bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients
Authors: Chung Christine H. , Seeley Erin H. , Roder Heinrich , Grigorieva Julia , Tsypin Maxim , Roder Joanna , Burtness Barbara A. , Argiris Athanassios , Forastiere Arlene A. , Gilbert Jill , Murphy Barbara , Caprioli Richard M. , Carbone David P. , Cohen Ezra E.W.
Published: March 2023

Abstract
Background: We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.

Methods: Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.

Results: In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.

Conclusions: Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 19(2); 358–65
Data from Identification of Adipophilin as a Potential Plasma Biomarker for Colorectal Cancer Using Label-Free Quantitative Mass Spectrometry and Protein Microarray
Authors: Matsubara Junichi , Honda Kazufumi , Ono Masaya , Sekine Shigeki , Tanaka Yoshinori , Kobayashi Michimoto , Jung Giman , Sakuma Tomohiro , Nakamori Shoji , Sata Naohiro , Nagai Hideo , Ioka Tatsuya , Okusaka Takuji , Kosuge Tomoo , Tsuchida Akihiko , Shimahara Masashi , Yasunami Yohichi , Chiba Tsutomu , Yamada Tesshi
Published: March 2023

Abstract
Background: The aim of this study was to identify a new plasma biomarker for use in early detection of colorectal cancer.

Methods: Using the combination of hollow fiber membrane (HFM)-based low-molecular weight protein enrichment and two-dimensional image converted analysis of liquid chromatography and mass spectrometry (2DICAL), we compared the plasma proteome of 22 colorectal cancer patients with those of 21 healthy controls. An identified biomarker candidate was then validated in two larger cohorts [validation-1 (n = 210) and validation-2 (n = 113)] using a high-density reverse-phase protein microarray.

Results: From a total of 53,009 mass peaks, we identified 103 with an area under curve (AUC) value of 0.80 or higher that could distinguish cancer patients from healthy controls. A peak that increased in colorectal cancer patients, with an AUC of 0.81 and P value of 0.0004 (Mann–Whitney U test), was identified as a product of the PLIN2 gene [also known as perilipin-2, adipose differentiation-related protein (ADRP), or adipophilin]. An increase in plasma adipophilin was consistently observed in colorectal cancer patients, including those with stage I or stage II disease (P < 0.0001, Welch's t test). Immunohistochemical analysis revealed that adipophilin is expressed primarily in the basal sides of colorectal cancer cells forming polarized tubular structures, and that it is absent from adjacent normal intestinal mucosae.

Conclusions: Adipophilin is a plasma biomarker potentially useful for the detection of early-stage colorectal cancer.

Impact: The combination of HFM and 2DICAL enables the comprehensive analysis of plasma proteins and is ideal for use in all biomarker discovery studies. Cancer Epidemiol Biomarkers Prev; 20(10); 2195–203. ©2011 AACR.
Data from Racial Comparison of Receptor-Defined Breast Cancer in Southern African Women: Subtype Prevalence and Age–Incidence Analysis of Nationwide Cancer Registry Data
Authors: Dickens Caroline , Duarte Raquel , Zietsman Annelle , Cubasch Herbert , Kellett Patricia , Schüz Joachim , Kielkowski Danuta , McCormack Valerie
Published: March 2023

Abstract
Background: Receptor-defined breast cancer proportions vary across Africa. They have important implications for survival prospects and research priorities.

Methods: We studied estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor statuses in two multiracial Southern African countries with routine diagnostic immunohistochemistry. A total of 12,361 women with histologically confirmed breast cancer diagnosed at age ≥20 years during (i) 2009–2011 from South Africa's national cancer registry (public sector) and (ii) 2011–2013 from Namibia's only cancer hospital were included. Crude, age, and age + laboratory–adjusted ORs of receptor status were analyzed using logistic regression, and age–incidence curves were analyzed using Poisson regression.

Results: A total of 10,047 (81%) women had known ER status. Ranking of subtypes was consistent across races: ER+/PR+HER2− was most common (race-specific percentage range, 54.6%–64.8%), followed by triple-negative (17.4%–21.9%), ER+/PR+HER2+ (9.6%–13.9%), and ER−PR−HER2+ (7.8%–10.9%). Percentages in black versus white women were 33.8% [95% confidence (CI), 32.5–35.0] versus 26.0% (24.0–27.9) ER−; 20.9% (19.7–22.1) versus 17.5% (15.4–19.6) triple-negative; and 10.7% (9.8–11.6) versus 7.8% (6.3–9.3) ER−PR−HER2+. Indian/Asian and mixed-ancestry women had intermediate values. Age–incidence curves had similar shapes across races: rates increased by 12.7% per year (12.2–13.1) across ER subtypes under the age of 50 years, and thereafter slowed for ER+ (1.95%) and plateaued for ER− disease (−0.1%).

Conclusions: ER+ breast cancer dominates in all Southern African races, but black women have a modest excess of aggressive subtypes.

Impact: On the basis of the predominant receptor-defined breast tumors in Southern Africa, improving survival for the growing breast cancer burden should be achievable through earlier diagnosis and appropriate treatment. Cancer Epidemiol Biomarkers Prev; 23(11); 2311–21. ©2014 AACR.
Data from Analytic Variability in Immunohistochemistry Biomarker Studies
Authors: Anagnostou Valsamo K. , Welsh Allison W. , Giltnane Jennifer M. , Siddiqui Summar , Liceaga Camil , Gustavson Mark , Syrigos Konstantinos N. , Reiter Jill L. , Rimm David L.
Published: March 2023

Abstract
Background: Despite the widespread use of immunohistochemistry (IHC), there are no standardization guidelines that control for antibody probe variability. Here we describe the effect of variable antibody reagents in the assessment of cancer-related biomarkers by IHC.

Methods: Estrogen receptor (ER), epidermal growth factor receptor (EGFR) 1, and human epidermal growth factor receptor 3 (HER3) were evaluated by quantitative immunofluorescence. Correlations between ER clones 1D5, SP1, F10, and ER60c, and EGFR monoclonal 31G7, 2-18C9, H11, and 15F8, and polyclonal 2232 antibodies were assessed in 642 breast cancer patients. HER3 was measured by RTJ1, RTJ2, SGP1, M7297, RB-9211, and C-17 antibodies in 42 lung cancer patients. Survival analysis was done with the use of multiple cutoff points to reveal any prognostic classification.

Results: All ER antibodies were tightly correlated (Pearson's r2 = 0.94-0.96; P < 0.0001) and western blotting confirmed their specificity in MCF-7 and BT474 cells. All EGFR antibodies but 2232 yielded specific results in western blotting; however, only 31G7 and 2-18C9 were strongly associated (Pearson's r2 = 0.61; P < 0.0001). HER3 staining was nonspecific and nonreproducible. High EGFR–expressing patients had a worse prognosis when EGFR was measured with H11 or 31G7 (log rank P = 0.015 and P = 0.06). There was no statistically significant correlation between survival and EGFR detected by 2-18C9, 15F8, or polyclonal 2232 antibodies.

Conclusions: Antibody validation is a critical analytic factor that regulates IHC readings in biomarker studies. Evaluation of IHC proficiency and quality control are key components toward IHC standardization.

Impact: This work highlights the importance of IHC standardization and could result in the improvement of clinically relevant IHC protocols. Cancer Epidemiol Biomarkers Prev; 19(4); 982–91. ©2010 AACR.
Data from Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer
Authors: Shitara Kohei , Muro Kei , Ito Seiji , Sawaki Akira , Tajika Masahiro , Kawai Hiroki , Yokota Tomoya , Takahari Daisuke , Shibata Takashi , Ura Takashi , Ito Hidemi , Hosono Satoyo , Kawase Takakazu , Watanabe Miki , Tajima Kazuo , Yatabe Yasushi , Tanaka Hideo , Matsuo Keitaro
Published: March 2023

Abstract
Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. Furthermore, there are several reports that evaluated genetic polymorphisms of MTHFR (methylenetetrahydrofolate reductase) or TYMS (thymidylate synthase) and efficacy of FU. However, to our knowledge, there are no reports that evaluate simultaneously the effects of folate intake and genetic polymorphisms on clinical outcome of gastric cancer patients.

Methods: We retrospectively analyzed the survival impact of estimated folate intake by a food frequency questionnaire and MTHFR and TYMS polymorphisms in 132 patients with advanced gastric cancer who were treated with first-line FU-based chemotherapy.

Results: Median overall survival was 11.3 months (95% confidence interval, 9.4-13.4 mo) and median progression-free survival was 5.2 months (95% confidence interval, 4.1-6.3 mo). Patients with folate intake of >260 μg/day (n = 88) showed longer overall survival compared with low folate intake (n = 44; overall survival, 12.2 versus 8.4 mo). In a multivariate Cox model, patients who had folate intake of >260 μg/day, MTHFR 677 TT polymorphism, and TYMS-3′ untranslated region 6-bp insertion were associated with better survival. Similar tendency was observed in progression-free survival. No interaction was observed between folate intake and favorable genotypes.

Conclusion: Folate intake and genetic polymorphisms of MTHFR and TYMS were associated with better clinical outcome by FU-based chemotherapy in advanced gastric cancer.

Impact: Our results suggested folate intake and folate-related genetic polymorphisms may play an important role in efficacy of FU-based chemotherapy in advanced gastric cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1311–9. ©2010 AACR.
Data from Occupational Exposure to Extremely Low-Frequency Magnetic Fields and Brain Tumor Risks in the INTEROCC Study
Authors: Turner Michelle C. , Benke Geza , Bowman Joseph D. , Figuerola Jordi , Fleming Sarah , Hours Martine , Kincl Laurel , Krewski Daniel , McLean Dave , Parent Marie-Elise , Richardson Lesley , Sadetzki Siegal , Schlaefer Klaus , Schlehofer Brigitte , Schüz Joachim , Siemiatycki Jack , van Tongeren Martie , Cardis Elisabeth
Published: March 2023

Abstract
Background: Occupational exposure to extremely low-frequency magnetic fields (ELF) is a suspected risk factor for brain tumors, however the literature is inconsistent. Few studies have assessed whether ELF in different time windows of exposure may be associated with specific histologic types of brain tumors. This study examines the association between ELF and brain tumors in the large-scale INTEROCC study.

Methods: Cases of adult primary glioma and meningioma were recruited in seven countries (Australia, Canada, France, Germany, Israel, New Zealand, and the United Kingdom) between 2000 and 2004. Estimates of mean workday ELF exposure based on a job exposure matrix were assigned. Estimates of cumulative exposure, average exposure, maximum exposure, and exposure duration were calculated for the lifetime, and 1 to 4, 5 to 9, and 10+ years before the diagnosis/reference date.

Results: There were 3,761 included brain tumor cases (1,939 glioma and 1,822 meningioma) and 5,404 population controls. There was no association between lifetime cumulative ELF exposure and glioma or meningioma risk. However, there were positive associations between cumulative ELF 1 to 4 years before the diagnosis/reference date and glioma [odds ratio (OR) ≥ 90th percentile vs. < 25th percentile, 1.67; 95% confidence interval (CI), 1.36–2.07; PLinear trend < 0.0001], and, somewhat weaker associations with meningioma (OR ≥ 90th percentile vs. < 25th percentile, 1.23; 95% CI, 0.97–1.57; PLinear trend = 0.02).

Conclusions: Results showed positive associations between ELF in the recent past and glioma.

Impact: Occupational ELF exposure may play a role in the later stages (promotion and progression) of brain tumorigenesis. Cancer Epidemiol Biomarkers Prev; 23(9); 1863–72. ©2014 AACR.
Data from Mean Telomere Length and Risk of Incident Colorectal Carcinoma: A Prospective, Nested Case-Control Approach
Authors: Zee Robert Y.L. , Castonguay Amy J. , Barton Nathaniel S. , Buring Julie E.
Published: March 2023

Abstract
Recent studies have shown telomere length shortening in colorectal carcinoma (CRC). However, to date, no prospective, epidemiologic data are available on examining mean leukocyte telomere length as a risk predictor. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a modified quantitative PCR protocol, among 191 incident CRC cases (all white males), matched to 306 controls by age, smoking status, and length of follow-up. An inverse correlation between T/S ratio and age was observed in our sample population (P = 0.038). However, the T/S ratios were similar between cases and controls (P = 0.650). Furthermore, in a multivariable adjusted analysis, we found no evidence for an association of the observed T/S ratios with CRC risk (adjusted odds ratio, 1.249; 95% confidence interval, 0.863-1.808; P = 0.238). In summary, the present investigation found no evidence for an association of leukocyte mean telomere length with risk of incident CRC and further suggests that leukocyte mean telomere length may not be a useful indicator for risk assessment.(Cancer Epidemiol Biomarkers Prev 2009;18(8):2280–2)
Data from Genetically Lowered Microsomal Epoxide Hydrolase Activity and Tobacco-Related Cancer in 47,000 Individuals
Authors: Lee Julie , Dahl Morten , Nordestgaard Børge G.
Published: March 2023

Abstract
Background: Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population.

Methods: We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers.

Results: Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8–1.5) and 1.5 (1.1–2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (Ptrend = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8–1.5) and 1.5 (1.1–2.0; Ptrend = 0.003), whereas HRs among never-smokers did not differ from 1.0.

Conclusions: Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings.

Impact: To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population. Cancer Epidemiol Biomarkers Prev; 20(8); 1673–82. ©2011 AACR.
Data from Interaction between Cigarette Smoking and Hepatitis B and C Virus Infection on the Risk of Liver Cancer: A Meta-analysis
Authors: Chuang Shu-Chun , Lee Yuan-Chin Amy , Hashibe Mia , Dai Min , Zheng Tongzhang , Boffetta Paolo
Published: March 2023

Abstract
Introduction: Chronic infection with hepatitis B (HBV) and C viruses (HCV) as well as cigarette smoking are established risk factors of hepatocellular carcinoma (HCC), but it is unclear whether an interaction exists between these factors in causing hepatocellular carcinogenesis. We conducted a meta-analysis to evaluate the interaction of HBV and HCV infection and cigarette smoking on the risk of HCC.

Methods: We systematically searched the PUBMED and the China National Knowledge Infrastructure databases. A total of 16 eligible publications were identified. Cigarette smoking and chronic HBV and HCV infections were dichotomized into present or absent. Additive (S) and multiplicative interaction indexes (V) between smoking and each of the two infections and their 95% confidence intervals (95% CI) were calculated for each study and then combined in a meta-analysis.

Results: We found a more than additive interaction between HBV infection and cigarette smoking (S = 1.44; 95% CI, 1.00-2.06; nine studies) and a more than multiplicative interaction (V = 1.60; 95% CI, 1.16-2.20; six studies) between HCV infection and cigarette smoking. No publication bias was detected.

Conclusion: Smoking seems to interact with both HBV and HCV in determining HCC risk. A pooled analysis of individual subject data, with appropriate adjustment with other risk factors, is warranted to confirm these results.

Impact: The results of this study imply the evidence of a synergistic effect between smoking and HBV or HCV infection on the risk of HCC. Thus, chronic carriers of HBV or HCV are recommended to avoid smoking. Cancer Epidemiol Biomarkers Prev; 19(5); 1261–8. ©2010 AACR.
Data from A Candidate Molecular Biomarker Panel for the Detection of Bladder Cancer
Authors: Urquidi Virginia , Goodison Steve , Cai Yunpeng , Sun Yijun , Rosser Charles J.
Published: March 2023

Abstract
Background: Bladder cancer is among the five most common malignancies worldwide, and due to high rates of recurrence, one of the most prevalent. Improvements in noninvasive urine-based assays to detect bladder cancer would benefit both patients and health care systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with bladder cancer.

Methods: Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of bladder cancer and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR).

Results: Transcriptome profiling data analysis identified 52 genes associated with bladder cancer (P ≤ 0.001) and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of bladder cancer with high accuracy.

Conclusions: Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected bladder cancer. The refinement and validation of the multigene urothelial cell signatures identified in this preliminary study may lead to accurate, noninvasive assays for the detection of bladder cancer.

Impact: The development of an accurate, noninvasive bladder cancer detection assay would benefit both the patient and health care systems through better detection, monitoring, and control of disease. Cancer Epidemiol Biomarkers Prev; 21(12); 2149–58. ©2012 AACR.
Data from The Effects of Test Preference, Test Access, and Navigation on Colorectal Cancer Screening
Authors: Daskalakis Constantine , Vernon Sally W. , Sifri Randa , DiCarlo Melissa , Cocroft James , Sendecki Jocelyn Andrel , Myers Ronald E.
Published: March 2023

Abstract
Background: Little is known about how colorectal cancer screening test preferences operate together with test access and navigation to influence screening adherence in primary care.

Methods: We analyzed data from a randomized trial of 945 primary care patients to assess the independent effects of screening test preference for fecal immunochemical test (FIT) or colonoscopy, mailed access to FIT and colonoscopy, and telephone navigation for FIT and colonoscopy, on screening.

Results: Preference was not associated with overall screening, but individuals who preferred FIT were more likely to complete FIT screening (P = 0.005), whereas those who preferred colonoscopy were more likely to perform colonoscopy screening (P = 0.032). Mailed access to FIT and colonoscopy was associated with increased overall screening (OR = 2.6, P = 0.001), due to a 29-fold increase in FIT use. Telephone navigation was also associated with increased overall screening (OR = 2.1, P = 0.005), mainly due to a 3-fold increase in colonoscopy performance. We estimated that providing access and navigation for both screening tests may substantially increase screening compared with a preference-tailored approach, mainly due to increased performance of nonpreferred tests.

Conclusions: Preference influences the type of screening tests completed. Test access increases FIT and navigation mainly increases colonoscopy. Screening strategies providing access and navigation to both tests may be more effective than preference-tailored approaches.

Impact: Preference tailoring in colorectal cancer screening strategies should be avoided if the objective is to maximize screening rates, although other factors (e.g., costs, necessary follow-up) should also be considered. Cancer Epidemiol Biomarkers Prev; 23(8); 1521–8. ©2014 AACR.
Data from Breast Cancer Susceptibility Variants and Mammographic Density Phenotypes in Norwegian Postmenopausal Women
Authors: Ellingjord-Dale Merete , Grotmol Tom , Lee Eunjung , Van Den Berg David J. , Hofvind Solveig , Couto Elisabeth , Sovio Ulla , dos-Santos-Silva Isabel , Ursin Giske
Published: March 2023

Abstract
Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors.

Methods: We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50–69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006–07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors.

Results: Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption.

Conclusion: This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic–environmental interactions.

Impact: Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD. Cancer Epidemiol Biomarkers Prev; 23(9); 1752–63. ©2014 AACR.
Data from Decline in Physical Activity Level in the Childhood Cancer Survivor Study Cohort
Authors: Wilson Carmen L. , Stratton Kayla , Leisenring Wendy L. , Oeffinger Kevin C. , Nathan Paul C. , Wasilewski-Masker Karen , Hudson Melissa M. , Castellino Sharon M. , Stovall Marilyn , Armstrong Gregory T. , Brinkman Tara M. , Krull Kevin R. , Robison Leslie L. , Ness Kirsten K.
Published: March 2023

Abstract
Background: We aimed to identify demographic and health-related predictors of declining physical activity levels over a four-year period among participants in the Childhood Cancer Survivor Study.

Methods: Analyses included 7,287 ≥5-year childhood cancer survivors and 2,107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. In addition, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.

Results: The median age at last follow-up among survivors and siblings was 36 (range, 21–58) and 38 (range, 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included body mass index ≥30 kg/m2 [RR = 1.32; 95% confidence interval (CI), 1.19–1.46, P < 0.01], not completing high school (RR = 1.31; 95% CI, 1.08–1.60, P < 0.01), and female sex (RR = 1.33; 95% CI, 1.22–1.44, P < 0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (P = 0.034), but not with the presence of cardiac (P = 0.10), respiratory (P = 0.92), or neurologic conditions (P = 0.21).

Conclusions: Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled, and/or referred for physical therapy.

Impact: Clinicians should be aware of low activity levels among subpopulations of childhood cancer survivors, which may heighten their risk for chronic illness. Cancer Epidemiol Biomarkers Prev; 23(8); 1619–27. ©2014 AACR.
Data from Follow-up to Abnormal Cancer Screening Tests: Considering the Multilevel Context of Care
Authors: Zapka Jane M. , Edwards Heather M. , Chollette Veronica , Taplin Stephen H.
Published: March 2023

Abstract
The call for multilevel interventions to improve the quality of follow-up to abnormal cancer screening has been out for a decade, but published work emphasizes individual approaches, and conceptualizations differ regarding the definition of levels. To investigate the scope and methods being undertaken in this focused area of follow-up to abnormal tests (breast, colon, cervical), we reviewed recent literature and grants (2007–2012) funded by the National Cancer Institute. A structured search yielded 16 grants with varying definitions of “follow-up” (e.g., completion of recommended tests, time to diagnosis); most included minority racial/ethnic group participants. Ten grants concentrated on measurement/intervention development and 13 piloted or tested interventions (categories not mutually exclusive). All studies considered patient-level factors and effects. Although some directed interventions at provider levels, few measured group characteristics and effects of interventions on the providers or levels other than the patient. Multilevel interventions are being proposed, but clarity about endpoints, definition of levels, and measures is needed. The differences in the conceptualization of levels and factors that affect practice need empirical exploration, and we need to measure their salient characteristics to advance our understanding of how context affects cancer care delivery in a changing practice and policy environment. Cancer Epidemiol Biomarkers Prev; 23(10); 1965–73. ©2014 AACR.
Data from Physical Activity, Tumor PTGS2 Expression, and Survival in Patients with Colorectal Cancer
Authors: Yamauchi Mai , Lochhead Paul , Imamura Yu , Kuchiba Aya , Liao Xiaoyun , Qian Zhi Rong , Nishihara Reiko , Morikawa Teppei , Shima Kaori , Wu Kana , Giovannucci Edward , Meyerhardt Jeffrey A. , Fuchs Charles S. , Chan Andrew T. , Ogino Shuji
Published: March 2023

Abstract
Background: Higher levels of physical activity are associated with lower colorectal carcinoma incidence and mortality, perhaps through influencing energy balance, cellular prosta7 systemic inflammation. Although evidence suggests interactive effects of energetics, sedentary lifestyle, and tumor CTNNB1 (β-catenin) or CDKN1B (p27) status on colon cancer prognosis, interactive effects of physical activity and tumor PTGS2 (the official symbol for COX-2) status on clinical outcome remain unknown.

Methods: Using molecular pathological epidemiology database of 605 stage I–III colon and rectal cancers in two prospective cohort studies (the Nurse's Health Study and the Health Professionals Follow-up Study), we examined patient survival according to postdiagnosis physical activity and tumor PTGS2 status (with 382 PTGS2-positive and 223 PTGS2-negative tumors by immunohistochemistry). Cox proportional hazards models were used to calculate colorectal cancer-specific mortality HR, adjusting for clinical and other tumor variables including microsatellite instability status.

Results: Among PTGS2-positive cases, compared with the least active first quartile, the multivariate HRs (95% confidence interval) were 0.30 (0.14–0.62) for the second, 0.38 (0.20–0.71) for the third, and 0.18 (0.08–0.41) for the fourth quartile of physical activity level (Ptrend = 0.0002). In contrast, among PTGS2-negative cases, physical activity level was not significantly associated with survival (Ptrend = 0.84; Pinteraction = 0.024, between physical activity and tumor PTGS2 status).

Conclusions: Postdiagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors but not among patients with PTGS2-negative tumors.

Impact: Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice, which may predict stronger benefit from exercise. Cancer Epidemiol Biomarkers Prev; 22(6); 1142–52. ©2013 AACR.
Data from Association between Body Mass Index and Cancer Survival in a Pooled Analysis of 22 Clinical Trials
Authors: Greenlee Heather , Unger Joseph M. , LeBlanc Michael , Ramsey Scott , Hershman Dawn L.
Published: March 2023

Abstract
Background: Data are inconsistent on the association between body mass index (BMI) at time of cancer diagnosis and prognosis. We used data from 22 clinical treatment trials to examine the association between BMI and survival across multiple cancer types and stages.

Methods: Trials with ≥5 years of follow-up were selected. Patients with BMI < 18.5 kg/m2 were excluded. Within a disease, analyses were limited to patients on similar treatment regimens. Variable cutpoint analysis identified a BMI cutpoint that maximized differences in survival. Multivariable Cox regression analyses compared survival between patients with BMI above versus below the cutpoint, adjusting for age, race, sex, and important disease-specific clinical prognostic factors.

Results: A total of 11,724 patients from 22 trials were identified. Fourteen analyses were performed by disease site and treatment regimen. A cutpoint of BMI = 25 kg/m2 maximized survival differences. No statistically significant trend across all 14 analyses was observed (mean HR = 0.96; P = 0.06). In no cancer/treatment combination was elevated BMI associated with an increased risk of death; for some cancers there was a survival advantage for higher BMI. In sex-stratified analyses, BMI ≥ 25 kg/m2 was associated with better overall survival among men (HR = 0.82; P = 0.003), but not women (HR = 1.04; P = 0.86). The association persisted when sex-specific cancers were excluded, when treatment regimens were restricted to dose based on body surface area, and when early-stage cancers were excluded.

Conclusion: The association between BMI and survival is not consistent across cancer types and stages.

Impact: Our findings suggest that disease, stage, and gender-specific body size recommendations for cancer survivors may be warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 21–29. ©2016 AACR.

See all the articles in this CEBP Focus section, “The Obesity Paradox in Cancer: Evidence and New Directions.”
Data from Improving the Quality of Biomarker Discovery Research: The Right Samples and Enough of Them
Authors: Pepe Margaret S. , Li Christopher I. , Feng Ziding
Published: March 2023

Abstract
Background: Biomarker discovery research has yielded few biomarkers that validate for clinical use. A contributing factor may be poor study designs.

Methods: The goal in discovery research is to identify a subset of potentially useful markers from a large set of candidates assayed on case and control samples. We recommend the PRoBE design for selecting samples. We propose sample size calculations that require specifying: (i) a definition for biomarker performance; (ii) the proportion of useful markers the study should identify (Discovery Power); and (iii) the tolerable number of useless markers amongst those identified (False Leads Expected, FLE).

Results: We apply the methodology to a study of 9,000 candidate biomarkers for risk of colon cancer recurrence where a useful biomarker has positive predictive value ≥ 30%. We find that 40 patients with recurrence and 160 without recurrence suffice to filter out 98% of useless markers (2% FLE) while identifying 95% of useful biomarkers (95% Discovery Power). Alternative methods for sample size calculation required more assumptions.

Conclusions: Biomarker discovery research should utilize quality biospecimen repositories and include sample sizes that enable markers meeting prespecified performance characteristics for well-defined clinical applications to be identified.

Impact: The scientific rigor of discovery research should be improved. Cancer Epidemiol Biomarkers Prev; 24(6); 944–50. ©2015 AACR.
Data from Evolving Information Needs among Colon, Breast, and Prostate Cancer Survivors: Results from a Longitudinal Mixed-Effects Analysis
Authors: Tan Andy S.L. , Nagler Rebekah H. , Hornik Robert C. , DeMichele Angela
Published: March 2023

Abstract
Background: This study describes how cancer survivors' information needs about recurrence, late effects, and family risks of cancer evolve over the course of their survivorship period.

Methods: Three annual surveys were conducted from 2006 to 2008 in a cohort of Pennsylvania cancer survivors diagnosed with colon, breast, or prostate cancer in 2005 (round 1, N = 2,013; round 2, N = 1,293; round 3, N = 1,128). Outcomes were information seeking about five survivorship topics. Key predictors were survey round, cancer diagnosis, and the interaction between these variables. Mixed-effects logistic regression analyses were performed to predict information seeking about each topic, adjusting for demographic variables, clinical characteristics, and clustering of repeated observations within individuals.

Results: Information seeking about reducing risks of cancer recurrence was the most frequently reported topic across survivors and over time. Breast cancer survivors were more likely to seek about survivorship topics at round 1 compared with other survivors. In general, information seeking declined over time, but cancer-specific patterns emerged: the decline was sharpest for breast cancer survivors, whereas in later years female colon cancer survivors actually sought more information (about how to reduce the risk of family members getting colon cancer or a different cancer).

Conclusion: Cancer survivors' information needs varied over time depending on the topic, and these trends differed by cancer type.

Impact: Clinicians may need to intervene at distinct points during the survivorship period with information to address concerns about cancer recurrence, late effects, and family members' risks. Cancer Epidemiol Biomarkers Prev; 24(7); 1071–8. ©2015 AACR.
Data from Single-Nucleotide Polymorphisms in Vitamin D–Related Genes May Modify Vitamin D–Breast Cancer Associations
Authors: O'Brien Katie M. , Sandler Dale P. , Kinyamu H. Karimi , Taylor Jack A. , Weinberg Clarice R.
Published: March 2023

Abstract
Background: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; >38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by SNPs in vitamin D–related genes.

Methods: The Sister Study enrolled 50,884 U.S. women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case–cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of HRs (RHRs) for the 25(OH)D–breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D–related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D.

Results: The SNP with the smallest interaction P value was rs4328262 in VDR (P = 0.0008); the 25(OH)D HR was 0.92 [95% confidence interval (CI), 0.68–1.24] among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR = 0.67; 95% CI, 0.53–0.85). Five other VDR SNPs showed evidence of interaction at P < 0.05, as did one SNP in CYP2R1 and one in RXRA. As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (P = 0.04). In gene-based tests, only VDR showed strong evidence of interaction (P = 0.04).

Conclusions: SNPs in vitamin D–related genes may modify the association between serum 25(OH)D and breast cancer.

Impact: This work strengthens the evidence for protective effects of vitamin D. Cancer Epidemiol Biomarkers Prev; 26(12); 1761–71. ©2017 AACR.
Data from Eating Disorders and Breast Cancer
Authors: O'Brien Katie M. , Whelan Denis R. , Sandler Dale P. , Weinberg Clarice R.
Published: March 2023

Abstract
Background: Eating disorders such as anorexia nervosa and bulimia nervosa affect overall and reproductive health and may also affect breast cancer risk. We studied the association between self-reported eating disorders and breast cancer risk in a prospective cohort study.

Methods: In 2003–2009, the Sister Study enrolled women ages 35–74 years who had a sister with breast cancer but had never had it themselves. Using data from 47,813 women, we estimated adjusted HRs and 95% confidence intervals (CI) for the association between eating disorders and invasive breast cancer over a median of 5.4 years of follow-up.

Results: Three percent (n = 1,569) of participants reported a history of an eating disorder. Compared with women who never had an eating disorder, women who reported eating disorders in the past had reduced breast cancer risk (HR = 0.62; 95% CI, 0.42–0.92).

Conclusions: In this large prospective, observational cohort study, we observed an inverse association between having a history of an eating disorder and invasive breast cancer.

Impact: Historical eating disorders may be associated with a long-term reduction in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 26(2); 206–11. ©2016 AACR.
Data from A Cohort Study of Metformin Exposure and Survival in Patients with Stage I–III Colorectal Cancer
Authors: Spillane Susan , Bennett Kathleen , Sharp Linda , Barron Thomas I.
Published: March 2023

Abstract
Background: Preclinical evidence suggests a beneficial effect of metformin in colorectal cancer. This study aimed to investigate associations between metformin exposure and colorectal cancer–specific survival using population-level data.

Methods: Adult patients with stage I–III colorectal cancer diagnosed from 2001 to 2006 were identified from the National Cancer Registry Ireland. Use of metformin and other antidiabetic medications was determined from a linked national prescription claims database. Multivariate Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for associations between prediagnostic metformin exposure (versus nonmetformin antidiabetic drugs) and colorectal cancer–specific mortality. Models were stratified by antidiabetic drug coprescription and intensity of metformin exposure.

Results: The cohort included 207 diabetics who received metformin, 108 diabetics not exposed to metformin, and 3,501 nondiabetic patients. In multivariate analyses, a nonsignificant reduction in colorectal cancer–specific mortality was observed for metformin-exposed patients relative to other treated diabetics (HR, 0.61; 95% CI, 0.37–1.01). In stratified analyses, no significant association was observed for patients receiving low-intensity metformin or metformin in combination with other antidiabetic drugs. High-intensity exclusive metformin use was associated with a significant reduction in colorectal cancer–specific mortality (HR, 0.44; 95% CI, 0.20–0.95).

Conclusions: Significant associations between metformin exposure and colorectal cancer–specific mortality were observed only for high-intensity exclusive metformin use in the diabetic cohort.

Impact: This study provides moderate evidence of an association between metformin exposure and improved colorectal cancer survival in a diabetic population. Additional studies in larger cohorts, with detailed information on diabetes severity, are required to confirm these results. Cancer Epidemiol Biomarkers Prev; 22(8); 1364–73. ©2013 AACR.
Data from Review of Mass Spectrometry–Based Metabolomics in Cancer Research
Authors: Liesenfeld David B. , Habermann Nina , Owen Robert W. , Scalbert Augustin , Ulrich Cornelia M.
Published: March 2023

Abstract
Metabolomics, the systematic investigation of all metabolites present within a biologic system, is used in biomarker development for many human diseases, including cancer. In this review, we investigate the current role of mass spectrometry–based metabolomics in cancer research. A literature review was carried out within the databases PubMed, Embase, and Web of Knowledge. We included 106 studies reporting on 21 different types of cancer in 7 different sample types. Metabolomics in cancer research is most often used for case–control comparisons. Secondary applications include translational areas, such as patient prognosis, therapy control and tumor classification, or grading. Metabolomics is at a developmental stage with respect to epidemiology, with the majority of studies including less than 100 patients. Standardization is required especially concerning sample preparation and data analysis. In the second part of this review, we reconstructed a metabolic network of patients with cancer by quantitatively extracting all reports of altered metabolites: Alterations in energy metabolism, membrane, and fatty acid synthesis emerged, with tryptophan levels changed most frequently in various cancers. Metabolomics has the potential to evolve into a standard tool for future applications in epidemiology and translational cancer research, but further, large-scale studies including prospective validation are needed. Cancer Epidemiol Biomarkers Prev; 22(12); 2182–201. ©2013 AACR.
Quality Measurement for Soft Tissue Sarcomas in Germany: First Results of the Certified Sarcoma Centres
Authors: Rückher Johannes , Grießhammer Ellen , Langer Thomas , Wenzel Gregor , Utzig Martin , Hohenberger Peter , Lindner Lars H. , Jakob Jens , Wesselmann Simone
Published: March 2023

Introduction: Soft tissue sarcomas (STSs) are rare diseases. A high level of standardization and centralization was lacking in Germany until 2018. Methods: By developing an evidence-based guideline and a certification system for sarcoma centres, foundations for structured, guideline-based, and centralized sarcoma care were defined. First results of the certified sarcoma centres are presented. Results: The first 3 years of data collection show good results for case volume, presentation rates in pretherapeutic and postoperative tumour boards, psycho-oncological counselling, and study rates. However, other indicators (e.g., preoperative or postoperative radiotherapy for operated high-risk STS without GIST, counselling rates social services) still have potential for improvement. Based on these results, the set of indicators could be further improved. Conclusions: A sarcoma-specific quality assurance scheme that includes guideline-derived quality indicators was developed. In future, a broader database will allow further insights into sarcoma care in Germany.
Senescent Tumor Cells Are Frequently Present at the Invasion Front: Implications for Improving Disease Control in Patients with Locally Advanced Prostate Cancer
Authors: Schwarz Sebastian , Nientiedt Cathleen , Prigge Elena-Sophie , Kaczorowski Adam , Geisler Christine , Lucena Porcel Carlota , von Knebel Doeberitz Magnus , Hohenfellner Markus , Duensing Stefan
Published: March 2023

Introduction: Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular, seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis. A better understanding of the functional state of invading prostate cancer cells is crucial to develop novel therapeutic strategies for patients with locally advanced disease. Methods: The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer. Prostate cancer specimens were stained by double-immunohistochemistry for the proliferation marker Ki-67 and the senescence marker p16INK4A. The migratory properties of senescent prostate cancer cells were analyzed in vitro using a wound healing assay and immunofluorescence microscopy for p16INK4A. Results: We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone. Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A-positive and Ki-67-negative, i.e., senescent, tumor cells. While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression. Senescence was associated with an accelerated migration of prostate cancer cells in vitro. Conclusion: This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer.