Abstract ML1: The Contribution of NSABP Clinical Trials to the Management of Early Breast Cancer

For over a half century the NSABP has conducted clinical trials to ascertain optimal therapy in patients with early breast cancer. The trials, performed in chronologic sequential manner, provide a well- documented compilation of evolving biologic theories disclosing both flaws and occasional episodes of perspicacity in a disinterested manner. In the process, this endeavor has contributed to establishing standards of care; a tribute to the 100,000 women who participated. Two landmark studies started in the 1970s (B04, B06) initiated the retreat from radical mastectomy and established the propriety of breast preserving operations. They convinced the surgeon that treatment failures were not a consequence of inattention to operative detail but were due to the presence of micro-metastatic disease. Thus the decline of the radical mastectomy and the ascent of adjuvant therapy are inextricably intertwined and the latter would not have occurred without the former. In 1975 the NSABP demonstrated that adjuvant chemotherapy (oral L-PAM) given to N+ patients could significantly prolong disease free survival (DFS). These data were eclipsed in 1976 by the CMF results but taken together these two pivotal trials launched an initiative which is still relevant in the present therapeutic arena. Between 73-05 NSABP consecutive adjuvant therapy trials increased the ten year DFS from 30% to 75% in N+ patients. Perhaps viewed in harsh hindsight, some of these studies might seem banal, however, the incremental gains in DFS and the number of lives saved are incontrovertible. In 1988 a preoperative chemotherapy program (B18, B27) established the association of pCR and improved survival. The results were instrumental in the FDA considering accelerated approval on the basis of a surrogate end point, such as pCR (2012). The salutary effect of adding tamoxifen to chemotherapy in N+ patients was first shown in 1981 (B09). A concerted effort was made to define a cut point in quantitative ER that would be both prognostic and predictive. Although this effort was unsuccessful it did serve as the forerunner of and the stimulus for the 21 gene recurrence score panel. Protocol B14 (82-88) confirmed that tamoxifen was beneficial in N- ER+ pre- and post-menopausal women. Protocol B20 further showed that the addition of chemotherapy to tamoxifen was superior to tamoxifen alone. These two trials served as the validation for the 21 gene recurrence score panel (2004) and to date this assay has been performed in 550,000 N- ER+ women to determine whether chemotherapy could be omitted. As a result the overall use of chemotherapy in the United States has been significantly reduced. Perhaps the most dramatic results in the 50 year history of the group were obtained in NSABP B31 where trastuzumab was added to chemotherapy in N+ Her2+ patients. The initial joint analysis from NSABP B31 and North Central N9831 disclosed a hazard ratio of .48 and an absolute 18% increase in DFS (2005). These results were hailed as the harbinger of a completely altered approach to the treatment of breast cancer by an exuberant editorialist who may yet be proven correct. Symbolically the age of therapy targeting genetic aberrations in the adjuvant setting was initiated. Citation Format: Wolmark N. The Contribution of NSABP Clinical Trials to the Management of Early Breast Cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ML1.