Presence of Epithelial Cells in Nipple Aspirate Fluid is Associated with Subsequent Breast Cancer: a 25-Year Prospective Study

Division of Infectious Diseases, School of Public Health, University of California, Berkeley, CA 94720, USA.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 08/2006; 98(1):63-70. DOI: 10.1007/s10549-005-9132-5
Source: PubMed


Fluid and epithelial cells obtained from the breasts of non-pregnant, non-lactating women by nipple aspiration, can be used for early diagnosis of breast neoplasms. However, since nipple aspirate fluid (NAF) with cells is obtainable from less than half of women sampled, the question arises: Is this method capable of targeting the women most likely to develop breast cancer? We approached this question with a 25-year prospective study to determine if subjects yielding NAF with or without epithelial cells were more likely to develop breast cancer during the follow-up period than subjects from whom no NAF or epithelial cells were obtained. Logistic regression analysis was used to determine relative risk (RR) with 95% confidence intervals (CI). The follow-up cohort of 972 was representative of the eligible cohort of 1605 for factors related to breast cancer risk and nipple aspiration outcome, and representative of the general population for breast cancer risk. After a mean follow-up period of 25 years, women with epithelial cells in NAF were significantly more likely to develop breast cancer (RR=1.92; CI=1.22-3.01; p<or=0.005), especially invasive breast cancer (RR=2.27; CI=1.27-4.03; p<or=0.005), than women with no NAF, or NAF without epithelial cells. These risks were higher for women<55 years of age at the time of sampling (RR=2.1 for any breast cancer, 2.5 for invasive breast cancer). We conclude that presence of NAF with epithelial cells is associated with subsequent breast cancer risk and may be a useful marker for women at higher risk.

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    • "All suitable DL specimens were screened by a cytologist experienced in the evaluation of NAFs. According to the grading of specific features (cell arrangement, size, variation, nuclear characteristics, nucleoli and background findings as nonepithelial cells, microcalcifications and necrosis) the interpretation of the sample included: normal/benign (category 0), mild atypical (category I), markedly atypical (category II) or malignant (category III) disorders [9,10]. "
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    ABSTRACT: Ductal lavage (DL) involves evaluation of the ductal system of the breast for detection of intra-ductal carcinomas and precursor lesions by collecting breast epithelial cells using a small-gauge catheter inserted into a ductal orifice on the nipple. The aim of this survey was to analyze cytologic features of samples obtained from low-risk women with DL and to elucidate the efficacy of this diagnostic modality in evaluating fluid production, cannulating and determining atypical breast epithelial cells. Into this prospective study were consecutively registered 80 women between ages 28 to 67. Nipple aspiration was performed to identify all fluid-yielding ducts. According to the grading of specific features the interpretation of the sample included: normal/benign (category, 0), mild atypical (category, I), markedly atypical (category, II) or malignant (category, III) disorders. Ninety five percent (316/334) of the nipple aspirate fluid samples were classified as category 0, 4.8% (16/334) as category I and 0.2% (2/334) as category II changes. Category III disorders were not detected. Therefore, in 80% of the women examined results were within normal limits while 17.5% of the participants presented mild atypical and 2.5% markedly atypical rates. DL collection procedure proved to be rapid as well as acceptable by the women studied. It retains the advantage over other methods of nipple aspirate fluid in that it is easy to perform, thereby removing most clinician variability. It also helped low risk women to discriminate those with breast disorders that require additional investigation, further follow-up or administration of preventive medication.
    Journal of Gynecologic Oncology 04/2012; 23(2):110-4. DOI:10.3802/jgo.2012.23.2.110 · 2.49 Impact Factor
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    • "The resulting molecular signatures help reveal the biological spectrum of breast cancers, providing diagnostic tools as well as prognostic and predictive gene signatures [4], [5]. Breast cancer detection is currently based on physical examination and imaging (mammography, ultrasound, and MRI) [6], although emerging methods include direct examination of the cytomorphology of exfoliated cells [7], and the molecular analysis of tumor biomarkers in nipple aspirate fluid or in ductal lavage [8], [9], [10]. In the last decade, biomarker discoveries for breast cancer detection have focused on blood and/or tissue, using proteomic [11], [12], [13], [14], [15], [16], transcriptomic [17], [18], [19], [20], [21], and genomic approaches [22], [23]. "
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    ABSTRACT: A sensitive assay to identify biomarkers using non-invasively collected clinical specimens is ideal for breast cancer detection. While there are other studies showing disease biomarkers in saliva for breast cancer, our study tests the hypothesis that there are breast cancer discriminatory biomarkers in saliva using de novo discovery and validation approaches. This is the first study of this kind and no other study has engaged a de novo biomarker discovery approach in saliva for breast cancer detection. In this study, a case-control discovery and independent preclinical validations were conducted to evaluate the performance and translational utilities of salivary transcriptomic and proteomic biomarkers for breast cancer detection. Salivary transcriptomes and proteomes of 10 breast cancer patients and 10 matched controls were profiled using Affymetrix HG-U133-Plus-2.0 Array and two-dimensional difference gel electrophoresis (2D-DIGE), respectively. Preclinical validations were performed to evaluate the discovered biomarkers in an independent sample cohort of 30 breast cancer patients and 63 controls using RT-qPCR (transcriptomic biomarkers) and quantitative protein immunoblot (proteomic biomarkers). Transcriptomic and proteomic profiling revealed significant variations in salivary molecular biomarkers between breast cancer patients and matched controls. Eight mRNA biomarkers and one protein biomarker, which were not affected by the confounding factors, were pre-validated, yielding an accuracy of 92% (83% sensitive, 97% specific) on the preclinical validation sample set. Our findings support that transcriptomic and proteomic signatures in saliva can serve as biomarkers for the non-invasive detection of breast cancer. The salivary biomarkers possess discriminatory power for the detection of breast cancer, with high specificity and sensitivity, which paves the way for prediction model validation study followed by pivotal clinical validation.
    PLoS ONE 12/2010; 5(12):e15573. DOI:10.1371/journal.pone.0015573 · 3.23 Impact Factor
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    • "Information gained from DL might improve early breast cancer detection, facilitate breast cancer risk assessment, and yield novel reagents for developing biomarkers and intermediate end-points in chemoprevention trials [1]. Epithelial atypia in cells collected from nipple aspirate fluid (NAF) and by random peri-aereolar fine needle aspiration (RPFNA) has been associated prospectively with an increased risk of non-invasive and invasive breast cancer [2-5]. It was hypothesized that women with cellular atypia in DL samples would also be at increased breast cancer risk. "
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    ABSTRACT: Ductal lavage (DL) has been proposed as a minimally-invasive, well-tolerated tool for obtaining breast epithelial cells for cytological evaluation of breast cancer risk. We report DL tolerability in BRCA1/2 mutation-positive and -negative women from an IRB-approved research study. 165 BRCA1/2 mutation-positive, 26 mutation-negative and 3 mutation unknown women underwent mammography, breast MRI and DL. Psychological well-being and perceptions of pain were obtained before and after DL, and compared with pain experienced during other screening procedures. The average anticipated and experienced discomfort rating for DL, 47 and 48 (0-100), were significantly higher (p < 0.01) than the anticipated and experienced discomfort of mammogram (38 and 34), MRI (36 and 25) or nipple aspiration (42 and 27). Women with greater pre-existing emotional distress experienced more DL-related discomfort than they anticipated. Women reporting DL-related pain as worse than expected were nearly three times more likely to refuse subsequent DL than those reporting it as the same or better than expected. Twenty-five percent of participants refused repeat DL at first annual follow-up. DL was anticipated to be and experienced as more uncomfortable than other procedures used in breast cancer screening. Higher underlying psychological distress was associated with decreased DL tolerability.
    BMC Women's Health 07/2009; 9(1):20. DOI:10.1186/1472-6874-9-20 · 1.50 Impact Factor
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