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A Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel With or Without Trastuzumab in Metastatic Breast Cancer

      Abstract

      Introduction

      Weekly administration of nanoparticle albumin-bound (nab) paclitaxel as a first-line treatment for metastatic breast cancer (MBC) has not been fully investigated. The addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is less understood. This phase II study evaluated the efficacy and safety of weekly nab paclitaxel in the first-line MBC setting. Patients whose tumors overexpressed HER2 also received trastuzumab.

      Patients and Methods

      Patients with locally advanced or metastatic breast cancer received nab paclitaxel (125 mg/m2) by 30-minute intravenous infusion weekly for 3 of 4 weeks. Patients who were HER2-positive received concurrent trastuzumab.

      Results

      Seventy-two patients were enrolled; HER2 expression was detected in 22 patients. The overall response rate (ORR) was 42.2% (95% CI, 30%–55%); 5 patients had a complete response (CR) and 22 patients had a partial response (PR). Additionally, 17 patients experienced stable disease (SD), providing an overall benefit (CR + PR + SD) of 68.8%. Patients with HER2-positive tumors had an ORR of 52.4%; the ORR was 38.1% in the HER2-negative population (P = .3). Median progression-free survival was 14.5 months (range, 1–49.3 months) and survival rates at 1 year and 2 years were 69% and 62%, respectively. The most commonly observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%).

      Conclusion

      Our findings demonstrate that weekly nab paclitaxel has a favorable safety profile and is well tolerated as a first-line treatment for MBC. An ORR of 42% and an overall benefit of 69% is extremely encouraging, particularly in the HER2-positive population where 52% of patients responded.

      Keywords

      Introduction

      An estimated 40,000 people will die of breast cancer in 2010.
      • Jemal A.
      • Siegel R.
      • Xu J.
      • et al.
      Cancer Statistics, 2010.
      For those patients with metastatic breast cancer (MBC), solvent-based taxanes (paclitaxel and docetaxel) are considered standard treatment.
      • Conlin A.K.
      • Seidman A.D.
      Taxanes in breast cancer: an update.
      National Comprehensive Cancer Network
      Clinical Practice Guidelines in Oncology.
      Alternative therapies are essential for this patient population, as median survival is 2–3 years
      • Mayer E.L.
      • Burstein H.J.
      Chemotherapy for metastatic breast cancer.
      and the 5-year survival rate is approximately 20%.

      Altekruse SF, Kosary CL, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975–2007. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2007. Based on November 2009 SEER data submission, posted to the SEER web site, 2010.

      Although paclitaxel and docetaxel have significant efficacy in breast tumors, their hydrophobic nature necessitates the use of synthetic solvents; polyoxyethylated castor oil (Cremophor® EL) for paclitaxel and polysorbate 80 for docetaxel.
      Taxol (paclitaxel) Injection [package insert].
      Taxotere (docetaxel) Injection Concentrate [package insert].
      These solvents directly contribute to many of the toxicities observed in treated patients, most notably hypersensitivity reactions and peripheral neuropathy.
      • Harries M.
      • Ellis P.
      • Harper P.
      Nanoparticle albumin-bound paclitaxel for metastatic breast cancer.
      • Miele E.
      • Spinelli G.P.
      • Miele E.
      • et al.
      Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer.
      Such toxicities limit the dose and duration of drug treatment and the opportunity to combine taxanes with other agents that have overlapping toxicity profiles.
      • Harries M.
      • Ellis P.
      • Harper P.
      Nanoparticle albumin-bound paclitaxel for metastatic breast cancer.
      Tumor penetration and drug activity may also be compromised by solvent-associated entrapment of active drug in micelles formed in the plasma compartment, thus altering the taxane pharmacokinetics.
      • ten Tije A.J.
      • Verweij J.
      • Loos W.J.
      • et al.
      Pharmacological effects of formulation vehicles: implications for cancer chemotherapy.
      Moreover, both drugs require the use of premedications and in the case of paclitaxel, special tubing and in-line filters are necessary because of leeching of DEHP (di-[2-ethylhexyl]phthalate) caused by Cremophor® EL.
      • Miele E.
      • Spinelli G.P.
      • Miele E.
      • et al.
      Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer.
      Nanoparticle (or nab) paclitaxel (ABI-007, Abraxane®, Abraxis BioScience, Los Angeles, CA), an albumin-bound 130-nm particle form of paclitaxel, was developed in response to these toxicity and drug delivery concerns. The absence of synthetic solvents allows for easier administration of nab-paclitaxel, including a shorter infusion schedule and no need for special infusion kits. Hypersensitivity reactions are rare and premedication is not required.
      • Ibrahim N.K.
      • Desai N.
      • Legha S.
      • et al.
      Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
      Both the absence of solvents and the presence of albumin allow higher doses of paclitaxel to be delivered via nab paclitaxel than with solvent-based paclitaxel. Indeed, drug transport into tumors is enhanced by albumin receptor (gp60)-mediated transcytosis across endothelial cells in preclinical models
      • Desai N.
      • Trieu V.
      • Yao Z.
      • et al.
      Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.
      and by the association with the albumin-binding protein SPARC (osteonectin; secreted protein, acidic and rich in cysteine).
      • Desai N.P.
      • Trieu V.
      • Hwang L.Y.
      • et al.
      Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.
      In preclinical
      • Desai N.
      • Trieu V.
      • Yao Z.
      • et al.
      Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.
      and clinical
      • Ibrahim N.K.
      • Desai N.
      • Legha S.
      • et al.
      Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
      • Ibrahim N.K.
      • Samuels B.
      • Page R.
      • et al.
      Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      • Nyman D.W.
      • Campbell K.J.
      • Hersh E.
      • et al.
      Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
      studies, the equitoxic paclitaxel dose of nab paclitaxel was approximately 50%–70% higher than that of solvent-based paclitaxel.
      These higher doses afforded by nab paclitaxel appear to translate into increased drug efficacy without an increase in toxicity. Patients with MBC receiving nab paclitaxel every 3 weeks (300 mg/m2) experienced an overall response rate (ORR) of 48%, with a response rate of 64% in those patients receiving nab paclitaxel as first-line treatment for MBC.
      • Ibrahim N.K.
      • Samuels B.
      • Page R.
      • et al.
      Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
      A phase III randomized study comparing 3-week cycles of nab paclitaxel (260 mg/m2) and solvent-based paclitaxel (175 mg/m2) reported ORRs of 33% and 19% for each treatment group, respectively. Those patients receiving nab paclitaxel as first-line treatment for MBC had a response rate of 42%, compared with 27% for patients receiving solvent-based paclitaxel.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      Randomized studies that established the advantages of a weekly taxane schedule compared with an every-3-week schedule
      • Perez E.A.
      • Suman V.J.
      • Rowland K.M.
      • et al.
      Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252.
      • Seidman A.D.
      • Berry D.
      • Cirrincione C.
      • et al.
      Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.
      • Sparano J.A.
      • Wang M.
      • Martino S.
      • et al.
      Weekly paclitaxel in the adjuvant treatment of breast cancer.
      • Verril M.W.
      • Lee J.
      • Cameron D.A.
      • et al.
      Anglo-Celtic IV: First results of a UK National Cancer Research Network randomised phase 3 pharmacogenetic trial of weekly versus 3 weekly Paclitaxel in patients with locally advanced or metastatic breast cancer (ABC).
      prompted the examination of a weekly nab paclitaxel schedule. In a direct comparison between weekly (100 mg/m2 or 150 mg/m2) and every-3-week nab paclitaxel (300 mg/m2) and docetaxel (100 mg/m2), either dose of weekly nab paclitaxel was superior as a first-line treatment for MBC.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      Additional studies have further demonstrated that weekly administration of nab paclitaxel is both safe and efficacious,
      • Nyman D.W.
      • Campbell K.J.
      • Hersh E.
      • et al.
      Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      even in taxane-refractory patients.
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
      Regardless of dose or schedule, nab paclitaxel had a favorable safety profile when compared with docetaxel. These studies have demonstrated an increased efficacy of nab paclitaxel without a concurrent increase in toxicity when given weekly versus every 3 weeks. Despite the lack of premedications, severe hypersensitivity reactions were not observed.
      • Ibrahim N.K.
      • Desai N.
      • Legha S.
      • et al.
      Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
      • Ibrahim N.K.
      • Samuels B.
      • Page R.
      • et al.
      Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      • Nyman D.W.
      • Campbell K.J.
      • Hersh E.
      • et al.
      Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
      To date, few studies have investigated the effect of weekly nab paclitaxel in the first-line MBC setting.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      • Conlin A.K.
      • Hudis C.A.
      • Bach A.
      • et al.
      Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
      Less information is available regarding nab paclitaxel when used in combination with trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The addition of trastuzumab to standard chemotherapy (an anthracycline plus cyclophosphamide or paclitaxel alone)
      • Slamon D.J.
      • Leyland-Jones B.
      • Shak S.
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      or docetaxel
      • Marty M.
      • Cognetti F.
      • Maraninchi D.
      • et al.
      Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
      has a significant clinical benefit in this patient population. A recent study investigating the combination of weekly nab-paclitaxel, carboplatin, and trastuzumab showed this regimen to be both well tolerated and efficacious with an ORR of 62.5% in patients with previously untreated HER2-positive MBC.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      The current phase II study sought to evaluate the safety, efficacy, and tolerability of nab paclitaxel given weekly as a first-line treatment of MBC for both HER2-positive and HER2-negative breast tumors. The addition of trastuzumab was also examined in those patients whose tumors overexpressed HER2.

      Patients and Methods

      Patient Selection

      This open-label multicenter phase II trial was conducted in the community-based Veeda Oncology Network (formally the International Oncology Network) practices. The protocol was approved by a central institutional review board (IRB) with jurisdiction over sites that registered patients on study. Local IRB approval was obtained by individual sites where required. All patients signed an informed consent form before admission into the study.
      From March 2005 to September 2006, the Network enrolled patients with histologically or pathologically confirmed diagnosis of locally advanced or metastatic breast cancer. Patients must have had measurable disease, but were permitted to have either HER2-positive or HER2-negative breast cancer. Additional eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, age 18 years or older, estimated life expectancy of at least 12 weeks, absolute neutrophil count ≥ 1500/ μL, platelets ≥ 100,000/μL, hemoglobin ≥9 g/dL, creatinine ≤ 2 mg/dL or calculated creatinine clearance > 40 mL/min, and bilirubin ≤ upper limit of normal (ULN). For patients with no liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must have been ≤ 1.5 × ULN. For patients with liver metastases, AST and ALT must have been ≤ 2.5 × ULN.
      Patients were not eligible if they had previously received nab paclitaxel or any previous chemotherapy for their metastatic disease. However, previous adjuvant chemotherapy, including taxane-containing regimens, was permitted provided that it was completed ≥ 12 months before enrollment. Previous hormonal, aromatase inhibitor therapy, or immunotherapy for metastatic or locally advanced breast cancer was permitted but must have been terminated before enrollment. Previous radiation therapy was also permitted provided that < 25% of the bone marrow had been treated, the patient recovered from the acute toxic effects of treatment before trial enrollment, and treatment was completed ≥ 4 weeks before enrollment. In addition, patients with serious intercurrent medical or psychiatric illness, a second primary malignancy (except carcinoma in situ of the cervix or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated > 5 years previously and with no evidence of recurrence), parenchymal or leptomeningeal brain metastases, or a history of hypersensitivity to taxanes or any of the components in taxanes or nab paclitaxel were not eligible. Female patients could not be pregnant or lactating.

      Treatment and Procedures

      Patients received single-agent nab paclitaxel 125 mg/m2 as a 30-minute intravenous (I.V.) infusion once a week for 3 weeks; a dose chosen based on data previously presented.
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Long term disease control in taxane-refractory metastatic breast cancer treated with nab paclitaxel.
      • Nyman D.W.
      • Campbell K.J.
      • Hersh E.
      • et al.
      A phase I trial of ABI-007, nanoparticle paclitaxel, administered to patients with advanced non-hematologic malignancies.
      A cycle was defined as 4 weeks and nab paclitaxel was not given on week 4. Trastuzumab was given concurrently to patients who were HER2 positive at an initial dose of 4 mg/kg (as a 90-minute I.V. infusion) and then at 2 mg/kg infused over 30 minutes on a weekly schedule. Patients continued to receive treatment until progressive disease (PD) or unacceptable toxicity. Patients who discontinued nab paclitaxel for reasons other than PD were permitted to receive single-agent trastuzumab until disease progression. Patients were removed from the study if they experienced a treatment delay > 2 weeks. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria (NCI-CTC) version 3.0. Dose adjustments for nab paclitaxel (to 100 mg/m2 and then to 80 mg/m2) were made based on hematologic and nonhematologic toxicities when appropriate.
      Pretreatment evaluations consisted of medical history; physical examination with assessment of ECOG PS and peripheral neuropathy; laboratory studies including complete blood count, serum chemistry profile (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total and direct bilirubin, alkaline phosphatase, AST and/or ALT, potassium, magnesium, chloride, sodium, and total calcium); and radiologic evaluation (computed tomography [CT] or magnetic resonance imaging [MRI]). Serum pregnancy tests were required for women of childbearing potential. HER2-positive patients who received trastuzumab were required to have a baseline left ventricular ejection fraction (LVEF) within 90 days of study entry (measured by either echocardiogram or multiple gated acquisition [MUGA] scan) ≥ the lower limits of normal for the radiology facility.
      During treatment, patients underwent weekly blood counts and a toxicity assessment. Serum chemistries and a physical examination, with assessment of ECOG PS and peripheral neuropathy, were performed before each cycle. A radiologic evaluation was performed every 8 weeks. HER2-positive patients who received trastuzumab were required to undergo cardiac monitoring and LVEF assessment via echocardiogram or MUGA scan every 16 weeks.

      Response Criteria

      Response was assessed every 8 weeks by radiologic evaluation, using Response Evaluation Criteria in Solid Tumors (RECIST).
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
      All objective responses were confirmed by a follow-up scan at least 4 weeks following documentation of the response.

      Statistical Analysis

      The endpoints of this study were the ORR, progression-free survival (PFS), 1- and 2-year survival rates, and the safety profile of patients with locally advanced or metastatic breast cancer, who were administered nab paclitaxel weekly as first-line treatment. All analyses were completed with MedCalc software, version 11.0. The sample size of 72 patients was based on an STPlan's exact method of binomial distribution to detect an increase in response rate from 21% to 35%, based on a significance level of 0.05 and a power of 80%.
      An average of 4 patients per month were recruited over a 17-month period. All 72 patients recruited for this trial received study drug and were considered in the intent-to-treat (ITT) population. Only patients who had received at least 2 courses of chemotherapy were considered evaluable for response. A patient was considered a responder if a complete response (CR) or partial response (PR) was found at least once during the course of the study and confirmed 4 weeks later. The overall benefit rate was calculated as the proportion of CR + PR + stable disease (SD) responses. Those who died during therapy and before progression were counted as PD as of the date of death. The distribution of response classifications (CR, PR, SD, and PD) was examined. The ORR was analyzed as the proportion of patients showing a CR or PR while on study. Its 95% CI is presented. A subanalysis was run comparing the responses of those patients who were HER2-positive versus HER2-negative.
      Progression-free survival was estimated using the Kaplan-Meier method
      • Kaplan E.L.
      • Meier P.
      Nonparametric estimation from incomplete observations.
      and summarized by the median and 95% CI. Progression-free survival was measured from the date of first treatment to either the date the patient was first recorded to have disease progression or the date of death if the patient died from any cause before progression. Patients who were lost to follow-up were censored as of the last date of contact. Patients who had not progressed or who died were censored at the date of last follow-up.
      Death was assumed from any cause and measured as the time from the start of treatment to the date of death or the last date the patient was known to be alive. Using the Kaplan-Meier method,
      • Kaplan E.L.
      • Meier P.
      Nonparametric estimation from incomplete observations.
      the proportion of patients surviving at 1 and 2 years was estimated, and the median survival duration and its 95% CI were recorded. Patients who received 1 dose of study drug were included in the safety analysis. Adverse events were coded using the NCI-CTC, version 3.0. These were summarized by frequencies and percents. Chemotherapy administered was described in terms of the total number of cycles administered, the median (range) of cycles/doses administered, and reasons for dose modifications.

      Results

      Patients

      Seventy-two patients were enrolled in this study. Patient characteristics are presented in Table 1 Patients had an ECOG PS of 0 or 1, though 1 patient with an ECOG PS of 2 was allowed to enroll in the study and was later found to be evaluable. A majority of patients had received previous adjuvant treatment, chemotherapy being the most common. Specifically, 15 patients previously received taxanes and 2 patients received previous trastuzumab. HER2 expression was detected in 22 patients (30.6%). For unknown reasons, testing was not performed in 2 patients.
      Table 1Patient Characteristics (N = 72)
      Characteristic, n (%)Value
      Sex
       Male2 (2.8)
       Female70 (97.2)
      Median Age, Years63.5
       Range41–90
      Race
       Black9 (12.5)
       Hispanic4 (5.6)
       Caucasian58 (80.6)
       Asian1 (1.4)
      ECOG Performance Status
       043 (59.7)
       128 (38.9)
       21 (1.4)
      Previous Adjuvant Treatment
       No18 (25)
       Yes
      Patients could have more than 1 type of adjuvant treatment.
      54 (75)
       Biologic10 (14)
         Trastuzumab2 (2.7)
        Chemotherapy49 (68)
         Taxane15 (20.8)
        Hormonal14 (19)
        Radiation17 (24)
        Surgery4 (6)
      HER2 Status
       Positive22 (30.6)
       Negative48 (66.7)
       Unknown2 (2.8)
      Abbreviations: ECOG = Eastern Cooperative Oncology Group; HER2 = Human Epidermal growth factor Receptor 2.
      a Patients could have more than 1 type of adjuvant treatment.

      Treatment Administration and Safety

      Seventy-two patients were treated with study drug and evaluated for safety. Patients received a median of 6 cycles (range, 1–22 cycles) and a median of 5.9 months of treatment (range, 6 days to 25.1 months). The median dose intensity was 100% of the planned dose intensity. The median dose of nab paclitaxel received by patients was 125 mg/m2/week, with a minimum dose of 94 mg/m2/week and a maximum dose of 130 mg/m2/week. Dose modifications because of toxicity occurred in 14 patients (19.4%). Nine patients (12.5%) experienced a dose modification because of other causes. Twenty patients whose tumors were HER2-positive received trastuzumab.
      At least 1 adverse event was experienced by 65 patients (90.3%), though the vast majority of adverse events were grade 1 or grade 2 (Table 2). The most frequently observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%). Of the 46 patients who complained of pain, 8 patients had arthralgia, 6 had back pain, and 5 had headaches. The remaining instances of pain were comprised of varied pain, including extremity pain, myalgia, tumor pain, and bone pain. Adverse events that occurred in ≥ 10% of patients are presented in Table 2 There were 3 instances of a grade 4 event; 1 case each of arrhythmia, colitis, and cerebrovascular ischemia. A total of 9 patients experienced cardiac problems, of whom 5 had received trastuzumab. Of these 5 patients, there were 3 grade 1 events (1 case each of tachycardia, arrhythmia, and left ventricular diastolic dysfunction); 1 grade 2 tachycardia event; and 1 grade 4 arrhythmia event.
      Table 2Adverse Events Experienced by ≥ 10% of Patients
      Adverse Event Preferred TermNumber of Patients (N = 72)
      G1G2G3G4Total (%)
      Percent of adverse events is based on the number of patients who received at least 1 dose of study drug (N = 72).
      Pain191611046 (64)
      Fatigue17205042 (58)
      Sensory Neuropathy19146039 (54)
      Infection2229033 (46)
      Nausea2241027 (38)
      Alopecia5190024 (33)
      Anemia11121024 (33)
      Diarrhea1560021 (29)
      Nail Changes1153019 (26)
      Edema1161018 (25)
      Constipation1031014 (19)
      Dyspnea374014 (19)
      Vomiting1022014 (19)
      Desquamation661013 (18)
      Fever1111013 (18)
      Anorexia560011 (15)
      Neutropenia118010 (14)
      Cardiac event53019 (13)
      Allergic Rhinitis72009 (13)
      Cough63009 (13)
      Hemorrhage81009 (13)
      Muscle Weakness43209 (13)
      Blurred Vision53008 (11)
      Heartburn62008 (11)
      Leucopenia61108 (11)
      Tearing62008 (11)
      Chills52007 (10)
      Dizziness61007 (10)
      Dysgeusia52007 (10)
      Insomnia52007 (10)
      Mood Alteration25007 (10)
      Pulmonary, Other52007 (10)
      a Percent of adverse events is based on the number of patients who received at least 1 dose of study drug (N = 72).
      During the study, 25% (n = 18) of the patients recorded a total of 30 serious adverse events (SAEs); most events were due to pain, infection, or gastrointestinal or pulmonary symptoms. Of the 30 SAEs, 25 were considered related to drug treatment. The majority of events (n = 22) resolved, though 3 events were continuing, 4 resolved with sequelae, and 1 event was fatal caused by PD.
      All 72 patients eventually stopped treatment for various reasons, including disease progression (33.3%), adverse events (26.4%), physician decision (16.7%), withdrawal of consent (12.5%), treatment delay > 2 consecutive weeks (9.7%), and noncompliance (1.4%). Adverse events responsible for treatment discontinuation spanned several body systems. The most frequent responsible events were neuropathy, nail changes, enteritis, and allergic rhinitis. Thirteen patients died on study; 12 of PD and 1 of an unknown cause.

      Objective Tumor Response

      The ORR (the rate of CR + the rate of PR) in the evaluable population was 42.2% (95% CI, 30%–55%). Five patients experienced a CR and 22 patients a PR. In addition, 17 patients experienced SD, providing an overall benefit (CR + PR + SD) of 68.8% (Table 3). An ORR of 52.4% (3 CRs and 8 PRs) was achieved in patients with HER2-positive tumors, while the ORR was 38.1% (2 CRs and 14 PRs) in the HER2-negative population, though these differences were not statistically significant (P = .3). The overall benefits in the HER2-positive and HER2-negative populations were 71.4% and 66.7%, respectively. The ORR in patients whose tumors were HER2-positive and who received trastuzumab was 57.9%. However, this value was not statistically different from those patients who did not receive trastuzumab (35.6%; P = .17). Moreover, among the 15 patients who received previous taxanes, the ORR was 38.5%; a value not statistically different from those patients not previously treated with taxanes (43.1%; P = 1.0). Eight patients were not assessable for response because of withdrawal of consent (n = 1), noncompliance (n = 2), disease progression before completing 2 cycles of treatment (n = 2), and unacceptable toxicities (1 case each of grade 4 cerebral ischemia, grade 3 desquamation, and grade 3 neuropathy).
      Table 3Best Response to Treatment
      Treatment ResponseEvaluable Population (N = 64)Evaluable Population HER2-Positive (n = 21)Evaluable Population HER2-Negative (n = 42)Evaluable Population HER2-Unknown (n = 1)
      CR532-
      PR22814-
      SD174121
      PD20614-
      ORR (CR + PR)27 (42.2%)11 (52.4%)16 (38.1%)0
      95% CI for ORR30%–55%30%–75%24%–54%-
      Overall Benefit
      The overall benefit rate was defined as the number of CR + PR + all SD (with no minimum time period on SD).
      (CR + PR + SD)
      44 (68.8%)15 (71.4%)28 (66.7%)0
      Abbreviations: CR = complete response; HER2 = human epidermal growth factor receptor 2; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
      a The overall benefit rate was defined as the number of CR + PR + all SD (with no minimum time period on SD).

      Survival

      At the time of analysis, 59 patients (82%) had PD or died. Progression-free survival for the ITT population is shown in Figure 1. The median PFS for the ITT population was 14.5 months (range, 1–49.3 months). At 48 months, 8% of patients remain progression-free. Progression-free survival at 12, 24, and 36 months was 59%, 24%, and 15%, respectively. Further analysis for each HER2 sub-group revealed that median PFS was higher for the HER2-positive subset (18.7 months) compared with the HER2-negative subset (12.8 months). However, this difference was not statistically significant. Overall survival for the ITT population is presented in Figure 2. At the time of analysis, 41 patients (56.9%) had died, while 31 patients (43.1%) were alive. Overall survival rates for the ITT population at 12, 24, 36, and 48 months were 69%, 62%, 41%, and 14%, respectively. Median survival was 29 months (range, 1–49.3 months). Median survival time for the HER2-positive subset was higher (36.8 months) than the HER2-negative subset (27.3 months). This difference did not reach statistical significance. The median follow-up time was 17.0 months (range, 3 weeks to 44.6 months).
      Figure thumbnail gr1
      Figure 1Kaplan-Meier Analysis of Progression-Free Survival in the Intent-to-Treat Population
      Figure thumbnail gr2
      Figure 2Kaplan-Meier Analysis of Overall Survival in the Intent-to-Treat Population

      Discussion

      This multicenter phase II study evaluated the efficacy and safety of weekly nab paclitaxel, given with or without trastuzumab, as a first-line treatment for MBC. We report an ORR of 42.2%, overall benefit of 68.8%, median PFS of 14.5 months, and a median OS of 29 months. The dose and weekly schedule of nab paclitaxel were well tolerated and most adverse events were manageable. Our results show that weekly nab paclitaxel is a promising first-line treatment for patients with HER2-negative and HER2-positive MBC. The addition of trastuzumab was very beneficial, as demonstrated by an ORR of 57.9% in patients who received this combination.
      The absence of synthetic solvents in nab paclitaxel provides many advantages over the solvent-based taxanes, including ease of administration and the ability to deliver higher doses of paclitaxel without a concurrent increase in drug toxicity.
      • Ibrahim N.K.
      • Desai N.
      • Legha S.
      • et al.
      Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
      • Ibrahim N.K.
      • Samuels B.
      • Page R.
      • et al.
      Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      • Nyman D.W.
      • Campbell K.J.
      • Hersh E.
      • et al.
      Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
      Moreover, nab paclitaxel exhibits limited, but encouraging, efficacy in patients who are refractory to taxane treatment
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
      or who have received previous anthracycline treatment.
      • Ibrahim N.K.
      • Samuels B.
      • Page R.
      • et al.
      Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      Previous studies directly comparing docetaxel or paclitaxel to nab paclitaxel report higher response rates and longer durations of PFS and OS in patients treated with the latter.
      • Gradishar W.J.
      • Tjulandin S.
      • Davidson N.
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      Indeed, the most encouraging results were observed in those patients treated on a weekly schedule rather than an every-3-week schedule.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      This is not surprising considering the strong evidence affirming the benefits of paclitaxel given on a weekly rather than an every-3-week schedule.
      • Perez E.A.
      • Suman V.J.
      • Rowland K.M.
      • et al.
      Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252.
      CALGB 9840 and Anglo-Celtic IV, both phase III trials, established the superiority of weekly paclitaxel in terms of improved response rate,
      • Seidman A.D.
      • Berry D.
      • Cirrincione C.
      • et al.
      Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.
      • Verril M.W.
      • Lee J.
      • Cameron D.A.
      • et al.
      Anglo-Celtic IV: First results of a UK National Cancer Research Network randomised phase 3 pharmacogenetic trial of weekly versus 3 weekly Paclitaxel in patients with locally advanced or metastatic breast cancer (ABC).
      thus providing more evidence that weekly paclitaxel be the standard treatment schedule in MBC. Indeed, this regimen is also superior in the adjuvant setting, as reported by the ECOG 1199 trial.
      • Sparano J.A.
      • Wang M.
      • Martino S.
      • et al.
      Weekly paclitaxel in the adjuvant treatment of breast cancer.
      Few studies have investigated the effect of weekly single-agent nab paclitaxel in the first-line treatment setting of MBC.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      • Conlin A.K.
      • Hudis C.A.
      • Bach A.
      • et al.
      Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
      Patients who received 100 mg/m2/week or 150 mg/m2/week of nab paclitaxel experienced response rates of 45% and 49%, respectively, according to the independent radiologist assessment and 63% and 74%, respectively, according to investigator assessment.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      Continuous, uninterrupted weekly nab paclitaxel (130 mg/m2) in combination with bevacizumab was associated with an ORR of 46%.
      • Conlin A.K.
      • Hudis C.A.
      • Bach A.
      • et al.
      Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
      A recent study that investigated the combination of weekly nab paclitaxel, carboplatin, and trastuzumab in 32 patients with HER2-positive MBC reported an ORR of 62.5%.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      Our reported ORR of 42%, which was attained in a multicenter, nonacademic setting, is consistent with these data. Additionally, patients who were HER2-positive and who received trastuzumab experienced an ORR of 57.9%. Not surprisingly, pain, fatigue, and nausea were common, though most events were grades 1 or 2. These rates are consistent with other studies of weekly nab paclitaxel.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
      More than half of the patients in our population experienced sensory neuropathy, though only 6% of patients had a grade 3 event and there were no grade 4 events. These findings concur with other studies using a similar nab paclitaxel dose and schedule, and patient population. Only 3% of patients with first-line MBC who received weekly nab paclitaxel (100 mg/m2) in combination with carboplatin and trastuzumab experienced grade 3 sensory neuropathy.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      Likewise, single-agent weekly nab paclitaxel was associated with 8% of patients experiencing grade 3 neuropathy at a 100 mg/m2 dose and 14% at a 150 mg/m2 dose.
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      Interestingly, a schedule of uninterrupted weekly nab paclitaxel (130 mg/m2) coincided with much higher rates of grade 3 (38%) and grade 4 neuropathy (1%),
      • Conlin A.K.
      • Hudis C.A.
      • Bach A.
      • et al.
      Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
      suggesting that a 3-week-on/1-week-off schedule is preferred. Moreover, patients who were heavily pretreated appeared to experience somewhat higher rates of sensory neuropathy (19% with the 125 mg/m2 dose).
      • Blum J.L.
      • Savin M.A.
      • Edelman G.
      • et al.
      Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
      In contrast to other studies of weekly nab paclitaxel,
      • Gradishar W.J.
      • Krasnojon D.
      • Cheporov S.
      • et al.
      Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      we observed a lower incidence of neutropenia. The reasons for this difference are unclear, but may be caused by the addition of carboplatin to the treatment regimen
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      or differences in the patient populations.
      Approximately 25%–30% of breast cancers overexpress the HER2 gene.
      • Slamon D.J.
      • Clark G.M.
      • Wong S.G.
      • et al.
      Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
      This overexpression is associated with a poorer prognosis when compared with patients whose tumors are HER2-negative, as shown by shorter PFS and OS.
      • Slamon D.J.
      • Clark G.M.
      • Wong S.G.
      • et al.
      Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
      • Seshadri R.
      • Firgaira F.A.
      • Horsfall D.J.
      • et al.
      Clinical significance of HER-2/neu oncogene amplification in primary breast cancer The South Australian Breast Cancer Study Group.
      Trastuzumab inhibits tumor growth when used alone, but additive and synergistic effects have been observed when combined with docetaxel and paclitaxel, respectively.
      • Baselga J.
      • Norton L.
      • Albanell J.
      • et al.
      Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts.
      • Pegram M.D.
      • Lopez A.
      • Konecny G.
      • et al.
      Trastuzumab and chemotherapeutics: drug interactions and synergies.
      The addition of trastuzumab to other chemotherapy agents, including docetaxel, vinorelbine, doxorubicin, cyclophosphamide, and paclitaxel, has a significant clinical benefit in patients with untreated MBC.
      • Slamon D.J.
      • Leyland-Jones B.
      • Shak S.
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      • Marty M.
      • Cognetti F.
      • Maraninchi D.
      • et al.
      Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
      • Redana S.
      • Donadio M.
      • Nolè F.
      • et al.
      Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.
      Further, trastuzumab was active and well tolerated when used as a single agent in patients who preferred not to receive chemotherapy for their metastatic disease.
      • Vogel C.L.
      • Cobleigh M.A.
      • Tripathy D.
      • et al.
      Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.
      Though the advantages of trastuzumab have been thoroughly reported, only 1 other study has investigated the combination of trastuzumab and nab paclitaxel.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      We report a beneficial effect of trastuzumab in our HER2-positive patient population as shown by an ORR of 57.9%, though there was no statistical difference in terms of ORR between those who received trastuzumab and those who did not. Moreover, a subgroup analysis revealed that both median PFS and OS were higher in the HER2-positive group compared with the HER2-negative group; however, these differences were not statistically significant. Notwithstanding, we believe that these survival data are clinically significant, even in the absence of statistical significance. The failure to show statistical significance may be caused by our sample distribution as there was only half the number of HER2-positive patients compared with the HER2-negative patients. Nevertheless, cardiac toxicity is a concern with trastuzumab administration.
      • Slamon D.J.
      • Leyland-Jones B.
      • Shak S.
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      However, more recent studies suggest that this side effect is manageable and within the expected range for this type of therapy.
      • Marty M.
      • Cognetti F.
      • Maraninchi D.
      • et al.
      Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
      In the current study, 5 patients who received trastuzumab experienced cardiac problems. All events were grade 1 or grade 2, with the exception of 1 grade 4 arrhythmia event.
      Though the efficacy parameters reported in the current study are very encouraging, the response rate and duration of survival is still limited in this metastatic setting. At 48 months of follow-up, only 14% of our patients were still alive and less than half of our patients responded to treatment. The use of predictive biomarkers may be one way to improve drug response by customizing treatment. SPARC may be one such predictive marker.
      • Desai N.P.
      • Trieu V.
      • Hwang L.Y.
      • et al.
      Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.
      This albumin-binding protein is overexpressed in > 50% of breast cancers.
      • Kim Y.W.
      • Park Y.K.
      • Lee J.
      • et al.
      Expression of osteopontin and osteonectin in breast cancer.
      Implicated in tumor progression and angiogenesis, SPARC upregulation is typically associated with a worse prognosis.
      • Podhajcer O.L.
      • Benedetti L.G.
      • Girotti M.R.
      • et al.
      The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host.
      However, SPARC overexpression may account for preferential accumulation of nab paclitaxel, and other albumin-bound agents, at the tumor site.
      • Desai N.
      • Trieu V.
      • Yao Z.
      • et al.
      Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.
      In a retrospective study of patients with head and neck cancer, response to nab paclitaxel was higher for those patients with SPARC-positive tumors.
      • Desai N.
      • Trieu V.
      • Damascelli B.
      • et al.
      SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients.
      Likewise, in terms of which patients respond to trastuzumab therapy, evidence suggests that deficiencies in PTEN (phosphatase and tensin homolog) protein levels may be predictive.
      • Nahta R.
      • Shabaya S.
      • Ozbay T.
      • et al.
      Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens.
      Our study enrolled patients before these developments; thus the expression of SPARC and PTEN in our population is unknown.
      Other areas of research have focused on combining nab paclitaxel with other chemotherapy agents, including gemcitabine
      • Roy V.
      • LaPlant B.R.
      • Gross G.G.
      • et al.
      North Central Cancer Treatment Group
      Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531).
      or bevacizumab,
      • Conlin A.K.
      • Hudis C.A.
      • Bach A.
      • et al.
      Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
      • Link J.S.
      • Waisman J.R.
      • Nguyen B.
      • et al.
      Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer.
      • Danso M.A.
      • Blum J.L.
      • Robert N.J.
      • et al.
      Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer.
      or all 3 agents.
      • Lobo C.
      • Lopes G.
      • Baez O.
      • et al.
      Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.
      The addition of a platinum agent, like carboplatin, to a paclitaxel/trastuzumab regimen is very beneficial in the MBC setting.
      • Perez E.A.
      • Suman V.J.
      • Rowland K.M.
      • et al.
      Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252.
      • Robert N.
      • Leyland-Jones B.
      • Asmar L.
      • et al.
      Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer.
      Replacing paclitaxel with nab paclitaxel further translated into increased efficacy when given in conjunction with carboplatin and trastuzumab.
      • Conlin A.K.
      • Seidman A.D.
      • Bach A.
      • et al.
      Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
      The use of sequential neoadjuvant therapy consisting of weekly nab paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide has also been shown to be beneficial in patients with locally advanced breast cancer.
      • Robidoux A.
      • Buzdar A.U.
      • Quinaux E.
      • et al.
      A phase II neoadjuvant trial of sequential nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer.
      Finally, preclinical data suggest that the addition of nab paclitaxel to radiation therapy produced supra-additive effects when given before radiation.
      • Wiedenmann N.
      • Valdecanas D.
      • Hunter N.
      • et al.
      130-nm albumin-bound paclitaxel enhances tumor radiocurability and therapeutic gain.
      These studies and others will perhaps clarify the best treatment options for this patient population.

      Conclusion

      The current study provides “real-world” data regarding the use of weekly nab paclitaxel in a multicenter nonacademic setting. Encouraging efficacy data and a well-tolerated safety profile further establish weekly nab paclitaxel as a promising treatment regimen in the first-line metastatic setting, suggesting that it could be a favorable alternative to weekly treatment with solvent-based taxanes. Moreover, the addition of trastuzumab was beneficial to those patients whose tumors overexpressed HER2.

      Disclosures

      Mark Keaton has served on a Speaker's Bureau for Abraxis BioScience Inc. All other authors report to have no relevant relationships to disclose.

      Acknowledgments

      The authors thank the enrolled patients and clinicians who contributed to their care, and the Veeda Oncology Network for project support. In addition, we are grateful to Jennifer Newcomb-Fernandez, PhD, for editorial assistance and Des Ilegbodu, DrPH, for statistical assistance. This study was supported by Abraxis BioScience Inc.

      References

        • Jemal A.
        • Siegel R.
        • Xu J.
        • et al.
        Cancer Statistics, 2010.
        CA Cancer J Clin. 2010; (published online July 7, 2010)
        • Conlin A.K.
        • Seidman A.D.
        Taxanes in breast cancer: an update.
        Curr Oncol Rep. 2007; 9: 22-30
        • National Comprehensive Cancer Network
        Clinical Practice Guidelines in Oncology.
        Breast Cancer. 2010; : v2
        • Mayer E.L.
        • Burstein H.J.
        Chemotherapy for metastatic breast cancer.
        Hematol Oncol Clin North Am. 2007; 21: 257-272
      1. Altekruse SF, Kosary CL, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975–2007. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2007. Based on November 2009 SEER data submission, posted to the SEER web site, 2010.

      2. Taxol (paclitaxel) Injection [package insert].
        Bristol-Myers Squibb Co, Princeton, NJ2007
      3. Taxotere (docetaxel) Injection Concentrate [package insert].
        sanofi-aventis, Bridgewater, NJ2008
        • Harries M.
        • Ellis P.
        • Harper P.
        Nanoparticle albumin-bound paclitaxel for metastatic breast cancer.
        J Clin Oncol. 2005; 23: 7768-7771
        • Miele E.
        • Spinelli G.P.
        • Miele E.
        • et al.
        Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer.
        Int J Nanomedicine. 2009; 4: 99-105
        • ten Tije A.J.
        • Verweij J.
        • Loos W.J.
        • et al.
        Pharmacological effects of formulation vehicles: implications for cancer chemotherapy.
        Clin Pharmacokinet. 2003; 42: 665-685
        • Ibrahim N.K.
        • Desai N.
        • Legha S.
        • et al.
        Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
        Clin Cancer Res. 2002; 8: 1038-1044
        • Desai N.
        • Trieu V.
        • Yao Z.
        • et al.
        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. 2006; 12: 1317-1324
        • Desai N.P.
        • Trieu V.
        • Hwang L.Y.
        • et al.
        Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.
        Anticancer Drugs. 2008; 19: 899-909
        • Ibrahim N.K.
        • Samuels B.
        • Page R.
        • et al.
        Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
        J Clin Oncol. 2005; 23: 6019-6026
        • Gradishar W.J.
        • Tjulandin S.
        • Davidson N.
        • et al.
        Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
        J Clin Oncol. 2005; 23: 7794-7803
        • Nyman D.W.
        • Campbell K.J.
        • Hersh E.
        • et al.
        Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
        J Clin Oncol. 2005; 23: 7785-7793
        • Perez E.A.
        • Suman V.J.
        • Rowland K.M.
        • et al.
        Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252.
        Clin Breast Cancer. 2005; 6: 425-432
        • Seidman A.D.
        • Berry D.
        • Cirrincione C.
        • et al.
        Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.
        J Clin Oncol. 2008; 26: 1642-1649
        • Sparano J.A.
        • Wang M.
        • Martino S.
        • et al.
        Weekly paclitaxel in the adjuvant treatment of breast cancer.
        N Engl J Med. 2008; 358: 1663-1671
        • Verril M.W.
        • Lee J.
        • Cameron D.A.
        • et al.
        Anglo-Celtic IV: First results of a UK National Cancer Research Network randomised phase 3 pharmacogenetic trial of weekly versus 3 weekly Paclitaxel in patients with locally advanced or metastatic breast cancer (ABC).
        J Clin Oncol. 2007; 25 (abstract LBA1005): 33s
        • Gradishar W.J.
        • Krasnojon D.
        • Cheporov S.
        • et al.
        Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.
        J Clin Oncol. 2009; 27: 3611-3619
        • Conlin A.K.
        • Seidman A.D.
        • Bach A.
        • et al.
        Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer.
        Clin Breast Cancer. 2010; 10: 281-287
        • Blum J.L.
        • Savin M.A.
        • Edelman G.
        • et al.
        Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes.
        Clin Breast Cancer. 2007; 7: 850-856
        • Conlin A.K.
        • Hudis C.A.
        • Bach A.
        • et al.
        Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).
        J Clin Oncol. 2009; 27 (abstract 1006): 42s
        • Slamon D.J.
        • Leyland-Jones B.
        • Shak S.
        • et al.
        Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
        N Engl J Med. 2001; 344: 783-792
        • Marty M.
        • Cognetti F.
        • Maraninchi D.
        • et al.
        Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
        J Clin Oncol. 2005; 23: 4265-4274
        • Blum J.L.
        • Savin M.A.
        • Edelman G.
        • et al.
        Long term disease control in taxane-refractory metastatic breast cancer treated with nab paclitaxel.
        J Clin Oncol. 2004; 22 (abstract 543): 14s
        • Nyman D.W.
        • Campbell K.J.
        • Hersh E.
        • et al.
        A phase I trial of ABI-007, nanoparticle paclitaxel, administered to patients with advanced non-hematologic malignancies.
        J Clin Oncol. 2004; 22 (abstract 2027): 14s
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors.
        J Natl Cancer Inst. 2000; 92: 205-206
        • Kaplan E.L.
        • Meier P.
        Nonparametric estimation from incomplete observations.
        J Am Stat Assoc. 1958; 53: 457-481
        • Slamon D.J.
        • Clark G.M.
        • Wong S.G.
        • et al.
        Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
        Science. 1987; 235: 177-182
        • Seshadri R.
        • Firgaira F.A.
        • Horsfall D.J.
        • et al.
        Clinical significance of HER-2/neu oncogene amplification in primary breast cancer.
        J Clin Oncol. 1993; 11: 1936-1942
        • Baselga J.
        • Norton L.
        • Albanell J.
        • et al.
        Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts.
        Cancer Res. 1998; 58: 2825-2831
        • Pegram M.D.
        • Lopez A.
        • Konecny G.
        • et al.
        Trastuzumab and chemotherapeutics: drug interactions and synergies.
        Semin Oncol. 2000; 27 (discussion 92–100): 21-25
        • Redana S.
        • Donadio M.
        • Nolè F.
        • et al.
        Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.
        BMC Cancer. 2010; 10: 28
        • Vogel C.L.
        • Cobleigh M.A.
        • Tripathy D.
        • et al.
        Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.
        J Clin Oncol. 2002; 20: 719-726
        • Kim Y.W.
        • Park Y.K.
        • Lee J.
        • et al.
        Expression of osteopontin and osteonectin in breast cancer.
        J Korean Med Sci. 1998; 13: 652-657
        • Podhajcer O.L.
        • Benedetti L.G.
        • Girotti M.R.
        • et al.
        The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host.
        Cancer Metastasis Rev. 2008; 27: 691-705
        • Desai N.
        • Trieu V.
        • Damascelli B.
        • et al.
        SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients.
        Transl Oncol. 2009; 2: 59-64
        • Nahta R.
        • Shabaya S.
        • Ozbay T.
        • et al.
        Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens.
        Curr Pharmacogenomics Person Med. 2009; 7: 263-274
        • Roy V.
        • LaPlant B.R.
        • Gross G.G.
        • et al.
        • North Central Cancer Treatment Group
        Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531).
        Ann Oncol. 2009; 20: 449-453
        • Link J.S.
        • Waisman J.R.
        • Nguyen B.
        • et al.
        Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer.
        Clin Breast Cancer. 2007; 7: 779-783
        • Danso M.A.
        • Blum J.L.
        • Robert N.J.
        • et al.
        Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer.
        J Clin Oncol. 2008; 26 (abstract 1075): 59s
        • Lobo C.
        • Lopes G.
        • Baez O.
        • et al.
        Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.
        Breast Cancer Res Treat. 2010; 123: 427-435
        • Robert N.
        • Leyland-Jones B.
        • Asmar L.
        • et al.
        Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer.
        J Clin Oncol. 2006; 24: 2786-2792
        • Robidoux A.
        • Buzdar A.U.
        • Quinaux E.
        • et al.
        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. 2010; 10: 81-86
        • Wiedenmann N.
        • Valdecanas D.
        • Hunter N.
        • et al.
        130-nm albumin-bound paclitaxel enhances tumor radiocurability and therapeutic gain.
        Clin Cancer Res. 2007; 13: 1868-1874