Journal of Mammary Gland Biology and Neoplasia, Vol. 8, No. 1, January 2003 ( C  2003) Novel Agents for Chemoprevention, Screening Methods, and Sampling Issues Mary Jo Fackler, 1 Ella Evron, 2 Seema A. Khan, 3 and Saraswati Sukumar 1,4 An aggressive approach to breast cancer control based on preventing the disease must com- plement efforts at effective treatment. To date clinical trials testing new chemopreventative agents have not generally met with the kind of success expected. A wide range of new breast cancer chemopreventative agents are poised to be tested in clinical trials. We review these novel agents and approaches, including those for which clinical trials have been initiated and those that are promising in the preclinical arena. Further progress in this area requires not only new agents, but novel methods for screening for risk assessment, sampling and development of intermediate biomarkers. We review these novel potential surrogate endpoints, including new imaging techniques, breast sampling approaches, and methods to assess biomarkers in breast epithelium. Factors that could contribute to a meaningful choice of the chemopreventive agents and the design of clinical trials are discussed. KEY WORDS: breast cancer; ductal lavage; prevention; sampling; early detection. INTRODUCTION Emerging evidence from large, comprehensive gene expression profiling platforms performed in sev- eral laboratories at the forefront of this research is building a portrait of breast cancer that was unex- pected. Rather than a stepwise change in the expres- sion pattern of genes, occurring over time during pro- gression of the tumor, according to this new data, the signature for aggressive behavior is present even when the tumor is locally invasive (1–3). Indeed, the tumor may have metastasized long before it was ever detected (1–2). In this scenario, successful treatment of the local lesion rarely translates to disease free 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. 2 Institute of Oncology Rabin Medical Center – Belinson Campus, Petach Tikva, Israel. 3 Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 4 To whom correspondence should be addressed at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, CRB Room 410, 1650 Orleans Street, Baltimore, Maryland 21231-1000; e-mail: sukumsa@jhmi.edu. survival (2–3). We already know this to be true (1–3). Even among women diagnosed with node negative breast cancer, the recurrence rate remains at nearly 25% (4). On the basis of these findings, many promi- nent researchers in our field have stated emphatically that the time has come for an aggressive approach to cancer control based on preventing the disease, an ef- fort which must complement efforts at effective treat- ment (5–9). If breast cancer is the final result of a series of mutations acquired by an epithelial cell, it is reason- able to hypothesize that arresting cell growth and re- versing these lesions would stop a cancer cell in its Abbreviations used: ASA, acetylsalicylic acid; BCPT, breast cancer prevention trial; CNB, core needle biopsy; COX-2, cyclooxyge- nase enzyme-2; DL, ductal lavage; EGFR-TK, epidermal growth factor receptor tyrosine kinase; ER, estrogen receptor; FNA, fine needle aspiration; IEN, intraepithelial neoplasia; NAF, nip- ple aspiration fluid; NSAIDs, nonsteroidal anti-inflammatory drugs; QM-MSP, quantitative multiplex methylation-specific PCR; RAR, retinoic acid receptor; rFNA, random fine needle aspiration; RXR, rexinoid receptor; SAHA, suberoylanilide hy- droxamic acid; SERMS, selective estrogen receptor modulators; SWOG, Southwest Oncology Group; TSA, trichostatin A; VEGF, vascular endothelial growth factor. 75 1083-3021/03/0100-0075/0 C  2003 Plenum Publishing Corporation