A critical need for molecular markers of breast cancer risk and risk reduction

Carcinogenesis is a chronic disease process underlying the clonal evolution of cells progressing to the point of uncontrolled growth, metastatic potential, and molecular heterogeneity. By convention, chemoprevention drugs are developed from a molecular perspective with the goal of interrupting carcinogenesis before the occurrence of invasive lesions or extreme heterogeneity. The most successful demonstration of cancer chemoprevention to date has been an overall 49% reduction of invasive breast cancer, with a similar reduction in premalignant lesions by tamoxifen in the Breast Cancer Prevention Trial (BCPT) [1]. It is noteworthy that the main effect of tamoxifen is likely to be mediated through the estrogen receptor (ER), as reflected by a 70% reduction of lesions that are ER-positive in contrast to little or no effect on the incidence of ER-negative lesions. For interventions that are related to ER as a target, a number of drug development issues remain to be addressed including dose, schedule, and the comparative net clinical benefit of various selective ER modulators versus pure anti-estrogens, aromatase inhibitors, and combinations. In the BCPT there were 13,388 participants, and there were more than 22,000 in the STAR trial. The large sample size that may be needed for a randomized clinical trial to observe a prevention effect severely limits the opportunity to explore a multiplicity of important questions in clinical chemoprevention.

Molecular studies have been helpful in classifying breast cancers according to categories of response to intervention. For instance, cytogenetic studies combined with molecular profiling suggest that ER-focused interventions are likely to address a particular subset of tumors arising from the luminal cell population [2]. As tumor subsets become better characterized, the need for additional prevention studies can be anticipated to address larger subsets (e.g. a combination of drugs for overlap) versus smaller subsets of individuals at risk. In order to reduce the sample size of future prevention trials, new molecular approaches are needed. One strategy would be to use non-invasive molecular tests to identify individuals at increased breast cancer risk so that populations for prevention trials could be further enriched according to that risk. Of the approaches currently under investigation, proteomic studies theoretically offer an opportunity to improve risk identification. Investigators who are performing proteomic studies for early detection are encouraged to expand their investigations to see whether it is possible to delineate according to ER status and between non-invasive conditions such as hyperplasia and DCIS versus invasive cancer.

Another strategy for increasing the efficiency of breast cancer prevention trials is the validation of intermediate endpoint biomarkers [3] to secure validated intermediate endpoint biomarkers (VIEBs). If molecular entities in serum could be identified on the basis that they are predictably correlated with the future development of breast cancer, then a reduction in the VIEB level could serve as evidence of a preventive effect. Early work in this area suggests that nucleic acids in serum might be used to identify individuals with premalignant lesions [4].

Clinical correlation is needed for VIEBs and other molecular indicators of risk so that targets in addition to the ER can also be more efficiently studied. Targets of interest for breast cancer prevention include the EGFR family, RAR/RXR and mediators of inflammation or oxidative damage.