Adjuvant systemic therapy for early breast cancer: progress and controversies.

The diagnosis and management of breast cancer have changed considerably over the past 4 decades. The introduction of adjuvant endocrine therapy (ovarian ablation) and adjuvant chemotherapy in the 1960s was a paradigm-changing event, based on improved understanding of the natural history of human breast cancer and the increased realization that micrometastases were in existence in most patients at the time of initial diagnosis (1, 2). The initial steps were timid, and the first few clinical trials were substantially underpowered to answer with any degree of certainty whether “prophylactic” chemotherapy or endocrine therapy could reduce the odds of recurrence and mortality in patients with primary breast cancer. Although most North American oncologists accepted adjuvant chemotherapy for premenopausal patients with axillary lymph node-positive breast cancer by the late 1970s, marked controversy characterized the use of this treatment for other subgroups of patients with primary breast cancer. Adjuvant endocrine therapy was also viewed with much skepticism. The Early Breast Cancer Trialists’ Collaborative Group established a database of all randomized clinical trials (whether published or not) of primary breast cancer. Meta-analyses of all available data explored the effect of systemic and locoregional therapies on odds of recurrence and mortality. These meta-analyses were conducted at 5-year intervals, starting in 1985, and have contributed immensely to the general acceptance of various forms of adjuvant therapy as standard treatment (3–8). However, some of the conclusions of the meta-analyses have been questioned on the basis of biological mechanisms, whereas others were in conflict with the results of some of the largest multicenter clinical trials. To resolve controversies and summarize accepted advances in the field, the NIH has organized over the past 3 decades several Consensus Development Conferences about the management of primary breast cancer (9, 10). The most recent one, held in early November 2000 at the NIH campus, demonstrated that additional progress had been made, and as expected, new controversies replaced old ones. An independent panel of experts in multidisciplinary clinical trials in oncology reviewed information from clinical trials presented by breast cancer experts and thought leaders. At the end of the meeting, the panel issued a comprehensive, evidence-based report on the status of adjuvant chemotherapy. Since the stated goal of the conference was to review adjuvant systemic therapy, a number of other, ongoing controversies related to the management of early breast cancer (i.e., sentinel lymph node mapping) were not addressed. Let’s review both areas of accepted progress and remaining controversy.