SELECTION CRITERIA FOR BREAST-CANCER CHEMOPREVENTION SUBJECTS

Early phase chemoprevention trials differ from standard therapeutic cl inical trials because asymptomatic, healthy people are treated with a potentially toxic intervention for a prolonged period of time. Current subject selection protocols have relied upon epidemiological methods to identify high-risk individuals. Most available data provide risk es timates for various individual risk factors, but few have reported ris k estimates for combinations of risk factors. Selection criteria for t he large tamoxifen intervention trial (NSABP P1) were developed from t he work of Gail et al. [1]. The Gail model takes into account non-gene tic factors (e.g., nulliparity, age at menarche, preexisting pathologi cal conditions) and genetic factors (family history). Using a lifetime risk of 10% of developing breast cancer as a standard to intervene, N SABP P1 uses the Gail algorithm to select pre- and postmenopausal wome n for a primary intervention trial. This approach has been criticized for being insufficiently selective (i.e., all women greater-than-or-eq ual-to 60 yrs), but appears to be the best available method to select subjects for a chemoprevention trial. Other approaches have been based on identification of very high-risk women with acknowledged pathologi c conditions [lobular carcinoma in situ, ductal carcinoma in situ (DCI S)]. Attempting to use these proliferative lesions as pathologic endpo ints for drug effect has not been attempted. DCIS as a risk factor for tamoxifen intervention was excluded because of controversies over its management and because of frequent difficulties in distinguishing mic roinvasive from non-invasive lesions. Women treated for early stage br east cancer (Stage I) may be subjects for early stage chemopreventive interventions. We propose the use of intermediate endpoint biomarkers and genetic markers as entry criteria for early phase chemoprevention trials. For colorectal cancer chemoprevention, we have used a two-step selection process. The first step was based on epidemiologic risk ass essment. Entry into the study required that a potential intermediate b iomarker be positive and quantifiable. The relationship between modula tion of a pre-transformational biomarker and development of cancer ult imately needs proof in a primary interventional trial; however, this m ethodology may permit screening of potential chemopreventive agents at lower cost and more rapid tum-around times. In early chemopreventive agent testing for breast cancer chemoprevention, we propose a similar two-step procedure. Epidemiological and/or pathological criteria for r isk would be followed by a procedure to obtain cellular material. The cellular material would be assayed for pre-transformational cellular c hange. Identifying predictive genes in familial breast cancer cohorts such as the modified BRCA1 gene promises to select individuals at high familial and potentially physiological or environmental risk. The ide ntification of the abnormal gene product in individuals and families w ill provide another important group of subjects for chemopreventive in terventions. The identification of high-risk subjects for breast cance r chemoprevention, particularly those with familial genetic risk, carr ies important ethical problems. Such women may have difficulties obtai ning health and life insurance, deciding to have children, and obtaini ng work. Chemoprevention trials with genetic selection criteria will n eed to develop methods of dealing with these issues. (C) 1993 Wiley-Li ss, Inc.