nab-Paclitaxel for the Treatment of Aggressive Metastatic Breast Cancer

Review

nab-Paclitaxel for the Treatment of Aggressive Metastatic Breast Cancer Stefan Glück Abstract Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple-negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis. Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Aggressive, Metastatic breast cancer, nab-Paclitaxel, Poor prognosis, Triple-negative breast cancer

Introduction Breast cancer ranks second only to lung cancer as the most common cause of cancer-related death in women, and invasive breast cancer affects approximately 1 in every 8 women (13%) in the United States during their lifetimes.1 Breast cancer is a heterogeneous and genetically and phenotypically diverse disease composed of several biological subtypes that exhibit distinct clinical courses and responses to therapy. Thus, determining prognosis and treatment options remains an important part of patient care, especially as some breast tumors may initially respond to a given therapy but subsequently develop resistance and progress.2 In addition, some breast tumors may progress more rapidly than others.3 Although the exact mechanisms that underlie how quickly tumors progress have not been fully elucidated, several clinical and molecular features have been identified that are associated with poor Department of Medicine, Division of Hematology/Oncology, Sylvester Comprehensive Care Center, University of Miami, Leonard M. Miller School of Medicine, Miami, FL Submitted: Oct 30, 2013; Revised: Feb 11, 2014; Accepted: Feb 12, 2014 Address for correspondence: Stefan Glück, MD, PhD, FRCPC, Sylvester Professor, Department of Medicine, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Leonard M. Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL 33136 E-mail contact: [email protected]

1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.02.001

prognosis.4-12 Taxanes are considered among the most active classes of compounds against breast cancer,13 and this review will focus specifically on the experience to date with nanoparticle albuminbound paclitaxel (nab-paclitaxel) for the treatment of metastatic triple-negative breast cancer (TNBC) or metastatic breast cancer (MBC) characterized by other factors associated with aggressive disease. Molecular profiling of breast cancer is based on variations in gene expression and is increasingly used to characterize breast cancer beyond traditional histopathologic criteria (ie, grade, histology, and immunohistochemical analysis of hormone receptors and human epidermal growth factor receptor-2 [HER2] overexpression) and as a predictor of response to therapy and clinical outcome. A seminal study identified 5 distinct tumor subtypes based on unique gene profiles that correlated with prognosis: normal-like, luminal A, luminal B, HER2þ, and basal-like.12 These molecular subtypes shared similar but not identical characteristics to those used for clinical subtyping by immunohistochemistry (IHC). For example, HER2 classified as a distinct subtype on the basis of a unique gene-expression signature, which corresponded to tumors that demonstrate an overexpression of the HER2 gene product by IHC. Basal-like tumors also showed similarity to the so-called triplenegative (TN) clinical subtype (lacking overexpression of HER2 and expression of estrogen and progesterone receptors). Although the

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nab-Paclitaxel for Aggressive MBC correlation between molecular and clinical classification of breast cancer subtypes is not identical, the ability to define subsets of breast cancer with unique prognostic profiles is similar. Both techniques have identified HER2-overexpressing and TN or basal-like tumors as having the worst prognoses in terms of both relapse-free and overall survival (Fig. 1).12,14 The HER2 gene is amplified in fewer than 25% of breast cancers.15 In addition to having a generally poor prognosis with respect to relapse-free and overall survival (OS), HER2þ breast cancer is characterized by a higher incidence of brain metastases compared with that of other subtypes.3 Indeed, brain metastases develop at a frequency as high as 50% in patients with advanced breast cancer.16 As for molecular features, HER2þ breast cancer exhibits a high frequency of mutations in TP53 (72%) and PIK3CA (39%), among others.17 These gene expression signatures may be used to further characterize and subtype patients at different stages of breast cancer. Additionally, mutations in TP53 may be predictive of response to taxane-containing therapy in patients with HER2þ and HER2 breast cancer, perhaps by rendering tumors less able to adapt and survive in response to taxane-induced mitotic arrest.18 Data from gene-expression profiles and mutational analyses may ultimately guide treatment selection for specific breast cancer patient populations. TNBC accounts for 13% to 14% of all breast cancers.3,4,19 Reports have suggested that most histologically defined TN tumors are molecularly classified as basal-like.20,21 However, the exact proportion remains somewhat undefined, with recent molecular profiling studies suggesting the percentage of TNBCs that are basallike to be as low as 47% and as high as 86%.17,22 One study suggested that TNBC may actually be made up of 6 distinct molecular subtypes.22 Thus, while basal-like breast cancer may represent the largest class of TNBC tumors, it is certainly not the only class. TNBC is associated with a lower likelihood of survival than non-TNBC among patients with all stages of disease,4 even though the metastatic potential of TNBC appears to be similar to that of

other subtypes.23 TN, basal-like breast tumors have a high frequency of TP53 mutations (82%-84%)12,17 and a reduction or loss of other genes involved in the DNA damage response, including ATM, RB1, and BRCA1,17,18,24-26 suggesting an overall decrement in the ability of these cells to repair breaks in DNA. A number of other pathological and clinical features, in addition to data from subtyping based on IHC or gene-expression profiles, have been recognized as valuable prognostic indicators in breast cancer. Tumor grade and stage, disease-free interval, site of metastasis, and number of metastatic sites are all significantly associated with shorter survival.5-10 Evaluation of these factors is particularly important in the absence of information on hormone receptors and HER2 status.

Discussion HER2þ

Treatment options and outcomes for HER2þ breast cancer have improved significantly over the past decade with the availability of several agents targeting the HER2 pathway. To date, 4 targeted agents have been approved for the treatment of HER2þ breast cancer, including trastuzumab, lapatinib, pertuzumab, and more recently, trastuzumab emtansine (T-DM1).27-30 Thus, although HER2þ tumors usually are aggressive, the abundance of efficacious treatment options has dramatically improved the prognosis for patients with HER2þ disease.31-37 As such, this review will not focus further on this subtype.

TNBC Current treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend that patients with TNBC receive chemotherapy.2 These guidelines note that there is no compelling evidence that combination therapies are superior to single-agent chemotherapy regimens. The list of preferred singleagent therapies includes anthracyclines, antimetabolites, taxanes, and other microtubule inhibitors. Although current guidelines do

Figure 1 Survival Rates According to Stratification Based on (A) Immunohistochemical/Fluorescence In Situ Hybridization Analysis for ER, PR, and HER2 and (B) Molecular Subtyping Using BluePrint and MammaPrint

Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor. Reprinted with permission from Glück S, et al. Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat 2013;139:759-67.

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Stefan Glück not recommend platinum agents, the defects in the DNA repair pathway known to be associated with TNBC have led some investigators to investigate the antitumor activity of platinum agents, which cause DNA damage.23,38 Investigators have also evaluated inhibitors of poly(ADP-ribose) polymerase (PARP), a protein known to regulate DNA repair, in this breast cancer subtype.23,39 Early trials of PARP inhibitors (iniparib, olaparib, and veliparib) have shown promising results,39-41 but whether these agents will prove more effective than standard treatments already being used to treat TNBC in randomized, controlled trials remains to be seen. There is a need to improve current treatment options for all types of aggressive MBC, including TNBC, BC that is refractory to standard treatments, and BC characterized by other markers of poor prognosis.

nab-Paclitaxel for Aggressive Breast Cancer The Development of nab-Paclitaxel. The chemotherapeutic agent paclitaxel (Taxol) acts as an inhibitor of mitosis by inhibiting microtubule dynamics during cell division.42,43 Because paclitaxel is highly insoluble in water, it was initially formulated as a solvent-based paclitaxel (sb-paclitaxel) with ethanol and Cremophor EL (now known as Kolliphor EL), a castor oil derivative.44 Cremophor EL is known to form drug-trapping micelles, and encapsulation in solvent micelles decreases the fraction of unbound drug, limiting its distribution and clearance.44-48 sb-Paclitaxel is also associated with adverse events, including hypersensitivity reactions, peripheral neuropathy, and neutropenia, and is administered with steroid and antihistamine prophylaxis over a prolonged period of time (3 hours).43 Efforts to improve the therapeutic index of sb-paclitaxel resulted in the development of nab-paclitaxel (Abraxane). nab-paclitaxel is created by a process of high-pressure homogenization of paclitaxel in the presence of human serum albumin.49 This process creates albumin-paclitaxel particles that are a mean 130 nm in size.50 On injection, particles of nab-paclitaxel dissolve into free or unbound paclitaxel and paclitaxel that is bound to biomolecules, such as albumin (either injected or endogenous).51 It has been hypothesized that albumin-mediated delivery may lead to enhanced transport of nab-paclitaxel to tumors.51-53 The use of albumin also allows nab-paclitaxel to be delivered without any chemical solvent or the steroid or antihistamine pretreatment typically required to prevent hypersensitivity reactions with sb-paclitaxel.51 The improved tolerability profile of nab-paclitaxel compared with that of sb-paclitaxel at equimolar doses allows the delivery of a higher dose than that of sb-paclitaxel.54 The approved use of nab-paclitaxel for treatment of MBC is a 30-minute infusion of 260 mg/m2 every 3 weeks (q3w), compared with the standard sb-paclitaxel regimen of a 3-hour infusion of 175 mg/m2 q3w.43,50 In a phase III trial, nab-paclitaxel demonstrated a longer median time to progression (23.0 vs. 16.9 weeks; hazard ratio [HR], 0.75; P ¼ .006), higher overall response rate (ORR) (33% vs. 19%; P ¼ .001), and longer median OS in patients who had previously received treatment for metastatic disease (56.4 vs. 46.7 weeks; HR, 0.73; P ¼ .024) compared with those of sb-paclitaxel.54 A higher rate of grade 3 peripheral neuropathy was observed with nab-paclitaxel compared with that of sb-paclitaxel (10% vs. 2%; P < .001; no case of grade 4 in either arm); however, this may be attributed to the higher paclitaxel dose intensity delivered (49% higher) and the shorter infusion

time (30 minutes vs. 3 hours) of nab-paclitaxel. The median time to improvement of grade 3 peripheral neuropathy to a lower grade was 22 days for patients in the nab-paclitaxel arm versus 79 days for patients in the sb-paclitaxel arm.55 Despite the higher dose, nabpaclitaxel was associated with a lower incidence of grade 4 neutropenia (9% vs. 22%; P < .001). The findings of this phase III trial led to approval by the US Food and Drug Administration (FDA) of nab-paclitaxel for treatment of MBC after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically contraindicated).50,56

Clinical Trials of nab-Paclitaxel for Treatment of Aggressive Breast Cancer TNBC. Data on patients treated with nab-paclitaxelebased regimens for metastatic TNBC have been reported from 3 different trials (Table 1 and described below).57-59 To date, data have been reported only from 1 trial in which a TNBC-exclusive population of patients was treated with nab-paclitaxel.60 In that phase II trial, 34 patients were treated in the first-line setting with the combination of nab-paclitaxel, carboplatin, and bevacizumab. The ORR for these patients was 85%, and the median progression-free survival (PFS) was 9.2 months. The most common grade  3 adverse events were neutropenia (56%) and thrombocytopenia (19%). The high ORR seen in this trial reflects promising antitumor activity for this combination. A phase II trial on the combination of nab-paclitaxel, gemcitabine, and bevacizumab for the first-line treatment of HER2 MBC (n ¼ 29) included 13 patients with TNBC.58 The ORR for these patients was 69%, and the 18-month OS rate was 83%. Interestingly, there was no significant difference between the PFS or OS of patients with TNBC compared with those of patients with hormone receptorepositive disease. This surprising finding indicates a high degree of activity for this regimen in TNBC. Safety data were not reported separately for the TNBC subgroup. These data appear promising; however, the small patient population (only 13 patients with TNBC) must be noted. A phase III trial on patients with HER2e MBC conducted by the Cancer and Leukemia Group B (CALGB Trial 40502) was reported at the annual meeting of the American Society of Clinical Oncology in 2012.59 The trial compared sb-paclitaxel 90 mg/m2 the first 3 of 4 weeks (qw 3/4) plus bevacizumab 10 mg/kg every 2 weeks (q2w; n ¼ 283) with nab-paclitaxel 150 mg/m2 qw 3/4 plus bevacizumab 10 mg/kg q2w (n ¼ 271) or ixabepilone 16 mg/kg qw 3/4 plus bevacizumab 10 mg/kg q2w (n ¼ 245). Although a protocol amendment made the use of bevacizumab optional following the withdrawal of FDA approval for bevacizumab in MBC,61 98% of patients in CALGB 40502 did receive bevacizumab. PFS (primary endpoint) was similar for sb-paclitaxel plus bevacizumab versus nab-paclitaxel plus bevacizumab (median 10.6 vs. 9.2 months, respectively; HR, 1.19; 95% CI, 0.96-1.49; P ¼ .12). In the subset of patients with TNBC, the hazard ratio was actually < 1 for the same treatment-arm comparison (HR, 0.93; 95% CI, 0.62-1.40; P ¼ .735). Safety data were not reported separately for the TNBC subgroup, and final results of CALGB 40502 have not yet been published. However, the interim analysis reported high rates of neurotoxicity (25% of patients had grade  3 sensory neuropathy),

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nab-Paclitaxel for Aggressive MBC Table 1 nab-Paclitaxel for Treatment of Patients With Metastatic Triple-Negative Breast Cancer

Author, Year

Phase

Regimen

Lobo et al, 201058

II

Hamilton et al, 201060

II

Blackwell, in progress62

II

Forero-Torres et al, in progress63

II

nab-P 150 mg/m2 q2w þ Gem 1500 mg/m2 q2w þ Bev 10 mg/kg q2w nab-P 100 mg/m2 qw 3/4 þ Carbo AUC ¼ 2 qw 3/4 þ Bev 10 mg/kg q2w nab-P 100 mg/m2 qw 3/4 þ Carbo AUC ¼ 2 qw 3/4 nab-P qw 3/4 þ Tigatuzumab q2wb nab-P qw 3/4b

Patients Line of With TNBC, Treatment n/ntotal

ORR, %

Median PFS, mo

Median OS, mo

First-line

13/29

69

NR

NR

First-line

34/34

85

9.2

NR

First-line

70a

NR

NR

NR

Any line

40a

NR

NR

NR

20a

NR

NR

NR

Abbreviations: AUC ¼ area under the curve; Bev ¼ bevacizumab; Carbo ¼ carboplatin; Gem ¼ gemcitabine; nab-P ¼ nab-paclitaxel; NR ¼ not reported; ORR ¼ overall response rate; OS ¼ overall survival; PFS ¼ progression-free survival; qw ¼ once weekly; q2w ¼ every 2 weeks; qw 3/4 ¼ first 3 of 4 weeks; TNBC ¼ triple-negative metastatic breast cancer. a Target recruitment number. b Doses not reported.

dose reductions (45% by cycle 3), and discontinuations by cycle 5 (> 40%) for the nab-paclitaxel plus bevacizumab treatment arm, suggesting that the starting dose and/or protocol-defined dose reduction schedule for nab-paclitaxel was not ideal. Furthermore, the high rate of grade  3 hematologic adverse events for the nab paclitaxel plus bevacizumab arm (51%) and the withdrawal of FDA approval of bevacizumab for MBC suggest that this regimen will not be pursued in subsequent trials.59,61

4

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Patients With Other Disease Features Associated With Poor Prognosis. A recent retrospective subset analysis examined the efficacy and safety in patients with either visceral-dominant metastases or a disease-free interval (DFI)  2 years who received nab-paclitaxel for the treatment of MBC in a phase III trial (n ¼ 454) or a phase II trial (n ¼ 300).54,64-66 In the phase III trial, nab-paclitaxel 260 mg/m2 q3w was compared with sb-paclitaxel 175 mg/m2 q3w.54 Although patients could have received previous chemotherapy for metastatic disease, this subset analysis focused only on patients who had not received prior therapy (ie, treatment in the first-line setting in the phase III trial).64 The phase II trial examined 4 different regimens as first-line treatment for patients with MBC: nab-paclitaxel 300 mg/m2 q3w, nab-paclitaxel 100 mg/m2 qw 3/4, nab-paclitaxel 150 mg/m2 qw 3/4, or docetaxel 100 mg/m2 q3w.65,66 In general, the efficacy (Table 2) and safety results of the poor prognostic factor subgroups were similar to those of the intention-to-treat populations.64 For patients in the phase III trial with visceral-dominant metastases, the nab-paclitaxel arm demonstrated a higher ORR (42% vs. 23%; P ¼ .022) and a longer median PFS and OS, although differences in these survival values were not statistically significant. Among patients in the phase III trial who had a DFI  2 years, ORR, PFS, and OS also appeared to favor nab-paclitaxel; however, none of these results were statistically significant, likely because of the small number of patients in these groups. The poor prognostic factor subset analysis of the phase II trial also demonstrated similar results to those of the intention-to-treat populations.64 In patients with visceral-dominant metastases, the qw 3/4 nab-paclitaxel arms demonstrated higher ORRs compared with those of docetaxel (63% for the 100 mg/m2 arm and 76% for

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the 150 mg/m2 arm vs. 37% for the docetaxel arm; P ¼ .002 and P < .001, respectively). The nab-paclitaxel 150 mg/m2 arm also demonstrated a longer median PFS than that of the docetaxel arm (13.1 vs. 7.8 months; P ¼ .019). Although the 150 mg/m2 arm also had a longer median OS than that of the docetaxel arm (32.1 vs. 21.4 months), this difference did not reach statistical significance. The same trends generally held true for the subgroup of patients with a DFI  2 years; however, none of these comparisons were statistically significant. The subgroups of patients in the retrospective analysis exhibited similar safety results as the intention-to-treat populations.64 In the phase III trial, patients who received nab-paclitaxel and had visceraldominant metastases or a DFI  2 years experienced the following rates of grade  3 adverse events: 24% to 39% had neutropenia, 10% to 12% had sensory neuropathy, and 12% to 15% had fatigue. For the poor prognostic factor subgroups who received sb-paclitaxel, 58% to 67% experienced grade  3 neutropenia, 0% to 5% experienced grade  3 sensory neuropathy, and 2% to 3% experienced grade  3 fatigue. In the phase II trial, 25% to 45% of patients with markers of poor prognosis experienced neutropenia, 5% to 22% experienced sensory neuropathy, and 0% to 5% experienced fatigue. For docetaxel, these rates were 94% to 100% for neutropenia, 11% to 12% for sensory neuropathy, and 19% to 21% for fatigue. Taken together, the results of this retrospective subset analysis of patients who received single-agent nab-paclitaxel in the phase II or III trial described previously suggest that the benefits observed for nab paclitaxel over sb-paclitaxel and docetaxel in the intention-totreat populations of these trials were maintained in patients with factors characteristic of poor prognosis.64 In a separate phase II trial, 3 regimens of nab-paclitaxel plus bevacizumab were tested for efficacy and safety as first-line treatment for HER2 MBC (Table 2).67 A subgroup analysis retrospectively explored efficacy in patients with markers of poor prognosis in this trial similar to those in the analysis described previously; there appeared to be no difference in the efficacy or safety of patients with visceral-dominant metastases or a DFI < 2 years compared with the intention-to-treat population. A pooled treatmentearm analysis

Stefan Glück Table 2 Subgroup Analyses of nab-Paclitaxel for Patients With Unknown Molecular Subtype but With Clinical/Pathological Factors Associated With Poor Prognosis Author, Year O’Shaughnessy et al, 201364

Phase III (n ¼ 454)

Line of Treatment First-line with visceraldominant metastases First-line with DFI  2 years

O’Shaughnessy et al, 201364

II (n ¼ 300)

First-line with DFI  2 years

O’Shaughnessy et al, 201364

Seidman et al, 201367

Seidman et al, 201367

First-line with visceraldominant metastases

II (n ¼ 212)

First-line with visceraldominant metastases

First-line with DFI < 2 years

n

ORR, %

Median PFS, mo

Median OS, mo

nab-P 175 mg/m2 q3w

74

42

5.6

15.1

sb-P 260 mg/m2 q3w nab-P 175 mg/m2 q3w sb-P 260 mg/m2 q3w nab-P 300 mg/m2 q3w

64 42 30 61

23 43 33 44

3.8 5.0 3.5 10.9

14.2 14.6 11.7 27.7

nab-P 100 mg/m2 qw 3/4 nab-P 150 mg/m2 qw 3/4 Doc 100 mg/m2 q3w nab-P 300 mg/m2 q3w nab-P 100 mg/m2 qw 3/4 nab-P 150 mg/m2 qw 3/4 Doc 100 mg/m2 q3w nab-P 260 mg/m2 q3w þ Bev 15 mg/kg q3w nab-P 260 mg/m2 q2w þ Bev 10 mg/kg q2w nab-P 130 mg/m2 qw þ Bev 10 mg/kg q2w nab-P 260 mg/m2 q3w þ Bev 15 mg/kg q3w nab-P 260 mg/m2 q2w þ Bev 10 mg/kg q2w nab-P 130 mg/m2 qw þ Bev 10 mg/kg q2w

60 59 67 20 21 14 19 65

63 76 37 35 52 64 21 45

7.5 13.1 7.8 7.4 7.3 14.1 5.5 7.6

19.6 32.1 21.4 16.6 19.1 18.6 14.4 19.8

51

39

5.8

18.9

70

46

9.0

24.6

33

33

7.3

19.1

28

50

5.8

21.9

36

44

8.8

22.3

Regimen

Abbreviations: Bev ¼ bevacizumab; DFI ¼ disease-free interval; Doc ¼ docetaxel; nab-P ¼ nab-paclitaxel; ORR ¼ overall response rate; OS ¼ overall survival; PFS ¼ progression-free survival; qw ¼ once weekly; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks; qw 3/4 ¼ first 3 of 4 weeks; sb-P ¼ solvent-based paclitaxel.

revealed that the most common grade  3 adverse events were sensory neuropathy (44% for both groups), fatigue (24% for both groups), and neutropenia (22% for patients with a DFI < 2 years and 19% for patients with visceral-dominant metastases). The authors stated that having either of these poor prognostic factors, “should not preclude patients who would otherwise be eligible from receiving nab paclitaxel plus bevacizumab.”

Conclusion Taxane use is recommended across all lines of therapy to treat breast cancer.2 However, it is possible that the full potential of taxanes in this disease has not been completely realized. Although the development of targeted therapies has certainly improved overall care for patients with breast cancer, many patients develop disease that either lacks the epitopes against which these therapies are directed or is resistant to such treatments. A hypothetical explanation for some cases of resistance to targeted therapies is that in some tumors, ER or other drug targets may be present but not functional, eliminating any potential effect of targeted inhibition on downstream signaling. For patients with tumors that lack targetable epitopes or are resistant to targeted therapy, cytotoxic therapy remains an indispensable treatment option, and taxanes represent 1 of the most active classes of chemotherapy against breast cancer.2,13 A conservative approach to therapy for MBC may be desirable for patients with slowly progressing disease or for patients whose key

objective of therapy is to maintain quality of life, even if that means sacrificing some duration of survival. Indeed, current treatment guidelines suggest that sequential single-agent therapy may be preferable to concurrent combination therapy because of the higher toxicity and lack of statistically significant OS benefit observed from combination therapies over monotherapy, despite noted advantages in ORR and PFS for combination regimens.2 Nevertheless, there are sets of patients who may benefit from more-aggressive therapies to quickly halt rapidly progressing disease or to potentially alleviate disease-related symptoms. nab-Paclitaxel, either as a single agent or in combination with other agents, has demonstrated promising efficacy in groups of patients with aggressive MBC, including disease that is triple-negative or characterized by visceral-dominant metastases or short DFI. The studies of nab-paclitaxelecontaining regimens for metastatic TNBC described in this review demonstrated promising efficacy data, such as ORRs of 69% and 89%.57,58 Overall, the findings from phase III studies in other disease states suggest that nab-paclitaxel in combination with gemcitabine or carboplatin is active in patients with metastatic disease, and nab-paclitaxel plus gemcitabine (with or without bevacizumab) has already demonstrated activity in phase II MBC trials.58,68-70 Although a phase II MBC trial that investigated the addition of bevacizumab to nab-paclitaxel plus gemcitabine exhibited promising efficacy in a small cohort of patients with TNBC, the FDA approval of

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nab-Paclitaxel for Aggressive MBC bevacizumab for MBC has been withdrawn, rendering the addition of bevacizumab less relevant for future study.58,61 Further research is needed to answer questions as to the overall effectiveness and the ideal nab-paclitaxel regimen for metastatic TNBC. The ongoing phase II/III open-label, randomized tnAcity trial (Triple-Negative Albumin-Bound Paclitaxel Combination International Treatment study; planned n ¼ 790) evaluating the efficacy and safety profiles of 2 nab-paclitaxel combination regimens (with either gemcitabine or carboplatin) as first-line treatment for metastatic TNBC may offer answers to these questions.71 The phase II segment will compare the safety and efficacy profiles of the following combination regimens: nab-paclitaxel 125 mg/m2 the first 2 of 3 weeks (qw 2/3) plus gemcitabine 1000 mg/m2 qw 2/3, nab-paclitaxel 125 mg/m2 qw 2/3 plus carboplatin area under the curve (AUC) ¼ 2 qw 2/3, and gemcitabine 1000 mg/m2 qw 2/3 plus carboplatin AUC ¼ 2 qw 2/3. The nab-paclitaxel regimen selected from the phase II portion will be compared with gemcitabine plus carboplatin in the phase III portion of the trial. The primary outcome measure for both segments will be PFS. The promising results of the nab-paclitaxel studies described above suggest that continued development of such regimens may lead to clinical benefit in patients with aggressive disease. Ongoing research will further define the optimal nab-paclitaxel regimens for patients with different types of aggressive MBC. Subset analyses of randomized trials support the use of single-agent nab-paclitaxel for disease characterized by the presence of poor prognostic factors,64 and the efficacy and safety profiles for nab-paclitaxel in previous studies may make nab-paclitaxel an ideal combination partner with other cytotoxic therapies or novel targeted agents.

Acknowledgments Medical writing assistance was provided by John McGuire, PhD, MediTech Media, funded by Celgene Corporation. The author was involved in and is fully responsible for the outline of the manuscript and all important decisions about its content and editorial decisions.

Disclosure Dr Glück has received research funding from and participated in an advisory board for Celgene Corporation.

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Clinical Breast Cancer Month 2014

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