High-Risk Breast Duct Epithelium
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Observational

Summary: 
      Background:

        -  Breast cancer is the most common malignancy in women, occurring in over 230,000 women
           annually in the United States.

        -  The vast majority of breast cancers originate in the single layer of epithelial cells
           that line the ductal/lobular system of the breast milk ducts. The premalignant changes
           which occur in the transformed epithelium are not well understood, however several
           cytologic or histologic changes have been identified which are associated with an
           increased risk for breast cancer, including ductal or lobular hyperplasia, hyperplasia
           with atypia, and lobular or ductal carcinoma in situ.

        -  The identification of cytological or histological abnormalities in breast epithelial
           cells is an important component of risk assessment.

      Objective:

      Primary objectives are:

        -  To determine the incidence and nature of cytologic changes in ductal epithelial cells
           from the high-risk breast, in specimens collected by breast ductal lavage, and to
           determine if these cytologic findings are different from those of female normal
           volunteers not at increased risk for breast cancer.

        -  To characterize by breast duct endoscopy, high risk breast ductal epithelium and
           architecture, and correlate these findings with the cytologic findings referenced in
           above bullet.

        -  To determine what is the global gene expression pattern of high risk breast epithelial
           cells from the high risk breast, and does this differ from that of breast epithelial
           cells from female normal volunteersnot at increased risk for breast cancer. The gene
           expression profile will be determined by cDNA microarray and validated by RT-PCR.

      Eligibility:

      Eligibility for high risk individuals will include:

        -  Women with a unilateral invasive or noninvasive (DCIS) breast cancer of epithelial
           origin.

        -  Women without breast cancer, but with a Gail Index greater than 1.67 percent, or a
           cumulative lifetime risk greater than or equal to double the age- and race-matched
           general population risk.

        -  Women known to be BRCA1/2 or other hereditary genes mutation carriers.

        -  Women with cytologic or histologic evidence of ductal hyperplasia, atypical ductal
           hyperplasia, or lobular carcinoma in situ.

        -  Women may be either premenopausal or postmenopausal. Postmenopausal is defined by the
           absence of menstrual periods for at least 12 months.

        -  Postmenopausal women who have previously undergone a hysterectomy without oophorectomy
           must have a serum FSH level of > 40 IU/ml, and a serum estradiol level of less than40
           pg/ml to document postmenopausal status.

      Eligibility for normal volunteers will include:

        -  Women who are premenopausal or postmenopausal with a Gail model risk index less than
           1.67 percent, and without a cumulative lifetime risk greater than or equal to double the
           age- and racematched general population risk.

        -  Women who have previously undergone a hysterectomy without oophorectomy must have a
           serum FSH level of >40 IU/ml, and a serum estradiol level of less than 40 pg/ml to
           document postmenopausal status.

        -  Both breasts must be free of any suspicious areas by physical examination and, for women
           over 30 years of age by mammogram. There must be no history of atypical hyperplasia,
           invasive or in situ carcinoma.

      Both groups must have acceptable white blood cell and platelet counts.

      Design:

      Breast ductal epithelial cells will be collected by breast ductal lavage from (a) the breast
      in women at increased risk for breast cancer, and (b) the breast of female normal volunteers
      who are not at increased risk for breast cancer.

      Ductal epithelial cell specimens will be analyzed cytologically for the presence of
      hyperplasia, atypia, or in situ changes.

      Breast duct endoscopy will be performed in breast cancer patients and in normal volunteers
      with cytologic atypia on ductal lavage to determine ductal architectural changes associated
      with increased risk for breast cancer, and to provide correlation with cytologic atypia.

      The gene expression profile of normal and high-risk ductal epithelial cells will be studied
      by cDNA-microarray to determine changes in gene expression associated with increased risk for
      breast cancer.

      Additional molecular profiling experiments which will be performed as lavage cells are
      available include DNA whole exome sequencing, Comparative Genomic Hybridization (CGH),
      proteomic tissue lysate arrays, and identification of mammary stem cells.

      A total of 104 high-risk subjects and 110 normal volunteers will be studied, divided
      approximately evenly between premenopausal and postmenopausal women....
    

Detailed description: 
      Background:

      Breast cancer is the most common malignancy in women, occurring in over 230,000 women
      annually in the United States.

      The vast majority of breast cancers originate in the single layer of epithelial cells that
      line the ductal/lobular system of the breast milk ducts. The premalignant changes which occur
      in the transformed epithelium are not well understood: however, several cytologic or
      histologic changes have been identified which are associated with an increased risk for
      breast cancer, including ductal or lobular hyperplasia, hyperplasia with atypia, and lobular
      or ductal carcinoma in situ.

      The identification of cytological or histological abnormalities in breast epithelial cells is
      an important component of risk assessment.

      Objective:

      Primary objectives:

      To determine the incidence and nature of cytologic changes in ductal epithelial cells from
      the high-risk breast, in specimens collected by breast ductal lavage, and to determine if
      these cytologic findings are different from those of female normal volunteers not at
      increased risk for breast cancer.

      To characterize by breast duct endoscopy high-risk breast ductal epithelium and architecture,
      and correlate these findings with the cytologic findings referenced in above bullet.

      To determine what is the global gene expression pattern of high-risk breast epithelial cells
      from the high-risk breast, and does this differ from that of breast epithelial cells from
      female normal volunteers not at increased risk for breast cancer. The gene expression profile
      will be determined by cDNA microarray and validated by RT-PCR.

      Eligibility:

      Eligibility for high-risk individuals will include:

      Women with a unilateral invasive or noninvasive (DCIS) breast cancer of epithelial origin.

      Women without breast cancer, but with a Gail Index > 1.67 percent, or a cumulative lifetime
      risk greater than or equal to double the age- and race-matched general population risk.

      Women known to be BRCA1/2 or other hereditary genes mutation carriers.

      Women with cytologic or histologic evidence of ductal hyperplasia, atypical ductal
      hyperplasia, or lobular carcinoma in situ.

      Women may be either premenopausal or postmenopausal. Postmenopausal is defined by the absence
      of menstrual periods for at least 12 months.

      Postmenopausal women who have previously undergone a hysterectomy without oophorectomy must
      have a serum FSH level of > 40 IU/mL, and a serum estradiol level of < 40 pg/mL to document
      postmenopausal status.

      Eligibility for normal volunteers will include:

      Women who are premenopausal or postmenopausal with a Gail model risk index < 1.67 percent,
      and without a cumulative lifetime risk greater than or equal to double the age- and
      race-matched general population risk.

      Women who have previously undergone a hysterectomy without oophorectomy must have a serum FSH
      level of > 40 IU/mL, and a serum estradiol level of < 40 pg/mL to document postmenopausal
      status.

      Both breasts must be free of any suspicious areas by physical examination and, for women over
      30 years of age, by mammogram. There must be no history of atypical hyperplasia, invasive, or
      in situ carcinoma.

      Both groups must have acceptable white blood cell and platelet counts.

      Design:

      Breast ductal epithelial cells will be collected by breast ductal lavage from (a) the breast
      in women at increased risk for breast cancer, and (b) the breast of female normal volunteers
      who are not at increased risk for breast cancer.

      Ductal epithelial cell specimens will be analyzed cytologically for the presence of
      hyperplasia, atypia, or in situ changes.

      Breast duct endoscopy will be performed in breast cancer patients and in normal volunteers
      with cytologic atypia on ductal lavage to determine ductal architectural changes associated
      with increased risk for breast cancer, and to provide correlation with cytologic atypia.

      The gene expression profile of normal and high-risk ductal epithelial cells will be studied
      by cDNA microarray to determine changes in gene expression associated with increased risk for
      breast cancer.

      Additional molecular profiling experiments which will be performed as lavage cells are
      available include DNA whole exome sequencing, comparative genomic hybridization (CGH),
      proteomic tissue lysate arrays, and identification of mammary stem cells.

      A total of 104 high-risk subjects and 110 normal volunteers will be studied, divided
      approximately evenly between premenopausal and postmenopausal women.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pre- or postmenopausal women who have or have previously had invasive or noninvasive breast
        cancer of epithelial origin, or women without breast cancer but at an increased risk of
        breast cancer. Pre- or postmenopausal women who are not at an increased risk for breast
        cancer.
      
Keywords: Breast Cancer; Natural History