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Author's Affiliation: University of Kansas Medical Center, Kansas City, Kansas
Requests for reprints: Carol J. Fabian, Division of Clinical Oncology, Breast Cancer Prevention Center, Kansas Masonic Cancer Research Chair, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7418. Phone: 913-588-7791; Fax: 913-588-3679; E-mail: cfabian{at}kumc.edu.
Non–lesion-directed minimally invasive breast tissue sampling is currently used in the research setting both for risk stratification and for acquisition of material for response biomarkers in phase II chemoprevention trials. Prospective data linking morphology to eventual development of cancer are currently available only for nipple aspirate fluid harvest (NAF) and random periareolar fine needle aspiration (RPFNA). The finding of atypia with either of these two techniques increases relative risk to a level at least as great as that which would be expected with atypical hyperplasia in a diagnostic biopsy (1, 2). Both techniques improve risk predictions based on the widely used Gail model. NAF has been shown to improve discriminatory accuracy for average risk (3), and RPFNA improves discriminatory accuracy for high-risk (4) cohorts. The main drawback for NAF is that 
15% to 50% of women do not produce it and, even if produced, NAF generally contains few epithelial cells (1, 5). Although RPFNA produces an evaluable cytomorphology specimen in more than 90% of high-risk women (2), if severe atypia is encountered, the location of the abnormality is uncertain. It was hoped that ductal lavage would overcome the drawbacks of both the NAF and RPFNA procedures. Ductal lavage might provide more cells and evaluable cytomorphology more frequently than NAF. The ability to identify and recannulate specific ducts would theoretically give ductal lavage an advantage over RPFNA by reducing sampling variance in prevention trials as well as providing a means of identifying the site of very abnormal cells if and when they are encountered.
At first, the future seemed bright for ductal lavage. Dooley et al. (5) in a multicenter study reported that 60% of high-risk women presenting for breast tissue–based risk assessment were able to produce NAF, successfully underwent duct cannulation, and had evaluable epithelial cells in their ductal lavage specimen. Further, the median number of cells from evaluable specimens was increased from 120 with NAF to 4,000 to 13,500 with ductal lavage (5). Other investigators reported similar results (6, 7). Investigators highly skilled in this technique have reported that even non–NAF-producing ducts could be cannulated, and epithelial cells harvested (8–10); however, a lavage is more likely to yield adequate cells if women undergoing this procedure produce NAF and are premenopausal (11, 12). Based on these preliminary studies, an industry-sponsored trial was initiated in which women undergo ductal lavage at intervals and are then followed for the development of breast cancer.
A study by Khan et al. (9) markedly diminished hope that ductal lavage might be used as a reliable early detection tool because the sensitivity of lavage in breasts known to have cancer was only 13% to 42%, depending on whether mild or severe atypia was used as the indicator lesion. This seeming paradox may be explained by the fact that not all cancers are associated with fluid production, nor do they all originate in ducts that empty into the lactiferous sinus (13).
In this issue, Arun et al. (14) report that the efficiency of ductal lavage in producing evaluable benign epithelial specimens for chemoprevention trials in high-risk women is dramatically less than for RPFNA. For their report, they combined the results of two pilot chemoprevention trials in which both ductal lavage and RPFNA were done as baseline tissue eligibility screening procedures in 86 women with a median age of 53 years. Their results in this largely postmenopausal cohort for whom both ductal lavage and RPFNA were attempted indicate that ductal lavage produces sufficient cells for cytomorphology analysis in 31% of women compared with 96% for RPFNA (14). The proportion with evaluable cytomorphology is lower than that reported by others for a mix of premenopausal and postmenopausal women (7, 9, 10, 15) but is within range of what others report for postmenopausal women (11). The proportion of samples containing hyperplastic cells was 15% for ductal lavage and 38% for RPFNA, despite the fact that evaluable samples were obtained from three times as many women with RPFNA as ductal lavage. As has previously been reported, atypical cells may be observed in RPFNA samples in women with no NAF or an acellular lavage specimen (16, 17). Cytologic atypia has also been reported in ductal lavage specimens obtained from non–fluid-producing ducts (9, 10).
Merely having evaluable cytomorphology is generally not sufficient for entry onto a phase II clinical trial. Generally, there must be some evidence of hyperplasia +/– atypia and proliferation (18). Given the data from Arun's study, if hyperplastic morphology were required for entry into a prevention trial, the number of women screened for one tissue eligible subject would be 3:1 for RPFNA but 20:1 for ductal lavage. This type of screening success rate for ductal lavage is too low to consider ductal lavage as being practical for a chemoprevention trial, even if sampling and interpretive variance were found to be low with ductal lavage. A recent study by Johnson-Maddux et al. indicated that sampling and/or interpretive variance with ductal lavage specimens is not trivial. Only 48% of women producing atypical ductal lavage samples on the first attempt were found to have atypical samples on a subsequent attempt (15). Thus, the combination of sampling and interpretive variance with lavage is unlikely to be less than for RPFNA (18, 19).
Ozanne and Esserman (20) have suggested that both ductal lavage and RPFNA are cost-effective means to motivate women at increased Gail model risk to take tamoxifen as primary prevention therapy. However, it is probably prudent to still consider RPFNA and ductal lavage as procedures to be used in the clinical research setting (20). There is great interest in using molecular markers in NAF, ductal lavage, and RPFNA in addition to cytomorphology for risk prediction and detection of subclinical cancer (21, 22). As an example, Fackler et al. (23) have recently reported that quantitative multiplexed methylation-specific PCR, used to detect tumor suppressor gene silencing when applied to ductal lavage samples, doubles the sensitivity for cancer identification compared with cytomorphology alone. Even in the research setting, however, it is currently unclear whether ductal lavage will ultimately find a niche in risk stratification and phase II chemoprevention trials, given that RPFNA is both less expensive than ductal lavage (20) and more likely to produce an evaluable specimen.
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Received 5/ 2/07; accepted 5/11/07.
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-difluoromethylornithine: breast tissue, imaging, and serum and urine biomarkers. Clin Cancer Res 2002;8:3105–17.Key Article
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