Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review

Abstract

Background:

Guideline panels recognize the need to increase the accuracy of identifying women at high risk of developing breast cancer who would benefit from prevention strategies. The characterization of proliferative epithelial disease found in nipple aspirate fluid (PED-NAF) may be a relevant risk factor.

Objective:

To comprehensively review the published literature to characterize and summarize abnormal cytology detected by NAF and the association of PED-NAF with subsequent risk of developing breast cancer.

Research design and methods:

Literature identified by systematic searches in MEDLINE PubMed and the Cochrane Library was screened for articles containing primary data on NAF cytology based on predefined inclusion and exclusion criteria.

Main outcome measures:

Study characteristics, cytological group distribution, and incidence of breast cancer.

Results:

Thirty articles were included after full-text review, of which 16 were analyzed, containing data on 20,808 unique aspirations from over 17,378 subjects. Seven (44%) of the studies used the King cytological classification system. Among aspirations from women free of breast cancer, 51.5% contained fluid, in which over 27.7% had PED on cytology. In the two prospective studies of 7850 cancer-free women, abnormal cytology by NAF carried a 2.1-fold higher risk (95% CI, 1.6–2.6; p < 0.001) of developing breast cancer, compared with women from whom no fluid could be obtained.

Conclusions:

PED-NAF among women free of breast cancer, compared with no fluid being obtained, has an independent risk of developing breast cancer comparable to the risk of a woman with a positive family history of breast cancer. These findings have implications for augmenting risk prediction and clinical decisions concerning breast cancer surveillance and chemoprevention. As with all reviews, heterogeneity across studies may have influenced the results. The limited literature calls for prospective studies on asymptomatic women with long-term follow-up.

Keywords: :

• Atypical ductal hyperplasia
• Breast cancer
• Cytopathology
• Early detection
• Nipple aspirate fluid
• Proliferative epithelial disease

Transparency

Declaration of funding

The study is supported by Atossa Genetics. Publication of the study results was not contingent on sponsor’s approval or censorship of the manuscript; analysis and its reporting was directed without influence from the sponsors. Author contributions – J.H.: design, data analysis and interpretation, writing of manuscript; S.-C.C.: design, data interpretation, review of manuscript; Q.L.: design, literature search and data extraction, data analysis and interpretation, writing of manuscript; P.K.: data interpretation, review of manuscript; S.C.Q.: design, data interpretation, review of manuscript.

Declaration of financial/other relationships

S.C.Q. and S.-C.C. have disclosed that they are affiliated with Atossa Genetics. J.H., Q.L., and P.K. have disclosed that they are employees of Cedar Associates LLC, which received funding to be the research coordinating center for this study. The primary research was solely the responsibility of the authors that are not affiliated with Atossa Genetics Inc.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Dr. Susan Love and Dr. Margaret Wrensch reviewed the manuscript and provided feedback. Patricia Choy contributed to literature screening and data extraction. Cole Johnson and Kevin Cheung helped with data extraction. The project was supported by Atossa Genetics Inc.