Principles of Primary Systemic Therapy

Abstract

Early, non-metastatic breast cancer (BC) is treated with a combination of surgery, radiotherapy and systemic therapies, such as cytotoxic chemotherapy and targeted drugs, including endocrine therapy and HER2-targeting antibodies for ER-positive and HER2-positive BC, respectively. Although systemic therapies were initially developed post-operatively (adjuvant), their use has later expanded to the primary, pre-operative setting (neoadjuvant or primary systemic therapy—PST).

Initial interest in PST focused on timely eradication of micrometastatic disease, in vivo testing of chemosensitivity and the possibility of down-staging in order to increase resectability of initially inoperable tumors and to employ more conservative surgical approaches. Despite the obvious theoretical advantages and opportunities for improving outcomes, effectively using cytotoxic drugs and facilitating surgery, the use of PST initially met some skepticism due to delay of surgery and the caveat of jeopardizing the prognosis especially of patients who do not respond to the systemic treatment. However, based on high quality evidence derived from meta-analyses of individual data from thousands of patients enrolled in prospective randomized trials it is today clear that long-term patient outcomes following adjuvant vs. neoadjuvant chemotherapy are similar. This meta-analysis also showed that PST was associated with increased rates of breast-conserving surgery (65% vs. 49%), but also increased rates of local relapses (21.4% vs. 15.9%) compared with adjuvant therapy.

Pathological complete response (pCR), defined as the disappearance of all invasive cancer foci at surgery, was early recognized as an important efficacy outcome measure of primary systemic therapy. As detailed later in this chapter, pCR represents a strong predictor of long-term outcomes across BC subtypes, and in addition to providing useful prognostic information, it can also guide the use of subsequent treatment in patients who have received primary systemic therapy.