Preoperative chemotherapy, also referred to as neoadjuvant chemotherapy or primary systemic therapy, today constitutes one of the standards of care in patients with newly diagnosed early stage breast cancer. This approach was initially introduced in the 1970s for the treatment of patients with locally advanced breast cancer (LABC) where it was found to result in high response rates, allow surgery for these initially unresectable tumors, and improve survival when compared to historical controls (1, 2).

The success of preoperative chemotherapy for locally advanced disease together with emerging data on the benefits of adjuvant chemotherapy has led to the conduct of a number of studies in patients with operable breast cancer. These studies, some of which will be discussed in this chapter, have provided a number of important clinical insights regarding preoperative chemotherapy that are applicable to the management of patients with breast cancer. First, the majority of patients achieve a clinical response to induction chemotherapy, and the progression of disease during therapy, a legitimate concern, is rare. Second, preoperative chemotherapy results in surgical downstaging of tumors and allows breast conservation in women who, otherwise, would have needed a mastectomy. Furthermore, preoperative chemotherapy does not limit or interfere with posterior surgery and radiation therapy. Third, disease-free control and overall survival are similar between preoperative and postoperative (adjuvant) therapy. Fourth, the same chemotherapy agents and sequence of administration used in the adjuvant setting is also used in the preoperative space. As such, there are not preoperative or adjuvant-restricted chemotherapy regimens. Fifth, emerging data suggests that a good response to therapy resulting in absence of tumor at the time of surgery (pathological complete remission [pCR]) may be a surrogate marker of improved disease-free survival and overall survival. Finally, investigational agents are being increasingly studied in the preoperative setting even before the launch of large adjuvant studies as the number of patients required is smaller than in the adjuvant settings and follow up is shorter as a result of using the pCR rate, an early readout as a surrogate marker of improved diseasefree survival and overall survival.

While preoperative chemotherapy is not for every patient and a large number of those patients with newly diagnosed breast cancer for whom chemotherapy is recommended will continue to be treated in the adjuvant setting, preoperative chemotherapy is a treatment approach to be considered and is likely to become a space for the rapid approval of active compounds in the early disease setting.

The first prospective preoperative study was launched in 1973 by investigators from the Milan Cancer Institute. The primary objective was to downstage the tumor and facilitate surgical resection. Women with stage III breast cancer received combination chemotherapy with adriamycin and vincristine for three cycles, followed by radiation therapy followed by additional chemotherapy. This preoperative approach was not only effective in downstaging the tumors
but also improved survival (3, 4). In the late 1970s and the 1980s, several preoperative trials assessed the benefit of chemotherapy in women with LABC, and, in addition to improving the rates of operability, most suggested a survival benefit as well (5, 6). Based on these results and the lack of effective alternative strategies, the administration of preoperative chemotherapy with or without radiation therapy prior to surgery thus became the standard for initially inoperable, nonmetastatic breast cancer.

The success of preoperative chemotherapy in downstaging tumors and improving survival prompted further evaluation in operable tumors as well. Furthermore, there was a suggestion from preclinical models that chemotherapy before tumor removal may result in better outcomes than administration after surgery due to early eradication of micrometastasis (7, 8). Consequently, in the late 1980s and the 1990s, a new series of clinical trials were launched in the United States and Europe that compared preoperative and adjuvant therapies. The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a large phase III study (NSABP B-18), in which 1,523 women with operable breast cancer were randomly assigned to pre- or postoperative doxorubicin and cyclophosphamide (adriamycin cyclophosphamide [AC]; 60/600 mg/mg² for four cycles) (9). Preoperative chemotherapy was associated with a higher rate of breast conservation surgery (68% vs. 60%; p = .001) as compared to adjuvant therapy. However, there was no difference in the Disease Free Survival (DFS, 55% vs. 58%) or Overall Survival (OS, 72% vs. 72%) observed between the preoperative and adjuvant groups. Among those patients who received preoperative therapy, achieving pCR was associated with significant improvement in DFS (HR = 0.47; p <.0001) and OS (HR = 0.32; p <.0001) compared with those who had residual tumor at the time of surgery. Similar results were observed in other randomized trials comparing preoperative and adjuvant regimens (10, 11 and 12).

Although any of these trials showed superiority in DFS or OS, the demonstration of equivalence between preoperative and adjuvant chemotherapy set the stage for the development in the preoperative setting of a number of treatment regimens that were developed in parallel with new adjuvant approaches. Today, similar guiding principles apply for the choice of agents, sequencing, and duration of therapy between the preoperative and adjuvant setting. In addition, new targeted agents are today being tested preoperatively. Figure 54-1 outlines the evolution of preoperative chemotherapy over the past 30 years.

A number of conditions have to be met in order to consider the administration of preoperative therapy. First, appropriate tumor tissue in the diagnostic specimen should be available for histological diagnosis, including assessment of hormone receptor (HR) and Human epidermal receptor-2 (HER2) status. Ideally, enough tumor tissue for additional studies, such as gene-signature profile, should also be available. Second, it is helpful to place clips to mark the tumor location as it aids the radiologist, surgeon, and pathologist in providing posttreatment assessment. Third, biopsy of clinically palpable axillary lymph nodes, and sentinel lymph node biopsy in the absence of palpable lymph nodes, may be considered before initiating preoperative therapy. The management of sentinel lymph node (SLN) is detailed in Chapter 56. The determination of pathological involvement of axillary lymph nodes has prognostic significance and could influence the radiation therapy decision after surgery. Finally, preoperative chemotherapy requires a fully integrated, strong multidisciplinary team.

The commonly used preoperative regimens are summarized in Table 54-1. The salient features are reviewed below.

In addition to the standard anthracyclines and taxanes discussed above, other chemotherapeutic agents have been studied in the preoperative setting. While they have shown clinical activity, they are not considered to be standard of care at this time.