—  PAPANICOLAOU SOCIETY OF CYTOPATHOLOGY   —

The Role of Cellular Atypia in the Quantitative Assessment of Breast Cancer Risk:
Implications for Management


Victor Vogel
Magee Women's Hospital
Pittsburgh, PA


  1. Background: Ductal lavage enables collection of normal, atypical, suspicious and malignant cells from the breast similar to a cervical Pap smear
    1. Most breast cancer originates in the breast ducts
    2. Cytology has been performed for decades on breast ductal fluid from:
      1. Spontaneous nipple discharge
      2. Nipple aspirate fluid (NAF)
    3. Ductal lavage is a straightforward procedure that uses a microcatheter to recover hundreds to thousands of epithelial cells
    4. Cell counts are typically low (40,000-100,000)
  2. Rationale for Analyzing NAF- Yielding Ducts
    1. Fluid secretion correlates with hyperplasia (e.g. lactation)
    2. NAF yield correlates with increased breast cancer risk (1.8-fold increase in breast cancer risk, Wrensch et al. 1991, 2001)
    3. Hyperplasia correlates with increased breast cancer risk (1.9-fold increase, Dupont and Page, 1985)
    4. Hypothesis: NAF-yielding ducts = high-risk ducts
  3. Ductal Lavage: access to ductal cells
    1. Minimally invasive method of collecting epithelial cells from the mammary ductal system
    2. Cytological examination is used to determine the presence of benign, atypical, suspicious and malignant cells
    3. Opens the possibility of repeatable tracking of pre-malignant and malignant cells that may not be identifiable through mammography or physical examination
      1. Ductal lavage should currently be used only as an adjunct to standard breast cancer detection methods including mammography and physical exam
      2. Its role as a risk assessment tool remains to be fully defined
  4. Ductal lavage technique (http://www.producthealth.com/professionals)
    1. Topical anesthetic cream, eg, EMLA cream (i.e., 2.5% lidocaine and 2.5% prilocaine) is applied to the nipple with an occlusive dressing for at least 1 hour.
    2. The nipple is scrubbed with a dekeratinizing mild abrasive gel (Omni Prep Skin Prep).
    3. After at least one minute of breast self-massage, nipple aspiration is performed by placing a suction cup attached to a syringe over the nipple and applying 10-15 ml of suction. The lactiferous sinus is then manually compressed.
    4. All fluid-yielding ducts should undergo ductal lavage to determine whether atypical breast epithelial cells are present.
    5. A separate microcatheter is used to cannulate each duct to avoid cellular cross-contamination.
    6. The microcatheter is inserted 1 to 1.5 cm into the duct, past the duct sphincter, and 1-3 ml of 1% lidocaine without epinephrine is infused into the duct to provide anesthesia.
    7. Approximately 3-6 ml of sterile normal saline is infused into the duct and then the breast is compressed to facilitate recovery of ductal fluid into the collection chamber of the catheter. This sequence is repeated several times instilling about 10-15 cc of normal saline and collecting approximately 5 cc of effluent.
    8. The location of each lavaged duct is marked on a 64-square nipple grid to allow for future cannulation of the same duct.
    9. The ductal lavage effluent is placed into tubes half-filled with Cytolyt to preserve and fix the cells. Cytology specimens are collected and analyzed separately for each duct.
    10. The ductal lavage fluid is processed using the Thin Prep™ technique (Cytyc, Topsfield, MA) for cytologic interpretation.
  5. Ductal lavage may provide:
    1. Unique, useable information
    2. Opportunity for early intervention
    3. Helps determine which high-risk women may require more active management
    4. Potential repeatable testing in the same ductal system to track cells over time
  6. Examples of ductal lavage findings
  7. Clinical Trial Summary
  8. Epidemiology of ductal lavage and nipple aspirate fluid cytology
    1. Pre-malignant and malignant cells first found through ductal cell analysis in the 1950s.
    2. Ductal cells collected through nipple aspiration.
      1. Adequate for research, but low cell yields often made cytological analysis difficult
      2. Early investigators included Papanicolaou and Petrakis
  9. Cell Collection Using Nipple Aspirate Fluid Compared to Ductal Lavage
    1. Nipple aspiration, when successful, recovers microliters of fluid
    2. Only 1-50 cells in most NAF specimens (rarely >100) = poor cytology
    3. Fluid/cells collected in NAF likely represent only first 1 cm of the ducts
    4. Abnormal cells are difficult to trace back to a ductal system
  10. Ductal Lavage Compared With Nipple Aspiration
    1. Instead of 1-50 cells, thousands (and up to millions of cells) can be recovered in ductal lavage
    2. Average epithelial cell yield per duct in multi-center study = 40,000
    3. Result: improved quality of cytology
    4. Fluid/cells collected from the proximal and distal segments of the ductal system
    5. Unlike pooled NAF, cells can be traced back to a specific ductal system
  11. Relationship between atypical cells and breast cancer
    1. Atypical Cells Shown to Be Predictive of Clinical Outcomes
      1. Fabian et al; (JNCI 2000) :
      2. Breast cancer development within 3 years:
        1. 15% of subjects with 10-year Gail Index >4 with atypical cells
        2. 4% of subjects with 10-year Gail Index >4, without atypical cells
  12. Clinical epidemiology of ductal lavage (errors in clinical application analogous to statistical errors in clinical trials)
    1. Type I (α , p value) Adoption of an ineffective strategy
      1. Dietary reduction of risk of breast cancer
      2. BSE
      3. High-dose chemotherapy with stem cell rescue
      4. Taxanes for adjuvant therapy (i.e., node negative patients)
    2. Type II (β ; 1- β = power) Rejecting an effective strategy
      1. Adjuvant tamoxifen therapy in pre-menopausal women
      2. Lumpectomy as primary therapy of breast cancer
      3. Mammography in premenopausal women
  13. How do we resolve the unanswered issues with ductal lavage?
    1. Prospective clinical trials!
    2. Establish sensitivity and specificity (and the predictive value of a positive test)
    3. Weigh the risks and benefits
      1. As a risk assessment tool
      2. As a diagnostic/screening tool
    4. The clinical dilemma: what to do in the face of inadequate information?
  14. Using ductal lavage in breast cancer risk management
    1. Women who are at increased risk of breast cancer
    2. Factors used in NCI Breast Cancer Risk Prediction Model (http://bcra.nci.nih.gov/brc/)
      1. Age
      2. Number of 1st degree female relatives with a history of breast cancer
      3. Age at first live birth or nulliparity
      4. Number of breast biopsies
      5. History of atypical hyperplasia
      6. Age at menarche
      7. Race
    3. Validation of the Gail Breast Cancer Risk Prediction Model in the BCPT
  15. Risk Reduction through Drug Therapy
    1. Tamoxifen treatment reduces invasive breast cancer risk in high-risk women
      1. 1998 NSABP P-1 study: 13,388 high risk women
      2. Tamoxifen reduced risk of invasive cancer 49%
      3. Tamoxifen approved by FDA for risk reduction in high-risk women
      4. Detection of atypical cells can further stratify risk and may serve as an intermediate biomarker, especially when coupled with biologically active molecules
    2. NSABP Protocol P-2 Schema
  16. Proportion of eligible women enrolling in two chemoprevention trials by presence of atypical hyperplasia
    1. Breast Cancer Prevention Trial (BCPT, P-1) ; 23% enrolled who had no atypia; 32% with atypia enrolled; 39% relative increase in enrollment
    2. STAR trial (P-2); 21% enrolled who had no atypia; 36% with atypia enrolled; 71% relative increase in enrollment
  17. Using ductal lavage information
    1. Ductal lavage can determine the presence of benign, atypical, suspicious and malignant cells
    2. Atypical cells have value in determining risk of breast cancer
  18. Range of options to consider
    1. Close surveillance
    2. Risk reduction through drug therapy
    3. Surgical intervention
  19. Risk Assessment Working Group Risk Management Algorithms
  20. Evidence-based expert opinion (Hollingsworth et al, in press)
    1. Women who are appropriate candidates for ductal lavage include those who are at elevated risk for breast cancer based on:
    2. 5-year Gail risk score > 1.7%
    3. Two or more 2nd degree affected relatives with breast cancer. (Offering ductal lavage to these potential candidates is not yet supported by evidence-based consensus at present.)
    4. Using hormone replacement therapy for greater than 10 years
    5. History of biopsy-proven atypical ductal or lobular hyperplasia, (ADH/ALH) lobular carcinoma in situ (LCIS) and unwilling to take tamoxifen therapy without information that atypical cells remain
    6. Known BRCA 1/2 mutation or suspected BRCA 1/2 mutation if a finding of atypical cells would influence clinical management (e.g., instituting tamoxifen therapy or prophylactic mastectomy)

References

  1. Wrensch MR, Petrakis NL, Miike R, King EB, Chew K, Neuhaus J, Lee MM, Moore R. Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. J Natl Cancer Inst 2001;93:1791-1798.
  2. Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993;71A:1258-1265.
  3. Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Kamel S, Zeiger S. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst; 2000:92:1217-1227.
  4. Dooley WC, Ljung BM, Veronesi U, et al. Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 2001;93;1624-1632.
  5. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998:90:1371-1388.
  6. Vogel VG (Editor). Management of Patients at High Risk for Breast Cancer. Blackwell Science Inc. Malden, MA, 2001.
  7. O'Shaughnessy, JA. "Ductal Lavage," in Vogel VG, and Bevers T, Editors. Handbook of breast cancer risk assessment: Evidence-based guidelines for evaluation, prevention, counseling, and management. Jones and Bartlett Publishers, Sudbury, Mass., 2003.
  8. Vogel VG, Costantino JP, Wickerham DL, Cronin WM. Enrollment in the Breast Cancer Prevention Trial and the Study of Tamoxifen and Raloxifene among women with atypical hyperplasia J Natl Cancer Inst 94:1504, 2002.
  9. Vogel VG, Costantino JP, Wickerham DL, Cronin WM. Re: Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study (Enrollment in the Breast Cancer Prevention Trial and the Study of Tamoxifen and Raloxifene among women with atypical hyperplasia) J Natl Cancer Inst 94:1504, 2002.
  10. Hollingsworth, AB, Singletary SE, Morrow M, Francescatti DS, O'Shaughnessy JA, Hartman AR, Haddad B, Schnabel FR, Vogel VG. Initial Report of the Breast Cancer Risk Assessment Working Group (submitted for publication)