DEVELOPMENT OF BREAST-CANCER CHEMOPREVENTIVE DRUGS

Breast cancer is the second highest cause of cancer mortality (19%) es timated for U.S. women in 1993 and accounts for the highest proportion of new cancer cases (32%) in this population. The rate of documented cases increased during the early 1970s and again in 1980-87, probably due to early mammographic detection. Increased knowledge of personal r isk may also have been a consideration; however, 60% of women diagnose d with breast cancer have no known risk factor(s), such as family hist ory, early age at menarche, late age at menopause, nulliparity, late a ge at first live birth, socioeconomic status, contraceptive use, postm enopausal estrogen replacement, or high fat intake. To prevent cancer, one strategy undertaken by the NCI is cancer chemoprevention, or inte rvention with chemical agents at the precancer stage to halt or slow t he carcinogenic process. An objective of the NCI, DCPC is to develop p romising cancer chemopreventive chemical agents as drugs for human use . Briefly, the process begins with identification of potential agents (e.g., pharmaceuticals, natural products, minor dietary constituents) from surveillance and analysis of the literature and from in vitro pre screen assays. Data on both efficacy (i.e., biological activities that either directly or indirectly indicate inhibition of carcinogenesis) and toxicity are gathered these sources. Various criteria are used to select and prioritize agents for entry into the NCI, DCPC preclinical testing program. The program begins with battery of in vitro efficacy screens using both animal and human cells to select agents for further testing; agents positive in these assays are considered for further t esting. In the assay used for breast cancer chemoprevention, 7,12-dime thylbenz(a)anthracene (DMBA)-induced mouse mammary organ culture, 64 c hemicals have inhibited formation of hyperplastic alveolar-like nodule s. A panel of organ-specific animal screening assays are then used to assess efficacy in vivo. Two assays relevant for breast cancer chemopr evention are inhibition of N-methyl-N-nitrosourea- and DMBA-induced ra t mammary gland carcinogenesis. Of 89 agents tested, 29 have inhibited cancer incidence, multiplicity, or both in at least one of the mammar y assays; 21 agents are currently on test. Highly promising agents are then placed in traditional preclinical toxicity tests performed in tw o species. Finally, the most promising and least toxic agents enter cl inical trials. Phase I clinical trials are designed to investigate hum an dose-related safety and pharmacokinetics of the drug. Phase II tria ls are small scale, placebo-controlled studies designed to determine c hemopreventive efficacy and optimal dosing regimens. Three Phase II tr ials are in progress or in the planning stage investigating tamoxifen citrate or N-(4-hydroxyphenyl)retinamide (4-HPR) as single agents; als o, both Phase I and Phase II trials evaluating the combination of 4-HP R and tamoxifen are in the planning stage. Phase III trials involve a large target population, with cancer incidence reduction as the endpoi nt. Tamoxifen citrate is being tested as a breast cancer chemopreventi ve in high-risk women in a Phase III trial funded by NCI and under the direction of the National Surgical Adjuvant Breast and Bowel Project. Prevention by 4-HPR of a second primary in the contralateral breast o f women surgically treated for Stage I/II breast cancer is being evalu ated in a Phase III trial in Italy. Finally, the efficacy of beta-caro tene or vitamin E in decreasing the incidence of breast, lung, and col on cancer is being determined in a Phase III trial involving nurses 45 years of age or older. Essential to the completion of Phase II clinic al trials is the use of populations with defined, measurable biologica l alterations in tissue occurring prior to malignancy (i.e., intermedi ate biomarkers) which can serve as surrogate trial endpoints, instead of the more time-consuming and costly endpoint of cancer incidence. In termediate biomarkers may be of several types, including histological/ premalignant lesions, or those based on genetic, biochemical, prolifer ative, or differentiation-related properties. The only well-establishe d premalignant lesions in the human breast are ductal and lobular carc inoma in situ (CIS). In 1993, an estimated 25,000 new cases of CIS wil l be diagnosed. These lesions are at high risk of progression to invas ive cancer and may be amenable to modulation by a chemopreventive agen t. In addition, other types of biomarkers could be identified within t he lesions. The goal of this workshop is to identify and discuss the b est chemopreventive agents and intermediate biomarkers for use as surr ogate endpoints in short-term Phase II breast cancer chemoprevention t rials, as well as to design protocols for such trials. (C) 1993 Wiley- Liss, Inc.