Meta-analysis of nanoparticle albumin-bound paclitaxel used as neoadjuvant chemotherapy for operable breast cancer based on individual patient data (JBCRG-S01 study)

Although taxane is a current gold standard chemotherapeutic agent for breast cancer (BC), adverse events (AEs) such as peripheral neuropathy and hypersensitivity are often problematic for patients. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is a novel taxane formulation that was developed to avoid the toxicities associated with cremophor/ethanol co-solvents, such as the aforementioned peripheral neuropathy and hypersensitivity reactions [1, 2]. Nab-PTX showed higher tumor suppression in a mouse model than conventional paclitaxel used at a high concentration [3]. As taxol plays an important role in BC therapy, nab-PTX was first utilized for metastatic BC, resulting in longer progression-free survival (PFS) than that achieved with either paclitaxel or docetaxel [4, 5]. Nab-PTX has been reported to induce specific AEs such as arthralgia, myalgia, and peripheral neuropathy, but they are transient and controllable [5]. These reports suggest wide applications of nab-PTX for BC therapy. However, a few large-scale phase III studies using a nab-PTX-containing regimen in a neoadjuvant setting have reported remarkable findings that nab-PTX is more effective than paclitaxel [6].

In Japan, nab-PTX was approved for use and insurance coverage in July 2010; it has been widely used in both neoadjuvant and metastatic settings. At least 35 phase II neoadjuvant studies using nab-PTX have been registered in the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR) [7]. Of these, several studies using a combination of nab-PTX and anthracycline as neoadjuvant chemotherapy (NAC) have been reported [8‐13]. However, these studies have not progressed to phase III randomized controlled trials (RCTs) and their sample sizes have been small. In addition, the results varied because the distribution of patient characteristics differed among the studies. Thus, to estimate the efficacy and safety of nab-PTX precisely in a neoadjuvant setting, we aimed to extract individual patient data (IPD) from studies on nab-PTX-containing regimens registered in UMIN-CTR and analyze the efficacy and safety of nab-PTX based on patient characteristics in a meta-analysis [14].

We analyzed the pCR rates using IPD data based on three pCR definitions [16]. Nodal involvement after NAC was associated with an increased risk of tumor recurrence and death, and a preferable prognosis was not associated with axillary residual tumors or intraductal tumors in the breast. Therefore, we recognize that ypT0 ypN0 and ypT0/is ypN0 are clinically useful pCRs, particularly in patients with aggressive phenotypes such as HER2-rich or TNBC subtypes [22‐24]. Our results indicated that the pCR rates of luminal-type tumors were 6.7, 10.2, and 13.4%, respectively, which are similar to the findings for anthracycline and taxane chemotherapy, supporting the power of nab-PTX for ER-positive subtypes [25]. Although the multivariate analysis demonstrated that TNBC is statistically associated with nab-PTX-related pCR (OR: 2.97), the pCR rate (31.5% for ypT0/is ypN0) was similar to previous findings for anthracycline and taxane chemotherapy [16, 22, 23]. However, recent studies have demonstrated that weekly nab-PTX administration induced a high pCR rate (41–49%) [26‐28]. In our study, the pCR rates for TNBC were 41.7% (20/48) by weekly nab-PTX and 28.8% (53/184) by q3w, respectively. The total dose of nab-PTX was higher with weekly administration than with q3w (Suppl. Table 3). Our findings might have been affected by the higher proportion of patients treated with q3w nab-PTX (83%), resulting in a low pCR rate. Recent publications suggest new strategies, including dose-dense chemotherapy, platinum-containing regimens, or combinations with molecular-targeted agents lead to better results, showing ≥ 50% pCR rates [29‐32]. It should be noted that TNBC-specific characteristics, including high NG, high Ki-67, and PD-L1 expression may have affected these results.

We hypothesized that nab-PTX would have a substantial effect on HER2-positive BC, and we subsequently found that the pCR (ypT0/is ypN0) rates were 63.5% for HER2-rich and 40.6% for luminal/HER2 subtypes. As reported in the NOAH trial and GeparQuattro study, the HER2-positive subtype showed good responses to anthracycline followed by taxane with trastuzumab, with pCR rates of 38–43.5% [33, 34]. The pooled analysis indicated an additional power of 30–50% using trastuzumab [23]. In the NeoALTTO study, the pCR rate of the HER2-rich subtype reached 61.3% after treatment with paclitaxel and dual blockage using trastuzumab and lapatinib [35]. The NeoSphere trial also reported that the pCR rate was 63.2% after treatment with docetaxel combined with trastuzumab and pertuzumab [36]. In our study, the pCR rates reached 63.5% (ypT0/is ypN0) for the HER2-rich subtype with nab-PTX and trastuzumab, and this was similar to the value obtained with a dual anti-HER2 blockage regimen. In the GeparSepto trial, the combination of nab-PTX and dual blockage using pertuzumab and trastuzumab demonstrated remarkable results, showing that the pCR (ypT0 ypN0 and ypT0/is ypN0) rates reached 74.6 and 81.4%, respectively, for the HER2-rich subtype [28]. We obtained results similar to those with the combination of docetaxel/paclitaxel and dual HER2 blockage described above. Despite no statistically significant difference, the pCR (ypT0/is ypN0) rates for the HER2-rich subtype were 59.7% (q3w) and 76.5% (weekly). The ORs for the HER2-rich and luminal/HER2 subtypes in the multivariate analysis were 15.14 and 6.33, respectively, which reflect the cases with high NG and/or Ki-67 expression, as shown in Table 2.

As shown in Table 4, our AE data were obtained using both nab-PTX and anthracycline. Hematological toxicities are reportedly common for both drugs [6, 26‐28]. These results suggest that the toxicities of neoadjuvant nab-PTX are tolerable. Weekly nab-PTX produced more frequent and severe AEs than q3w nab-PTX for the following three reasons. (1) The total dose with weekly administration was considerably higher than that with q3w regimen. (2) Weekly administration resulted in more frequent hospital visits to observe AEs than q3w administration. (3) Our data were obtained from IPD with almost no missing data points, which enabled us to perform precise analyses.

Patients with pCR showed a better prognosis in all subtypes. In particular, the DFS in both HER2-rich and TNBC subtypes was longer with pCR than without pCR. Only TNBC patients with pCR were associated with an improved OS. Our study showed no difference in OS between pCR and non-PCR groups with the HER2-rich subtype, as observed in the NeoSphere study [37]. Although the NeoALLTO study showed a significant association between pCR and both DFS and OS, the OS of HER2-positive BC patients after NAC remains unclear because newly developed anti-HER2 therapies for metastatic BC may strongly affect long-term survival [38]. Our data demonstrated that nab-PTX for NAC induced higher pCR rate particularly in HER2-positive BC patients by combination with trastuzumab. These results may modify the adjuvant therapy against primary HER2-positive BC. If pathologically negative lymph node is found after surgery, trastuzumab monotherapy may be enough in the adjuvant setting. However, in cases of positive lymph node or residual invasive disease, escalating therapies using either pertuzumab or trastuzumab emtansine (T-DM1) may be employed [39, 40]. Patients with pCR who present long DFS could de-escalate the additional anti-HER2 therapies in the adjuvant setting and delay those in the metastatic setting. Although HER2-positive MBC may be sensitive to anti-HER2 therapy, it is the best drug for patients with primary breast cancer.

In this study, we assessed the risk of bias using RoBANS and classified it as moderate [19, 20]. As most of the studies in this meta-analysis were not RCTs, the moderate risk overall does not indicate low study quality. The heterogeneity among the 16 studies was moderate (I² = 68.8%). Unlike an RCT, the summary measure of a single-arm study directly reflects the distribution of the baseline characteristics. Actually, two studies showed low pCR rates in patients with luminal or TNBC subtypes, and high proportions of patients with cStage III. The existence of moderate heterogeneity indicates the need for IPD analysis to minimize heterogeneity.

In conclusion, nab-PTX is an acceptable chemotherapeutic agent for aggressive breast cancers such as HER2-rich, luminal/HER2, and TNBC subtypes in a neoadjuvant setting. Nab-PTX monotherapy is a useful option for TNBC. The combination of nab-PTX and anti-HER2 can achieve desirable pCR rates in patients with HER2-positive subtypes and manageable toxicity. Antibody drug conjugates, such as T-DM1 and trastuzumab deruxtecan (T-Dxd), are being developed in this field. Furthermore, trastuzumab and pertuzumab combined with taxane, and anti-microtubule agents are still considered standard preoperative or adjuvant therapy. Although there is a need for further clinical studies to replace the conventional docetaxel or paclitaxel with nab-PTX, nab-PTX will be considered as a potential chemotherapeutic agent in combination with anti-HER2 antibodies to enhance their efficacy.