Primary systemic therapy in operable breast cancer

Purpose: Laboratory studies suggest that primary systemic therapy (PST) cou ld improve control of micrometastatic disease and impact on overall surviva l (OS), This article examines the rationale for and preclinical and clinica l data of PST in operable breast cancer and the potential role of intermedi ate biomarkers as predictive and/or prognostic factors for response and sur vival. Design and Method: We conducted an extensive literative review (including M EDLINE) on preclinical studies, single-arm feasibility studies, large rando mized single- and multi-institutional trials, and laboratory correlate stud ies of PST in breast cancer. Results: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PS T for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significan t (less than 10%) absolute increase in the use of breast-conservation treat ment (BCT) with similar rates of local control. Although one study showed b etter disease-free survival (DFS) and another showed better OS, most studie s did not show any survival advantage of primary versus adjuvant systemic t herapy. Thus far, pathologic complete response seems ta be the best predict or of survival, but clinical response assessment correlates poorly with pat hologic response. Pilot studies demonstrated feasibility of procuring tissu e at diagnosis and after treatment for assays of potential intermediate bio markers, initial data suggest a potential correlation between markers of pr oliferation and apoptosis and in vivo chemotherapy sensitivity. Conclusion: Thus tar, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing tria ls should determine if specific subsets of patients at risk would benefit f rom additional systemic therapy and the potential role of intermediate biom arkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strateg ies should not replace standard adjuvant approaches, Rather they represent an acceptable alternative to women with palpable, operable tumors and an ex cellent arena for clinical trials. (C) 2000 by American Society of Clinical Oncology.