Medicine Section - Epithelial Cell Cytology in Breast Cancer Risk Assessment and High Risk Patient Management (Ductal Lavage and Suction Collection Systems)

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

Different collection systems have been investigated as techniques to obtain nipple aspirates; the collected epithelial cells are then examined cytologically.  These techniques have been evaluated as a diagnostic and risk assessment tool in patients at high risk of breast cancer but without clinical or mammographic findings. For example, the finding of atypical hyperplasia may be associated with an increased risk of breast cancer. Malignant cells may also be identified in rare cases.

Ductal lavage involves several steps. First, fluid yielding mammary ducts are identified using nipple aspiration.  Next a microcatheter is inserted into the natural nipple opening of the individual mammary ducts, saline solution is infused, and ductal fluid withdrawn. The fluid is then analyzed microscopically for cytologic abnormalities.  The FirstCyte Breast Test (Cytyc) is a device used for ductal lavage that has been cleared for marketing by the U.S. Food and Drug Administration (FDA).

A suction collection system, the HALO NAF Collection system (Neomatrix) has also received FDA clearance as a technique to collect ductal epithelial cells.  In this system, small breast cups are placed on the woman’s breast and adjusted to fit.  The system is then engaged and automatically warms the breast and applies light suction to bring nipple aspirate fluid to the surface.  Similar to ductal lavage, the fluid is then analyzed microscopically for cytologic abnormalities.

Note: This policy addresses breast epithelial cell cytology (ductal lavage) only. For discussions of breast duct endoscopy, see Regence Medical Policy, Medicine, Policy No. 112.

Policy/Criteria

Cytologic analysis of epithelial cells from nipple aspirations as a technique to assess breast cancer risk and manage patients at high risk of breast cancer is considered investigational.  Techniques of collecting nipple aspiration fluid include but are not limited to, ductal lavage and suction.

Scientific Background

Validation of a diagnostic technology requires data regarding its technical performance, its diagnostic performance (i.e., sensitivity, specificity and positive and negative predictive value) compared to a gold standard, and finally data regarding how the diagnostic information will be used in the management of the patient and whether beneficial health outcomes result.

Technical Performance

Nipple aspiration alone can be used to collect epithelial cells for cytologic analysis; ductal lavage is designed to harvest an increased number of cells for analysis. In a multicenter clinical trial of 507 women who underwent nipple aspiration followed by ductal lavage, nipple aspiration produced an adequate sample in 27% of women, while ductal lavage produced an adequate sample in 78% of women. (2) A median of 13,500 cells per duct was collected by ductal lavage compared to a median of 120 epithelial cells per breast collected by nipple aspiration.

Diagnostic Performance

Dooley and colleagues reported on a multicenter clinical trial of 507 women who underwent ductal lavage. (2) A total of 57% of women had a prior history of breast cancer and 39% had a five-year Gail risk for breast cancer of 1.7% or more. (It should be noted that the patient selection criteria for this study are similar to those used in the large randomized trial of tamoxifen as a breast cancer chemprotective therapy). Using a Gail index of equal to or greater than 1.7%, all women over the age of 60 years would be considered at high risk. For ductal lavage, 24% of women had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (less than 1%). Ductal lavage detected abnormal cells 3.2 times more often than nipple aspiration.  However, whether or not this increased sensitivity is accompanied by decreased specificity and thus a decreased overall risk of cancer using ductal lavage is unknown.

It is difficult to identify a gold standard test to validate the diagnostic performance of ductal lavage. For example, since ductal lavage is performed in patients without mammographic abnormalities, there is no obvious target for diagnostic confirmation with a tissue sample. In cases where cells suspicious for malignancy have been reported, some patients may have undergone either surgical resection of the involved duct or a broader surgical resection. However, there have been no studies published regarding the diagnostic performance in this setting. No studies have been reported on the results of ductal lavage in patients with mammographic abnormalities who are scheduled to undergo biopsy.

No published studies were identified that focused on suction techniques to collect nipple fluid.

How the diagnostic information will be used to benefit the management of patients.

Cytologic results of nipple aspiration can be broadly subdivided into those with an insufficient sample, those with malignant cells, those with hyperplasia, including atypical hyperplasia, or those with benign cells. Currently, no published studies have specifically used the results of ductal lavage or suction techniques to direct patient management.  No published studies were identified of suction technique to collect nipple aspiration; therefore, the following discussion focuses on ductal lavage alone.

The following discussion suggests some potential applications:

• Insufficient Sample
  
  There would be presumably no impact on the management of the patient when an insufficient sample was produced. Based on the preliminary results published, this would occur in about 43% of the patients.

• Hyperplasia without Atypia

Hyperplasia is relatively common among high-risk women (31%-42%) and, to a somewhat lesser extent, among various populations of women not specifically selected to be at high risk (12%-37%). Although hyperplasia without atypia is associated with increased cancer risk in some studies, its relatively high prevalence in both high- and low-risk populations decreases its utility as a risk marker.

• Hyperplasia with Atypia
  
  The association between histologic atypical hyperplasia and an increased risk of breast cancer has been most frequently studied in the setting of patients with mammographic abnormalities. The natural history of atypical hyperplasia may be different in women without mammographic abnormalities, potentially representing a spontaneously resolving cytologic abnormality.
  
  Two studies offer related data. Wrensch and colleagues reported on a prospective study of 2,701 women at average risk of breast cancer who underwent nipple aspiration and then were followed for an average of 12 years. (3) The relative risk of cancer in women with cytologic atypia was 4.9 compared to non-yielders of nipple fluid or 2.8 compared to women with normal cytology. In women with cytologic atypia and a family history, the relative risk was 18.1 compared to non-yielders of fluid without family history. After 21 years of follow-up, the relative risks were lower, suggesting that risk decreased over time. (4)
  
  Fabian and colleagues reported on a group of 480 women without mammographic abnormalities who were considered at high risk of breast cancer and who underwent two random periareolar fine needle aspirations at six-month intervals. (5) Risk factors included a family history of breast cancer, a prior history of a precancerous lesion (i.e., hyperplasia with atypia or carcinoma in situ), or a prior history of breast cancer. In 21% of patients, results of the fine needle aspiration revealed hyperplasia with atypia. After follow-up of 45 months, the relative risk of cancer in women with cytologic atypia was 5.0 compared to women without atypical results. The two strongest predictors of cancer development were risk assessment based on the Gail model, and the presence of hyperplasia with atypia on fine needle aspiration.
  
  The relative risk results for nipple aspiration or fine needle aspiration cytology have been equated with a relative risk of 5.3 in women with histologic atypia compared to women without proliferative disease on biopsy of a lesion, reported in a retrospective study. (6) However, due to the different follow-up intervals, different baseline risk populations studied, and different referent populations, these results cannot be quantitatively compared. Thus, it is not known whether cancer risk associated with cytologic atypia is of the same magnitude as cancer risk associated with histologic atypia on biopsy of a lesion.
  
  Cytologic hyperplasia with atypia alone in low- to moderate-risk populations had poor sensitivity (4.2%) and low positive predictive value (13.8%). (4) Thus, this procedure has poor utility for general population screening to identify those at increased risk.
  
  For women already at high risk of breast cancer by Gail model analysis, the following treatment options are available: increased surveillance (i.e., increased frequency of breast self-examination or clinical exam or an increased frequency of mammography), a prophylactic mastectomy, or chemoprevention with tamoxifen or an aromatase inhibitor. Increased surveillance is recommended for all, and prophylactic mastectomies considered only by a relatively few women who have other strong risk factors (i.e., BRCA1 or BRCA2 mutation). The net benefits of tamoxifen, taking into account possible adverse events, are greatest for women of younger age with greater Gail risk, yet patients are reluctant to select chemoprevention. (7) For high risk women with no history of histologic hyperplasia with atypia of a biopsied lesion, it has been proposed that findings of cytologic atypia on ductal lavage may revise the risk estimate upward, increase the likelihood of choosing chemoprevention, and decrease cancer incidence. However, no studies have specifically explored decision making or outcomes regarding these treatment alternatives in mammographically normal women with hyperplasia with atypia by cytologic analysis.

Indirect evidence exists in the form of the National Surgical Adjuvant Breast and Bowel Project P-1 trial, which randomized 13,388 high-risk patients (i.e., Gail risk greater than 1.7%) to receive either chemoprevention with tamoxifen or placebo. (8) The principal outcomes were the subsequent incidence of in situ or invasive cancer over the next five years. This trial reported that overall tamoxifen was associated with a 49% reduction in incidence of invasive breast cancer. When hyperplasia with atypia was present, tamoxifen was associated with an 86% reduction in the incidence of subsequent breast cancer. However, in this trial, hyperplasia with atypia was presumably diagnosed in patients with mammographic abnormalities. Whether or not women with cytologic atypia by ductal lavage benefit to the same extent is unknown. It is possible that knowledge of added risk as a result of cytologic analysis may influence those at greatest risk and most likely to benefit to choose tamoxifen therapy. It is also possible that knowledge of a negative cytologic analysis result would influence patients to avoid tamoxifen when they might otherwise benefit. No evidence exists to evaluate potential net benefit or harm in decision-making or, ultimately, in patient outcomes.

The role of hyperplasia with atypia as part of the decision making for prophylactic mastectomy is based on the hypothesis that atypia precedes the development of cancer. However, any patient with a BRCA1 or BRCA2 mutation may be considered a candidate for prophylactic mastectomy. The emergence of atypia may suggest a more immediate need for prophylactic mastectomy, and thus may affect the timing of the surgery. However, this strategy has not been formally tested.

• Malignant Cells
  
  The results of the multi-institutional trial, currently summarized on the manufacturer's Web site (9) but not published in the peer-reviewed literature, report that malignant cells were identified in only two of 383 patients (0.5%). Therefore, it is unlikely that ductal lavage will be routinely used to diagnose malignancy. In the rare event of malignant cells, imaging, ductogram, or ductoscopy are possible follow-up procedures, but a negative imaging result or ductogram does not exclude significant pathology and the overall sensitivity of ductography is unknown. The value of terminal duct excision is also unknown. Prophylactic mastectomy on the basis of a malignant lavage is not encouraged. (10)

• Benign Cells
  
  Without an understanding of the sensitivity of ductal lavage, it is not possible to interpret a finding of benign cells, as this could represent a false negative result.

The above conclusions are supported by a 2002 TEC Assessment (11) that offered the following observations and conclusions:

• No studies directly compare routine surveillance vs. routine surveillance plus epithelial cell cytology analysis in the follow-up of high-risk women for the detection of long-term outcomes. No studies compared the outcomes of patients whose management was determined by the results of routine surveillance vs. routine surveillance plus epithelial cell cytology analysis. No studies have used ductal lavage, nipple aspiration, or random periareolar fine-needle aspiration to influence patient management in the population of interest.
• There is some indirect evidence from the NSABP Breast Cancer Prevention Trial (P-1), which enrolled women at high risk and randomly assigned them to placebo or tamoxifen for five years. Women with a history of hyperplasia with atypia who received tamoxifen had a risk ratio for subsequent breast cancer of 0.14, compared to those who received placebo over a median follow-up time of 54.6 months. Thus, high-risk women with a history of hyperplasia with atypia benefited to a greater degree than the study population as a whole. It was noted, however, that the number of women in this subgroup was small, and that this was only one of five subgroups examined. Women without a history of hyperplasia with atypia who received tamoxifen also benefitted with a risk ratio of 0.56. Thus, the lack of a history of hyperplasia with atypia does not preclude improved outcomes with tamoxifen treatment.
• The results of the P-1 trial cannot address whether or not participants, particularly those with a negative history, had cytologic evidence of hyperplasia or hyperplasia with atypia at the time of enrollment. It is possible that some of the women who were negative for a history of hyperplasia with atypia would have been positive at study entry by random cytology, and may have accounted for at least part of the benefit in this subgroup. Nevertheless, it cannot be ruled out that women with no detectable hyperplasia with atypia may still benefit from tamoxifen treatment.
• Considering the above, the assessment concluded that the evidence was insufficient to support the use of cytologic hyperplasia with atypia as a clinically useful intermediate biomarker outside of clinical trials at this time. The existing evidence is of high clinical interest, but further follow-up studies of risk and trials of intervention in women with this marker are needed.

An updated search of the MEDLINE database through April 2006 did not identify any articles that addressed the limitations in the literature discussed here.  Therefore, the policy statement is unchanged.  No studies were identified that focused on suction techniques to collect nipple aspirates.  The following literature focuses on ductal lavage.  Khan and colleagues published a study of 32 women who underwent ductal lavage in 44 breasts with known cancer prior to mastectomy. (12) In addition, ductal lavage was performed on eight breasts in seven women prior to prophylactic mastectomy, two of which were found to harbor occult cancer. The results of ductal lavage were compared with histologic specimens from the same lavaged ducts. The sensitivity of ductal lavage was 43% and the specificity was 96%. The authors hypothesize that the low sensitivity of the test may be related to the fact that cancer contained in ducts fail to yield fluid or have benign or mildly atypical cytology.  In a subsequent study focusing on women with microcalcifications, Kahn reported that similar to patients with larger invasive cancers, smaller cancers, such as ductal carcinoma in-situ (DCIS), often do not yield nipple fluid, leading to low sensitivity. (13) Brogi and colleagues report the results of a similarly designed study of ductal lavage in 26 women scheduled to undergo mastectomy for breast cancer. Only 48% of the lavaged specimens revealed any evidence of atypia. (14) Johnson-Maddux and colleagues studied the reproducibility of cytologic atypia in repeat nipple duct lavage in 108 patients unselected for breast cancer risk. (15) Repeat lavage was performed in those with atypia found in the first lavage sample.  Atypia was found in the second lavage sample in only 48% of cases.  The authors conclude that the reproducibility of repeat lavage is low and that atypia may be either physiologic or artifactual.

A variety of review articles and commentaries have been published which discuss potential applications of ductal lavage. (16,17)  Both of these articles cite the same studies as discussed in the TEC Assessment; however, to date, there are no controlled trials that formally investigate the proposed applications of ductal lavage.  Currently, two clinical trials are ongoing. In a multi-institutional study sponsored by Cytyc, women at increased risk for breast cancer will undergo ductal lavage of fluid producing ducts every 6 months for 3 years. The end point is association of ductal lavage cytologic results with development of breast cancer. The National Cancer Institution has sponsored a multi-institution study in which results of random periareolar fine needle aspiration with be compared with ductal lavage in high risk premenopausal women before and after 12 months of treatment with celecoxib. (18)

In 2003, the American Society of Breast Surgeons issued an "official statement" regarding ductal lavage, which reads in part (19):

"Ductal lavage is a minimally invasive method of collecting breast epithelial cells for cytologic examination. Because most breast cancer originates from the same layer of epithelial cells that line the milk ducts, it appears that atypical changes in breast epithelial cells will confer similar relative risk increases regardless of the method of collection. There is no reason to believe that the long-term risk associated with atypia diagnosed by ductal lavage will be different from other methods of determining cytologic atypia.

The American Society of Breast Surgeons supports the use of ductal lavage as a cell-based risk assessment tool in high-risk and borderline risk women to assist them in making more informed decisions regarding risk reduction and management options. This information can help to guide consideration of a variety of management options ranging from risk reduction therapy (tamoxifen or enrollment in the STAR trial) to closer surveillance or even prophylactic mastectomy. Long-term studies are necessary to better define the risk assessment contribution of cytologic atypia detected via these and other methods. The American Society of Breast Surgeons encourages participation in such trials."

The reference list for this official statement does not include any articles not considered in the above discussion or in the TEC Assessment.

An updated search of the literature based on MEDLINE, through April 2007, did not return any studies where the results of epithelial breast cell cytology are used prospectively to determine appropriate management in patients at high risk for breast cancer or breast cancer recurrence.  Therefore, conclusions cannot be made concerning whether or not epithelial cell cytology results improve health outcomes of the patient at risk for breast cancer.  For example, two new studies were identified both of which address the feasibility of using ductal lavage and ductoscopy to obtain adequate samples of breast epithelial cells for risk assessment. (20, 21) However, neither study addressed the impact on management decisions or health outcomes.

A search of the MEDLINE database through June 4, 2008 returned a number of publications that questioned the technical and diagnostic performance of ductal lavage. One study assessed the reproducibility of repeated ductal lavage in 65 high monitoring of breast epithelium. (22) Another study compared breast tissue acquisition by ductal lavage with random periareolar fine needle aspiration (immediately following lavage) in 86 women at high risk for breast cancer. (23) Sample retrieval was successful in 100% of the women by needle aspiration, and 97% had adequate samples (ten or more epithelial cells). In contrast, samples were retrieved in only 51% of subjects using ductal lavage; the sample was considered adequate in 71% of these, resulting in a total yield of 31%.  The authors concluded that fine needle aspiration is a more practical option for clinical trials. A third study performed ductal lavage on 150 women (irrespective of the calculated risk level); 67 were patients with breast cancer. (24) Adequate samples (ten cells or more) for diagnosis were obtained from 90% of women but only 67% of ducts. Out of 83 women without breast cancer, atypia was diagnosed in 34% of the 44 women with a 5-year Gail risk of <1.7% and 28% of the 39 women who had a 5-year Gail risk of 1.7% or greater.

In summary, a number of recent studies suggest poor technical and diagnostic performance of ductal lavage. This technology has not been shown to improve the net health outcome.

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No.2.01.45
2. 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(21):1624-32
3. Wrensch MR, Petrakis NL, King EB et al. Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid. Am J Epidemiol 1992;135(2):130-41
4. Wrensch MR, Petrakis NL, Miike R et al. Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. J Natl Cancer Inst 2001;93(23):1791-8
5. Fabian CJ, Kimler BF, Zalles CM et al. Short-term breast cancer prediction by random periareolar fine needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 2000;92:1217-21
6. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. NEJM 1985;312(3):146-51
7. Port ER, Montgomery LL, Heerdt AS et al. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 2001;8(7):580-5
8. Fisher B, Costantino JP, Wicerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-88
9. Cytyc Corporation FirstCyte Web site www.cytyc.com/women/women_breast_cancer_clinical_trial.shtml(Verified 6/4/08)
10. Morrow M, Vogel V, Ljung BM et al. Evaluation and management of the woman with an abnormal ductal lavage. J Am Coll Surg 2002;194(5):648-56
11. 2002 TEC Assessment; Use of Epithelial Cell Cytology in Breast Cancer Risk Assessment and High-Risk Patient Management
12. Khan SA, Wiley EL, Rodriquez N, Baird C et al. Ductal lavage findings in women with known breast cancer undergoing mastectomy. J Natl Cancer Inst 2004;96:1510-7
13. Khan SA, Wiley EL, Rodriguez N et al. Ductal lavage findings in women with mammographic microcalcifications undergoing biopsy. Ann Surg Oncol 2005;12(9):689-96
14. Brogi E, RobsonM, Panageas KS et al. Ductal lavage in patients undergoing mastectomy for mammary carcinoma: a correlative study. Cancer 2003;98:2170-76
15. Johnson-Maddux A, Ashfaq R, Cler L et al. Reproducibility of cytologic atypia in repeat nipple duct lavage. Cancer 2005;103(6):1129-36
16. O’Shaughnessy JA.  Ductal lavage: clinical utility and future promise. Surg Clin North Am 2003;83:753-69
17. Newman LA.  Ductal lavage: what we know and what we don’t. Oncology 2004;18:179-85
18. Fabian CJ, Kimler BF, Mayo MS. Ductal lavage for early detection – what doesn’t come out in the wash. J Nat Cancer Instit 2004;96:1488-89
19. The American Society of Breast Surgeons. Official Statement. Ductal lavage and cell-based risk assessment. www.breastsurgeons.org/officialstmts/officialstmt4.shtml   (Verified 6/4/08)
20. Zalles CM, Kimler BF, Simonsen M et al. Comparison of cytomorphology in specimens obtained by random periareolar fine needle aspiration and ductal lavage from women at high risk for development of breast cancer. Br Cancer Res Treat 2006;97:191-7
21. Danforth DN, Abati A, Filie A et al. Combined breast ductal lavage and ductal endoscopy for the evaluation of the high-risk breast: A feasibility study. J Surg Oncol 2006;94:555-64
22. Patil DB, Lankes HA, Nayar R et al. Reproducibility of ductal lavage cytology and cellularity over a six month interval in high risk women. Breast Cancer Res Treat 2007 Dec 21. [Epub ahead of print]
23. Arun B, Valero V, Logan C et al. Comparison of ductal lavage and random periareolar fine needle aspiration as tissue acquisition methods in early breast cancer prevention trials. Clin Cancer Res 2007; 13(16):4943-8
24. Bushnaq ZI, Ashfaq R, Leitch AM et al. Patient variables that predict atypical cytology by nipple duct lavage. Cancer 2007; 109(7):1247-54

Cross References

Breast Duct Endoscopy (Ductoscopy), Regence Medical Policy Manual, Medicine, Policy No. 112

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