What is the role of ductal lavage in assessing breast cancer risk?

OVERVIEW: Studies have concluded that women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. A recent report by Dooley et al compared ductal lavage to nipple aspiration with regard to safety, tolerability and the ability to detect abnormal breast epithelial cells. Ductal lavage was proven to be safe, well tolerated and superior to nipple aspiration in collecting large numbers of epithelial cells. Most importantly, ductal lavage detected abnormal intraductal breast cells 3.2 time more often than nipple aspiration. Detection of cellular atypia can provide high-risk patients and their physicians important information to further assess the patient’s risk and decide on risk-reduction therapies. Ductal lavage is also an important tool to be studied in ongoing clinical trials. In December, 2001, nearly 600 surgeons, many of whom had previously attended the Miami Breast Cancer Conference responded to a survey examining how women at high risk for developing breast cancer are identified and managed.

What factors determine a patient’s need for ductal lavage in your practice?

	Patients who request it	60%
	High-risk patients (by quantitative risk assessment)	53.8%
	Patients with breast cancer (contralateral breast)	39.3%

DEFINING THE ROLE OF DUCTAL LAVAGE

There are two things about the study that are important. First, most of the high-risk women did not have atypical cells. That’s important information for women who tend to overestimate their risk and it may not be as high as they believed it to be. Secondly, for the quarter of the women in whom cellular atypia was detected, we can be more confident about offering measures to reduce their risk, such as tamoxifen or surgery. Previously, determining a women’s risk was based solely on her medical history. Ductal lavage provides valuable information about the presence or absence of cellular atypia in the breast without invasive surgery.

Ductal lavage is not a replacement for mammography. It is not a breast cancer detection tool. It is a risk assessment tool that can identify women at significant risk for breast cancer. Candidates for ductal lavage include women with a history who want to monitor their risk; women who have had one breast cancer and are concerned about a second; patients who have had breast biopsies that revealed benign changes but want to see if these changes are evolving; patients who are considering tamoxifen or chemoprevention to reduce their risk; and patients who are considering genetic testing or have had genetic testing and carry an abnormal gene.

The procedure is very easy to perform. It can be done quickly in an examination room without any special preparation. Patients tolerate it very well, experience minimal discomfort and report to us that they would do it again.

—Victor G. Vogel, MD

The identification of cellular atypia by ductal lavage and the increased relative risk it confers take on further potential importance in light of the findings of the National Surgical Adjuvant Breast and Bowel Project P-1 Study...However, how to balance the benefits and risks of tamoxifen is still a matter of debate, particularly for women 50 or more years of age. Ductal lavage can provide a woman with some information about whether she has evidence of cellular changes associated with increased breast cancer risk at the time she is weighing the risks and benefits of tamoxifen therapy.

Ductal lavage also offers the potential opportunity to follow a specific ductal system over time and to identify it should surgical therapy be indicated. Indeed, in the current clinical trial, the feasibility of utilizing ductal lavage to detect and direct the surgical resection of several ductal carcinomas in situ that were occult on mammography and clinical breast examination has been demonstrated. To date, 11 subjects with abnormal ductal lavage findings have had additional imaging and breast surgery to further evaluate their cytologic findings. Four of the subjects have had a pathologically confirmed ductal carcinoma in situ located in the same region as the ductal system with the abnormal ductal lavage findings.

In summary, ductal lavage is a safe and well-tolerated method of accessing specific milk ducts to collect and detect atypical and malignant cells within the breast. Ductal lavage is statistically significantly more sensitive than nipple aspiration for the detection of cellular atypia. Detection of intraductal cellular abnormalities can provide women at elevated risk for breast cancer and their physicians additional information to aid their decision about risk-reduction therapy and ongoing surveillance.

—Dooley WC et al. J Natl Cancer Inst 2001;93(21): 1624-32.
Abstract

Ductal lavage is a safe and minimally invasive procedure that can provide a woman who is at elevated risk for developing breast carcinoma with additional information regarding that risk. In a woman with an elevated Gail risk who has no history of biopsy-proven atypical hyperplasia, a finding of cytologic atypia on ductal lavage provides risk assessment information that is independent of her Gail risk. This information can assist the woman and her physician in weighing the risks and benefits of hormone replacement therapy, antiestrogen therapy, and, in very high-risk women, prophylactic mastectomies.

Women must be counseled carefully regarding ductal lavage. Ductal lavage does not replace mammography, but it can provide additional insight into risk status. If benign cells are identified by ductal lavage, a high-risk woman remains at high risk for breast carcinoma. Long-term outcome studies will determine whether benign cytology findings on ductal lavage lower a woman’s risk of developing breast carcinoma, but this has not yet been established. Although ductal lavage has detected occult tumors in high-risk women, its sensitivity and specificity for breast cancer detection are not yet known. This fact must be weighed carefully in any decision-making process concerning surgical ductal exploration.

The management of the woman at high-risk for the development of breast carcinoma is an area of increasing clinical importance now that tamoxifen has shown to be of proven benefit, and because prophylactic mastectomy clearly decreases breast carcinoma risk in BRCA 1/2 mutation carriers. Ductal lavage offers additional information regarding risk to both women and their physicians as they ponder the complex decisions regarding hormone replacement therapy and antiestrogen risk-reduction therapy. Ongoing and future clinical studies will provide more information regarding the positive and negative predictive values of ductal lavage for breast carcinoma detection; and the reproducibility, reliability, and clinical utility of ductal lavage for tracking the progression and regression of intraepithelial neoplasia with and without the use of antiestrogen therapy.

—O’Shaughnessy JA et al. Cancer. 2002 Jan
15:94(2):292-298.

Nipple aspirate cytology has several potential uses in research on breast cancer detection and pre vention. For example results from our studies of the two groups of women clearly demonstrate that nipple aspirate cytology is an independent and relatively strong predictor of breast cancer risk, especially among women who have had a previous breast biopsy for benign breast disease. Studies of biochemical and molecular markers in breast duct fluids obtained by nipple aspiration may discover markers that might be more sensitive predictors of breast cancer risk than conventional cytology. More over, nipple aspirate cytology provides a more complete picture of the natural history of proliferative changes in the breasts of women in the general population who do not have apparent breast disease than breast biopsy, which is performed only in response to abnormalities found at physical examination or detected by mammography. Studies that combine the results of nipple aspiration cytology with observations of areas of high radiographic density in mammograms may further facilitate the detection of disease in women at high risk for breast cancer. Finally, nipple aspirate cytology and duct fluid analysis may find use by providing i n t e rmediate endpoints in studies of breast cancer pathogenesis and in clinical trials of new chemopreventive agents against breast cancer and benign breast disease. We strongly support the efforts of clinical investigators to find applications for this easy-to-perform , noninvasive procedure .

—Wrensch MR et al. J Natl Cancer Inst 2001;93(23): 1791-8.
Abstract

BREAST CANCER RISK IN WOMEN WITH ABNORMAL CYTOLOGY IN NIPPLE ASPIRATES OF BREAST FLUID NO PROTOCOL LINK

REMARKABLY SIMILAR INCREASES IN RELATIVE RISK CONFERRED BY CYTOLOGY AND PATHOLOGY

FNA Cytology — Fabian, et al

NAF Cytology — Wrensch, et al.

Pathology Studies — Dupont and Page — Dupont et al

Wrensch et al studied 2300 women for an average of 12.7 years to determine the relationship between atypical findings on analysis of nipple aspirate fluid (NAF) and the development of breast cancer. The results of their study showed a 4.9-fold increase for the subsequent development of breast cancer in women with the finding of cellular atypia in NAF specimens without a family history. For patients with cellular atypia and a family history of breast cancer, the relative risk was raised to 18-fold. FNA cytology studies and pathology studies have shown similar increases in relative risk.

Wrensch MR et al. J Natl Cancer Inst 2001;93(23):1791-8. Abstract
Dupont WD, Page DL. N Engl J Med 1985;312(3):146-51. Abstract
Dupont WD et al. Cancer 1993;71(4):1258-65. Abstract
Fabian C et al. J Natl Cancer Inst 2000;92:1217-27. Abstract

DUCTAL LAVAGE: THE PROCEDURE

1. Gentle suction is applied to the nipple to elicit fluid.			3. 10-20 mL of saline is slowly introduced into the milk duct in 2 – 4 mL increments to lavage the duct and collect epithelial cells.
2. Microcatheter is inserted into duct.			4.The breast is massaged to bring fluid forward.

DUCTAL LAVAGE FOR THE DETECTION OF CELLULAR ATYPIA IN WOMEN AT HIGH RISK FOR BREAST CANCER CLOSED PROTOCOL

Eligibility: High-risk women (Gail Index >=1.7, personal history of breast cancer, DCIS, LCIS or BRCA1/BRCA2 positive) with a normal mammogram and clinical breast exam within the past 12 months. Women with prior irradiation or significant surgery on the breast to be lavaged, current chemotherapy or tamoxifen/SERM therapy were ineligible.

Dooley et al compared ductal lavage to nipple aspiration with regard to safety, tolerability and the ability to detect abnormal breast epithelial cells. 507 women were enrolled and nipple aspiration and ductal lavage were attempted for NAF yielding ducts. Cytologic analysis was performed on satisfactory specimens. Dooley WC et al. J Natl Cancer Inst 2001;93(21):1624-32. Abstract

STUDY RESULTS: SPECIMEN ADEQUACY FOR DIAGNOSIS NAF 27% Ductal lavage 78%

STUDY RESULTS: ABILITY TO DETECT ABNORMAL CELLS Mildly Atypical NAF 6% Ductal lavage 17% Markedly Atypical NAF 3% Ductal lavage 6% Malignant NAF < 1% Ductal lavage < 1% Dooley WC et al. J Natl Cancer Inst. 2001;93(21):1624-32. Abstract

DUCTAL LAVAGE AND CLINICAL MANAGEMENT PATHWAY

Reproduced with permission: O’Shaughnessy et al. Cancer 2002; 94 (2)

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