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1.  Endometrial thickness and risk of breast and endometrial carcinomas in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Postmenopausal women with higher circulating estrogen levels are at increased risk of developing breast and endometrial carcinomas. In the endometrium, excess estrogen relative to progesterone produces a net proliferative stimulus, which may result in endometrial thickening. Therefore, we tested the hypothesis that endometrial thickness is a biological marker of excess estrogen stimulation that is associated with risk of breast and endometrial carcinomas. Endometrial thickness was measured in 1,272 postmenopausal women, aged 55–74, who underwent transvaginal ultrasound (TVU) screening as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Serial endometrial thickness measurements were available for a subset of women at one (n=1,018), two (n=869) and three years (n=641) after baseline. We evaluated associations between endometrial thickness and breast (n=91) and endometrial (n=14) carcinoma by estimating relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression with age as the time metric. Models incorporating baseline endometrial thickness and as a time-varying covariate using all measurements were examined. Median follow-up among study participants was 12.5 years (range: 0.3–13.8 years). Compared to baseline endometrial thickness of 1.0 – 2.99 mm, women with baseline endometrial thickness greater than or equal to 5.0 mm had an increased risk of breast (RR: 2.00, 95% CI 1.15, 3.48) and endometrial (RR: 5.02, 95% CI 0.96, 26.36) carcinomas in models adjusted for menopausal hormone use and BMI. Our data suggest that increased endometrial thickness as assessed by TVU was associated with increased risk of breast and endometrial carcinomas.
doi:10.1002/ijc.28404
PMCID: PMC3858514  PMID: 23907658
transvaginal ultrasound; screening; etiology
2.  Diagnostic Accuracy of MALDI Mass Spectrometric Analysis of Unfractionated Serum in Lung Cancer 
Purpose
There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls.
Patients and Methods
We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training–testing paradigm with application of the model profile defined in a training set to a blinded test cohort.
Results
Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A.
Conclusions
We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.
doi:10.1097/JTO.0b013e31814b8be7
PMCID: PMC4220686  PMID: 17909350
Mass spectrometry; Biomarker; Blood; Diagnosis
3.  Flexible Sigmoidoscopy in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Added Yield from a Second Screening Examination 
Background
Among randomized trials evaluating flexible sigmoidoscopy (FSG) for its effect on colorectal cancer mortality, only the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial screened its participants more than one time. We report outcomes from the PLCO screening FSG program and evaluate the increased yield produced by a second FSG.
Methods
Participants were screened by 60-cm FSG in 10 regional screening centers at study entry and 3 or 5 years later, depending on the time of random assignment. Results from subsequent diagnostic intervention were tracked and recorded in a standardized fashion, and outcomes were compared according to sex and age. The protocol discouraged repeat FSG in persons with colorectal cancer or adenoma diagnosed after the initial FSG.
Results
Of 77 447 enrollees, 67 073 (86.6%) had at least one FSG and 39 443 (50.9%) had two FSGs. Diagnostic intervention occurred in 74.9% after a positive first FSG and in 78.7% after a positive repeat FSG. The second FSG increased the screening yield by 32%: Colorectal cancer or advanced adenoma was detected in 37.8 per 1000 persons after first screening and in 49.8 per 1000 persons after all screenings. The second FSG increased the yield of cancer or advanced adenoma by 26% in women and by 34% in men. Of 223 subjects who received a diagnosis of colorectal carcinoma within 1 year of a positive FSG, 64.6% had stage I and 17.5% had stage II disease.
Conclusions
Repeat FSG increased the detection of colorectal cancer or advanced adenoma in women by one-fourth and in men by one-third. Screen-detected carcinomas were early stage (stage I or II) in greater than 80% of screened persons. Colorectal cancer mortality data from the PLCO, as the definitive endpoint, will follow in later publications.
doi:10.1093/jnci/djr549
PMCID: PMC3283538  PMID: 22298838
4.  Effects of ERCC2 Lys751Gln (A35931C) and CCND1 (G870A) polymorphism on outcome of advanced-stage squamous cell carcinoma of the head and neck are treatment dependent 
Background
Germline variation in DNA damage response may explain variable treatment outcomes from squamous cell carcinoma of the head and neck (SCCHN). Grouping patients according to stage and radiation treatment, we compared SCCHN survival according to ERCC2 A35931C (Lys751Gln, rs13181) and CCND1 G870A (Pro241Pro, rs9344) genotypes.
Methods
Recruiting a hospital-based SCCHN case series (all white, 24.7% female, mean age 58.4 years), this treatment outcome cohort study genotyped n=275 stage III-IV cases initially treated with radiation (with or without chemotherapy) and n=80 stage III-IV and n=130 stage I-II cases initially treated without radiation or chemotherapy and used Kaplan-Meier and Cox regression analysis to compare genotype groups according to overall, disease-specific, progression-free, and recurrence-free survival.
Results
ERCC2-35931 AA predicted worse survival in stage III-IV treated with radiation (multiply adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.40; HR over the first three follow-up years 1.92, 95% CI 1.28-2.88) and better survival in stage III-IV not treated with radiation (HR 0.26, 95% CI 0.11-0.62). Unassociated with survival in stage III-IV treated with radiation (HR 1.00, 95% CI 0.67-1.51), CCND1-870 GG predicted better survival in stage III-IV not treated with radiation (HR 0.14, 95% CI 0.04-0.50). Survival in stage I-II did not depend on ERCC2 A35931C or CCND1 G870A genotype.
Conclusions
Promoting tumor progression in untreated patients, germline differences in DNA repair or cell cycle control may improve treatment outcome in patients treated with DNA damaging agents.
Impact
ERCC2 A35931C may help distinguish advanced stage SCCHN with better outcomes from radiation treatment.
doi:10.1158/1055-9965.EPI-11-0520
PMCID: PMC3210907  PMID: 21890746
5.  Baseline mammographic breast density and the risk of invasive breast cancer in postmenopausal women participating in the NSABP Study of Tamoxifen and Raloxifene (STAR) 
Mammographic breast density is an established risk factor for breast cancer. However, results are inconclusive regarding its use in risk prediction models. The current study evaluated 13,409 postmenopausal participants in the NSABP Study of Tamoxifen and Raloxifene. A measure of breast density as reported on the entry mammogram report was extracted and categorized according to The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classifications. An increased risk of invasive breast cancer was associated with higher mammographic breast density (P<0.001). The association remained significant after adjusting for age, treatment, and smoking history (HR 1.35, 95%CI 1.16-1.58), as well as when added to a model including the Gail score (HR 1.33, 95%CI 1.14-1.55). At five years after random assignment, time-dependent AUC improved from 0.63 for a model with Gail score alone to 0.64 when considering breast density and Gail score. Breast density was also significant when added to an abbreviated model tailored for estrogen receptor-positive breast cancers (P=0.02). In this study, high BI-RADS breast density was significantly associated with increased breast cancer risk when considered in conjunction with Gail score but provided only slight improvement to the Gail score for predicting the incidence of invasive breast cancer. The BI-RADS breast composition classification system is a quick and readily available method for assessing breast density for risk prediction evaluations; however, its addition to the Gail model does not appear to provide substantial predictability improvements in this population of postmenopausal healthy women at increased risk for breast cancer.
doi:10.1158/1940-6207.CAPR-12-0273
PMCID: PMC4131535  PMID: 23060039
Breast cancer risk; breast density; tamoxifen; raloxifene; Gail model
6.  Body Mass Index and the Risk for Developing Invasive Breast Cancer among High-risk Women in NSABP P-1 and STAR Breast Cancer Prevention Trials 
High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, while women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (p=0.01). Compared to BMI < 25, adjusted hazard ratios for premenopausal women were 1.59 for BMI 25 – 29.9 and 1.70 for BMI ≥ 30. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than age 35, but not postmenopausal women.
doi:10.1158/1940-6207.CAPR-11-0482
PMCID: PMC4131545  PMID: 22318751
Breast cancer risk; body mass index; menopausal status; tamoxifen; raloxifene
7.  Polymorphisms in NAT2 and GSTP1 Are Associated With Survival in Oral and Oropharyngeal Cancer 
Cancer epidemiology  2013;37(4):505-511.
Introduction
Functional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC).
Methods
OOSCC cases (N=159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan-Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups.
Results
Kaplan-Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P=0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10–0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0. 54–2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31–1.59) (P-for-NAT2/treatment-interaction=0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P=0.04) but this association was not modified by treatment.
Conclusions
Our results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required.
doi:10.1016/j.canep.2013.02.009
PMCID: PMC3690299  PMID: 23523331
head and neck neoplasms; NAT2; GSTP1; polymorphism single nucelotide; SNP
8.  Genetic variation in ESR2 and estrogen receptor-beta expression in lung tumors 
Cancer epidemiology  2013;37(4):518-522.
Objective
To investigate the association between inherited variation in the estrogen receptor beta (ERβ) gene (ESR2) and ERβ lung tumor expression, a phenotype that possibly affects survival differently in men and women.
Methods
We genotyped 135 lung cancer patients for 22 ESR2 single nucleotide polymorphisms (SNPs) and measured nuclear and cytoplasmic ERβ expression by immunohistochemistry (IHC) in their primary lung tumor. Distributing Allred ERβ IHC scores according to ESR2 genotype classified under a dominant genetic model, we used rank sum tests to identify ESR2 SNPs significantly associated (p<0.05) with ERβ expression.
Results
35%, 35%, and 29% of lung tumors showed no/low (Allred <6), intermediate (Allred 6 to 7), and maximal (Allred 8) cytoplasmic ERβ expression, whereas 13%, 27%, and 60% showed no/low, intermediate, and maximal nuclear ERβ expression. For SNPs rs8021944, rs1256061 and rs10146204, ERβ expression was higher according to the rank sum test in lung tumors from patients with at least one minor allele. For each of these three SNPs, the odds of maximal (Allred 8) relative to no/low (Allred <6) ERβ expression was 3-fold higher in tumors from patients with at least one minor allele than in tumors from patients homozygous for the common allele.
Conclusion
Inherited variability in ESR2 may determine ERβ lung tumor expression.
doi:10.1016/j.canep.2013.03.020
PMCID: PMC3684046  PMID: 23619141
lung cancer; genetic polymorphism; estrogen receptor
9.  Childhood Passive Smoke Exposure is Associated With Adult Head and Neck Cancer 
Cancer epidemiology  2013;37(4):417-423.
Introduction
Passive smoke is carcinogenic but its association with head and neck squamous cell carcinoma (HNSCC) is uncertain.
Methods
We conducted a case-control study of childhood passive smoke exposure (CPSE) and HNSCC in 858 cases and 806 frequency-matched controls using an interviewer-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression controlling for adult smoking in the total study population, and in never-smokers only (184 cases and 415 controls). CPSE was also studied in oropharyngeal separately from other HNSCC using polytomous logistic regression.
Results
CPSE was associated with HNSCC (OR, 1.28; 95% CI, 1.01-1.63) after controlling for adult smoking and other factors. This association was similar in magnitude, although not statistically significant, among subjects who never smoked as adults (OR, 1.19, 95% CI, 0.80-1.76). CPSE was associated more strongly with oropharyngeal cancer (a HNSCC subtype commonly associated with human papillomavirus (HPV) infection) than with HNSCC at non-oropharyngeal sites (OR, 2.02; 95% CI, 1.01-4.06, N=52 cases vs. OR, 1.04; 95% CI, 0.68-1.60, N=132 cases; P-for-heterogeneity=0.08).
Conclusions
Data from this large US-based case control study suggest a role for CPSE in HNSCC etiology.
doi:10.1016/j.canep.2013.03.011
PMCID: PMC3706460  PMID: 23619143
adolescent; child; head and neck neoplasms; infant; oropharyngeal neoplasms; tobacco smoke pollution
10.  Validation of a blood protein signature for non-small cell lung cancer 
Clinical Proteomics  2014;11(1):32.
Background
CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations.
Results
Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation.
Conclusions
Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
doi:10.1186/1559-0275-11-32
PMCID: PMC4123246  PMID: 25114662
Lung cancer; Biomarker; SOMAmer; Proteomic; Squamous cell carcinoma; Diagnosis; Preanalytic variability; Sample bias
11.  Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma 
Head and Neck Pathology  2013;7(4):344-355.
There is current interest in anti-angiogenesis therapies for head and neck squamous cell carcinomas (HNSCC), although the utility of these therapies in human papillomavirus (HPV) positive and HPV-negative HNSCC is unclear. Therefore, we explored heterogeneity in expression of a distal factor in angiogenesis (EGFR, the epidermal growth factor receptor), a proximal factor in angiogenesis (VEGF, the vascular endothelial growth factor) and a putative factor in angiogenesis (NOTCH1) in a HNSCC case series using immunohistochemistry in N = 67 cases (27 HPV-positive, 40 HPV-negative, by in situ hybridization). Box plots and the Wilcoxon rank sum or Kruskal–Wallis tests were used to compare staining scores (intensity × percent of cells staining) by HPV status and lifestyle factors. Associations between EGFR, VEGF, and NOTCH1 were assessed using box plots and Spearman correlation (ρ) in all cases, and stratified by HPV status. HPV-negative HNSCC over-expressed EGFR [median (range): 30 (0–300)] relative to HPV-positive HNSCC [7.5 (0–200)] (P = 0.006). VEGF and NOTCH1 were unrelated to HPV status (P > 0.05). EGFR was associated with VEGF in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive HNSCC (ρ = 0.25, P = 0.20). NOTCH1 and VEGF were associated in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive tumors (ρ = −0.12, P = 0.57). NOTCH1 was not associated with EGFR (P > 0.05). Our results are suggestive of heterogeneity in HNSCC angiogenesis. Future studies should explore angiogenesis mechanisms in HPV-positive and HPV-negative HNSCC.
Electronic supplementary material
The online version of this article (doi:10.1007/s12105-013-0447-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s12105-013-0447-y
PMCID: PMC3824798  PMID: 23645351
Head and neck neoplasms; Receptor, epidermal growth factor; Receptor, NOTCH1; Vascular endothelial growth factors; Angiogenic proteins
12.  Smoking behavior one year after computed tomography (CT) screening for lung cancer: Effect of physician referral for abnormal CT findings 
Background
Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study (PLuSS).
Methods
PLuSS recruited 50 to 79 year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes one year after study entry in a subgroup that contained n=2094 active cigarette smokers without interval lung cancer diagnosis (50.7% women, median age 57 years, 40 year median duration of cigarette smoking, and 65.2% ≥ 20 cigarettes per day). Analyses compared efforts to quit in relation to physician referral for abnormal CT.
Results
Since study entry, 58.5% (95% confidence interval (CI) 56.3%, 60.6%) reported any quit attempt and 27.2% (95% CI 25.3%, 29.1%) any quit interval longer than 30 days. One year after study entry, 15.5% (95% CI 14.0%, 17.1%) reported not smoking for more than 30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n=156; 7.4%) to persons not referred for any reason (n=1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval longer than 30 days increased 18.8% (95% CI 11.1%, 26.5%) and 17.7% (95% CI 9.4%, 26.0%), respectively. The fraction quit more than 30 days at one year increased 12.2% (95% CI 4.9%, 19.5%).
Conclusions
Persons who experienced referral because of abnormal CT reported more smoking cessation.
doi:10.1158/1055-9965.EPI-09-0895
PMCID: PMC2789354  PMID: 19959699
13.  Age-period-cohort analysis of cancers not related to tobacco, screening, or HIV: Sex and race differences 
Cancer causes & control : CCC  2010;21(8):1227-1236.
Objective
To identify trends in a residual category of cancers not typically associated with tobacco, screening, or human immunodeficiency virus (HIV) infection.
Methods
For persons aged 20–84 years, we used sex- and race-specific age-period-cohort (APC) models to describe temporal patterns of incidence (1975–2004) and mortality (1970–2004) in the U.S. for a residual cancer category that excluded non-Hodgkin lymphoma, Kaposi sarcoma, and cancer of the oral cavity and pharynx, esophagus, pancreas, larynx, lung and bronchus, urinary bladder, kidney and renal pelvis, colon and rectum, prostate, female breast, and cervix uteri.
Results
Age-specific incidence rose (0.1 – 0.9% per year, on average) in every sex-race group, with factors related to both time period and birth cohort membership appearing to accelerate the increases in women. Age-specific mortality fell (0.6 – 0.9% per year, on average) for black and white men and women, with the declines decelerating in white women but accelerating in the other sex-race groups. Extrapolations of APC models predicted higher age-adjusted incidence rates in white women (11%), black women (5%), and white men (4%) in 2005-09, relative to 2000-04, and lower rates in black men (−3%), accompanied by lower age-adjusted mortality rates in every sex-race group (−8% in black men, −3% in black women, −1% in white men, and −1% in white women).
Conclusions
The possibility that increased incidence in women over time reflects changes in underlying risks, diagnostic practices, or better case ascertainment should be actively explored. Declining mortality may signify improvements in cancer care.
doi:10.1007/s10552-010-9550-5
PMCID: PMC2904415  PMID: 20373012
14.  Erythrocyte Omega-6 and Omega-3 Fatty Acids and Mammographic Breast Density 
Nutrition and cancer  2013;65(3):410-416.
Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman’s correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area.
doi:10.1080/01635581.2013.760744
PMCID: PMC3657737  PMID: 23530640
15.  Comparison of Survival Outcomes Between Patients With Malignant Mixed Mullerian Tumors and High-Grade Endometrioid, Clear Cell, and Papillary Serous Endometrial Cancers 
Introduction
Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes.
Methods
We conducted a retrospective cohort study of EC cases treated at Magee-Women’s Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification.
Results
This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P < 0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high-grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41–0.98).
Conclusions
This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings.
doi:10.1097/IGC.0b013e31821a62dd
PMCID: PMC3827731  PMID: 21666484
Mortality; Aggressive endometrial cancers; Carcinosarcoma
16.  Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers 
Mathematical biosciences  2012;240(1):20-34.
It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers “in the pipeline”. We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6,878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9, 11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8 years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0, 2.4) % of all diagnosed cancers among females and 7.1 (6.7, 8.0) % among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males.
doi:10.1016/j.mbs.2012.05.008
PMCID: PMC3412888  PMID: 22705252
CT screening; multistage; longitudinal model; lung cancer
17.  Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk 
Background
Systematic genome-wide reductions of methylated cytosine (5-mC) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis, possibly as a consequence of inadequate folate intake. Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies.
Methods
To minimize disease- and/or treatment-related effects, we studied leukocyte 5-mC levels in prospectively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial., Leukocyte 5-mC level was determined by an HPLC/Tandem Mass Spectrometry method and expressed as the relative amount of methyl- to total cytosine residues, or %5-mC. We estimated the association between colorectal cancer risk and %5-mC categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through logistic regression modeling.
Results
We observed no dose-dependent association between colorectal cancer and %5-mC categories (lowest tertile vs. highest: OR=1.14, 95% CI=0.80–1.63; P trend=0.51). However, among subjects whose 5-mC levels were at the highest tertile, we observed an inverse association between natural folate intake and colorectal cancer (highest tertile of natural folate vs. lowest: OR=0.35, 95% CI=0.17–0.71; P trend=0.003; P interaction=0.003).
Conclusions
This prospective investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk, but a suggestive risk modification between 5-mC level and natural folate intake.
Impact
Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.
doi:10.1158/1055-9965.EPI-12-0700-T
PMCID: PMC3493855  PMID: 23001241
5-mC; PLCO; folate; colorectal
18.  CYP2A6 Genotype and Smoking Behavior in Current Smokers Screened for Lung Cancer 
Substance use & misuse  2013;48(7):490-494.
Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20–29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.
doi:10.3109/10826084.2013.778280
PMCID: PMC3788637  PMID: 23528144
smoking cessation; smoking initiation; cigarette smoking; genetics; cytochrome P450; nicotine metabolism
19.  Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer 
Molecular carcinogenesis  2011;51(Suppl 1):E11-E20.
DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P<0.05. The strongest associations were observed for rs2074508 in GTF2H4 (Padditive=0.003), rs10500298 in LIG1 (Precessive=2.7×10−4), rs747658 and rs3219073 in PARP1 (rs747658: Padditive=5.8×10−5; rs3219073: Padditive=4.6×10−5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: Pdominant=0.006; rs3213255: Precessive=0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66–2.95 and OR: 3.44, 95% CI: 2.58–4.59, respectively; Ptrend<0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.
doi:10.1002/mc.20858
PMCID: PMC3289753  PMID: 21976407
SNP; case-control; lung cancer
20.  Use of fertility drugs and risk of ovarian cancer: results from a US-based case-control study 
Background
Previous studies examining associations between use of fertility drugs and ovarian cancer risk have provided conflicting results. We used data from a large case-control study to determine whether fertility drug use significantly impacts ovarian cancer risk when taking into account parity, gravidity, and cause of infertility.
Methods
Data from the Hormones and Ovarian Cancer Prediction (HOPE) study were used (902 cases, 1802 controls). Medical and reproductive histories were collected via in-person interviews. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Models were adjusted for age, race, education, age at menarche, parity, oral contraceptive use, breastfeeding, talc use, tubal ligation, and family history of breast/ovarian cancer.
Results
Ever use of fertility drugs was not significantly associated with ovarian cancer within the total HOPE population (OR: 0.93, 95%CI: 0.65–1.35) or among women who reported seeking medical attention for infertility (OR: 0.87, 95%CI 0.54–1.40). We did observe a statistically significant increased risk of ovarian cancer for ever use of fertility drugs among women who, despite seeking medical attention for problems getting pregnant, remained nulligravid (OR: 3.13, 95%CI 1.01–9.67).
Conclusions
These results provide further evidence that fertility drug use does not significantly contribute to ovarian cancer risk among the majority of women; however, women who despite infertility evaluation and fertility drug use remain nulligravid, may have an elevated risk for ovarian cancer.
Impact
Our results suggest that fertility drug use does not significantly contribute to overall risk of ovarian cancer when adjusting for known confounding factors.
doi:10.1158/1055-9965.EPI-12-0426
PMCID: PMC3415595  PMID: 22707710
ovarian cancer; fertility drugs; infertility; case-control
21.  Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression 
CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12, and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors, and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (χ2 p=0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (χ2 p<0.001). CXCL12 and ER were not significantly associated (χ2 p=0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p=0.006) and longer recurrence-free survival (RFS) (log-rank p=0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases.
doi:10.1002/ijc.27317
PMCID: PMC3291748  PMID: 22025313
clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis
22.  Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer 
Carcinogenesis  2012;33(7):1332-1339.
Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P interaction = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11–1.85, P trend = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30–0.84, P trend = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.
doi:10.1093/carcin/bgs158
PMCID: PMC3499048  PMID: 22552404
23.  CASE–CONTROL STUDY OF ORAL AND OROPHARYNGEAL CANCER IN WHITES AND GENETIC VARIATION IN EIGHT METABOLIC ENZYMES 
Head & neck  2008;30(9):1139-1147.
Background
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
Methods
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Results
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
Conclusion
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
doi:10.1002/hed.20867
PMCID: PMC3627181  PMID: 18642288
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
24.  A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals Found to be Cancer-Free by CT Screening 
Journal of Thoracic Oncology  2012;7(4):698-708.
Introduction
Clinical decision-making in the setting of CT screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules.
Methods
To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP® multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non small cell lung cancer and 56 age-, sex- and smoking-matched CT-screened controls.
Results
We identified a panel of 10 serum biomarkers – prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, Cyfra 21.1, and serum amyloid A – that distinguished lung cancer from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0%±3.8% from 20-fold internal cross-validation. We then iteratively evaluated this model in independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using ELISAs in a second independent case/control population further validating the robustness of the panel.
Conclusions
The performance of this 10-biomarker panel based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in Stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary nodules detected by screening CT.
doi:10.1097/JTO.0b013e31824ab6b0
PMCID: PMC3308353  PMID: 22425918
Lung cancer; serum protein biomarkers; CT screening; Luminex xMAP® immunoassays; pulmonary nodules
25.  VASCULAR ENDOTHELIAL GROWTH FACTOR AND BREAST CANCER RISK 
Cancer causes & control : CCC  2008;20(3):375-386.
Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case-control study of 407 pre- and postmenopausal women (N=203 cases, N=204 controls). Logistic regression was used to model breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/mL) than controls (291.4 pg/mL; p=0.21). In a multivariable model the odds of breast cancer was 37% higher for women with VEGF levels ≥314.2 pg/mL compared to those with levels below 314.2 pg/mL, albeit not significantly (p=0.16). There was no interaction between VEGF and menopausal status (p=0.52). In this case-control study VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.
doi:10.1007/s10552-008-9252-4
PMCID: PMC3575594  PMID: 18987982
Angiogenesis; breast neoplasms; premenopausal; postmenopausal

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