Adherence to repeat screening flexible sigmoidoscopy in the Prostate,Lung, Colorectal,and Ovarian (PLCO) Cancer Screening Trial

BACKGROUND: Acceptance of screening flexible sigmoidoscopy has been poor, in part because of providers' concerns regarding the acceptability of the procedure. In the current prospective study, the authors used adherence to repeat testing to assess the acceptability of screening flexible sigmoidoscopy. METHODS: The current study was a prospective study of a randomized clinical trial drawing volunteers from the community. Subjects included 10,164 Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants who were available for follow-up 3 years after undergoing a baseline screening flexible sigmoidoscopy examination. The authors measured adherence and identified those factors that appeared to affect adherence to repeat sigmoidoscopy. RESULTS: Overall, 18.3% of women and 10.0% of men did not undergo a repeat sigmoidoscopy. Among individuals who attended the Year-3 clinic, 10.4% of women and 5.1% of men specifically refused repeat sigmoidoscopy when it was offered (risk of refusal in women compared with men, 2.04; 95% confidence interval, 1.76-2.36). Another factor found to be associated with refusal included a technically inadequate baseline sigmoidoscopy. CONCLUSIONS: Gender and past experiences with sigmoidoscopy may impact adherence to repeat screening. Nonetheless, among research volunteers in a randomized clinical trial of screening, excellent adherence to repeat screening flexible sigmoidoscopy could be achieved.     

Alcohol, genetics and risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

We tested the hypothesis that genes involved in the alcohol oxidation pathway modify the association between alcohol intake and breast cancer. Subjects were women aged 55-74 at baseline from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Incident breast cancers were identified through annual health surveys. Controls were frequency matched to cases by age and year of entry into the trial. A self-administered food frequency questionnaire queried frequency and usual serving size of beer, wine or wine coolers, and liquor. Three SNPs in genes in the alcohol metabolism pathway were genotyped: alcohol dehydrogenase 2, alcohol dehydrogenase 3, and CYP2E1. The study included 1,041 incident breast cancer cases and 1,070 controls. In comparison to non-drinkers, the intake of any alcohol significantly increased the risk of breast cancer, and this risk increased with each category of daily alcohol intake (OR 2.01, 95% CI 1.14, 3.53) for women who drank three or more standard drinks per day. Stratification by genotype revealed significant gene/environment interactions. For the ADH1B gene, there were statistically significant associations between all levels of alcohol intake and risk of breast cancer (all OR > 1.34 and all lower CI > 1.01), while for women with the GA or AA genotype, there were no significant associations between alcohol intake and risk of breast cancer. Alcohol intake, genes involved in alcohol metabolism and their interaction increase the risk of breast cancer in post-menopausal women. This information could be useful for primary care providers to personalize information about breast cancer risk reduction.     

Inflammatory potential of diet and risk of pancreatic cancer in the Prostate,Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Inflammation plays a central role in pancreatic cancer etiology and can be modulated by diet. We aimed to examine the association between the inflammatory potential of diet, assessed with the Dietary Inflammatory Index (DII®), and pancreatic cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial prospective cohort. Our study included 101,449 participants aged 52–78 years at baseline who completed both baseline questionnaire and a diet history questionnaire. Energy‐adjusted DII (E‐DII) scores were computed based on food and supplement intake. Cox proportional hazards models and time dependent Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with participants in the lowest E‐DII quintile (most anti‐inflammatory scores) as referent. After a median 8.5 years of follow‐up, 328 pancreatic cancer cases were identified. E‐DII scores were not associated with pancreatic cancer risk in the multivariable model (HR_Q5vsQ1 = 0.94; 95% CI = 0.66–1.35; p‐trend = 0.43). Time significantly modified the association (p‐interaction = 0.01). During follow up <4 years, there was suggestive evidence of an inverse association between E‐DII and pancreatic cancer (HR_Q5vsQ1 = 0.60; 95% CI = 0.35–1.02; p‐trend = 0.20) while there was a significant positive trend in the follow up ≥4 years (HR_Q5vsQ1 = 1.31; 95% CI = 0.83–2.08; p‐trend = 0.03). Similar results were observed for E‐DII from food only. Our study does not support an association between inflammatory potential of diet and pancreatic cancer risk; however, heterogeneous results were obtained with different follow‐up times. These divergent associations may result from the influences of undetected disease in the short‐term.     

Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate,Lung, Colorectal,Ovarian (PLCO) Cancer Screening Trial

Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55–74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy.     

Hormone Replacement Therapy,Reproductive History,and Colorectal Adenomas: Data from the Prostate,Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (United States)

Objective Findings from some epidemiologic studies of colorectal cancer and adenoma suggest that the protective effect of post-menopausal hormone replacement therapy (HRT) may differ across categories of age and body mass index (BMI). We conducted an analysis of women participating in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to investigate the relationship between HRT use and prevalent adenoma, both overall and across different population subgroups.Methods Women aged 55–74 were randomized to screening by flexible sigmoidoscopy at ten PLCO screening centers between September 1993 and September 2001. We identified 1468 women with at least one left-sided adenoma and 19,203 without adenoma or colorectal cancer. Information about HRT and reproductive factors was obtained from a self-administered questionnaire.Results Compared to never use of HRT, current use was associated with a decreased prevalence of left-sided adenoma (odds ratio (OR) 0.85; 95% confidence interval (CI) 0.75–0.97). We found no evidence of dose–response with increasing duration of use for current or former users. The association with current HRT use was stronger among women aged 65+ (OR 0.69; 95% CI 0.56–0.84), with a BMI<30 (OR 0.82; 95% CI 0.71–0.95) and who regularly use aspirin or ibuprofen (OR 0.77; 95% CI 0.65–0.91). Other reproductive factors were not significantly associated with adenoma prevalence.Conclusions Our findings suggest that current HRT use may protect against colorectal adenoma, and that this protective effect is short-lived following cessation of use.     

Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Mutagen challenge and DNA repair assays have been used in case-control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called 'reverse causation'. We therefore used Epstein-Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (OR(adjusted)) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5-2.5; OR = 1.4, 95% CI: 0.7-3.1; OR = 2.1, 95% CI: 1.0-4.4, respectively, P(trend) = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (P(trend) = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk.     

Hormone Replacement Therapy and Colorectal Cancer Incidence and Mortality in the Prostate,Lung, Colorectal,and Ovarian Cancer Screening Trial

Introduction

Hormone replacement therapy has been shown to reduce colorectal cancer incidence, but its effect on colorectal cancer mortality is controversial. The objective of this study was to determine the effect of hormone replacement therapy on survival from colorectal cancer.

Dietary carbohydrate,glycemic index,glycemic load,and risk of prostate cancer in the Prostate,Lung, Colorectal,and Ovarian Cancer Screening Trial (PLCO) cohort

Objective  

To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.     

Insulin-like Growth Factor (IGF)-I, IGF-binding Protein-3 and Colorectal Adenomas in Japanese Men

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0–4.5, trend P =0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (≥5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.     

Diabetes mellitus and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Objective  A history of diabetes has been fairly consistently related to a reduced prostate cancer risk, but previous investigations have not always addressed whether the relation with diabetes varies by prostate cancer aggressiveness or the association between diabetes and prostate cancer is modified by physical activity level and body mass, variables closely related to glucose metabolism. Methods  We prospectively examined the diabetes–prostate cancer risk relationship among 33,088 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results  During 8.9 years follow-up, we ascertained 2,058 incident prostate cancer cases. Diabetes history was related to decreased risk of total prostate cancer (RR = 0.80, 95% CI = 0.68–0.95). The apparent protection afforded by diabetes was primarily due to the inverse relation with non-aggressive disease (i.e., the combination of low grade (Gleason sum <8) and low stage (clinical stages I or II); RR = 0.75; 95% CI = 0.62–0.91). In contrast, no association was noted between diabetes and aggressive disease (i.e., high grade or high stage (Gleason sum ≥8 or clinical stages III or IV); RR = 1.04, 95% CI = 0.74–1.45). In further analyses, the association between diabetes and aggressive prostate cancer was suggestively positive for men who were lean (RR = 1.64, 95% CI = 0.87–3.07; BMI < 25 kg/m²) and it was positive for men who were the most physically active (RR = 1.63; 95% CI = 1.07–2.62; 3+ hours vigorous activity/week). By comparison, no relations of diabetes to aggressive prostate cancer were noted for their heavier or physically less active counterparts (p-value for tests of interaction = 0.10 and 0.03 BMI and physical activity, respectively). Conclusion  In this study, diabetes showed divergent relations with prostate cancer by tumor aggressiveness. Specifically, diabetes was inversely associated with early stage prostate cancer but it showed no relation with aggressive prostate cancer. Exploratory analyses suggested a positive association between diabetes and aggressive prostate cancer in the subgroup of men with a low BMI.     

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

OBJECTIVE: Epidemiological studies suggest that individuals with elevated plasma concentrations of insulin-like growth factor (IGF-I) are at increased risk of developing cancer. We assessed whether dietary intake of total energy, protein, alcohol, phytoestrogens and related foods, and tomatoes and lycopene was associated with plasma levels of IGF-I and IGF binding proteins (IGFBPs) in Dutch women. METHODS: A cross-sectional study was conducted in 224 premenopausal and 162 postmenopausal women, aged 49-69, participating in the Prospect-EPIC study in the Netherlands. Diet was assessed using a food frequency questionnaire. RESULTS: In postmenopausal women, higher alcohol intake was associated with lower plasma IGFBP-1 concentrations (alcohol 1.4 to 20 g/day: 20% decrease in IGFBP-1; p = 0.04), and higher intake of plant lignans was associated with higher IGFBP-1 concentrations (plant lignans 0 to 1 mg/day: 59% increase in IGFBP-1; p =0.02). Higher soy intake was associated with higher plasma IGFBP-2 concentrations in premenopausal women (soy 0 to 2.5 g/day: 3% increase in IGFBP-2; p = 0.04). No independent associations of dietary factors with IGF-I or IGFBP-3 concentrations were observed. However, in premenopausal women alcohol intake was inversely associated with IGF-I and positively associated with IGFBP-3 after mutual adjustment. CONCLUSIONS: In this study population, with limited variation in dietary intake, total energy, protein, phytoestrogens and lycopene were not associated with IGF-I and IGFBP-3. Alcohol was inversely, and some measures of phytoestrogen intake were positively associated with plasma IGFBP-1 or -2 concentrations. The roles of IGFBP-1 and -2 in relation to IGF-I bioactivity and cancer deserve further investigation.     

Proteomic biomarkers in combination with CA 125 for detection of epithelial ovarian cancer using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

BACKGROUND:

When epithelial ovarian cancer is detected at an early stage (I‐II), the 5‐year survival rate is between 70% and 90%; whereas, when it is detected in late stages (III‐IV), the 5‐year survival rate slips to <30%. In a previous report, the authors observed that proteomic biomarkers and cancer antigen 125 (CA 125) exhibited a sensitivity of 84% at a specificity of 98% for identifying sera from patients who had stage I disease at the time of surgery, significantly improving the sensitivity of CA 125 alone. The challenge, however, is to detect ovarian cancer before clinical diagnosis. The current study was part of a large effort to compare different multimarker biomarker panels for the early detection of ovarian cancer. Several biomarkers were evaluated alone and in combination with CA 125 in prediagnostically collected sera from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

METHODS:

Proximal prediagnostic sera from 118 women with ovarian cancer (cases) and from 951 age‐matched women (controls) (8 controls per case, including 4 randomly selected from the general population, 2 with CA 125 levels ≥35 U/mL, and 2 with a positive family history of breast/ovarian cancer) were analyzed using the CA 125 immunoassay and surface‐enhanced laser desorption and ionization time‐of‐flight mass spectrometry to measure 7 proteins (apolipoprotein A1, truncated transthyretin, transferrin, hepcidin, β‐2 microglobulin, connective tissue activating protein III), and interalpha‐trypsin inhibitor heavy‐chain 4). Data were analyzed by 2 statistical strategies that combined the 7 markers and CA 125 into 1 predictive score for disease classification.

RESULTS:

CA 125 levels were elevated (≥35 U/mL) in 61.5% of 65 patients who had CA 125 data available from samples that were collected <12 months before cancer diagnosis; however, levels of the additional 7 biomarkers were not different between cases and the 3 control groups individually or combined. Two panels that combined CA 125 and the 7 biomarkers failed to improve the sensitivity of CA 125 alone.

CONCLUSIONS:

In contrast to earlier findings from analyzes of postdiagnostically collected sera, the addition of 7 biomarkers to CA 125 did not improve sensitivity for preclinical diagnosis beyond CA 125 alone. Cancer 2012;. © 2011 American Cancer Society.     

IGF-1 and IGFBP-3: Risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

IGF-1 and IGFBP-3 may influence risk of prostate cancer through their roles in cellular growth, metabolism and apoptosis, however, epidemiologic results have been inconsistent. The role of obesity in prostate cancer risk is not clearly understood, but hyperinsulinemia-related increases in bioactive IGF-1 levels, associated with obesity, could be a component of the relationship between the IGF-axis and prostate cancer. We conducted a nested case-control study in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to examine associations between IGF-1 and IGFBP-3 and risk of prostate cancer. A total of 727 incident prostate cancer cases and 887 matched controls were selected for this analysis. There was no clear overall association between IGF-1, IGFBP-3 and IGF-1:IGFBP-3 molar ratio (IGFmr) and prostate cancer risk, however, IGFmr was associated with risk in obese men (BMI > 30, p-trend = 0.04), with a greater than 2-fold increased risk in the highest IGFmr quartile (OR 2.34, 95% CI 1.10-5.01). Risk was specifically increased for aggressive disease in obese men (OR 2.80, 95% CI 1.11-7.08). In summary, our large prospective study showed no overall association between the insulin-like growth factor axis and prostate cancer risk, however, IGFmr was related to risk for aggressive prostate cancer in obese men.