Nipple fluid production and atypical breast duct cells in women at high risk of breast cancer have been associated with further increased risk. Most publications on ductal lavage for cell collection report cannulating fluid-yielding ducts only. We report lavage of fluid-yielding and non-fluid-yielding ducts in women at high inherited breast cancer risk.
A pilot breast cancer screening study including ductal lavage was conducted in 75 women at high inherited risk, 56 (74.7%) of whom had BRCA1/2 mutations. Ductal lavage was attempted in any duct identifiable with a catheter.
Ducts were successfully catheterized in 60 of 75 patients (80%). Successfully catheterized patients were younger (median age 41 versus 53 years, P = 0.0003) and more often premenopausal (51.7% versus 20%, P = 0.041). Thirty-one successfully catheterized patients [51.6%, 95% confidence interval (39.4-63.9%)] had non-fluid-yielding ducts only. Seventeen patients [28.3% (18.5-40.9%)] had atypical cells. Twelve of seventeen [70.6% (46.8-87.2%)] samples with atypia were from non-fluid-yielding ducts. Patients with non-fluid-yielding ducts (versus fluid-yielding ducts) were more likely to have had prior cancer (48.4% versus 17.2%, P = 0.014) or chemotherapy (45.2% versus 17.2%, P = 0.027); this was also true in patients with atypia from non-fluid-yielding ducts.
Successfully lavaged women were younger and more often premenopausal. Atypical cells can be found in non-fluid-yielding ducts in patients at high inherited breast cancer risk. Non-fluid-yielding ducts, and atypia from non-fluid-yielding ducts, are more common in patients with prior cancer and chemotherapy. Larger studies are needed to identify risk factors and prognostic significance associated with atypia and non-fluid-yielding ducts in high-risk populations, and define their role as biomarkers.
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"However, not all women produce NAF and in our experience only about 40% of BRCA mutation carriers are fluid yielders (Locke I, unpublished data). This figure is similar to that reported in a previous study of NA and DL in BRCA mutation carriers and may reflect the increasing use of risk reduction strategies, such as bilateral prophylactic oophorectomy and chemopreventative agents, which are associated with a reduced rate of NAF production and consequently limit the utility of methylation profiling of NAF in this group as a risk assessment tool [27,34]. DL has the advantage of providing a more cellular yield than NAF; furthermore DL is often possible in non-NAF producers, potentially making it a more clinically useful source of DNA for methylation studies. "
[Show abstract][Hide abstract]ABSTRACT: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk.
The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-beta, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid.
Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls (p = 0.13).
We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers.
Full-text · Article · Feb 2007 · Breast cancer research: BCR
"Because a diagnosis of atypia through a variety of modalities has consistently been associated with elevated risk for breast cancer development, it is being widely evaluated as a risk marker in studies that sample breast tissue. The ductal lavage technique has consistently revealed atypical hyperplasia in at least a third of the specimens collected from all populations of women, including breast cancer patients [24,25,39], asymptomatic high-risk women [31,33,34], and healthy volunteers recruited from the general population (unpublished data). Due to these findings, the cytological evaluation of ductal lavage specimens has been heralded as a potential risk assessment tool. "
[Show abstract][Hide abstract]ABSTRACT: Opportunities for the detection, prediction, and treatment of breast cancer exist at three biological levels: systemically via the blood, at the whole organ level, and within the individual ductal lobular structures of the breast. This review covers the evaluation of approaches targeted to the ductal lobular units, where breast cancer begins. Studies to date suggest the presence of 5 to 12 independent ductal lobular systems per breast, each harboring complex cellular fluids contributed by local and systemic processes. New techniques for accessing and interrogating these systems offer the potential to gauge the microenvironment of the breast and distill biological risk profiles.
Full-text · Article · Feb 2006 · Breast cancer research: BCR
"However, the large numbers of women who have undergone risk-reducing BSO in our study may have reduced the overall breast cancer risk in our cohort. The majority of samples with atypia in our study (90%) were from FY ducts, in contrast to 29% reported by Kurian et al. . It is difficult to postulate a biological explanation for this discrepancy but it is possible that it is due to a combination of the small numbers of samples with atypia in each study, in addition to the known difficulties in cytological interpretation. "
[Show abstract][Hide abstract]ABSTRACT: CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer.
Full-text · Article · Nov 2005 · Breast cancer research: BCR