The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). This study closed to new patient enrollment in November 2006, having accrued 2605 high-risk women (1029 surgery arm;1576 screening arm). Prospective follow-up ended in November 2011, and the finishing touches are now being put on the final analytic data base. Accomplishments to date include: (1) successfully completing subject accrual;(2) completing the research-based BRCA1/2 mutation testing for the 1,500 mutation-unknown study participants;(3) completing the central pathology review of 1037 RRSO samples;(4) publishing a report detailing the rationale and design of the study, along with baseline characteristics of the women in each cohort;(5) developing a preliminary model of the factors which influence the choice of RRSO versus screening;(6) contributing 1,576 screening subjects to a published pooled analysis (with the Cancer Genetics Network: total = 4,000 subjects) of determinants of baseline CA-125 levels and of the performance characteristics of the ROCA algorithm;(7) creating a unique biospecimen repository for future translational research;and (8) negotiating a collaboration between GOG and CIMBA under which DNA and clinical data from our 1400 mutation carriers are being contributed to multiple pooled candidate gene association studies of breast cancer risk, and two genome-wide association studies (GWAS), one for each BRCA gene. 19 published manuscripts have resulted from this collaboration, the most recent of which appeared in Nature Genetics and described a consortium of consortia analysis of TERT locus variants and telomere length as modifiers of breast and ovarian cancer risk. A manuscript describing what will be the definitive genotype/phenotype analysis of breast and ovarian cancer risk in 30,000 BRCA mutation carriers is now under review, and data from another dozen candidate SNPs are in various stages of analysis and manuscript preparation. Ancillary analyses are now underway related to (1) histopathology findings from baseline RRSO surgical pathology material, which will provide the best available estimate of the prevalence of clinically-occult ovarian cancer at the time of RRSO (manuscript submitted);(2) an analysis of the performance characteristics of the ROCA ovarian cancer screening algorithm in the pooled GOG-199/CGN data set (manuscript nearing completion);(3) testing/validation of the medical decision-making model related to choice between surgery and screening;(4) a description of baseline quality of life by study arm;and (5) an analysis of the prospective risk of breast and ovarian cancer based on the prospective follow-up of this cohort. Multiple biospecimen-based translational research projects are both underway and planned. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families reached its accrual goal of 200 women from BRCA1/2 mutation-positive families;prospective follow-up ended in February 2010. A published analysis of baseline mammographic density (MD) has revealed no differences between mutation carriers and low-risk women. Analyses of MRI volume in carriers versus non-carriers and correlations between with MD are nearing completion. Our digitized mammographic images have been used in a collaboration with investigators from the University of Chicago to identify various novel imaging characteristics that are are strongly correlated with BRCA mutation status and which may prove to be better predictors of breast cancer risk than standard MD. We have described the results of breast duct lavage (BDL) in the largest cohort of BRCA mutation carriers yet reported, and quantified the tolerability of the BDL procedure. Our experience has led us to abandon BDL as a research/risk stratification tool. DNA samples from mutation-positive BI participants have been contributed to our collaboration with CIMBA. Based on pilot data documenting that femtogram quantities of estrogen metabolites are detectable in both NAF and BDL fluid, a larger study comparing estrogen levels in sample trios (serum, BDL, NAF) from the same individuals is underway (manuscript under review). We have published a series of psychosocial analyses based on this cohort;current efforts target life issues in young mutation carriers, and the impact of ambiguous screening test results on patient mood and screening behavior A Pilot Study of a 3-month Intervention for Increasing Physical Activity in Sedentary Women at Risk of Breast Cancer reached its accrual goal. It asked whether a physician recommendation for increasing physical activity along with the use of a pedometer will be effective in increasing physical activity in a sedentary population of women at increased breast cancer risk [NCI Protocol #04-C-0276]. In brief, the study intervention appeared to be feasible, although no significant change in various intermediate endpoints was identified in this small pilot. A larger, adequately-powered study is required to assess the impact of intervention on clinically meaningful outcomes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACP010145-14
Application #
8763620
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2013
Total Cost
$1,537,139
Indirect Cost
Name
Division of Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
Zip Code
Greene, Mark H; Mai, Phuong L (2015) The fallopian tube: from back stage to center stage. Cancer Prev Res (Phila) 8:339-41
Loud, Jennifer T; Gierach, Gretchen L; Veenstra, Timothy D et al. (2014) Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers. Breast Cancer Res Treat 143:517-29
Mai, Phuong L; Loud, Jennifer T; Greene, Mark H (2014) A major step forward for BRCA1/2-related cancer risk management. J Clin Oncol 32:1531-3
Gierach, Gretchen L; Li, Hui; Loud, Jennifer T et al. (2014) Relationships between computer-extracted mammographic texture pattern features and BRCA1/2 mutation status: a cross-sectional study. Breast Cancer Res 16:424
Werner-Lin, Allison; Hoskins, Lindsey M; Doyle, Maya H et al. (2012) 'Cancer doesn't have an age': genetic testing and cancer risk management in BRCA1/2 mutation-positive women aged 18-24. Health (London) 16:636-54
Hoskins, Lindsey M; Roy, Kevin M; Greene, Mark H (2012) Toward a new understanding of risk perception among young female BRCA1/2 "previvors". Fam Syst Health 30:32-46
Peters, June A; Kenen, Regina; Hoskins, Lindsey M et al. (2011) Unpacking the blockers: understanding perceptions and social constraints of health communication in hereditary breast ovarian cancer (HBOC) susceptibility families. J Genet Couns 20:450-64
Skates, Steven J; Mai, Phuong; Horick, Nora K et al. (2011) Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status. Cancer Prev Res (Phila) 4:1401-8
Gierach, Gretchen L; Loud, Jennifer T; Chow, Catherine K et al. (2010) Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer. Breast Cancer Res Treat 123:245-55
Loud, Jennifer T; Thiebaut, Anne C M; Abati, Andrea D et al. (2009) Ductal lavage in women from BRCA1/2 families: is there a future for ductal lavage in women at increased genetic risk of breast cancer? Cancer Epidemiol Biomarkers Prev 18:1243-51

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