Evolution of Knowledge Related to Breast Cancer Heterogeneity: A 25-Year Retrospective

This Commentary will put into perspective two of our articles that appeared in the Journal of Clinical Oncology in 1983 that contributed to the evolution of knowledge related to breast cancer heterogeneity. We will consider those articles within a broader context that includes some of our other contributions to that aspect of breast cancer biology. Until about 1960, physicians paid little attention to the proposition that breast cancers might be heterogeneous. Although pathologic examination clearly indicated tumor heterogeneity, they considered the varied outcomes of patients following surgery to be the principal indicators of that phenomenon. Anecdotal information, however, began to indicate that older patients fared better than younger patients, large tumors led to a poorer prognosis than did small tumors, and women with positive axillary nodes did worse than those with negative nodes. During the late 1960s, we began to conduct clinical investigations that were aimed at defining predictors of outcome more precisely. Those studies eventually led to a greater awareness of the significance of tumor heterogeneity. In 1970, we were the first to report findings that we obtained from more than 2,000 breast cancer patients in several randomized trials that demonstrated that a greater incidence of treatment failure was associated with tumors that presented with increasing numbers of positive axillary nodes. Our data demonstrated the propriety of grouping women according to how many of their axillary lymph nodes were tumor positive, that is, one to three or four or more. That categorization subsequently became universally accepted and continues to be an important prognostic factor. Other pathobiologic factors have been found to be more effective in determining therapy. During the late 1960s, tumor size also began to be viewed as a marker of breast cancer heterogeneity. Neoplastic surgery was based on the concept that the time of a tumor’s existence, as measured by size, determined surgical success and that the earlier the operation (ie, the smaller the tumor), the better the chance for a cure. In an effort to determine the validity of that concept, we obtained information that led us to conclude that size did not necessarily relate to either “earliness” or “lateness” of a tumor and that outcome was related to tumor and/or host factors. Our findings eventually led us to formulate a hypothesis that was alternative to the one on which Halstedian radical cancer surgery was based. The results of clinical trials conducted to evaluate that hypothesis ultimately led to the acceptance of breast-conserving surgery in the mid-1980s. Another issue that was debated during the late 1960s related to the general belief that tumor location influenced prognosis. At that time, the presence of an inner quadrant or subareolar lesion evoked pessimism because it had been demonstrated that such tumors metastasized to internal mammary lymph nodes. As a consequence, not only was the prognosis apt to be worse, but more extensive radical surgery was also required. Information that we reported in 1969 from more than 1,000 patients failed to demonstrate that primary tumor location influenced prognosis. On the contrary, our findings showed that it was the biologic nature of a breast cancer, rather than its location, that was more important for making such a determination. Thus, there was no justification for anticipating that a surgical approach based on tumor location would be more rewarding than would any other approach. Those findings played a significant role in the elimination of radical internal mammary lymph-node dissection for the treatment of breast cancer. While our investigations were in progress, others were establishing the foundation from which the modern era of steroid hormone action would arise. With the discovery of estrogen receptors (ER) and their identification in mammary tumor cells, the determination of the presence of ER in breast cancers began to achieve clinical importance. It was anticipated that two categories of tumors would be identified: those with ER (which could subsequently benefit from endocrine therapy) and those without ER (which would not). It was also believed that ER status could serve as a prognostic indicator and that women whose tumors contained ER would fare better than those whose tumors did not. Those findings, and the 1962 discovery of the drug tamoxifen, whose antiestrogenic properties had already been proven in animal investigations, were to have a profound effect on future research related to both the therapy and the prevention of breast cancer. Although several studies were conducted with tamoxifen in a few patients with metastatic disease during the 1970s, ER determination had not been carried out in any of those trials. With the increased use of tamoxifen for the management of advanced breast cancer, the need for more information about tumor ER JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 13 MAY 1 2008