Garnet L. Anderson

Bead-Based ELISA for Validation of Ovarian Cancer Early Detection Markers

Purpose: Efforts to validate ovarian cancer early detection biomarkers with immunoassays are challenged by the limited specimen volumes available. We sought to develop a specimen-efficient assay to measure CA125 in serum, assess its reproducibility, validity, and performance, and test its potential for multiplexing and combining with human epididymis protein 4 (HE4), a promising novel ovarian cancer marker. Experimental Design: Four pairs of commercially available anti-CA125 antibodies and one pair of anti-HE4 antibodies were evaluated for accuracy in measuring known concentrations of antigen on a bead-based platform. The two best pairs were further assessed for reproducibility, validity, and the ability to discriminate between blinded serum samples obtained from ovarian cancer cases (n = 66) and women without ovarian cancer (n = 125). Results: Suitability for use in a bead-based assay varied across CA125 antibody pairs. Two CA125 bead-based assays were highly reproducible (overall correlations between replicates ≥ 0.95; coefficients of variation < 0.2) and strongly correlated with the research standard CA125II RIA (correlations ≥ 0.9). Their ability to distinguish ovarian cancer cases from non-cases based on receiver operating characteristic analyses (area under the curve, AUC, of 0.85 and 0.84) was close to that of the CA125II RIA (AUC, 0.87). The HE4 bead-based assay showed lower reproducibility but yielded an AUC of 0.89 in receiver operating characteristics analysis. Multiplexing was not possible but a composite marker including CA125 and HE4 achieved an AUC of 0.91. Conclusion: Optimization procedures yielded two bead-based assays for CA125 that perform comparably to the standard CA125II RIA, which could be combined with an HE4 bead-based assay to improve diagnostic performance, and requires only 15 μL of sample each.

Statistical design and monitoring of the carotene and retinol efficacy trial (CARET)

CARET is a chemoprevention trial of beta-carotene and vitamin A with lung cancer as the primary outcome. Participants at high risk for lung cancer are drawn from two populations: asbestos-exposed workers and heavy smokers. The intervention is a daily combination of 30 mg beta-carotene and 25,000 IU vitamin A as retinyl palmitate. Nearly 18,000 participants will be followed for a mean 6 years, yielding over 100,000 person-years of follow-up. We project that this sample size will have 80% power to detect a 23% decrease in the incidence of lung cancer cases. The purpose of this paper is to present the values of the key sample size parameters of CARET; our schemes for monitoring CARET for sample size adequacy, incidence of side effects, and efficacy of the study vitamins; an overview of the data collected; and plans for the primary, secondary, and ancillary analyses to be performed at the end of the trial. These approaches to the design, monitoring, and analysis of CARET are applicable for many other prevention trials.

Tubal sterilization and risk of subsequent hospital admission for menstrual disorders

OBJECTIVE Our objective was to investigate tubal sterilization and subsequent hospitalization for menstrual disorders. STUDY DESIGN Automated discharge data were used in a population-based cohort study of 7253 women aged 20 to 49 years with tubal sterilization (1968 through 1983) at Group Health Cooperative of Puget Sound. Comparisons were with an age-matched cohort of 25,448 nonsterilized women and a nonmatched cohort of 5283 spouses of men with vasectomies. RESULTS In the sterilization cohort, 282 had hospitalization for menstrual disorders (curettage, n = 191; hysterectomy, n = 66; nonsurgical, n = 25). Risk of hospitalization for menstrual disorders was 2.4 times greater after tubal sterilization (95% confidence interval 2.0 to 2.9). This risk was 6.1 times greater for sterilized women aged 20 to 24 years (95% confidence interval 0.72 to 3.2). Compared with the risk for nonsterilized women whose spouses had a vasectomy, the risk was 1.6 times greater (95% confidence interval 1.3 to 2.1). Hospitalization for menstrual disorders was not more common after unipolar sterilization than after other methods, as might have been expected if the menstrual disorder was related to impaired uteroovarian circulation. CONCLUSIONS Tubal sterilization is associated with a greater risk of hospitalization for menstrual disorders. A biologic association is not supported by these results.

Body mass index, physical activity, and mortality in women diagnosed with ovarian cancer: Results from the Women's Health Initiative☆

BACKGROUND Ovarian cancer is often diagnosed at late stages and consequently the 5-year survival rate is only 44%. However, there is limited knowledge of the association of modifiable lifestyle factors, such as physical activity and obesity on mortality among women diagnosed with ovarian cancer. The purpose of our study was to prospectively investigate the association of (1) measured body mass index (BMI), and (2) self-reported physical activity with ovarian cancer-specific and all-cause mortality in postmenopausal women enrolled in the Womens Health Initiative (WHI). METHODS Participants were 600 women diagnosed with primary ovarian cancer subsequent to enrollment in WHI. Exposure data, including measured height and weight and reported physical activity from recreation and walking, used in this analysis were ascertained at the baseline visit for the WHI. Cox proportional hazard regression was used to examine the associations between BMI, physical activity and mortality endpoints. RESULTS Vigorous-intensity physical activity was associated with a 26% lower risk of ovarian cancer specific-mortality (HR=0.74; 95% CI: 0.56-0.98) and a 24% lower risk of all-cause mortality (HR=0.76; 95% CI: 0.58-0.98) compared to no vigorous-intensity physical activity. BMI was not associated with mortality. CONCLUSIONS Participating in vigorous-intensity physical activity, assessed prior to ovarian cancer diagnosis, appears to be associated with a lower risk of ovarian cancer mortality.

The Role of Antioxidants and Vitamin A in Ovarian Cancer: Results From the Women's Health Initiative

Antioxidant nutrients and carotenoids have been inconsistently associated with ovarian cancer risk. We examined the relationship between intake of dietary and supplemental antioxidant nutrients including vitamins C, E, and selenium as well as carotenoids and vitamin A and ovarian cancer in 133,614 postmenopausal women enrolled in the Womens Health Initiative (WHI) study. Dietary intake was assessed using a food frequency questionnaire, and ovarian cancer endpoints were centrally adjudicated. Cox regression models were used to estimate the risk for invasive ovarian cancer in relation to each of the antioxidant nutrients and carotenoids under consideration using models stratified for a WHI study component. A total of 451 cases of invasive ovarian cancer were diagnosed over 8.3 yr of follow-up. Dietary intake at baseline was not significantly different for cases vs. controls. Cases reported greater intake of supplemental vitamin C (358.0 mg/day vs. 291.6 mg/day, respectively; P = 0.024). Multivariate modeling ( P for trend) of the risk for developing ovarian cancer did not suggest any significant relationships among dietary factors and ovarian cancer risk. The results from this prospective study of well-nourished, postmenopausal women suggest that intake of dietary antioxidants, carotenoids, and vitamin A are not associated with a reduction in ovarian cancer risk.

Inflammation and Oxidative Stress Markers and Esophageal Adenocarcinoma Incidence in a Barrett's Esophagus Cohort

Background: Persons with Barretts esophagus experience increased risk of esophageal adenocarcinoma. Prediagnostic inflammation markers predict several cancers, but their role in predicting esophageal adenocarcinoma is unknown. Methods: We investigated whether biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor (sTNF) receptors I and II], and of oxidative stress (F2-isoprostanes) predicted progression to esophageal adenocarcinoma in a prospective cohort of 397 patients with Barretts esophagus, 45 of whom developed esophageal adenocarcinoma. Biomarkers were measured in stored plasma samples from two time points during follow-up, the mean of which served as the primary predictor. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. Results: CRP level above the median was associated with an 80% increased risk of esophageal adenocarcinoma. The HR and 95% CI adjusted for age, gender, and further adjusted for waist–hip ratio and smoking were 1.98 (1.05–3.73) and 1.77 (0.93–3.37), respectively, with Ptrend for continuous CRP = 0.04. Persons with IL6 levels above the median also had almost 2-fold increased risk [HR and 95% CI adjusted for age and gender, and further adjusted for waist–hip ratio and smoking were 1.95 (1.03–3.72) and 1.79 (0.93–3.43), respectively, but no evidence of a trend was observed]. Concentrations of TNF receptors and F2-isoprostanes were not associated with esophageal adenocarcinoma risk. Conclusions: Further research is needed to evaluate the role of inflammation and associated markers in esophageal adenocarcinoma development in persons with Barretts esophagus. Impact: This prospective study suggests that inflammation markers, particularly CRP and IL6, may help identify persons at higher risk of progression to esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 23(11); 2393–403. ©2014 AACR.

Parity and Oral Contraceptive Use in Relation to Ovarian Cancer Risk in Older Women

Background: Several studies have suggested that the ovarian cancer risk reductions associated with parity and oral contraceptive use are weaker in postmenopausal than premenopausal women, yet little is known about the persistence of these reductions as women age. This question gains importance with the increasing numbers of older women in the population. Methods: We addressed the question using data from three large U.S. cohort studies involving 310,290 white women aged 50+ years at recruitment, of whom 1,815 developed subsequent incident invasive epithelial ovarian cancer. We used Cox regression, stratified by cohort, to examine age-related trends in the HRs per full-term pregnancy and per year of oral contraceptive use. Results: The parity-associated risk reductions waned with age (Ptrend < 0.001 in HR with increasing age), particularly among women aged 75 years or more, for whom we observed no association with parity. However, we observed no such attenuation in the oral contraceptive–associated risk reductions (P = 0.79 for trend in HR with increasing age). Conclusion: These findings suggest that prior oral contraceptive use is important for ovarian cancer risk assessment among women of all ages, while the benefits of parity wane as women age. Impact: This information, if duplicated in other studies, will be useful to preventive counseling and risk prediction, particularly for women at increased ovarian cancer risk due to a personal history of breast cancer or a family history of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1059–63. ©2016 AACR.

Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer

PURPOSE Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Womens Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer. METHODS We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry. RESULTS During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use. CONCLUSION In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk.

Tuba1 Sterilization and the Long-Term Risk of Hysterectomy

To assess the effect of tubal sterilization on the risk of hysterectomy, we studied 7414 women aged 20 to 49 years who had had a tubal sterilization at a health maintenance organization between January 1, 1968, and December 31, 1983. Compared with a population-based cohort of nonsterilized women, women sterilized while 20 to 29 years old were 3.4 times more likely to have had a subsequent hysterectomy (95% confidence interval, 2.4 to 4.7). Adjustment for the effects of potential confounders with a subset of 276 women did not appreciably alter this association. For multivariate comparisons with 5323 wives of vasectomized men, there was no significant elevation in the risk of hysterectomy following sterilization among women sterilized while 20 to 29 years old. Tubal sterilization was not associated with hysterectomy for married women who underwent tubal sterilization at age 30 or older. These results do not support a biological basis for the relationship between tubal sterilization and hysterectomy.