A working model for the time sequence of genetic changes in breast tumorigenesis.

INTRODUCTION Although steady gains have been made in the early diagnosis and treatment of breast cancer, 30%–50% of affected women still die from the disease. Attention has turned to the major potential of chemoprevention for decreasing breast cancer incidence and mortality. Chemoprevention refers to the administration of drugs to block or reverse carcinogenesis before the development of invasive cancer. The promise of chemoprevention in breast cancer was raised by the results of clinical trials of tamoxifen in women with clinically detectable breast cancers. These studies showed a benefit from tamoxifen in reducing tumor recurrence, prolonging survival, and reducing the incidence of contralateral breast cancer, as compared with placebo. The National Surgical Adjuvant Breast and Bowel Project P1 trials demonstrated that tamoxifen was also useful as a breast cancer preventive agent in many women at increased risk for the disease but without a prior history of invasive breast carcinoma. Chemoprevention trials typically use the occurrence of cancer as an endpoint, and thus require large sample sizes and long durations of study. To circumvent these problems, several researchers have explored the use of surrogate endpoint biomarkers (SEBs) that could be used in lieu of the occurrence of cancer as an indicator of efficacy. Neoplastic transformation is accompanied by a number of measurable phenotypic changes at both the cellular and molecular level, and it is expected that an effective chemopreventive agent would affect these changes through alterations in the expression of specific markers. SEB studies have typically used one of two models. The short-term ductal carcinoma in situ (DCIS) model uses women with DCIS with or without small invasive tumors who are randomized to receive drug or placebo in the interval between biopsy and definitive surgery. The directed core biopsy hyperplasia model randomizes women with core biopsy-detected hyperplasia to receive drug or placebo for a more extended period of time. An important issue in the conduct of an SEB trial is the selection of appropriate biomarkers. Clearly, they should be biologically relevant to the process of breast tumorigenesis. Equally important, they should be characteristic of the premalignant lesion that is being examined. Molecular changes that characterize the development of a metastatic phenotype, for example, may not be appropriate in a model system looking at DCIS or atypical hyperplasia, but changes associated with immortalization might be very useful in these models. The purpose of this review was to use published data to develop a working model of the time sequence of genetic changes in human breast tumorigenesis. Clearly, many of the genetic loci that have been associated with breast tumorigenesis have not yet been examined in sufficient detail to determine where they might fit in such a time sequence. This review is restricted to those relatively few markers where this question has been addressed, and should be considered as a work in progress. As background, Vogelsteins’s model system for colorectal tumorigenesis was reviewed. Two types of human breast cancer studies were included: (1) studies using normal and neoplastic breast tissue, which provide information about the occurrence of specific genetic changes (mutation, deletion, amplification) in different types of breast lesions, ranging from typical hyperplasia to metastatic carcinoma; and (2) studies using human mammary epithelial cell lines, which provide in-depth information about the effects of adding or deleting specific genes or chromosome segments on the processes of immortalization and transformation in normal mammary epithelial cells. No competing interests declared.