Genetics of Mammographic Appearances and Patterns (The GenMap Study)
Condition: Benign Breast Disease
MeSH terms: Breast Diseases; Fibrocystic Breast Disease
Study type: Observational

Summary: 
      High mammographic density (HMD) is the strongest risk factor for non-familial breast cancer
      apart from age and gender. Studies of sisters and twins suggest that approximately 67% of the
      variation in density is attributable to common genetic factors. However, to date, efforts to
      identify genetic determinants of HMD have achieved limited success. We and others (Boyd et al
      Lancet Oncol 2009) postulate that this lack of progress in identifying genetic determinants
      of density is related to a failure to study younger women and misclassification of density.
      As women age, their breast tissues undergo atrophy, which is manifested radiologically as a
      decrease in mammographic density, resulting in a convergence of density values and a masking
      of inter-person variation. This protocol is intended to demonstrate the feasibility of
      methods that we plan to use in a full-scale analysis of mammographic density among women
      under age 50 years who receive care at the University of Vermont, Fletcher Allen Health Care
      (FAHC) and have been followed through the Vermont Breast Cancer Surveillance System (VBCSS).

      The Hormonal and Reproductive Epidemiology Branch (HREB) is currently conducting a
      cross-sectional study entitled, Breast Radiology Evaluation and Study of Tissues (BREAST)
      Stamp Project which aims to understand why mammographically dense tissues are related to
      elevated breast cancer risk. This project is being conducted within the VBCSS using breast
      cancer awareness Stamp Act funds. The BREAST Stamp project has focused on women between the
      ages of 40-65 years who were referred for radiologically-guided biopsy to evaluate an
      abnormality identified on a screening mammogram. The study has successfully enrolled over 400
      women with collection of questionnaires, buccal and blood samples, and tissues. The study
      will continue recruiting through May 2010, with a targeted enrollment of 450-500 women.
      Through the infrastructure developed for the BREAST Stamp Project, mammographic volumetric
      density data, assessed using a novel method with density phantoms developed at UCSF, has been
      collected on approximately 25,000 screened women of all ages from February 2008-present.

      The current protocol describes a study in which we propose to capitalize on infrastructure
      that has been established through the BREAST Stamp Project. We propose to perform this study
      in two phases: Phase one will be a feasibility study: specifically, we propose to demonstrate
      that we can use a mailing to collect Oragene tube format saliva collection kits as a source
      of germline DNA and a short self-administered questionnaire. This collection of specimens and
      data will be used to inform the launch of phase two, the full-scale study to identify
      determinants of mammographic volumetric density among approximately 10,000 women less than 50
      years of age for whom raw images and density data are already collected. During the first
      phase we hope to demonstrate feasibility by achieving at least 60% participation with
      unbiased representation of subjects with regard to demographics and volumetric density
      measurements. Once feasibility of this approach is established, we propose to launch the
      full-scale study by contacting the remaining (approximately 10,000) women with existing
      volumetric density data to collect questionnaires and DNA samples necessary to delineate the
      genetic determinants of mammographic density, as well as to investigate hypothesized risk
      factors for mammographic density and breast cancer risk, such as alcohol intake, cigarette
      smoking, and breastfeeding history.
    

Detailed description: 
      High mammographic density (HMD) is the strongest risk factor for non-familial breast cancer
      apart from age and gender. Studies of sisters and twins suggest that approximately 67% of the
      variation in density is attributable to common genetic factors. However, to date, efforts to
      identify genetic determinants of HMD have achieved limited success. We and others (Boyd et al
      Lancet Oncol 2009) postulate that this lack of progress in identifying genetic determinants
      of density is related to a failure to study younger women and misclassification of density.
      As women age, their breast tissues undergo atrophy, which is manifested radiologically as a
      decrease in mammographic density, resulting in a convergence of density values and a masking
      of inter-person variation. This protocol is intended to demonstrate the feasibility of
      methods that we plan to use in a full-scale analysis of mammographic density among women
      under age 50 years who receive care at the University of Vermont, Fletcher Allen Health Care
      (FAHC) and have been followed through the Vermont Breast Cancer Surveillance System (VBCSS).

      The study capitalizes on infrastructure that has been established through the BREAST Stamp
      project that is being carried out in two phases: phase one is a feasibility study:
      specifically, we propose to demonstrate that we can use a mailing to collect Oragene tube
      format saliva collection kits as a source of germline DNA and a short self-administered
      questionnaire. We have completed the phase one feasibility portion of the protocol, which
      targeted 200 women by mail. As of January 25, 2011, of the 200 that were mailed invitations,
      195 women were contacted (5 subjects forms were returned because of bad addresses), and 106
      women enrolled. We are currently analyzing data from this feasibility study to determine
      participation rates, quality of completed questionnaires and saliva samples, and frequencies
      and distributions of key risk factors and demographics of participants. This collection of
      specimens and data will be used to inform the launch of phase two, the full-scale study to
      identify determinants of mammographic volumetric density among 10,000 women less than 50
      years of age for whom raw images and density data are already collected.
    

Observational model: Other
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Primary clinical (women undergoing mammography at the UVM Breast Cancer Surveillance
        Consortium site)
      
Keywords: Breast; Mammographic Density