Abstract
Neoadjuvant chemotherapy has the advantage of converting unresectable breast tumors to resectable tumors and allowing more conservative surgery in some mastectomy candidates. Chemotherapy agents, including taxanes, which are recommended in the adjuvant setting, are also considered in the neoadjuvant setting. Here, we review studies of nab-paclitaxel as a neoadjuvant treatment for patients with breast cancer. PubMed and conference or congress proceedings were searched for clinical studies of nab-paclitaxel in the neoadjuvant treatment of breast cancer. We also searched ClinicalTrials.gov for ongoing trials of nab-paclitaxel as a neoadjuvant agent in breast cancer. Twenty studies of nab-paclitaxel in the neoadjuvant setting were identified. In addition to reviewing key efficacy and safety data, we discuss how each trial assessed response, focusing on pathologic complete response and residual cancer burden scoring. Safety profiles are also reviewed. nab-Paclitaxel demonstrated antitumor activity and an acceptable safety profile in the neoadjuvant treatment of breast cancer. Ongoing and future trials will further evaluate preoperative nab-paclitaxel in breast cancer, including in combination with many novel immunological targeted therapies.
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Background
Introduction to neoadjuvant therapy
Breast cancer remains one of the most commonly diagnosed cancers in the United States, representing 29 % of annual cancer diagnoses in women [1]. More than 200,000 new cases of invasive breast cancer, with approximately 40,000 related deaths, were expected in 2015 [1]. The 5-year survival rate for all stages of breast cancer combined is 89 % [1]. However, patients with localized breast cancer have a higher 5-year survival rate of 99 % compared with those with regional disease in the axillary lymph nodes, which confers a 5-year survival rate of 85 % [1]. Metastatic dissemination further reduces 5-year survival rates to 25 % [1].
Surgery with the goal of removing the primary tumor and achieving negative tumor margins is the primary therapeutic approach for minimizing risk of recurrence and increasing survival of patients with early-stage breast cancer. Chemotherapy before surgery, or neoadjuvant chemotherapy, helps convert large, unresectable tumors to resectable tumors [2, 3]. In addition, neoadjuvant therapies can shrink operable tumors, allowing breast-conserving surgery to be performed instead of mastectomy [2, 3]. Regional disease may also be decreased with the use of sentinel lymph node biopsy, potentially reducing the need for axillary lymph node dissection [4].
In addition to treatment benefits, neoadjuvant studies provide valuable tissue samples for biomarker evaluation. Because loco-regional responses to neoadjuvant therapies correlate with long-term outcomes, neoadjuvant therapies also offer unique opportunities for early prediction of responses and individualization of treatment.
Using pathologic complete response (pCR) and residual cancer burden (RCB) as endpoints in neoadjuvant studies
The US Food and Drug Administration (FDA) supports pCR as an endpoint for evaluating new neoadjuvant agents for high-risk, early-stage breast cancer [5, 6]. pCR is defined by the FDA as the “absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current AJCC staging system)” or “absence of the residual invasive and in situ cancers in the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0ypN0)” [6]. In a large FDA-led meta-analysis, pCR defined as ypT0/isypN0 or ypT0ypN0 was more closely associated with improved survival compared with ypT0/is (defined as absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) [3, 5]. It is important to note that, according to the FDA, “high risk” specifically refers to “patients with early-stage breast cancer who have a high risk of distant disease recurrence and death despite use of optimal modern local and systemic adjuvant therapy” [6]. Inclusion of patients with low-grade, hormone receptor (HR)-positive tumors in neoadjuvant breast cancer trials using pCR as an endpoint is not recommended by the FDA; these patients generally have better long-term outcomes compared with patients with high-risk disease.
RCB also measures response to neoadjuvant agents [7]. RCB was initially devised to address the oversimplified dichotomized pCR data and is derived from the dimensions of the primary tumor, cellularity of the tumor bed, and axillary node burden. Although RCB is not routinely assessed in clinical trials, this measurement was used in some of the studies reviewed here.
Chemotherapy in the neoadjuvant setting
Neoadjuvant versus adjuvant treatment with doxorubicin and cyclophosphamide (AC) was first compared in operable breast cancer in NSABP B-18 [8]. No significant differences in overall survival (OS; 55 % for both groups; P = 0.90) or disease-free survival (DFS; 42 vs 39 %; P = 0.27) were found after 16 years of follow-up. However, neoadjuvant AC reduced node-positive disease, with a significantly increased percentage of negative axillary nodes (58 vs 42 %; P < 0.0001) and increased frequency of breast-conserving surgery (68 vs 60 %; P = 0.001) [8]. EORTC trial 10902 also found no differences in 10-year OS (64 vs 66 %; hazard ratio [HR] = 1.09; 95 % CI 0.83–1.42; P = 0.54) or DFS (48 vs 50 %; HR = 1.12; 95 % CI 0.90–1.39; P = 0.30) after preoperative vs postoperative chemotherapy (fluorouracil, epirubicin, and cyclophosphamide [FEC]) [9]. However, as reported by the phase III European Cooperative Trial in Operable Breast Cancer (ECTO), neoadjuvant vs adjuvant paclitaxelplus doxorubicin, followed by cyclophosphamide, methotrexate, and fluorouracil (AT → CMF) significantly increased the incidence of lumpectomy (63 vs 34 %; P < 0.001) despite no change in OS (HR = 1.10; P = 0.60) [10].
pCR was significantly correlated with DFS in the NSABP B-18 trial (HR = 0.47; P < 0.0001) or OS (HR = 0.32; P < 0.0001) [8], suggesting that pCR after neoadjuvant treatment may predict favorable long-term outcome. A meta-analysis conducted by the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC), which included approximately 12,000 patients in 12 randomized trials, confirmed better long-term outcomes in patients who achieved pCR (HR = 0.36; 95 % CI 0.31–0.42) [3]. In addition, the TECHNO trial of neoadjuvant trastuzumab plus chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer showed a correlation between pCR and improved DFS (HR = 2.5; 95 % CI 1.2–5.1; P = 0.013) [11].
Role of neoadjuvant paclitaxel in breast cancer
Multiple clinical trials support paclitaxel in the neoadjuvant treatment of breast cancer. ECTO established an in-breast pCR of 23 % and breast-plus-node pCR of 20 % after neoadjuvant AT followed by CMF [12]. The NOAH trial showed similar results, with an in-breast pCR of 17 % and breast-plus-node pCR of 16 % in HER2-negative patients treated with neoadjuvant AT followed by paclitaxel and CMF [13]. In patients with HER2+positive disease treated with neoadjuvant chemotherapy plus neoadjuvant and adjuvant trastuzumab, pCR rates were 43 % in breast and 38 % in breast-plus axilla [13].
SWOG 0012 compared 21-day AC followed by paclitaxel versus weekly AC with granulocyte colony-stimulating factor (G-CSF) support followed by paclitaxel [14]. Although pCR was slightly higher after weekly AC plus paclitaxel (24.3 vs 20.7 %; P = 0.45), a significantly higher pCR was achieved in patients with stage IIIB disease who received weekly AC versus 21-day AC (25.8 vs 9.3 %; P = 0.0057). Subsequently, phase III Neo-tAnGo found that paclitaxel followed by anthracyclines significantly improved pCR compared with anthracyclines followed by paclitaxel (20 vs 15 %; P = 0.03) [15].
CALGB 40603 evaluated neoadjuvant weekly paclitaxel followed by dose-dense AC ± bevacizumab and/or carboplatin for triple-negative breast cancer (TNBC) [16]. Carboplatin significantly increased breast pCR (60 vs 46 %; P = 0.0018) and breast-plus-axilla pCR (54 vs 41 %; P = 0.0029), whereas bevacizumab increased only breast pCR (59 vs 48 %; P = 0.0089).
Neoadjuvant lapatinib plus trastuzumab followed by neoadjuvant lapatinib plus trastuzumab plus paclitaxel significantly improved pCR vs neoadjuvant trastuzumab alone followed by neoadjuvant trastuzumab plus paclitaxel (51.3 vs 29.5 %; P = 0.0001) in patients with HER2+ breast cancer in the NeoALTTO study [17]. Similarly, NSABP B-41 reported higher pCR when neoadjuvant AC followed by trastuzumab plus lapatinib plus paclitaxel was compared with AC followed by trastuzumab plus paclitaxel (62 vs 52.5 %; P = 0.095) [18]. CALGB 40601 also demonstrated numerically increased pCR after weekly paclitaxel plus trastuzumab plus lapatinib versus weekly paclitaxel plus trastuzumab (51 vs 40 %; P = 0.11) [19].
These trials collectively support the efficacy of neoadjuvant paclitaxel in all subtypes of breast cancer. As a result, many National Comprehensive Cancer Network-preferred neoadjuvant regimens now include taxanes [20].
Development of nab-paclitaxel
Paclitaxel is formulated with Kolliphor EL (formerly Cremophor EL), which can elicit hypersensitivity reactions and peripheral neuropathy [21]. Nanoparticle albumin-bound paclitaxel (nab ®-paclitaxel, Celgene Corporation, Summit, NJ) minimizes these toxicities and obviates prophylactic antihistamine and steroid treatment [21, 22]. Compared with paclitaxel, nab-paclitaxel yields a 10-fold higher mean maximal concentration of free paclitaxel [23]. In addition, nab-paclitaxel is transported more rapidly across endothelial cell layers and exhibits greater tissue penetration and slower elimination of paclitaxel [24, 25]. According to preclinical models, increased intratumoral delivery and retention result in 33 % higher intratumoral drug concentrations [24].
A significantly improved overall response rate (ORR) (33 vs 19 %; P = 0.001) and time to tumor progression (23.0 vs 16.9 weeks; HR= 0.75; P = 0.006) were reported for nab-paclitaxel in a phase III trial of nab-paclitaxel (260 mg/m2 every 3 weeks [q3w]) vs paclitaxel (175 mg/m2 q3w) in metastatic breast cancer (MBC) [26]. nab-Paclitaxel was associated with a lower incidence of grade 4 neutropenia (9 vs 22 %; P < 0.001) and higher incidence of grade 3 sensory neuropathy (10 vs 2 %; P < 0.001). In a subsequent phase II trial of first-line nab-paclitaxel vs docetaxel for MBC, nab-paclitaxel 150 mg/m2 the first 3 of 4 weeks (qw 3/4) significantly prolonged PFS by independent (12.9 vs 7.5 months; P = 0.0065) and investigator (14.6 vs 7.8 months; P = 0.012) review vs docetaxel [22]. In addition, nab-paclitaxel improved ORR, although the difference was not significant. Grade 3 fatigue and grade 4 neutropenia were lower with nab-paclitaxel, whereas the incidence of grade 3/4 sensory neuropathy was similar. These trials support the overall efficacy and safety of nab-paclitaxel in MBC.
Methods
The search terms “nab-paclitaxel” or “nanoparticle paclitaxel” and “breast cancer” and “neoadjuvant” and “clinical trial” were applied to retrieve publications from PubMed and presentations from conferences and congresses, including American Society of Cancer Oncology annual meetings, Breast Cancer Symposium, and the San Antonio Breast Cancer Symposium. Results were evaluated for study design and key efficacy and safety data with a focus on TNBC.
Results
Twenty studies of neoadjuvant nab-paclitaxel in breast cancer were retrieved (Table 1). Most reported the results of phase II trials. Disease subtype varied among studies, as did treatment dose and schedule. Study design, including doses and sequencing of agents, and key results are summarized (Table 1). In addition, key safety data are provided (Table 2).
Unselected disease
nab-Paclitaxel (260 mg/m2 q3w) plus capecitabine was evaluated for previously untreated locally advanced breast cancer (LABC) in a phase II study (N = 14) [27]. The study was terminated early due to a low response rate. Grade 3/4 toxicities included hand-foot syndrome, neutropenia or neutropenic fever, syncope, and hypertension.
In another phase II trial, gemcitabine and epirubicin were combined with neoadjuvant nab-paclitaxel (175 mg/m2 every 2 weeks [q2w]) for LABC (N = 123) [28]. Pegfilgrastim was also administered. pCR occurred in 20 % of patients, and 3-year PFS and OS were 48 and 86 %, respectively. Among 44 patients with TNBC, 12 (27 %) had pCR. The most common grade 3/4 toxicity, occurring in 11 % of patients, was neutropenia. Grade 3 sensory neuropathy occurred in 3 (2 %) patients, with no grade 4 sensory neuropathy. Non-hematologic toxicities were uncommon.
nab-Paclitaxel (100 mg/m2 once weekly [qw]) followed by FEC was evaluated for previously untreated LABC in a phase II trial (N = 66) [29]. Patients with HER2+ disease also received trastuzumab. An in-breast pCR of 29 % and breast-plus-node pCR of 26 % were reported. Analysis by molecular subtype showed pCR in 28 % of TNBC, 70 % of HR-/HER2+, and 44 % of HR+/HER2+ patients. PFS and OS were 81 and 95 %, respectively, for the intent-to-treat (ITT) population. The regimen was tolerable, with no grade 4 toxicities due to nab-paclitaxel treatment. Grade 3/4 febrile neutropenia due to FEC occurred in 7 % of patients.
nab-Paclitaxel (125 mg/m2 qw; n = 30) and paclitaxel (80 mg/m2 qw; n = 90) were recently compared in combination with carboplatin in a phase II trial for LABC [30]. Trastuzumab was added for HER2+ disease. pCR rates were similar (26.7 vs 25.6 % with nab-paclitaxel vs paclitaxel, respectively; P = 0.904), and no differences were found with trastuzumab (43.6 vs 39.6 %; P = 0.769). One of two patients with TNBC achieved pCR with nab-paclitaxel. Interestingly, nab-paclitaxel showed benefit in patients with stage II disease, with a pCR of 36.8 versus 15.8 % with paclitaxel (P = 0.051). No grade 3/4 peripheral neurotoxicity was reported in either arm. However, grade 4 neutropenia increased with nab-paclitaxel (56.7 vs 21.1 %; P < 0.001).
nab-Paclitaxel with HER2-targeted therapies
Several studies examined nab-paclitaxel for HER2-overexpressing breast cancer. nab-Paclitaxel (260 mg/m2 q3w) plus lapatinib was investigated in a phase I study for early-stage, HER2+ breast cancer (N = 30) [31]. A pCR of 17.9 % (95 % CI 3.7–32.1 %) was reported, with fatigue and diarrhea being the most common grade 3 toxicities. No grade 4 toxicities were reported.
A recent phase II study of preoperative nab-paclitaxel (260 mg/m2 q2w) followed by vinorelbine plus trastuzumab in HER2-overexpressing breast cancer (N = 27) reported a pCR of 48 % [32]. Sub-analysis by HR status showed a pCR of 18 % in patients with estrogen receptor (ER)+/progesterone receptor (PR)+ disease and 69 % in patients with ER−/PR− disease. Six patients had grade 2/3 neuropathy, with no grade 4 neuropathy reported. Similarly, another phase II trial of neoadjuvant anthracycline followed by nab-paclitaxel (260 mg/m2 q3w) plus trastuzumab reported 49 % pCR in the ITT group for operable HER2+ breast cancer (N = 46) [33]. A pCR of 71 % was achieved in cases with ER− disease compared with 36 % in ER+ disease. Hematologic toxicities were the most common cause of treatment delays or dose reductions, with one case of peripheral neuropathy requiring dose reduction.
In general, compared with patients with HER2+/HR+ disease, those with HR−/HER2+ cancer had higher pCR rates. Response rates to lapatinib plus nab-paclitaxel were low.
nab-Paclitaxel with bevacizumab
Neoadjuvant nab-paclitaxel plus bevacizumab has also been evaluated as a potential treatment for breast cancer. In a study of weekly nab-paclitaxel (100 mg/m2), carboplatin, and bevacizumab with (n = 31) or without (n = 29) dose-dense AC, pCR was 11 and 27 % in the ITT group and TNBC subset, respectively [34]. Addition of dose-dense AC increased pCR to 54 %, with a pCR of 81 % in the TNBC subpopulation. Grade 3/4 toxicities included neutropenia, thrombocytopenia, and anemia, with no grade 3/4 neurosensory toxicities.
Weekly neoadjuvant nab-paclitaxel (100 mg/m2) ± bevacizumab followed by dose-dense AC was evaluated for HER2− LABC in phase II SWOG S0800 (N = 215) [35]. The overall pCR was 28 %, but a significantly higher pCR was achieved with bevacizumab (36 vs 21 %; P = 0.021). In HR+ patients, the difference was not significant (bevacizumab vs no bevacizumab, 25 vs 18 %; P = 0.41). However, HR- patients had significantly improved pCR with bevacizumab (59 vs 28 %; P = 0.014). Grade 3/4 toxicities were common and not significantly different between arms. In another phase II study, nab-paclitaxel (100 mg/m2 qw 3/4), carboplatin, and bevacizumab achieved a pCR of 21 % in the ITT group (N = 33), with a pCR of 55 % in TNBC patients [36]. Neutropenia and thrombocytopenia were the main toxicities.
These trials demonstrated efficacy of nab-paclitaxel with bevacizumab in combination with carboplatin or dose-dense AC for TNBC. However, hematologic toxicities were common and should be monitored with this treatment combination.
Recent trials
GEICAM (ITT N = 83; phase II) investigated neoadjuvant nab-paclitaxel (150 mg/m2 qw 3/4) in HER2− breast cancer and reported an ORR of 76.5 % [37]. RCB 0 + I was reported in 24.7 % of the treated population. In addition, 40 % of patients received breast-conserving surgery after nab-paclitaxel. Ki-67 > 20 % and high stromal Cav1 correlated with low RCB (RCB 0 + I), suggesting predictive roles for these markers. Grade 3/4 neutropenia (16 %), leukopenia (3.7 %), fatigue (3.7 %), and neuropathy (2.5 %) were the most common toxicities [38].
The phase III GeparSepto trial compared neoadjuvant paclitaxel 80 mg/m2 qw (n = 600) vs nab-paclitaxel (n = 606; dose reduced from 150 mg/m2 qw [n = 229] to 125 mg/m2 qw [n = 377] after study amendment) followed by epirubicin and cyclophosphamide (EC) as part of a neoadjuvant regimen for early-stage breast cancer [39]. Patients with HER2+ disease were also treated with trastuzumab plus pertuzumab. nab-Paclitaxel achieved significantly higher pCR vs paclitaxel, regardless of the pCR definition (ypT0 ypN0, 38 vs 29 %, P = 0.00065; ypT0/is ypN0, 43 vs 35 %, P = 0.004; ypT0/is ypN0/+, 49 vs 40 %, P = 0.002). The largest difference was in the TNBC subgroup in which nab-paclitaxel achieved a pCR of 48 versus 26 % with paclitaxel (P < 0.001). GeparSepto originally used 150 mg/m2 weekly nab-paclitaxel, which caused more peripheral neuropathy and more frequent discontinuations than paclitaxel. Thus, after recruitment of 464 patients, the study protocol was amended to use 125 mg/m2 weekly nab-paclitaxel. For patients who were randomized and started treatment before the amendment, pCR occurred in 34 versus 23 % (P = 0.022) of the patients in the nab-paclitaxel vs paclitaxel group. In patients randomized on or after study amendment and who started treatment, the pCR was 41 % in the nab-paclitaxel group and 32 % in the paclitaxel group (P = 0.013). In a subsequent study (N = 53), sequential nab-paclitaxel (260 mg/m2 q3w) and EC achieved pCR in 3 (5.7 %) and near-pCR in 7 (13.2 %) patients with stage II/III HER2− breast cancer [40]. Grade 3 toxicities were rare and included one case of peripheral neuropathy.
The randomized phase II Adjuvant Dynamic marker-Adjusted Personalized Therapy (ADAPT) Triple Negative trial of neoadjuvant nab-paclitaxel (125 mg/m2 qw 2/3) plus carboplatin (N = 154) or gemcitabine (N = 182) reported an overall pCR of 36 % with significant differences between arms (carboplatin, 45.9 % vs gemcitabine, 28.7 %; P < 0.001) [41]. Early response (P < 0.001) was predictive of pCR regardless of treatment arm.
Toxicities
Most neoadjuvant nab-paclitaxel trials in breast cancer demonstrated acceptable tolerability profiles (Table 2). A few studies compared nab-paclitaxel vs paclitaxel in the preoperative setting in patients with breast cancer. In the GeparSepto study, nab-paclitaxel (150 or 125 mg/m2 qw) followed by EC was associated with significantly improved pCR rates and comparable grade 3/4 adverse events vs paclitaxel followed by EC (neutropenia, 60.8 vs 61.7 %; febrile neutropenia, 4.6 vs 4.0 %; fatigue, 5 vs 4 %) [39]. However, in patients treated with either nab-paclitaxel 150 or 125 mg/m2 qw, grade 3/4 peripheral sensory neuropathy was significantly higher in the nab-paclitaxel arm vs paclitaxel arm (10.4 vs 3 %, P < 0.0001) [39]. In another phase II study comparing nab-paclitaxel with carboplatin vs paclitaxel with carboplatin as neoadjuvant therapy in patients with LABC, the nab-paclitaxel arm had less grade 3/4 neutropenia (30 vs 52 %) and leukopenia (23 vs 35 %), but slightly more thrombocytopenia (8 vs 0 %) and anemia (5 vs 3 %) [30]. Overall, nab-paclitaxel appears to be a promising neoadjuvant agent for breast cancer with an acceptable safety profile; however, toxicities, including peripheral neuropathy, should be monitored.
Discussion
Clinical trials of neoadjuvant nab-paclitaxel for breast cancer have yielded highly encouraging results. Most trials evaluated weekly or q3w nab-paclitaxel in combination with anthracyclines, carboplatin, or cyclophosphamide, or with targeted agents, such as bevacizumab or trastuzumab. pCR rates ranged from 7 to 54 %, with the TNBC subpopulation demonstrating particularly strong responses, ranging from 25.7 to 81 %. In general, pCR rates in TNBC were significantly higher than those observed in other breast cancer subtypes. Overall, neoadjuvant nab-paclitaxel was safe, although hematologic toxicities were reported in some studies. Results from the recent GeparSepto and ADAPT TNBC trials were especially promising, with significantly increased pCR rates after nab-paclitaxel followed by EC, or carboplatin in patients with TNBC. Additional ongoing trials will further examine the efficacy of nab-paclitaxel-based regimens in TNBC. In addition, the long-term effects of nab-paclitaxel need to be compared with those of paclitaxel.
While data in the neoadjuvant setting are limited, some clinical and economic data from model-based and retrospective analyses support the cost-effectiveness of nab-paclitaxel in MBC [42, 43]. An economic analysis of a phase II trial in MBC assessed the average cost of nab-paclitaxel and docetaxel use from a United Kingdom National Health Service perspective. Accounting for cost components, including chemotherapy, drug delivery, and hospitalization due to toxicity, the average costs of nab-paclitaxel 100 and 300 mg/m2 q3w were comparable to the cost of docetaxel 100 mg/m2 q3w (approximately £15,000 per patient for each nab-paclitaxel dose vs £12,000 per patient for docetaxel) [42]. Furthermore, a meta-analysis of randomized clinical trials in MBC found that nab-paclitaxel was associated with a lower incidence of grade 3/4 toxicities compared with paclitaxel and docetaxel and that this translated to lower overall costs with respect to managing these events [44].
Predictive biomarkers of response
Identification of predictive biomarkers continues to advance individualized treatment of cancer patients. The GeparSixto trial found a significant correlation between the percentage of stromal tumor-infiltrating lymphocytes and pCR after neoadjuvant carboplatin, anthracycline, and taxane [45]. An unmet need exists in identifying patients who are most likely to respond to nab-paclitaxel neoadjuvant therapy by establishing biomarkers of response. Secreted protein acidic and rich in cysteine (SPARC) interacts with albumin and is localized in tumor stroma. Thus, it was hypothesized that SPARC expression may affect the antitumor activity of nab-paclitaxel [46–48].The exact role of SPARC in tumor progression is unclear, as some studies suggest a pro-tumorigenic and angiogenic role, whereas others support an anti-tumorigenic role [48]. However, in an exploratory analysis from a large phase III trial of patients with metastatic pancreatic cancer, SPARC expression was neither predictive nor prognostic of OS [49]. Future neoadjuvant nab-paclitaxel-based trials that prospectively evaluate the predictive value of potential molecular and biological markers are warranted.
Ongoing trials
Based on encouraging results with sequential neoadjuvant nab-paclitaxel and FEC, the phase III Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial has been initiated. (Table 3) [29, 50]. Sequential neoadjuvant nab-paclitaxel and EC are also being evaluated in early-stage breast cancer in a phase II trial [51]. Based on the efficacy of carboplatin with nab-paclitaxel, particularly in TNBC, an ongoing phase II study is examining this combination in LABC or inflammatory TNBC [30, 34, 36, 41, 52, 53]. Neoadjuvant nab-paclitaxel will also be tested with carboplatin, AC, and bevacizumab with pegfilgrastim support for locally invasive TNBC [54]. nab-Paclitaxel plus carboplatin will be combined with trastuzumab for early HER2+ disease or with bevacizumab for HER2− cancers [55]. In addition, based on data showing increased expression of epidermal growth factor receptor (EGFR) in half of inflammatory breast cancers, the EGFR monoclonal antibody panitumumab will be combined with carboplatin, FEC, and nab-paclitaxel for HER2− IBC [56, 57]. The results of these ongoing neoadjuvant nab-paclitaxel-based trials may yield improved treatment options for patients with breast cancer.
Future directions: nab-paclitaxel and immune therapy
Upon exposure to chemotherapeutic agents, dying tumor cells induce immune responses and promote the release of tumor antigens [58, 59]. Preclinical data suggest synergistic activity between chemotherapy and checkpoint inhibitors [60]. In mouse models of pancreatic cancer resistant to immune checkpoint inhibition alone, addition of nab-paclitaxel to immune checkpoint inhibitors improved response and survival [61]. nab -Paclitaxel also demonstrated clinical benefit when combined with checkpoint inhibitors in multiple types of solid tumors. A phase Ib study of atezolizumab, a PD-L1 inhibitor, combined with nab-paclitaxel demonstrated activity in 5 evaluable patients with metastatic TNBC (4 partial responses, 1 stable disease) and tolerability [62]. First-line treatment of locally advanced or metastatic non-small cell lung cancer (N = 58) with atezolizumab plus nab-paclitaxel and carboplatin resulted in 25 % complete response and 31.25 % partial response rate, with an ORR of 56 % (95 % CI 30–80 %) [63]. Atezolizumab in combination with nab-paclitaxel vs placebo plus nab-paclitaxel as first-line treatment for metastatic TNBC is currently being evaluated in the phase III IMpassion130 trial (planned N = 350; NCT02425891) [64]. The combination of atezolizumab and nab-paclitaxel is also being evaluated as a neoadjuvant regimen in an ongoing phase II trial in early-stage TNBC [65]. Similarly, the combination of the PD-L1 inhibitor durvalumab plus nab-paclitaxel is being examined as neoadjuvant therapy for early-stage TNBC in an ongoing phase I/II trial [66]. An ongoing trial will also examine nivolumab, a PD-1 inhibitor, in combination with nab-paclitaxel for recurrent, HER2− MBC [67]. Results from these trials may provide further rationale for combining nab-paclitaxel with immune therapies as an exciting new treatment approach for early-stage breast cancer.
Conclusions
In summary, nab-paclitaxel appears to be an effective and well-tolerated neoadjuvant therapy for breast cancer. Ongoing and future trials will further evaluate nab-paclitaxel in all subtypes of breast cancer, including TNBC, which exhibits a particularly high sensitivity to this treatment strategy. Future studies should examine the long-term benefits of nab-paclitaxel vs paclitaxel and should explore combining nab-paclitaxel with novel immunological therapies. The inclusion of molecular or biological/immunological analyses in future trials should help identify predictive markers of response, which can be used to guide patient selection and ultimately improve response rates to neoadjuvant nab-paclitaxel-based regimens.
References
American Cancer Society (2015) Cancer facts and figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed 30 Oct 2015
Untch M, Konecny GE, Paepke S, von Minckwitz G (2014) Current and future role of neoadjuvant therapy for breast cancer. Breast 23:526–537
Cortazar P, Geyer CE Jr. (2015) Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 22:1441–1446
Holmes D, Colfry A, Czerniecki B, Dickson-Witmer D, Francisco Espinel C, Feldman E, Gallagher K, Greenup R, Herrmann V, Kuerer H, Malik M, Manahan E, O’Neill J, Patel M, Sebastian M, Wheeler A, Kass R (2015) Performance and practice guideline for the use of neoadjuvant systemic therapy in the management of breast cancer. Ann Surg Oncol 22:3184–3190
Bossuyt V, Provenzano E, Symmans WF, Boughey JC, Coles C, Curigliano G, Dixon JM, Esserman LJ, Fastner G, Kuehn T, Peintinger F, von Minckwitz G, White J, Yang W, Badve S, Denkert C, MacGrogan G, Penault-Llorca F, Viale G, Cameron D, Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration, International Group-North American Breast Cancer Group BIG-NABCG collaboration (2015) Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann Oncol 26:1280–1291
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2014) Guidance for industry: pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N (2008) Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 26:778–785
van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ, Cooperating Investigators of the EORTC (2009) Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat 115:101–113
Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agullo A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G (2009) Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European cooperative trial in operable breast cancer. J Clin Oncol 27:2474–2481
Untch M, Fasching PA, Konecny GE, Hasmuller S, Lebeau A, Kreienberg R, Camara O, Muller V, du Bois A, Kuhn T, Stickeler E, Harbeck N, Hoss C, Kahlert S, Beck T, Fett W, Mehta KM, von Minckwitz G, Loibl S (2011) Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 29:3351–3357
Gianni L, Baselga J, Eiermann W, Guillem Porta V, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Llombart Cussac A, Bozhok A, Martinez-Agullo A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G, European Cooperative Trial in Operable Breast Cancer Study Group (2005) Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 11:8715–8721
Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375:377–384
Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB (2011) Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol 29:1014–1021
Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C, Investigators Neo-tAnGo (2014) Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol 15:201–212
Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP (2014) Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13–21
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M, NeoALTTO Study Team (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379:633–640
Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N (2013) Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14:1183–1192
Carey LA, Berry DA, Ollila D, Harris L, Krop IE, Weckstein D, Henry NL, Anders CK, Cirrincione C, Winer EP, Perou CM, Hudis C (2013) Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol 31(suppl) [abstract 500]
National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Breast cancer. V3.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 30 Oct 2015
Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring SE, Bedikian A, Hortobagyi GN, Ellerhorst JA (2002) Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 8:1038–1044
Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P (2009) Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 27:3611–3619
Gardner ER, Dahut WL, Scripture CD, Jones J, Aragon-Ching JB, Desai N, Hawkins MJ, Sparreboom A, Figg WD (2008) Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res 14:4200–4205
Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel. Clin Cancer Res 12:1317–1324
Chen N, Li Y, Ye Y, Palmisano M, Chopra R, Zhou S (2014) Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel. J Clin Pharmacol 54:1097–1107
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O’Shaughnessy J (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794–7803
Veerapaneni A, Boisvert M, Choi A, Aggarwal A (2008) Capecitabine and ABI-007 chemotherapy as neoadjuvant treatment of locally advanced breast cancer. J Clin Oncol 26(suppl) [abstract 11535]
Yardley DA, Zubkus J, Daniel B, Inhorn R, Lane CM, Vazquez ER, Naot Y, Burris HA 3rd, Hainsworth JD (2010) A phase II trial of dose-dense neoadjuvant gemcitabine, epirubicin, and albumin-bound paclitaxel with pegfilgrastim in the treatment of patients with locally advanced breast cancer. Clin Breast Cancer 10:367–372
Robidoux A, Buzdar AU, Quinaux E, Jacobs S, Rastogi P, Fourchotte V, Younan RJ, Pajon ER, Shalaby IA, Desai AM, Fehrenbacher L, Geyer CE Jr, Mamounas EP, Wolmark N (2010) A phase II neoadjuvant trial of sequential nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer. Clin Breast Cancer 10:81–86
Huang L, Chen S, Yao L, Liu G, Wu J, Shao Z (2015) Phase II trial of weekly nab-paclitaxel and carboplatin treatment with or without trastuzumab as nonanthracycline neoadjuvant chemotherapy for locally advanced breast cancer. Int J Nanomed 10:1969–1975
Kaklamani VG, Siziopikou K, Scholtens D, Lacouture M, Gordon J, Uthe R, Meservey C, Hansen N, Khan SA, Jeruss JS, Bethke K, Cianfrocca M, Rosen S, Von Roenn J, Wayne J, Parimi V, Jovanovic B, Gradishar W (2012) Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib. Breast Cancer Res Treat 132:833–842
Zelnak AB, Leyland-Jones B, Gabram SG, Styblo TM, Rizzo M, Wood WC, Srinivasiah J, Jonas W, Schnell F, O’Regan RM (2012) High pathologic complete response (pCR) in HER2-positive breast cancer to novel non-anthracycline neoadjuvant chemotherapy. Presented at American Association for Cancer Research [abstract 2703]
Tanaka S, Iwamoto M, Kimura K, Matsunami N, Morishima H, Yoshidome K, Nomura T, Morimoto T, Yamamoto D, Tsubota Y, Kobayashi T, Uchiyama K (2015) Phase II study of neoadjuvant anthracycline-based regimens combined with nanoparticle albumin-bound paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive operable breast cancer. Clin Breast Cancer 15:191–196
Sinclair NF, Abu-Khalaf MM, Rizack T, Rosati K, Chung G, Legare RD, DiGiovanna M, Fenton MA, Bossuyt V, Strenger R, Sakr BJ, Lannin DR, Gass JS, Harris L, Sikov WM (2012) Neoadjuvant weekly nab-paclitaxel, carboplatin plus bevacizumab with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus bevacizumab in ER+/HER2-negative (HR+) and triple-negative breast cancer: a BrUOG study. J Clin Oncol 30(suppl) [abstract1045]
Nahleh ZA, Barlow WE, Hayes DF, Schott AF, Gralow JR, Perez EA, Sikov WM, Chennuru S, Mirshahidi H, Vidito S, Lew DL, Pusztai L, Livingston RB, Hortobagyi GN (2014) S0800: nab-paclitaxel, doxorubicin, cyclophosphamide, and pegfilgrastim with or without bevacizumab in treating women with inflammatory or locally advanced breast cancer. Poster presented at San Antonio Breast Cancer Symposium [abstract P3-11-16]
Mrozek E, Lustberg MB, Knopp MV, Spigos DG, Yang X, Houton LA, Ramaswamy B, Layman RM, Povoski SP, Agnese DM (2010) Phase II trial of neoadjuvant chemotherapy with weekly nanoparticle albumin-bound paclitaxel, carboplatin, and bevacizumab in women with clinical stages II-III breast cancer: pathologic response prediction by changes in angiogenic volume by dynamic contrast magnetic resonance imaging (DCE-MRI). J Clin Oncol 28(suppl) [abstract 604]
Martin M, Antolin S, Anton A, Plazaola A, Garcia-Martinez E, Segui MA, Sanchez-Rovira P, Palacios J, Calvo L, Esteban C, Espinosa E, Guerro A, Batista JN, Arance AM, Barnadas A, Carrasco EM, Rodreguez-Martin C, Caballero R, Casas M, Chacon JI (2014) Nabrax: neoadjuvant therapy of breast cancer with weekly single-agent nab-paclitaxel—final efficacy and biomarkers analysis of GEICAM 2011-02 trial. J Clin Oncol 32(suppl) [abstract 1051]
Martin M, Antolin S, Anton A, Plazaola A, Garcia-Martinez E, Segui MA, Sanchez-Rovira P, Esteban C, Garcia-Valdes E, Calvo L, Quindos M, Carrasco EM, Rodreguez-Martin C, Chacon JI (2013) Nabrax: neoadjuvant therapy of breast cancer with weekly nab-paclitaxel: final safety of GEICAM 2011-02. Presented at San Antonio Breast Cancer Symposium [abstract P3-14-15]
Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G, German Breast Group (GBG), Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators (2016) Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17:345–356
Shimada H, Ueda S, Saeki T, Shigekawa T, Takeuchi H, Hirokawa E, Sugitani I, Sugiyama M, Takahashi T, Matsuura K, Yamane T, Kuji I, Hasebe T, Osaki A (2015) Neoadjuvant triweekly nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for stage II/III HER2-negative breast cancer: evaluation of efficacy and safety. Jpn J Clin Oncol 45:642–649
Gluz O, Nitz U, Liedtke C, Christgen M, Grischke E, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kümmel S, Clemens M, Potenberg J, Staib P, Kohls A, Sotlar K, Pelz E, Kates RE, Würstlein R, Kreipe H, Harbeck N on behalf of the ADAPT investigators (2015) Comparison of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer: WSG-ADAPT TN randomized phase II trial. Presented at San Antonio Breast Cancer Symposium [abstract S6-07]
Dranitsaris G, Coleman R, Gradishar W (2010) nab-Paclitaxel weekly or every 3 weeks compared to standard docetaxel as first-line therapy in patients with metastatic breast cancer: an economic analysis of a prospective randomized trial. Breast Cancer Res Treat 119:717–724
Lazzaro C, Bordonaro R, Cognetti F, Fabi A, De Placido S, Arpino G, Marchetti P, Botticelli A, Pronzato P, Martelli E (2013) An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study. Clinicoecon Outcomes Res 5:125–135
Dranitsaris G, Cottrell W, Spirovski B, Hopkins S (2009) Economic analysis of albumin-bound paclitaxel for the treatment of metastatic breast cancer. J Oncol Pharm Pract 15:67–78
Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kummel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 33:983–991
Schnitzer JE, Oh P (1994) Albondin-mediated capillary permeability to albumin. Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins. J Biol Chem 269:6072–6082
Desai N, Trieu V, Damascelli B, Soon-Shiong P (2009) SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol 2:59–64
Yardley DA (2013) nab-Paclitaxel mechanisms of action and delivery. J Control Release 170:365–372
Hidalgo M, Plaza C, Musteanu M, Illei P, Brachmann CB, Heise C, Pierce D, Lopez-Casas PP, Menendez C, Tabernero J, Romano A, Wei X, Lopez-Rios F, Von Hoff DD (2015) SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial. Clin Cancer Res 21:4811–4818
ClinicalTrials.gov (2013) Neoadjuvant chemotherapy with nab-paclitaxel in women with HER2-negative high-risk breast cancer (ETNA). https://clinicaltrials.gov/ct2/show/NCT01822314. Accessed 30 Oct 2015
ClinicalTrials.gov (2015) IST neoadjuvant Abraxane in newly diagnosed breast cancer (neonab). https://clinicaltrials.gov/ct2/show/NCT01830244
Yardley DA, Raefsky E, Castillo R, Lahiry A, Locicero R, Thompson D, Shastry M, Burris HA 3rd, Hainsworth JD (2011) Phase II study of neoadjuvant weekly nab-paclitaxel and carboplatin, with bevacizumab and trastuzumab, as treatment for women with locally advanced HER2+ breast cancer. Clin Breast Cancer 11:297–305
ClinicalTrials.gov (2015) Carboplatin and paclitaxel albumin-stabilized nanoparticle formulation before surgery in treating patients with locally advanced or inflammatory triple negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT01525966. Accessed 14 Dec 2015
ClinicalTrials.gov (2015). Preoperative chemotherapy in triple negative invasive breast cancer that can be removed by surgery. https://clinicaltrials.gov/ct2/show/NCT00777673. Accessed 14 Dec 2015
ClinicalTrials.gov (2015) Carboplatin + nab-paclitaxel, plus trastuzumab (HER2+) or bevacizumab (HER2−) in the neoadjuvant setting. https://clinicaltrials.gov/ct2/show/NCT00618657. Accessed 14 Dec 2015
ClinicalTrials.gov (2015) Panitumumab, nab-paclitaxel and carboplatin for HER2 negative inflammatory breast cancer. https://clinicaltrials.gov/ct2/show/NCT01036087. Accessed 14 Dec 2015
Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT (2012) Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat 136:331–345
Hodge JW, Kwilas A, Ardiani A, Gameiro SR (2013) Attacking malignant cells that survive therapy: exploiting immunogenic modulation. Oncoimmunology 2:e26937
Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72
Camidge DR, Liu SV, Powderly J, Ready NE, Hodi FS, Gettinger SN, Giaccone G, Liu B, Wallin J, Funke R, Waterkamp D, Heist RS (2015) Atezolizumab (MPDL3280A) combined with platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a phase Ib safety and efficacy update. Presented at 16th World Conference on Lung Cancer 2015. [abstract ORAL02.07]
Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH (2015) Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 3:399–411
Adams S, Diamond J, Hamilton E, Pohlmann P, Tolaney S, Molinero L, Zou W, Liu B, Waterkamp D, Funke R, Powderly J (2015) Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Presented at San Antonio Breast Cancer Symposium [abstract P2-11-06]
Giaccone G, Camidge DR, Liu SV, Powderly J, Hodi FS, Gettinger SN, Heist RS, Liu B, Wallin J, Funke R, Waterkamp D, Ready NE (2015) Safety, activity and biomarkers of atezolizumab (MPDL3280A) with platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): a phase Ib study. Presented at 2015 European Cancer Congress [abstract 513]
ClinicalTrials.gov (2015) A study of atezolizumab (MPDL3280A) in combination with nab-paclitaxel compared with placebo with nab-paclitaxel for patients with previously untreated metastatic triple negative breast cancer (IMpassion130). https://clinicaltrials.gov/ct2/show/NCT02425891. Accessed 14 Dec 2015
ClinicalTrials.gov (2015) Neoadjuvant trial of nab-paclitaxel and MPDL3280A. https://clinicaltrials.gov/ct2/show/NCT02530489. Accessed 14 Dec 2015
ClinicalTrials.gov (2015) Neoadjuvant MEDI4736 concomitant with weekly nab-paclitaxel and dose-dense AC for stage I-III triple negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT02489448. Accessed 14 Dec 2015
ClinicalTrials.gov (2015) Safety study of nivolumab with nab-paclitaxel plus or minus gemcitabine in pancreatic cancer, nab-paclitaxel/carboplatin in stage IIIB/IV non-small cell lung cancer or nab-paclitaxel in recurrent metastatic breast cancer https://clinicaltrials.gov/ct2/show/NCT02309177. Accessed 14 Dec 2015
Khong HT, Dyess DL, Butler TW, Dumlao TL (2011) A phase I study of neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel, doxorubicin, and cyclophosphamide (NAC) in patients with stages II-III HER2-negative breast cancer. J Clin Oncol 29(suppl) [abstract e11519]
Li SM, Wu X, Frankel PH, Gao H, Sun G, Snoo FD, Rossi J, Wang E, Roepman P, Yen Y, Peeters J, Stork L, Somlo G (2012) Correlation between miRNA (miR) and gene expression profiles (GEP) and response to neoadjuvant chemotherapy (NT) in patients with locally advanced and inflammatory breast cancer (BC). J Clin Oncol 30(suppl) [abstract 10545]
Snider JN, Schwartzberg L, Young RR, Yunus F, Allen JW, Verrier C, Javed YA, Jahanzeb M, Sachdev JC (2013) Interim results of weekly nanoparticle bound (nab)-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide (AC) with concurrent bevacizumab for Triple Negative Breast Cancer. J Clin Oncol 31(suppl) [abstract 1068]
Norio Masumoto, Takayuki Kadoya, Ai Amioka, Keiko Kajitani, Akiko Emi, Hideo Shigematsu, Rumi Haruta, Tsuyoshi Kataoka, Kazuo Matsuura, Morihito Okada (2014) A phase II neoadjuvant trial of sequential triweekly nanoparticle albumin-bound paclitaxel and cyclophosphamide followed by 5-fluorouracil/epirubicin/cyclophosphamide in the treatment of operable breast cancer. J Clin Oncol 32(suppl) [abstract 1066]
Connolly RM, Leal JP, Goetz MP, Zhang Z, Zhou XC, Jacobs LK, Mhlanga J, Joo HO, Carpenter J, Storniolo AM, Watkins S, Fetting JH, Miller RS, Sideras K, Jeter SC, Walsh B, Powers P, Zorzi J, Boughey JC, Davidson NE, Carey LA, Wolff AC, Khouri N, Gabrielson E, Wahl RL, Stearns V (2015) TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer. J Nucl Med 56:31–37
Sinclair NF, Sakr BJ, Abu-Khalaf MM, Somlo G, Black RC, Chung GG, Rizack T, Strenger R, Fenton MA, DiGiovanna M, Constantinou M, Lannin DR, Legare RD, Chagpar AB, Sambandam ST, Bossuyt V, Rosati K, Harris L, Sikov WM (2013) Multicenter phase II trial of neoadjuvant carboplatin, weekly nab-paclitaxel, and trastuzumab in stage II-III HER2+ breast cancer: a BrUOG study. J Clin Oncol 31(suppl) [abstract 619]
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Medical writing assistance was provided by Rita Nahta, PhD, of MediTech Media and funded by Celgene Corporation. The authors are fully responsible for the content and editorial decisions for this manuscript.
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Naoto T. Ueno: clinical trial support of panitumumab—Celgene. Eleftherios P. Mamounas: consultant (advisory board)—Celgene, Pfizer, Novartis, Genomic Health Inc; speakers bureau—Genentech/Roche, Genomic Health Inc.
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Ueno, N.T., Mamounas, E.P. Neoadjuvant nab-paclitaxel in the treatment of breast cancer. Breast Cancer Res Treat 156, 427–440 (2016). https://doi.org/10.1007/s10549-016-3778-z
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DOI: https://doi.org/10.1007/s10549-016-3778-z