Presurgical Systemic Treatment of Nonmetastatic Breast Cancer: Facts and Open Questions

Abstract

Abstract Learning Objectives After completing this course, the reader should be able to: Identify the great advantages of primary systemic therapy from a research perspective and also the problems preventing the recommendation to adopt this treatment modality instead of adjuvant therapy in clinical practice.Define pathological complete response and discuss its clinical significance.Define the concept of a surrogate parameter of treatment efficacy and discriminate it from a prognostic parameter.Summarize the main characteristics and findings of randomized trials of primary systemic therapy in comparison with randomized trials of adjuvant therapy. CME This article is available for continuing medical education credit at CME.TheOncologist.com There are several advantages of administering primary systemic therapy (PST) instead of adjuvant therapy in the management of early breast cancer patients: (a) PST allows for a quantifiable evaluation of the sensitivity or resistance of any treated case and (b) the response assessment offers the opportunity to “cross over” to a different regimen for an individual patient, leading to more flexible, “tailored” therapies. Indeed, these advantages are tenable if one assumes that the primary tumor response serves as a surrogate marker of the efficacy of PST in terms of survival. Unfortunately, this has not yet been validated. The data that are actually available show that both clinical complete response (cCR) and pathological (p)CR have prognostic significance. pCR after chemotherapy has a greater prognostic impact than cCR; however, it is frequently observed in a subset of tumors—such as those that are estrogen receptor negative, are human epidermal growth factor receptor positive, and have elevated proliferative activity—but occurs rarely in their human epidermal growth factor receptor-2/neu counterparts. cCR is more sensitive than pCR, but its assessment presents many hindrances. cCR after chemotherapy can predict early on which tumors are destined to undergo pCR, suggesting a role for this endpoint guiding further treatment decisions early on. The pCR rate in small randomized PST studies comparing chemotherapy with chemotherapy plus trastuzumab was able to predict the difference in survival observed in large, randomized adjuvant trials with a similar study design. Conversely pCR cannot predict the outcome benefit of patients undergoing different hormonal therapies. In conclusion, pCR may be a reliable surrogate endpoint for PST efficacy in a subset of patients undergoing chemotherapy.