Systemic therapy was introduced in the management of inoperable breast cancers more than 40 years ago (
11,
12). Surgery or radiotherapy, or both, followed systemic therapy in these trials. For optimal utilization of all treatment modalities, all interested specialists (radiologist, pathologist, and surgical, radiation, and medical oncologists) should review the diagnostic data, examine the patient, and determine the optimal type and sequence of therapies before any treatment is implemented. Treatment strategies that include neoadjuvant systemic therapy have several potential advantages: early initiation of systemic therapy,
in vivo assessment of response, and reduction in the extent of primary tumor and regional lymphatic metastases. The potential (theoretical) shortcomings include delay in local treatment, induction of drug resistance, and unreliability of clinical staging. The practical advantages have exceeded, by far, the disadvantages. The ability to monitor response to therapy by serial measurements of the primary tumor, and the reduction in tumor volume that often permits breast conservation, are the two major clinical advantages of these treatment strategies. However, neoadjuvant systemic therapy also represents an unparalleled research platform, facilitating biomarker discovery, such as identification of predictors of response, pharmacodynamics markers of response (early tumor changes that predict response), and biomarkers associated with residual, therapy-resistant disease. Further, neoadjuvant systemic approach can allow for testing of the efficacy of novel combination therapies, expediting drug development.
Neoadjuvant Chemotherapy (NACT)
The first clinical trials with NACT (also called induction chemotherapy, primary chemotherapy, or preoperative chemotherapy) started in the late 1960s, but the earliest reports were published in the 1970s (
11,
12). Since then, multiple reports have documented the effectiveness of primary systemic therapy in patients with LABC (summarized in reference 6). Most reports of combined modality therapy of locally advanced breast cancer are based on anthracycline-containing combination chemotherapy regimens (see also
Chapter 44, Adjuvant Chemotherapy). Administration of combination chemotherapy produces major reductions in tumor volume in 60% to 90% of patients. Tumor reduction has been consistently documented in both the primary tumor and the enlarged regional lymph nodes (
6,
11,
12,
13,
14,
15,
16,
17 and
18, ). Although mixed responses (response in the primary tumor and no response in the regional lymph nodes, or vice versa) have been reported, they are uncommon (
18,
19 and
20). Clinical complete remissions have been reported in 10% to 20% of patients with LABC treated with anthracycline-containing combination chemotherapy regimens (
6,
18,
19,
20 and
21). Response rates, and especially complete response rates, improve if a taxane is added, especially in sequential regimens. The median number of cycles required to achieve a partial remission was reported to be four, and for a complete remission, five (
13). Pathological complete remission (pCR) (
20 and
21) is uncommonly obtained with chemotherapy in ER positive tumors, and is rare after neoadjuvant endocrine therapy. Since the introduction of trastuzumab, a number of reports indicated that, in combination with chemotherapy, trastuzumab produces pCR rates ranging from 20% to 70% in HER2-amplified or overexpressing breast cancers (
22). Clinical measurements of breast masses
are often inaccurate, and there is substantial interindividual variation among examiners (
23). Therefore, imaging methods are often used to more reliably document extent of disease (
24). The combination of physical examination with either mammography or ultrasound gives measurements that closely approach those achieved by histopathology, and it reduces error rates in serial monitoring of response to systemic therapy (
24). MRI may also be used to determine extent of disease (
25). The determination of clinical complete remission requires that no residual disease be present by physical examination and by imaging (mammography and/or ultrasound) in the breast or regional lymph nodes (
17). Even following these criteria, only half to two-thirds of patients thought to have a clinical complete remission are found to have a pathologic complete remission (i.e., no residual disease) (
17,
18,
20,
21,
24). Furthermore, a third of patients with no residual disease by histologic examination will have residual clinical or imaging abnormalities that preclude the diagnosis of clinical complete remission. Patients who achieve a histologically documented complete remission have a markedly improved long-term prognosis compared with patients who achieve incomplete or no responses (
17,
21,
26). Furthermore, these patients are often excellent candidates for breast-conserving strategies, with or without surgical intervention (
27). In recent years, in addition to refinements to the sequential evaluation of extent of disease during therapy utilizing mammography, sonography, and MRI, positron emission tomography (PET) has been evaluated. Several authors have reported that not only does PET (usually in combination with CT, PET/CT) identify metastatic lesions not found by other imaging modalities (
28) but also it is a very sensitive tool to monitor the functional status of the tumor. Thus, changes in PET imaging, such as marked reductions in standardized uptake values, are under evaluation for early determination of response to neoadjuvant systemic therapy (
29).
Most initial reports of combined-modality treatment of LABC were based on anthracycline-containing combination chemotherapy regimens, such as doxorubicin, and cyclophosphamide (AC) or fluorouracil, doxorubicin/epirubicin, and cyclophosphamide (FAC or FEC). Over the past two decades, multiple reports have documented the benefits of the use of anthracycline and taxane combinations (
27,
30,
31). These newer regimens were reported to have marked antitumor activity, with overall response rates in the 80% to 95% range. Unfortunately, the reported clinical and pathologic complete remission rates were only modestly higher than those reported with older combinations.
Table 58-1 summarizes prospective randomized trials that compare anthracycline- and taxane-containing regimens with anthracycline-containing combinations without a taxane (
26 and
27,
30,
31,
32,
33,
34,
35,
36,
37,
38,
39 and
40). In several randomized trials in which a taxane was administered sequentially, after the initial four cycles of an anthracycline/cyclophosphamide-containing neoadjuvant regimen, a significant increase in pathologic complete remission was reported (
26,
32). In a small, multicenter trial conducted on patients with LABC, the increase in clinical and pathologic complete response rate was associated with improved disease-free and overall survival rates (
32,
33,
34,
35,
36,
37,
38,
39,
40 and
41). Of note, both responders and nonresponders to the initial anthracycline-containing combination benefited from crossover to docetaxel. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-27 included a crossover to docetaxel after four cycles of neoadjuvant doxorubicin and cyclophosphamide (AC); the addition of docetaxel resulted in significant increases in overall and complete response rates, pathologic complete response rates, and increased breast-conserving surgery rates (
26). However, while there was a borderline improvement in relapse-free survival, the primary endpoint of the study, improved disease-free survival, was not significantly altered. However, this study was underpowered to detect clinically significant differences in survival. It is estimated that for each 10% increase in pCR rate a 2.6% improvement in survival might be observed (
26). Other drugs under investigation in the neoadjuvant setting are gemcitabine, vinorelbine, platinum analogs, ixabepilone, eribulin, trastuzumab, pertuzumab, trastuzumab emtansine, bevacizumab, and lapatinib. Single-agent trastuzumab was reported to achieve a 23% partial response rate after three weeks of treatment in patients with LABC in one study and a 45% response rate in another (
42,
43). In combination with a taxane or vinorelbine, or two-drug combination chemotherapy regimens, clinical CR rates of 24% to 59% were reported (
22,
44,
45). The corresponding pCR rates ranged from 18% to 45%. In a small randomized trial of sequential paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide, with or without trastuzumab, pCR rate increased from 26% to 65% with the addition of trastuzumab (
46). These results
were confirmed by a larger randomized trial that included 235 patients with HER-2/neu-positive primary breast cancer (
47). A large, multicenter confirmatory study has completed accrual patients with T2 and T3, HER-2-positive breast cancer (ACOSOG protocol Z1041). Gianni and collaborators also reported the initial results of a four-arm randomized trial comparing neoadjuvant docetaxel plus trastuzumab with docetaxel plus pertuzumab, docetaxel plus both antibodies, or the two antibodies without chemotherapy (
48). Pathological complete remission rates were 31%, 23%, 49%, and 18%, for the four arms, respectively, indicating that combining the two antibodies with chemotherapy provides the best result, while the two antibodies without chemotherapy were able to eradicate the primary tumor in almost 20% of patients.
Table 58-2 lists the more commonly used effective and well-tolerated neoadjuvant chemotherapy regimens.