Ductal Lavage: What We Know and What We Don’t

The success of the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial P-01 at showing that we now have an effective means to prevent breast cancer poses larger and more serious questions: Who should receive chemoprevention, and at what point in life should this occur? The design of the P-01 study allowed many women to enroll who, according to Gail model calculations, were at a less than 1% per year risk of subsequent breast cancer during the expected 5-year treatment period. These lower-risk individuals seemed to have less benefit than those patients at much higher risk. Other similar prevention studies seem to confirm this observation. The side effects of current prevention drugs are significant enough that many patients and their doctors still do not routinely consider chemoprevention of breast cancer as important as the prevention of heart attack and stroke by treating elevated blood pressure. In the case of hypertension, we know that there are certain levels at which the relative benefit can be seen quickly when antihypertensives are started. When we review the NSABP P-01 data, it is clear that those at highest risk-patients with a prior diagnosis of atypical hyperplasia-derive the greatest benefit from selective estrogen- receptor modulator (SERM) therapy. Need for Atypia Screening
Just as internists have a sphygmomanometer to screen for hypertension, we need a simple way to screen for atypical hyperplasia. This is where all the problems start, as neither physical exam nor mammography can routinely claim to detect atypical hyperplasias, except by chance. Even the emerging imaging technologies, such as magnetic resonance imaging (MRI) and nuclear imaging, fail to detect atypia. Only the old technologies of nipple aspiration, as shown by Wrensch and Petrakis,[1,2] and random pooled fine-needle aspiration, as shown by Fabian and Kimler,[3] have shown any ability to detect atypia. Neither has been shown to detect all atypia, but each (when atypia is found) is associated with a fivefold relative risk for malignancy development in the next 10 years. These data closely parallel the histopathologic studies of Dupont and Page,[4] which have defined our thinking on atypical hyperplasia. Current Understanding of Ductal Lavage
A new contender as a screening test for atypical hyperplasia, ductal lavage fares much better at atypia detection compared to nipple aspiration. Lavage detects only gross epithelial events that shed numerous cells intraluminally without obstructing the ducts. As soon as the ducts become obstructed, the ability to screen for abnormality rapidly fades; this can be seen in several reports of its use in invasive cancers. In her article, Dr. Lisa Newman correctly identifies the known and unknown aspects of our current knowledge about ductal lavage. The naysayers will point to the lack of 10- to 20-year follow-up data of lavaged patients and say we don't know how to interpret the results. We now have 20-year follow-up data from both histologic and cytologic studies showing the equivalence of ductal epithelial atypia in risk stratification of women for breast cancer development. If we were to ignore this wealth of data, we would need some rational explanation of why lavaged exfoliated ductal cells represent a biased and different population than those seen histologically or collected cytologically with nipple aspirate fluid or fine-needle aspiration. Ductal lavage is clearly enormously powerful for allowing repeated access to abnormal ductal cells for a variety of molecular and proteinomic investigations. Furthermore, the ability to follow patients on chemoprevention agents and detect biologic changes prior to the frank evolution of a clinical cancer is extremely important. The real burning question is not how do we use this in the laboratory to aid our understanding of the evolution and prevention of breast cancer, but how do we use this tool clinically while we are waiting for the science to catch up to clinical realities? The original lavage study shows that 24% of "high-risk" individuals shed atypical cells intraluminally, which can be identified. This subset is likely at greater risk, if we are to believe the 20 years of prior data, and very likely to show the greatest benefit from chemoprevention attempts. It seems obvious that if patients with lavaged atypia were started on SERMs, it would not take long for a large cooperative study to demonstrate effectiveness at reducing breast cancer incidence. Atypia is common in the contralateral breast of patients being treated for a current breast cancer. Hence, adding contralateral ductal lavage to some of our ongoing cooperative trials involving prevention drugs, and looking for a differential effect among women with and without ductal lavage atypia at contralateral prevention, would likely quickly confirm our inference from the prior studies. Future Directions
The greatest power of lavage, however, is only barely being investigated- the ability to identify anatomically where in the breast the premalignant/malignant changes are occurring before screening MRI, mammography, or physical exam. Imagine directing imaging to a ductal segment with intraluminal contrast. The whole world of general surgery outside of breast diseases has been revolutionized by endoscopy in the past 15 years. Now microendoscopes less than 1 mm in diameter can routinely be used to identify lesions and biopsy them when they measure less than 0.1 mm. This is a fresh challenge to our pathologists who have new specimens halfway between cytology and histology. New anatomy of the breast is being defined, along with an improved understanding of differing types of intraductal proliferation. With these novel technologies, we are destined to identify many more women with premalignant breast diseases. Conclusions
As our understanding evolves, perhaps we won't have to wait until cancer develops to start treatment. We can instead try to prevent progression and monitor our success or failure. Perhaps prevention needs to be directed at individual ductal trees, not systemically. For certain, the prevention of breast cancer needs to be almost as common as the treatment of hypertension to prevent myocardial infarction and cerebrovascular accident. We have our work cut out for us-defining who needs chemoprevention and when, which drugs to use, and how to administer them. We need to make the whole process as intuitive to the next generation of medical students as hypertension management was for us.