Introduction
Neoadjuvant chemotherapy (NAC) is widely used to cure breast cancer (BC), for both local control and for the eradication of micrometastases. In particular, it is essential for treating both human epidermal growth factor receptor 2 (HER2)-positive BC and triple-negative BC (TNBC) [
1,
2]. Since the pathological complete response (pCR) rate has been suggested as a prognostic factor for non-luminal BC, we performed NAC to obtain a better pCR rate and develop a new treatment regimen [
3]. The prognosis of HER2-positive BC has been significantly improved by the development of anti-HER2 therapy. In HER2-positive BC, several NAC trials have been performed. The NOAH study demonstrated that the addition of trastuzumab (T-mab) to combination chemotherapy significantly increased the pCR rate from 22 to 43% and prolonged event-free survival, which opened the window of NAC for HER2-positive BC [
4].
The addition of trastuzumab (T-mab), lapatinib, and their combination to paclitaxel showed a 29.5, 24.7, and 51.3% pCR rates, respectively [
5]. Furthermore, addition of T-mab, pertuzumab (P-mab), and their combination to docetaxel showed 31, 23, and 49% pCR rates, respectively [
6]. Simultaneously, the CLEOPATRA study for metastatic HER2-positive BC reported the efficacy of dual HER2 blockade by T-mab and P-mab, suggesting that this strategy may lead to a cure for HER2-positive BC [
7]. Several other clinical trials using a combination of T-mab and P-mab demonstrated a pCR rate of > 60% with anthracycline [
8,
9]. These results indicate that the addition and/or combination of anti-HER2 therapy with taxanes can reveal synergistic effects and improve pCR rates. We thus understand the usefulness of dual blockade using anti-HER2 agents, even in early BC. In the Neosphere study, the pCR rate of the dual blockade by T-mab and P-mab was 18%. However, the combination of these blockades and docetaxel increased the pCR rate up to 49%, suggesting that the selection and addition of chemotherapeutic agents is important [
6].
At present, there are three clinically available taxanes. Albumin-bound paclitaxel (nab-PTX; Abraxane
®) is a solvent-free formulation of paclitaxel that reversibly binds to albumin. Nab-PTX was reported to be delivered to the tumor at a concentration 1.3 times higher than that of paclitaxel when administered at the same dose, resulting in a stronger antitumor effect in vitro [
10]. Furthermore, nab-PTX was demonstrated to show higher clinical efficacy and cause hypersensitivity less commonly than paclitaxel or docetaxel [
11,
12]. Based on these results, nab-PTX was administered as NAC in combination with an anti-HER2 agent. We previously reported a phase II study, named PerSeUS-BC01, for operable BC using nab-PTX. In that study, we found that the pCR rate for the HER2-subtype was 60% [
13]. This result prompted us to further investigate the power of nab-PTX as NAC in Japan. Thus, we performed a meta-analysis of nab-PTX as NAC by collecting individual patient data from 16 phase II studies in Japan. In particular, the pCR rate for the HER2-subtype was 63.5% when combined with T-mab [
14]. Therefore, to investigate the power and safety of nab-PTX with T-mab and P-mab followed by epirubicin and cyclophosphamide (EC) as NAC, we conducted a prospective phase II study called PerSeUS BC04 (Perpetual Study estimated-by the United Sections in Gifu for Breast Cancer 04). Our study aim is to demonstrate the efficacy of nab-PTX in combination with anti-HER2-therapy.
Discussion
In this study of HER2-positive BCs, our protocol achieved a pCR rate of 53.5% (95% CI: 42.6–64.1%). The low threshold limit was below 45.5% and the
p value was 0.184, which were not statistically significant. Although there was a clinically significant difference, the number of cases in our study was 43, with a power of only 37.0% at a significance level of
α = 0.05. Thus, we needed 98 cases to obtain a significant difference. However, it is important to note that we obtained a pCR rate of 68.3% (95% CI; 45.1–86.1%) for the HER2-subtype and 38.1% (95% CI; 18.1–61.6%) for the luminal/HER2-subtype. Considering that our previous pCR rate data using nab-PTX with T-mab followed by EC demonstrated a pCR rate of 36.4% (8/22) for all HER2-positive BCs, 60% for the HER2-subtype, and 29.4% for the luminal/HER2-subtype [
13], the addition of P-mab promoted a pCR rate up to approximately 10%. The pCR rate in the Neosphere study was 63.2% for the HER2-subtype by administration of docetaxel with T-mab and P-mab [
7]. Furthermore, in the TRYPHAENA and BERENICE studies, it increased up to 65–81%, which was obtained not only due to taxane administration with T-mab and P-mab, but also due to the administration of additional anthracycline [
8,
9]. In contrast, the pCR rate of KRISTINE was 73.2% for the HER2-subtype due to the administration of TCH (docetaxel, carboplatin, and T-mab) with P-mab [
29]. Fasching et al. reported that the pCR rate could be improved by 20% with the addition of P-mab, even in routine clinical use [
30]. These data suggest that dual blockade by both T-mab and P-mab is essential, and the selection of a combinational chemotherapeutic agent is also important for NAC against HER2-positive BCs. As shown in Fig.
3a and 3c, clinical CR and PR were 31% (13/42) and 92.9% (39/42) after nab-PTX; however, they reached 58% (25/43) and 100% (43/43) after EC, suggesting that EC after nab-PTX also plays an additional role in antitumor efficacy.
We have been interested in nab-PTX from the three available taxanes because it has several advantages compared with other potential drugs. Paclitaxel can improve immunological status by decreasing regulatory T cells (Tregs) and increasing Th1 cytokines, such as IFNγ-and/or IL-2, in vitro and in vivo [
31,
32]. Nab-PTX can accelerate antitumor effects by activating M1 macrophages and MHCII/CD80/CD86, an important factor for activating helper T and naïve T cells [
33]. Moreover, anti-HER2 antibodies, such as T-mab and P-mab, exhibit antibody-dependent cell-mediated cytotoxicity [
34,
35]. Although the addition of immunotherapy revealed an apparent synergistic effect in a neoadjuvant setting for TNBC, this strategy was not effective for HER2-positive BCs, suggesting that at present, the selection of a chemotherapeutic agent is key for the success of NAC in HER2-positive BCs [
36].
TILs were also a predictive factor for the nab-PTX regimen (Fig.
4). Although our data were obtained from patients with a triweekly administration of nab-PTX (because only triweekly use was approved in Japan), the GeparSepto study of weekly administration of nab-PTX with T-mab and P-mab to the HER2-subtype reached up to 76% of pCR rate [
28]. These data suggest that nab-PTX combined with T-mab and P-mab can improve the intratumoral immunological environment and enhance the efficacy of HER2-positive BCs.
Nab-PTX also has a clinical advantage; namely, it shows a very low rate of hypersensitivity because AEs tend to bother patients, which often leads to the termination of the essential treatment. According to previous studies comparing conventional paclitaxel and docetaxel, nab-PXT demonstrated < 1% hypersensitivity of any grade without premedication with steroids [
11,
12]. In the current study, allergy to nab-PTX (a suspicious case) occurred in only one case (2.3%), indicating that scheduled administration was performed. All other AEs were controlled. As shown in Table
2, PTX-specific AEs, such as sensory neuropathy, arthralgia, myalgia, and liver dysfunction occurred at a high frequency, whereas nab-PTX was stably administered in combination with anti-HER2 therapy by controlling the appropriate supportive care, leading to preferred clinical outcome [
13,
18,
19]. However, according to data from a Japanese meta-analysis, the 5-year disease-free survival/overall survival after nab-PTX with T-mab plus anthracycline was 86.9/96.6% for HER2 and 90/97.1% for the luminal/HER2-subtype [
14]. Furthermore, the GeparSepto study demonstrated a statistically significant elongation of disease-free survival in the nab-PTX group [
37].
Our multi-institutional prospective phase II trial had some limitations. This was a single-arm study. The small sample size of each subtype may have influenced the results of the primary endpoint. Despite statistical analysis undertaken in a preplanned manner, the multivariable analysis was not performed because our sample size was not large enough.
In conclusion, we developed a new chemotherapeutic regimen for HER2-positive BCs. Nab-PTX in combination with T-mab and P-mab is a safe and effective treatment regimen, particularly for HER2-subtype BCs. The microenvironment of tumors, such as TIL, may be a predictive factor for anti-HER2 NAC therapy.
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