Is There a Future for Ductal Lavage? 55Commentary on Arun Et Al., P

Editorial

Is There a Future for Ductal Lavage? 55Commentary on Arun et al., p. 4943

CarolJ. Fabian

Non–lesion-directed minimally invasive breast tissue sam- undergo ductal lavage at intervals and are then followed for the pling is currently used in the research setting both for risk development of breast cancer. stratification and for acquisition of material for response A study by Khan et al. (9)markedly diminished hope that biomarkers in phase II chemoprevention trials. Prospective ductal lavage might be used as a reliable early detection tool data linking morphology to eventual development of cancer because the sensitivity of lavage in breasts known to have are currently available only for nipple aspirate fluid harvest cancer was only 13% to 42%, depending on whether mild or (NAF)and random periareolar fine needle aspiration (RPFNA). severe atypia was used as the indicator lesion. This seeming The finding of atypia with either of these two techniques paradox may be explained by the fact that not all cancers are increases relative risk to a level at least as great as that which associated with fluid production, nor do they all originate in would be expected with atypical hyperplasia in a diagnostic ducts that empty into the lactiferous sinus (13). biopsy (1, 2). Both techniques improve risk predictions based In this issue, Arun et al. (14)report that the efficiency of on the widely used Gail model. NAF has been shown to ductal lavage in producing evaluable benign epithelial speci- improve discriminatory accuracy for average risk (3), and mens for chemoprevention trials in high-risk women is RPFNA improves discriminatory accuracy for high-risk (4) dramatically less than for RPFNA. For their report, they com- cohorts. The main drawback for NAF is that f15% to 50% of bined the results of two pilot chemoprevention trials in which women do not produce it and, even if produced, NAF generally both ductal lavage and RPFNA were done as baseline tissue contains few epithelial cells (1, 5). Although RPFNA produces eligibility screening procedures in 86 women with a median age an evaluable cytomorphology specimen in more than 90% of of 53 years. Their results in this largely postmenopausal cohort high-risk women (2), if severe atypia is encountered, the for whom both ductal lavage and RPFNA were attempted location of the abnormality is uncertain. It was hoped that indicate that ductal lavage produces sufficient cells for ductal lavage would overcome the drawbacks of both the NAF cytomorphology analysis in 31% of women compared with and RPFNA procedures. Ductal lavage might provide more cells 96% for RPFNA (14). The proportion with evaluable cytomor- and evaluable cytomorphology more frequently than NAF. The phology is lower than that reported by others for a mix of ability to identify and recannulate specific ducts would premenopausal and postmenopausal women (7, 9, 10, 15)but theoretically give ductal lavage an advantage over RPFNA by is within range of what others report for postmenopausal reducing sampling variance in prevention trials as well as women (11). The proportion of samples containing hyper- providing a means of identifying the site of very abnormal cells plastic cells was f15% for ductal lavage and f38% for RPFNA, if and when they are encountered. despite the fact that evaluable samples were obtained from At first, the future seemed bright for ductal lavage. Dooley three times as many women with RPFNA as ductal lavage. et al. (5)in a multicenter study reported that 60% of high-risk As has previously been reported, atypical cells may be observed women presenting for breast tissue–based risk assessment were in RPFNA samples in women with no NAF or an acellular lavage able to produce NAF, successfully underwent duct cannulation, specimen (16, 17). Cytologic atypia has also been reported in and had evaluable epithelial cells in their ductal lavage ductal lavage specimens obtained from non–fluid-producing specimen. Further, the median number of cells from evaluable ducts (9, 10). specimens was increased from 120 with NAF to 4,000 to Merely having evaluable cytomorphology is generally not 13,500 with ductal lavage (5). Other investigators reported sufficient for entry onto a phase II clinical trial. Generally, there similar results (6, 7). Investigators highly skilled in this must be some evidence of hyperplasia +/- atypia and technique have reported that even non–NAF-producing ducts proliferation (18). Given the data from Arun’s study, if could be cannulated, and epithelial cells harvested (8–10); hyperplastic morphology were required for entry into a however, a lavage is more likely to yield adequate cells if prevention trial, the number of women screened for one tissue women undergoing this procedure produce NAF and are eligible subject would be f3:1 for RPFNA but 20:1 for ductal premenopausal (11, 12). Based on these preliminary studies, lavage. This type of screening success rate for ductal lavage is an industry-sponsored trial was initiated in which women 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 Author’s Affiliation: University of Kansas Medical Center, Kansas City, Kansas study by Johnson-Maddux et al. indicated that sampling and/or Received 5/2/07; accepted 5/11/07. interpretive variance with ductal lavage specimens is not trivial. Requests for reprints: Carol J. Fabian, Division of Clinical Oncology, Breast Only 48% of women producing atypical ductal lavage samples Cancer Prevention Center, Kansas Masonic Cancer Research Chair, University of on the first attempt were found to have atypical samples on a Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7418. Phone: 913-588-7791; Fax: 913-588-3679; E-mail: [email protected]. subsequent attempt (15). Thus, the combination of sampling F 2007 American Association for Cancer Research. and interpretive variance with lavage is unlikely to be less than doi:10.1158/1078-0432.CCR-07-1056 for RPFNA (18, 19).

Ozanne and Esserman (20)have suggested that both ductal have recently reported that quantitative multiplexed methyla- lavage and RPFNA are cost-effective means to motivate women tion-specific PCR, used to detect tumor suppressor gene at increased Gail model risk to take tamoxifen as primary silencing when applied to ductal lavage samples, doubles the prevention therapy. However, it is probably prudent to still sensitivity for cancer identification compared with cytomor- consider RPFNA and ductal lavage as procedures to be used in phology alone. Even in the research setting, however, it is the clinical research setting (20). There is great interest in using currently unclear whether ductal lavage will ultimately find a molecular markers in NAF, ductal lavage, and RPFNA in niche in risk stratification and phase II chemoprevention trials, addition to cytomorphology for risk prediction and detection given that RPFNA is both less expensive than ductal lavage of subclinical cancer (21, 22). As an example, Fackler et al. (23) (20)and more likely to produce an evaluable specimen.

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Carol J. Fabian

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