Refining breast cancer risk assessment with molecular markers: the next step?

It is now reasonably well established that tamoxifen reduces the incidence of new breast cancers (1). Prevention strategies are much more efficiently applied to populations most likely to develop the disease. Therefore, considerable effort has been focused on developing risk profile indices for breast cancer development (2,3). Currently available models have depended principally on clinical and morphologic criteria. Breast epithelial hyperplasia lacking atypia (EHLA) is at the most benign end of a spectrum of breast lesions associated with a risk of developing invasive carcinoma. Although it is present in up to one quarter of benign breast biopsy specimens, EHLA is generally ignored by clinicians because the relative increased risk of breast cancer associated with these lesions is modest (~twofold) when compared with the relative risks associated with atypical ductal hyperplasia or carcinoma in situ (both carry relative risks of fourfold or higher) (4,5). Indeed, EHLA was not included as an eligibility criterion for the National Surgical Breast and Bowel Project (NSABP) P01 breast cancer prevention trial (1). Therefore, it remains unknown whether tamoxifen reduces breast cancer risk associated with EHLA. In the NSABP P01 trial, the proportional decrease in risk of breast cancer for all eligible patients after 5 years of tamoxifen was nearly 50%. Subgroup analyses suggest that the reduction for women with atypical ductal hyperplasia was even higher. If tamoxifen is as effective for women with EHLA as it appears to be for those with atypical ductal hyperplasia, selected patients with EHLA may have a sufficiently high breast cancer risk to justify intervention. However, because of the lower overall risk and the common prevalence of EHLA, treating all such women with tamoxifen would result in an enormous number of patients taking the drug needlessly. Is there a “high risk” subgroup of women with EHLA? After more than a decade of study, it seems doubtful that further subclassification of EHLA at the morphologic level will be useful. Future progress is more likely to depend on delineating the molecular events that signal the changes in breast duct architecture that defines this lesion. In this regard, the association between breast cancer risk and the expression pattern of transforming growth factor-b receptor II (TGF-b-RII) in EHLA reported by Gobbi et al. in this issue of the Journal (6) deserves attention as an important, and arguably the first, step in this new direction. These investigators chose to examine TGF-b-RII expression as a potential marker of risk because prior studies have demonstrated that signal transduction through this receptor plays a key role in the negative regulation of breast epithelial cell growth (7,8). In an extraordinary effort, these investigators examined archival benign breast biopsy specimens from almost 10 000 women for evidence of EHLA. They identified 54 patients with EHLA who developed breast cancer and 115 matched control patients with EHLA who did not. Consistent with the inhibitory effects of TGF-b-RII on breast cancer proliferation, low levels of TGF-b-RII were associated with a substantially higher risk of subsequent breast cancer (> threefold for very low versus very high TGF-b-RII-expressing lesions). These findings suggest that loss of TGF-b-RII expression in EHLA may provide a means to identify patients at increased risk of breast cancer that may be within the range in which chemoprevention is considered (1,2). From a biologic standpoint, these findings indicate the importance of deregulated TGF-b signaling in the genesis of EHLA. Other investigators (9,10) have reported that TGF-b-RII is not commonly mutated in breast cancer, if at all. These results suggest that changes in TGF-b-RII expression may be in response to some other process, perhaps related to estrogen receptor function (11). Regardless, this process appears to extend to adjacent morphologically normal structures, since a similar relationship between a lower frequency of TGF-b-RII-expressing cells and a higher breast cancer risk was observed in normal lobules in the vicinity of the EHLA lesion in question (6). Where do we go from here? Can we use TGF-b-RII to distinguish women with high risk EHLA for routine or investigational clinical purposes? Given the history of marker study heterogeneity, such a conclusion is premature and might lead to improper overtreatment of a large group of women (12,13). However, this study has established a plausible and intriguing hypothesis that deserves further pursuit by the scientific community. Confirmation of these findings in an independent dataset would further encourage clinical investigators to consider designs for an EHLA intervention trial. What are the biologic parameters associated with TGF-b-RII underexpression? More extensive assessment of other components of TGF-b signal transduction pathway in the investigators’ dataset may provide further evidence of a mechanistic link between loss of TGF-b signaling and progression of EHLA toward malignancy. Such studies might even provide clues for future interventional studies that lead to upregulation of the TGF-b-RII system. This preliminary study raises a number of questions, but Gobbi et al. have shown us how molecular markers of risk might help define a new group of women in which the risk/benefit ratio for tamoxifen chemoprevention might favor intervention.