Biomarkers for risk assessment and prevention of breast cancer.

Breast carcinogenesis is a multistep and multipath disease process which occurs in the epithelium lining of the ductal system in the vast majority of cases. Several studies have shown that the relative risk of breast cancer is increased in every step of this progression and many tumour associated antigens or biomarkers appear during each phase of carcinogenesis. However, their ability to predict for a substantial likelihood of developing breast cancer remains unclear. The acquisition of breast tissue samples, representative of an individual's cellular stability and subcellular biochemical and molecular state could lead to definition of surrogates for risk, early detection, pharmacodynamic determination and finally chemopreventive intervention. The intraductal approach includes nipple aspiration fluid (NAF), ductal lavage (DL) and mammary ductoscopy (MD). These techniques together with random periareolar fine needle aspiration (RPFNA) represent the available techniques for the sampling of breast fluid and exfoliated epithelial cells. At the moment, these procedures are not considered a screening procedure for early breast cancer detection but might provide a powerful research tool for studying breast carcinogenesis in vivo. We summarize the current knowledge regarding the vast array of molecules involved at all stages of carcinogenesis, which can be studied by intraductal approach, and the possibility to utilize them as candidate biomarkers to refine risk assessment, and their possible use in prevention strategies.

Mammary ductoscopy: current issues and perspectives.

Until recently, the mammary duct had not been directly observed in vivo. Starting with the success of Teboul et al., studies of mammary ductoscopy (MD) for nipple discharge have been performed in Japan and other East Asian countries. Ductal lavage screening trials for breast cancer started in the 2000s. Concurrently, the number of English-language articles about MD increased. Sixty-nine English-language and 74 Japanese-language papers published in the last 19 years were reviewed. Important reports and studies were analyzed. MD has undergone significant technological development, and studies of MD have taken place in many countries. As a result, endoscopic images of the mammary duct have developed, and the endoscopic diagnosis for nipple discharge has become possible. MD-guided biopsy and surgery have been studied. Findings of MD are useful for diagnosing intraductal lesions with nipple discharge. As a result, MD has reduced the number and extent of microdochectomies. MD is also helpful in guiding breast-conserving surgery. Many pioneers have tried direct biopsy or interventions under MD, but further developments are necessary for its practical use.

[Mammary ductoscopy--diagnostic opportunites for the assessment of women with pathologic nipple discharge].

UNLABELLED: The aim of this study to analyse the diagnostic possibilities of mammary ductoscopy in the patients with pathologic nipple discharge. MATERIAL AND METHODS: The target of this prospective study are 29 patients who have been through ductal lavage and mammer ductoscopy. We used local anastetic to induct the lacrimal dilatators (dimeter from 0.35 to 1.00 mm from which we infuse and aspirate from 5 to 18 ml 1% Lidocain and 0.9% NaCl) through the openiting of the secreting cannal. After the ductal lavage follows ductoscopy with mammary ductoscope of Karl-Starz endoscope with outside diameter of 0.89 mm. RESULTS: The ductoscopy in which we visualized the ductal lumen was successful released on 23 of patients. A good correlasy was established between the macroscopic finding ductoscopy, the cytology study of ductal secret and the postoperative hystologic diagnosis. CONCLUSIONS: The mammar ductoscopy gives an important information which leads to target to approach for the assessment and treatment of women with pathologic nipple discharge.

The reliability of nipple aspirate and ductal lavage in women at increased risk for breast cancer--a potential tool for breast cancer risk assessment and biomarker evaluation.

PURPOSE: Ductal lavage, a technique used to sample epithelial cells from breast ducts, has potential use in risk assessment and biomarker evaluation among women at increased risk for breast cancer. However, little is known about the reliability of the procedure. METHODS: We evaluated the reliability of nipple aspirate (NAF) and ductal lavage at two time points 6 months apart in women at increased risk for breast cancer. Eligible women had a 5-year Gail risk >or=1.66% or lifetime risk of >20%, and/or a family history or personal history of breast cancer. All ducts that produced NAF were cannulated. The kappa statistic was used to evaluate reliability of NAF production, cellular yield, and cytologic diagnosis. RESULTS: Sixty-nine women (mean age, 47 years) were enrolled over 35 months. Forty-seven returned for a second visit. At baseline, 65% of premenopausal and 41% of postmenopausal women produced NAF (P = 0.05), of which 72% underwent successful lavage of at least one duct. Samples of inadequate cellular material for diagnosis were significantly more likely in postmenopausal women than in premenopausal women (P = 0.04). Of the women who returned for a second visit, 18 of 24 who produced NAF had at least one duct successfully cannulated. Twenty-four ducts in 14 women were lavaged twice. Among these ducts, cellular yield for the two time points was inconsistent (kappa = 0.33 +/- 0.13), and only fair cytologic agreement was observed (kappa = 0.32 +/- 0.15). Ductal lavage was associated with moderate discomfort. CONCLUSION: Currently, the use of ductal lavage is limited by technical challenges in duct cannulation, inconsistent NAF production, a high rate of inadequate cellular material for diagnosis, fair cytologic reproducibility, and low participant return rates.

C-reactive protein in nipple aspirate fluid: relation to women's health factors.

BACKGROUND: Proteins expressed in nipple aspirate fluid (NAF) have been associated with breast cancer risk and may serve to detect inflammatory or premalignant states. Obesity, hyperlipidemia, and metabolic syndrome are associated with increased rates of breast cancer and are systemic markers of chronic inflammation. OBJECTIVE: The aim of this study was to determine if one NAF protein, C-reactive protein (CRP), associated elsewhere in the human with cancer, relates to reproductive, nutrition, and body composition and activity factors. METHODS: Women (n = 59) aged 30 to 64 years from the midwestern United States and Kenya were evaluated regarding the relation between reproductive (age, pregnancy, and breast-feeding indices), nutrition (serum lipids, serum, or NAF carotenoid), body composition and activity (activity, waist-hip ratio, fat percentage (% fat), and body mass index [BMI]) factors and CRP in NAF. RESULTS: Age at first pregnancy (p < .05), gravidity (p < .05), wean time from breast-feeding last baby (p < .05), serum triglycerides (p = .01), % fat (p < .05), and BMI (p < .05) were related significantly to CRP levels in NAF. A model derived from selective women's reproductive, nutritional, and body composition and activity factors significantly (p < .05) accounted for the variance in breast microenvironment inflammation as measured by CRP in NAFs. DISCUSSION: Detecting CRP in NAF may indicate local mammary inflammation, which has been associated with carcinogenesis. Specific NAF risk modeling that addresses reproductive, nutritional, and body composition and activity factors may be used for further advances in the prevention of breast cancer and the early detection and treatment of the disease.

Analysis of nipple aspirate fluid for diagnosis of breast cancer: an alternative to invasive biopsy.

Over 40,000 women in the USA will die this year of breast cancer. Current generally accepted techniques to detect breast cancer are limited to breast examination and mammography. Abnormalities found by these techniques require an invasive needle or surgical biopsy to determine if cancer is present. The author's ultimate goal is to determine if a woman has breast cancer without the need for invasive biopsies, and do this before the abnormality is detectable by standard screening techniques. Herein, the technology is reviewed as it was, as it is today, and its future potential is discussed.

Nipple aspirate fluid cytology and the Gail model for breast cancer risk assessment in a screening population.

BACKGROUND: Recent guidelines suggest that chemoprevention with tamoxifen may be appropriate for women who have a 5-year risk of breast cancer greater than 1.66% calculated using the Gail model. OBJECTIVES: To determine whether nipple aspirate fluid (NAF) cytology combined with the Gail model provides breast cancer risk assessment that is superior to either method alone. METHODS: Prospective observational cohort of 6,904 asymptomatic women. Breast cancer cases were identified through follow-up with the women and linkage to cancer registries. We used proportional hazards modeling to recalculate the coefficients for the predictor variables used in the Gail model. NAF cytology was added to create a second model. The two models were compared using the concordance statistic (c-statistic). RESULTS: During 14.6 years of follow-up, 400 women were diagnosed with breast cancer. There were 940 (14%) women with hyperplasia and 109 (1.6%) women with atypical hyperplasia found in NAF. Adding NAF cytology results to the Gail model significantly improved the model fit (P < 0.0001). The c-statistic for the Gail model was 0.62, indicating only modest discriminatory accuracy. Adding NAF cytology to the model increased the c-statistic to 0.64. NAF cytology results had the largest effect on discriminatory accuracy among women in the upper third of Gail model risk. The relative incidence for the highest quintile of risk score compared with the lowest quintile was 7.2 for the Gail model and 8.0 for the model including NAF cytology. CONCLUSION: NAF cytology has the potential to improve prediction models of breast cancer incidence, particularly for high-risk women.

Atypia in the assessment of breast cancer risk: implications for management.

Proliferative disease accounts for as much as one-third of all biopsies for benign disease and 5-10% of proliferative lesions show atypia ductal or lobular hyperplasia. Nearly 40% of women with a family history of breast cancer and atypical hyperplasia subsequently develop breast cancer. A quantitative model developed by Gail and colleagues estimates the probability of developing breast cancer over time. Risk factors in the model include current age, ages at menarche and first live birth, number of previous biopsies, the presence of cellular atypia, and the number of first-degree relatives with breast cancer. Atypical hyperplasia approximately doubles the risk of developing invasive breast cancer within any quantitative risk profile. Ductal lavage provides a minimally invasive method of collecting breast epithelial cells. The procedure opens the possibility of repeatable tracking of breast cytology over time, but its role as a risk assessment tool remains to be fully defined.

The role of mammary ductoscopy in the assessment of breast disease.

Mammary ductoscopy (MD) allows direct visualization of the mammary ducts using sub-millimetre fiberoptic microendoscopes inserted through the ductal opening onto the nipple surface. MD is a useful diagnostic adjunct in patients with pathological nipple discharge (PND). Furthermore it can reduce the number and extent of duct excision operations for PND. However its potential use in the early detection of breast cancer, guiding breast conserving surgery (BCS) for cancer, therapeutic ablation of intraductal disease, and guiding risk-reducing strategies among high risk women requires further research and evaluation. Future developments include the development of a biopsy kit, combining MD with molecular diagnostic markers and real-time optical biopsy system for the diagnosis of premalignant and early malignant disease and radiofrequency for curative ablation of intraductal lesions.

Papillary secretion. Diagnostic assessment and treatment.

Papillary secretion is a common symptom in the breast clinic with many different underlying causes like intraductal papilloma, mammary duct ectasia, infected cysts and abscesses, breast cancer/carcinoma in situ (CIS) and rarely pituitary adenoma. The association with cancer/CIS is one of the two main concerns of the patient and must always be ruled out. The second item is that spontaneous and ongoing discharge causes embarrassment due to staining the clothes. Physical examination of the breast, imaging with mammography and ultrasonography should always be done and fine needle biopsy/core biopsy used with wide indications whenever there is any abnormal finding. With the use of modern ultrasonography in the combination with guided biopsy the use for ductography has diminished and might be saved for single duct investigations, especially if papilloma or single duct involvement is suspected. Surgery (when undertaken) due to benign discharge, should aim for radical excision of the underlying cause of the discharge sometimes only a dilated single duct with or without a papilloma or excision of the central ducts as in case of mammary duct ectasia. Discharge should be consistent, spontaneous and disturbing otherwise surgery should not be recommended in the absence of a suspicion of malignancy (negative triple test).

Ductal lavage for breast cancer risk assessment.

BACKGROUND: Effective chemoprevention is available for breast cancer, but it is associated with the potential for life-threatening adverse events. Accurate identification of women facing increased risk of breast cancer is therefore essential. Atypical hyperplasia is a histopathologic pattern that has been consistently associated with an elevated future risk of breast cancer. METHODS: The literature was reviewed to assess the strength of the association between atypical hyperplasia and breast cancer. The rationale for developing a nonsurgical modality to document the presence of atypia is discussed. RESULTS: Ductal lavage identifies atypical hyperplasia by retrieving epithelial cells shed into the ductal system with a specially designed catheter. Women with clinical evidence of increased breast cancer risk may consider ductal lavage as a means of determining whether abnormal proliferative activity is occurring in their breasts at a given point in time from ducts yielding fluid. CONCLUSIONS: Ductal lavage is a minimally invasive procedure that facilitates the detection of atypia via retrieval of breast ductal fluid that can be evaluated cytologically. It can facilitate the selection of women who may benefit from breast cancer risk reduction intervention.

Assessment of breast problems.

Patients with discrete breast lumps, irrespective of age, should be referred for assessment. Premenopausal women with equivocal lumps can be re-checked two weeks later and, if still present or dubious, sent to a breast clinic. Almost all women with breast pain do not need referral unless the symptoms are severe or prolonged. Careful examination will detect those individuals with underlying rib cage pain who can be reassured and given analgesics, if necessary, but not referred. Blood-containing nipple discharge is an indication for referral but such cases can be reassured that, in the absence of a lump, it is unlikely they have breast cancer. Most women who suspect their family history of breast cancer places them at increased risk can be safely reassured and do not need to be kept under surveillance. All those women who are eligible for the NHS screening programme should be encouraged to attend when invited.