.7% sensitivity using 20 μg Hb/g. When constrained on capacity, age/sex-adjusted estimates were generally lower. However, optimizing age/-sex-adjusted thresholds increased colonoscopy demand across models by 17% or greater compared with a universal threshold.

Conclusions: Age/sex-specific thresholds improve FIT accuracy with modest increases in colonoscopy demand.

Impact: Colonoscopy-capacity-adjusted and age/sex-specific f-Hb thresholds may be useful in optimizing individual screening programs based on detection accuracy, population characteristics, and clinical capacity. Cancer Epidemiol Biomarkers Prev; 27(6); 704–9. ©2018 AACR.
Data from Partnership Status and Socioeconomic Factors in Relation to Health Behavior Changes after a Diagnosis of Ductal Carcinoma In Situ
Authors: Khadanga Sherrie , Lakoski Susan G. , Hart Vicki , Sprague Brian L. , Ba Yi , Hampton John M. , Higgins Stephen T. , Ades Philip A. , Newcomb Polly A. , Trentham-Dietz Amy
Published: April 2023

Abstract
Background: Change in health behaviors can occur among women newly diagnosed with ductal carcinoma in situ (DCIS). We sought to understand whether partnership status and socioeconomic status (SES) affected behavioral changes in body weight, physical activity, alcohol consumption, and smoking.

Methods: The Wisconsin In Situ Cohort (WISC) study comprises 1,382 women diagnosed with DCIS with information on demographics, SES factors, and pre- and post-DCIS diagnosis health-related behaviors. Logistic regression models were used to determine the association between partnership status, education, and income with change in behavior variables.

Results: Higher educational attainment was associated with lower likelihood of stopping physical activity [OR, 0.45; 95% confidence interval (CI), 0.32–0.63; college vs. high school degree], or starting to drink alcohol (OR, 0.34; 95% CI, 0.15–0.80). Results suggested that higher family income was associated with lower likelihood of gaining >5% body mass index (P = 0.07) or stopping physical activity (P = 0.09). Living with a partner was not strongly associated with behavior changes.

Conclusion: Higher educational attainment and higher income, but not living with a partner, were associated with positive health behaviors after a DCIS diagnosis.

Impact: The associations between higher educational attainment and, to a lesser extent, higher income with positive health behaviors underscore the importance of considering SES when identifying those at risk for negative behavioral change after DCIS diagnosis. Cancer Epidemiol Biomarkers Prev; 25(1); 76–82. ©2015 AACR.
Data from Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women
Authors: Prizment Anna E. , Vierkant Robert A. , Smyrk Thomas C. , Tillmans Lori S. , Nelson Heather H. , Lynch Charles F. , Pengo Thomas , Thibodeau Stephen N. , Church Timothy R. , Cerhan James R. , Anderson Kristin E. , Limburg Paul J.
Published: April 2023

Abstract
Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.

Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer–specific death associated with each composite score.

Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38–0.75; Ptrend = 0.0004) and 0.66 (0.51–0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18–0.51; Ptrend < 0.0001) and 0.41 (0.27–0.63; Ptrend < 0.0001) for colorectal cancer–related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer–related death.

Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.

Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622–31. ©2016 AACR.