Because of the possibility that a preoperative treatment may improve the outcome by exposing micrometastases to early chemotherapy, neoadjuvant chemotherapy was investigated in patients with primary operable disease. Several randomized trials have been conducted, which compared neoadjuvant chemotherapy with the standard adjuvant approach in women with early disease [4–6]. Since it is known from the advanced setting that neoadjuvant treatment has the ability to shrink tumors, this treatment approach may also allow for breast-conserving treatment in patients who otherwise would have needed a mastectomy. The pioneer trial investigating these important issues was the B18 trial of the NSABP (National Surgical Adjuvant Breast and Bowel Project) [4]. In this study, 1,523 women with operable breast cancer were randomized to four cycles of AC (adriamycin, cyclophosphamide) either before or after definitive surgery. A pCR, which was defined as the absence of malignant tumor cells at the site of the primary tumor irrespective of nodal status, was seen in 13% of the patients. A higher rate of breast-conserving treatment was observed with neoadjuvant surgery (67 vs. 60%; p = 0.002). In tumors larger than 5 cm in diameter, the difference was more obvious in favor of the neoadjuvant approach (22 vs. 8%). There were no significant differences in disease free survival (DFS) and overall survival (OS), even though updated results with follow-up exceeding 15 years indicated a trend in favor of neoadjuvant treatment in women younger than 50 years for DFS (hazard ratio (HR), 0.85; p = 0.053) [10]. There were also no significant differences in ipsilateral breast cancer relapse rates between the neoadjuvant and adjuvant group (7.9 vs. 5.8%; p = 0.23). Two further trials [5, 6], one of which used not only anthracyclines but an anthracycline/taxane-containing regimen, confirmed the findings of the B18 trial. A recent meta-analysis of nine randomized trials involving 3,946 patients confirmed that no differences exist between neoadjuvant and adjuvant chemotherapy in terms of OS [7].

In view of these considerations, although a clear survival advantage has not been demonstrated yet, neoadjuvant chemotherapy can be considered a standard approach in the management of operable breast cancer in routine practice. There are limited contraindications to its use, that is, patients with small tumors with low aggressive features for whom systemic chemotherapy would not be a suitable approach. However, if the pretreatment information is sufficient to recommend a systemic approach, there is no risk of overtreatment with neoadjuvant chemotherapy.

The more recent neoadjuvant trials have focused on the addition of taxanes and alternative schedules such as dose-dense chemotherapy. To study the role of docetaxel in the neoadjuvant setting, the NSABP-27 trial [9] randomized 2,411 women with operable breast cancer (excluding patients with T4 tumors) to four cycles of AC alone, four cycles of AC followed by four cycles of docetaxel (Doc) before surgery, and in the third arm to four cycles of neoadjuvant AC followed by four cycles of adjuvant Doc after surgery. The addition of Doc preoperatively to AC increased significantly the pCR rate in the breast (14 vs. 26%; p > 0.001), and the proportion of patients with negative nodes (51 vs. 58%; p > 0.001) compared to four cycles of AC. However, despite the pCR rate being almost doubled by the addition of taxanes to AC preoperatively, the study did not demonstrate a significant improvement in outcome in terms of DFS and OS [10]. On the basis of these results, many investigators have concluded that early improvements in pCR rates cannot yet act as surrogate endpoints. However, there is another possible explanation for the lack of survival advantage, despite the significant pCR gain. The NSABP B-27 study was powered to detect a 25% reduction in the hazard ratio for mortality. None of the trials testing the addition of a taxane in the adjuvant setting has demonstrated benefits of this magnitude. If we take relapse-free survival into consideration, there were 231 events in the AC docetaxel arm as compared to 258 events in the AC arm. This 10% event rate reduction would have required > 10,000 patients enrolled to be detected statistically.

Paclitaxel has also been tested in the neoadjuvant setting. To evaluate the prognostic impact of the addition of paclitaxel to doxorubicin-based neoadjuvant chemotherapy, Mazouni et al. [11] performed a pooled analysis of results from seven consecutive neoadjuvant chemotherapy trials conducted at MD Anderson Cancer Center from 1974 to 2001, including 1079 patients. Patients with ER-negative cancer had higher overall pCR rate than those with ER-positive tumors (20.1% vs. 4.9%, p < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with or without a taxane (p < 0.001), respectively. In ER-positive patients, the pCR rates were 8.8% and 2.0% with or without a taxane (p < 0.001). In multivariate analysis, clinical tumor size (p < 0.001), ERnegative status (p < 0.001), and inclusion of a taxane (p = 0.01) were independently associated with pCR. The best results were observed with the administration of 12 weekly cycles of paclitaxel followed by four cycles of fluorouracil-epirubicin-cyclophosphamide (FEC) given every 3 weeks [12]. The superiority of weekly over q3wk paclitaxel has also been confirmed in the adjuvant setting [13].

It has been hypothesized that the administration of standard doses at shorter intervals (dose-dense approach) is more effective in avoiding tumor regrowth than the delivery of a single very high dose treatment. A meta-analysis of all randomized trials comparing dose-dense with standard chemotherapy in the neoadjuvant and adjuvant setting has been recently performed [14]. Patients who received dose-dense chemotherapy had better OS (HR of death = 0.84, 95% confidence interval [CI] = 0.72 to 0.98, p = 0.03) and better disease-free survival (HR of recurrence or death = 0.83, 95% CI = 0.73 to 0.94, p = 0.005) than those on the conventional schedule. However , no benefit was observed in patients with hormone receptor-positive tumors.

Three decades of neoadjuvant trials have failed to define the best chemotherapy approach. Breast cancer is a heterogenous disease, and it is now widely accepted that the disease is divided into several subtypes with different biological behaviors, and different chemosensitivity [28–30]. The efficacy of chemotherapy is scarce (or even absent) in the low-proliferating, highly endocrine-sensitive tumors (luminal A subtype); otherwise chemotherapy has a relevant antitumor effect in the majority of patients with highly proliferant tumor (Luminal B, triple negative, HER2 positive). Since all these kinds of intrinsic subtypes were included in the neoadjuvant trials, this heterogeneity may have diluted (and sometimes hidden) the differences between the different regimens.

In the last few years many trials, evaluating the role of targeted agents in the neoadjuvant setting, have been carried out (Table 17.3). The combination of trastuzumab with chemotherapy is the standard adjuvant treatment for HER2-positive breast cancer and has also been widely investigated in the preoperative setting. The first randomized trials evaluating the addition of trastuzumab to chemotherapy were conducted at the MD Anderson Cancer Center, and patients with stage II and IIIa HER2-overexpressing tumors randomized to four cycles of paclitaxel followed by four cycles of FEC with or without trastuzumab [15]. After treating 42 patients, the study was stopped prematurely due to the remarkably high pCR rate in the trastuzumab arm (65 vs. 25%; p = 0.02). This preliminary data was confirmed by two large studies [16, 17]. In the GeparQuattro study, the pCR rate (ypT0 ypN0) was 31.7% compared to 15.7% in the HER2-negative reference group [16]. The NOAH trial compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment) with no trastuzumab, in women with HER2-positive locally- advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Trastuzumab significantly improved event-free survival (3- year EFS 71 vs. 56%; hazard ratio, 0.59 [95% CI, 0.38–0.90]; p = 0.013) [17].