EDITORIAL

Breast Cancer Risk Prediction: Should Nipple Aspiration Fluid Cytology Be Incorporated Into Clinical Practice?

Carol J. Fabian, Bruce F. Kimler

Affiliations of authors: C. J. Fabian (Department of Internal Medicine), B. F. Kimler (Department of Radiation Oncology), University of Kansas Medical Center, Kansas City, KS.

Correspondence to: Carol J. Fabian, M.D., University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160–7320 (e-mail: cfabian{at}kumc.edu).

The burgeoning interest in biomarkers of short-term risk for breast cancer stems from their potential to supplement epidemiologic models in selection of individuals for risk-reduction therapy and to serve as response indicators in chemoprevention trials (1,2). The modified Gail model, which predicts short- and longer-term risk on the basis of a number of personal and family history variables, is validated, easy to use, and widely available (3,4) but has modest discriminatory value at an individual level (5). Using data from the Nurses' Health Study, Rockhill et al. (5) observed that only a small minority of women developing breast cancer within a 5-year period would have been identified as belonging to appropriate age–risk strata that would predict benefit from tamoxifen risk-reduction therapy (6). Because Gail risk estimates are heavily weighted by the number of previous biopsy examinations and affected first-degree relatives and because the majority of breast cancers develop in women who have not had a previous biopsy examination and/or affected first-degree relatives, this modest individual discriminatory value is not unexpected.

There is substantial evidence that hyperplasia and hyperplasia with atypia discovered in the course of a diagnostic procedure are substantial risk factors for breast cancer (7) and that both are highly prevalent and associated with occult in situ and invasive cancer in autopsies of women dying of other causes (8,9). In an autopsy series of 110 young and middle-aged women not known to have breast cancer at the time of their death, 82% had evidence of intraepithelial neoplasia (defined as hyperplasia with or without atypia or in situ cancer), often multicentric and bilateral, and 2% had microscopic invasive cancer (9). Atypical hyperplasia was also present in 95% of the women with in situ or invasive cancer, whereas there was only a 9% incidence of atypical hyperplasia and a 55% incidence of epithelial hyperplasia in all other women (9). Theoretically, individuals with the more diffuse and extensive intraepithelial neoplasia would be more likely to have these changes detected by random tissue sampling, would be at highest short-term risk for developing breast cancer, and thus should be good candidates for consideration of chemoprevention.

Nipple aspirate, ductal lavage, fine-needle aspiration (FNA), and core-needle biopsy either random or directed at a mammographically dense portion of the breast are all being studied as means of detecting occult intraepithelial neoplasia (1017). However, does detection of these changes imply increased risk for clinical cancer?

In this issue of the Journal, Wrensch et al. (18) provide long-term follow-up data on cancer incidence in their original cohort (group 1) of 3633 women from whom nipple aspirate fluid (NAF) was collected with a manual breast pump and the obtained cells classified as normal, hyperplastic, or atypical. Approximately two thirds of these women with a median age of 46 years at entry produced NAF and had adequate fluid and cells for analysis. The group 1 cohort as a whole appeared to be of moderate risk, with 12% having one or more first-degree relatives affected by cancer, 17% having had a previous breast biopsy examination, and 19% were nulliparous. At a median follow-up time of 21 years, 7.8% of these women had developed breast cancer. Women producing NAF exhibited a 50% greater risk than women not producing NAF, and women with hyperplasia with or without atypia had an approximately 60% greater risk than those with normal cytology. Although the 3271 women in group 2 were younger (median age = 40 years), a higher proportion had recognized risk factors, such as a previous breast biopsy examination (23% versus 17%) and nulliparity (31% versus 19%). At a median follow-up of 9 years, 3.5% had developed breast cancer. Despite the similarities in observed risk per year and the younger age, only 39% of group 2 women produced a satisfactory NAF specimen, and very few had evidence of hyperplasia with atypia. NAF producers in group 2 did not have a higher risk of breast cancer than nonproducers, unless they also showed evidence of hyperplasia; women with hyperplasia with or without atypia had a similar risk of breast cancer as did women with normal NAF cytology.

The ability to produce NAF in the adult, nonpregnant and nonlactating woman appears to be governed by many factors other than those exclusively associated with increased risk for breast cancer (19). Although observer variance in the interpretation of cytologic morphology may be a factor (20), the most likely reason that the group 2 results did not mirror those for group 1 appears to be the failure to obtain NAF and ductal cells for study in the majority of participants in group 2.

What can we then conclude from the update of this group's pioneering work? When samples are obtained from the majority of participants, both the production of NAF and the detection of hyperplasia therein appear to be associated with an increased risk of breast cancer development and/or detection in a group of women who were young to middle-aged. When NAF samples cannot be reliably obtained, the associations are less certain. Why production of NAF alone should be associated with an increased risk is unknown.

A key requirement of any risk biomarker assay is that it can be applied to the vast majority of at-risk individuals. Ductal lavage has been reported to produce material adequate for cellular analysis in 60% of high-risk women enrolled in a large NAF-ductal lavage study (12), but long-term follow-up correlating ductal lavage cytology results with breast cancer incidence is not available. Periareolar random FNA is minimally invasive and well tolerated and is associated with recovery of adequate cells for cytologic characterization in more than 90% of attempts in high-risk women with a median age of 44 years (14). We found that detection of hyperplasia with atypia in random FNA cytology specimens increased the short-term risk of breast cancer by a factor of 5 relative to those without atypia, when correcting for Gail risk (14). Random periareolar FNA has also been demonstrated to be a reliable and reproducible method for obtaining ductal cells for analysis before and after 6 months of administration of a potential chemoprevention drug in a phase II clinical trial (21). The ability to obtain adequate ductal cells for morphologic and molecular analyses will be compared between ductal lavage and random periareolar FNA in a soon-to-be initiated trial sponsored by the National Cancer Institute.

At present, evidence of hyperplasia with atypia obtained by either nipple aspiration or random periareolar FNA appears to be associated with increased short-term risk of breast cancer. However, the negative predictive value of nonproliferative cytology or attempts that do not yield a satisfactory specimen is less clearly defined. Thus, caution is advised as consideration is given to introducing these procedures into clinical practice for breast cancer risk assessment.

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