Evolving Approaches to Metastatic Breast Cancer Patients Pre-treated with Anthracycline and Taxane
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- Saji, S. BioDrugs (2013) 27: 469. doi:10.1007/s40259-013-0038-1
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Metastatic breast cancer is currently incurable and the goals of therapy focus on prolonging survival and maintaining quality of life by controlling symptoms and minimizing toxicity. Treatments for metastatic breast cancer include chemotherapeutic agents from various classes, such as taxanes, vinca alkaloids, anthracyclines and antimetabolites. This review provides an overview of chemotherapeutic agents for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes, focusing on a clinical evaluation of eribulin, the most recently approved agent for the treatment of metastatic breast cancer. Eribulin is a synthetic derivative of halichondrin B, a tumour growth inhibitor found in marine sponges, which prevents microtubule growth and sequesters the tubulin molecules into unusual aggregates, initiating apoptosis. Studies of eribulin have shown that the drug is effective in the treatment of previously treated metastatic breast cancer, and has an acceptable toxicity profile. Importantly, in the phase III EMBRACE study, eribulin treatment resulted in a survival advantage, a difficult endpoint to achieve with a single chemotherapeutic agent. An additional phase III study showed that eribulin has similar efficacy to capecitabine in women treated with no more than three prior therapies. Furthermore, pre-specified exploratory analyses suggest that particular patient subgroups may have greater therapeutic benefit with eribulin and may warrant further study to explore the potential mechanisms.
Breast cancer is the most common cancer in women. In 2008, 1.38 million new cases of breast cancer were diagnosed worldwide, and there were over 458,000 deaths . Over the last 25 years, the incidence of breast-cancer related deaths has declined in the USA and parts of Europe, mostly owing to improved detection and treatment . However, survival in patients with breast cancer depends heavily on the stage of the tumour, with US statistics demonstrating a 98 % survival rate at 5 years in patients with non-invasive disease, such as ductal carcinoma in situ, which decreases to 24 % in patients with metastatic disease . Unfortunately, approximately one-third of women with early-stage breast cancer will eventually develop metastatic disease , and metastatic breast cancer is currently incurable.
The goals of therapy in patients who have metastatic disease focus on prolonging survival and maintaining quality of life by controlling symptoms and minimizing toxicity. Treatment choice in breast cancer is influenced by the hormone receptor and human epidermal growth factor receptor 2 (HER2) status of the tumour, and patients with metastatic disease may benefit from treatment tailored to their individual genotype status. Several targeted therapies are under development, but systemic chemotherapy remains an important approach for patients with metastatic breast cancer, particularly in patients with hormone-refractory, hormone receptor-negative or rapidly progressing metastatic disease [4, 5].
This review provides an overview of chemotherapeutic agents for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes, focusing on a clinical evaluation of eribulin, the most recently approved agent for the treatment of metastatic breast cancer.
2 Chemotherapeutic Agents for Metastatic Breast Cancer
Mechanism of action
DNA intercalation and induction of cell death
Capecitabine, S-1, gemcitabine
Inhibits processes required for DNA synthesis
Stabilizes microtubules by inhibiting the shortening of microtubules
Inhibits microtubules by suppressing microtubule growth at the plus end
Inhibits microtubules by inhibiting the polymerization of tubulin dimers and depolymerization
Induces DNA adduct formation and cell death
Interferes with DNA coiling to inhibit transcription and replication
Whereas antimicrotubule agents such as taxanes and eribulin all act by sending the cell into apoptosis via mitotic arrest after tubulin binding, the mechanism of action of eribulin is unique amongst the antimicrotubule agents [14, 15]. Whereas paclitaxel inhibits microtubule shortening , eribulin prevents microtubule growth . Eribulin binds to the plus ends of the microtubule , inhibiting microtubule dynamics by suppressing microtubule polymerization . This in turn sequesters tubulin into non-functional aggregates .
Anthracyclines such as doxorubicin and epirubicin induce DNA intercalation and apoptosis of tumour cells . Antimetabolites, which include capecitabine and gemcitabine, inhibit processes required for DNA synthesis [11, 18] and the oral 5-fluorouracil (5-FU) analogue S-1 (a combination of the prodrug tegafur and two modulators of 5-FU) acts following its biotransformation to cytotoxic nucleotides . Other choices for breast cancer treatment include platinum analogues such as carboplatin and cisplatin, which induce DNA adduct formation , and irinotecan, which inhibits DNA synthesis via an interaction with topoisomerase I .
Several factors to be considered when selecting agents for patients previously treated with anthracyclines and taxanes include pre-treatment history, previous response, residual toxicity and tumour aggressiveness. The standard regimen for metastatic breast cancer patients previously treated with anthracyclines and taxanes remains to be established.
3 Clinical and Pharmacological Evaluation of Eribulin
3.1 Pharmacological Properties
Eribulin is a synthetic derivative of halichondrin B, a cell-cycle progression inhibitor found in marine sponges . Eribulin was approved for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes in the USA in 2010  and in Europe and Japan in 2011 [23, 24].
Pharmacokinetic parameters and dose-limiting toxicities in the phase I study of eribulin in Japanese patients with advanced solid tumours 
0.7 mg/m2 (n = 3)
1.0 mg/m2 (n = 3)
1.4 mg/m2 (n = 6)
2.0 mg/m2 (n = 3)
288.5 ± 43.0
380.6 ± 52.9
519.4 ± 107.2
717.6 ± 104.3
299.2 ± 124.5
379.6 ± 65.2
672.7 ± 113.7
1,370.1 ± 282.2
36.4 ± 11.2
42.9 ± 10.9
39.4 ± 8.3
59.9 ± 13.4
DLTa, n (%)
3.2 Clinical Properties
3.2.1 Phase II Studies
Phase II studies of eribulin in patients with metastatic breast cancer who have previously received an anthracycline and taxane
Any prior regimen of chemotherapy with A and T (median 4)
2–5 prior regimens of chemotherapy with A, T and CAP (median 4)
≤3 prior regimens of chemotherapy including A and T (median 3)
1.4 mg/m2 IV inf
d1 + 8 + 15 q4w
1.4 mg/m2 IV inf d1 + 8
1.4 mg/m2 IV inf d1 + 8
1.4 mg/m2 IV inf d1 + 8
10.2 [q4w cohort]
14.3 [q3w cohort]
10.2 [q4w cohort]
14.3 [q3w cohort]
10.2 [q4w cohort]
14.3 [q3w cohort]
11.9 [q4w cohort]
28.6 [q3w cohort]
Median duration of response (months)
Median PFS (months)
Median OS (months)
In Japanese patients with metastatic breast cancer previously treated with an anthracycline and a taxane (study 221) , eribulin appears to have a better efficacy than that observed in the others mentioned in Table 3. This open-label study of 80 patients who received 1.4 mg/m2 of eribulin demonstrated that eribulin had an objective clinical response rate of 21.3 % and a clinical benefit rate of 27.5 % in this patient population. However, this improved efficacy may be in part due to patient characteristics. In the previous two studies, patients had received a median of four previous regimens of chemotherapy containing an anthracycline plus a taxane and an anthracycline, taxane and capecitabine combination, respectively. In study 221, patients had received a median of three previous regimens of chemotherapy containing an anthracycline and a taxane. When the objective response rate was assessed according to the number of previous chemotherapy regimens in the metastatic setting, a higher response rate of 36 % was observed in patients who had no or one previous regimen, and patients who had a median of two or more previous regimens had a decrease in response. In addition, further investigation is needed to evaluate whether pharmacogenetic variation contributes to eribulin efficacy and safety, because P-glycoprotein (P-gp) may be involved in eribulin disposition and polymorphism of MDR1, the gene encoding P-gp, affects chemotherapeutic outcome.
3.2.2 Phase III Studies
Two phase III studies have investigated the efficacy of eribulin in metastatic breast cancer. EMBRACE (study 305; NCT00388726) compared eribulin with the physician’s choice of therapy in 762 patients, and another study compared eribulin with capecitabine in 1,102 women previously treated with no more than three regimens (study 301; NCT00337103) [30, 31].
The encouraging results of the three phase II trials discussed previously led to the initiation of the phase III EMBRACE study—a randomized, open-label, multinational study that investigated the efficacy of eribulin in heavily pre-treated women with locally recurrent or metastatic breast cancer . Patients were required to have previously received between two and five chemotherapy regimens including an anthracycline and a taxane, and two or more regimens for locally recurrent or metastatic breast cancer. A dosage of 1.4 mg/m2 of eribulin was administered intravenously over 2–5 min on days 1 and 8 of a 21-day treatment cycle, and patients in the treatment of physician’s choice (TPC) group received single-agent chemotherapy, cancer treatment-approved biological treatment, hormonal therapy, radiotherapy or symptomatic treatment . The proposed TPC was chosen for each patient and confirmed before central randomization. In the TPC arm, 96 % received chemotherapy including vinorelbine, gemcitabine and capecitabine, 4 % received hormonal therapy but no patient received supportive care alone. The primary endpoint of the EMBRACE study was overall survival.
Phase III studies of eribulin in patients with metastatic breast cancer who have previously received an anthracycline and taxane
305 (EMBRACE) 
Median OS, months
Median PFS, months
Tumour response (%)
In patients with measurable disease, significantly more patients had an objective response (assessed by independent review) in the eribulin treatment group (12 %) compared with the TPC group (5 %; p = 0.002) (Table 4). The clinical benefit rates were 23 % (95 % CI 18.9, 26.7) for eribulin and 17 % (12.1, 22.5) in the TPC group.
On the basis of the demonstration of a statistically significant prolongation of overall survival, eribulin mesylate was approved by the US Food and Drug Administration (FDA). This approval highlights the appropriate use of an innovative trial design and shows that improvement in overall survival is an achievable endpoint in the setting of advanced breast cancer.
Study 301 was a phase III, randomized, open-label, multinational study that also investigated the efficacy of eribulin in heavily pre-treated women with locally recurrent or metastatic breast cancer . Patients were required to have previously received at most three chemotherapy regimens (at most two for advanced disease) with each regimen including an anthracycline or a taxane. Patients were randomized to either 1.4 mg/m2 of eribulin (administered intravenously over 2–5 min on days 1 and 8 of a 21-day treatment cycle) or oral capecitabine (1,250 mg/m2 twice daily on days 1–14 of a 21-day treatment cycle) . The co-primary endpoints of study 301 were overall survival and progression-free survival.
Like the EMBRACE study, eribulin increased the median overall survival of patients compared with capecitabine (15.9 vs 14.5 months; HR 0.88, 95 % CI 0.77, 1.00; p = 0.056; Table 4), although this difference was not statistically significant. In contrast, the median progression-free survival of both arms was almost identical (assessed by independent review) (Table 4). Similarly, in patients with measurable disease, there was no apparent difference in the proportion of patients who had an objective response rate (assessed by independent review) in the eribulin treatment group (11 %) compared with capecitabine (12 %) (Table 4).
Subgroup analysis of overall survival in the phase III studies of eribulin by human epidermal growth factor receptor 2 (HER2) and oestrogen receptor (ER) status
305 (EMBRACE) 
HR (95 % CI)
HR (95 % CI)
0.81 (0.66, 0.99)
0.88 (0.77, 1.00)
0.76 (0.47, 1.24)
0.97 (0.69, 1.36)
0.81 (0.64, 1.02)
0.84 (0.72, 0.98)
0.81 (0.63, 1.04)
0.90 (0.74, 1.09)
0.78 (0.54, 1.13)
0.78 (0.64, 0.96)
0.71 (0.46, 1.10)
0.70 (0.55, 0.91)
Phase I studies have suggested that eribulin doses of 1.0–2.0 mg/m2 result in a manageable toxicity profile, and as a result the approved dosage of eribulin is a 2–5 min infusion of 1.4 mg/m2 on days 1 and 8 of a cycle lasting 21 days [12, 25, 26, 33]. Eribulin continued to exhibit an acceptable toxicity profile in both phase II [27, 28, 29] and phase III [30, 31] studies.
Consistent with the findings of the phase II trials [27, 28, 29], in the EMBRACE trial adverse events were reported in 497 (99 %) patients receiving eribulin and 230 (93 %) patients receiving the TPC; of these, 126 (25 %) and 64 (26 %) patients reported serious adverse events . The most common adverse events in either treatment group were asthenia or fatigue (54 and 40 % of patients receiving eribulin and the TPC, respectively) and neutropenia (52 and 30 %, respectively). More patients receiving eribulin reported grade 3 or 4 neutropenia (45 vs 21 %), leukopenia (14 vs 6 %) or peripheral neuropathy (8 vs 2 %) .
Peripheral neuropathy was the most common adverse event leading to discontinuation of eribulin in the EMBRACE trial, with 24 (5 %) patients discontinuing treatment . However, the incidence of peripheral neuropathy was similar in the eribulin treatment group (overall, 35 % of patients; grade 3, 8 %; grade 4, <1 %) and the taxane (overall, 45 % of patients; grade 3, 5 %; no grade 4) treatment group .
Similarly, the adverse events reported in study 301 were consistent with the previously known side effects of eribulin . Adverse events were reported in 94.1 % of patients receiving eribulin and 90.5 % of patients receiving capecitabine; 17.5 and 21.1 % of patients reported serious adverse events . More patients receiving eribulin had neutropenia (54 vs 16 %) and leukopenia (31 vs 10 %); however, the incidence of anaemia, thrombocytopenia and febrile neutropenia was similar between treatment groups . Other common adverse events reported in patients receiving eribulin included alopecia (35 %), nausea (22 %), fatigue (17 %) and asthenia (15 %). Peripheral sensory neuropathy was observed in 13 % of patients (grade 3, 4 % of patients; no grade 4) .
4 Ongoing Studies of Eribulin and Other Agents
Ongoing clinical studies investigating eribulin in patients with breast cancer
Trial details (estimated enrolment)
Phase I/II, OL, SG (56)
Eribulin + carboplatin, trastuzumab
Phase II, OL, SG (47)
Eribulin then dose-dense doxorubicin + cyclophosphamide
Phase II, R, PG, OL (152)
Eribulin then FAC vs paclitaxel then FEC
Phase II, R, PG, OL (76)
Eribulin + cyclophosphamide vs docetaxel + cyclophosphamide
Phase II, SG, OL (30)
Eribulin + carboplatin
TN, HER2+, HER2−
Phase II, PG, OL (148)
Eribulin or eribulin + trastuzumab in patients who do not achieve pCR following neo-adjuvant chemotherapy
Phase II, SG, OL (67)
Eribulin + capecitabine
Phase II, SG, OL (80)
Dose-dense doxorubicin + cyclophosphamide then eribulin
Phase II, SG, OL (52)
Eribulin + trastuzumab
Phase II, SG, OL (52)
Phase II, R, PG, OL (141)
Eribulin +/− ramucirumab
Phase I/II SG, OL (80)
Eribulin + PLX 3397
Phase I/II, R, OL (116)
Eribulin + capecitabine
Phase II, R, PG, OL (80)
Eribulin + lapatinib
Phase I/II, SG, OL (58)
Eribulin + cyclophosphamide
Phase I, SG, OL (54)
Tolerability, AUC, Cmax, QT time
Eribulin + sorafenib
So far, preliminary results of three studies of eribulin have been presented and suggest that eribulin would be efficacious and well tolerated as a treatment in other breast cancer populations. Preliminary results of two ongoing clinical trials that are investigating eribulin as first-line therapy either as monotherapy (NCT01268150)  or combination therapy (NCT01269346)  were presented at the 2012 San Antonio Breast Cancer Symposium. These results showed that as first-line therapy for patients with locally recurrent or metastatic breast cancer, eribulin appears to have anti-tumour activity and an acceptable safety profile, both when given as monotherapy and in combination with trastuzumab [50, 51].
The treatment of early-stage breast cancer with eribulin is also being investigated (NCT01328249) and preliminary results of this trial were presented at the 2012 San Antonio Breast Cancer Symposium . This study, which is investigating the efficacy and safety of adjuvant eribulin in patients with early-stage breast cancer who have received dose-dense doxorubicin and cyclophosphamide, suggests that eribulin has an acceptable safety profile in this patient group.
Agents (current phase in the trial)
Liposomal doxorubicin (approved)
Pemetrexed (phase III)
Antimicrotubule agents (new formulation)
Nanoparticle albumin-bound (nab)–paclitaxel (approved)
EndoTAG-1 (phase II)
Paclitaxel poliglumex (phase II)
Antimicrotubule agents (novel taxane)
Larotaxel (phase II)
Tesetaxel (phase II)
Cabazitaxel (phase II)
Antimicrotubule agents (novel non-taxane)
Vinflunine (phase III)
Indibulin (phase I/II)
Satraplatin (phase II)
NKTR-102 (phase III)
Because metastatic breast cancer remains incurable with currently available systemic therapies, novel approaches are crucial. Studies of eribulin have shown that the drug is effective in the treatment of previously treated metastatic breast cancer, and has an acceptable toxicity profile. Importantly, in the phase III EMBRACE study, eribulin treatment resulted in a survival advantage, a difficult endpoint to achieve with a single chemotherapeutic agent. An additional phase III study showed that eribulin has similar efficacy to capecitabine in women treated with no more than three prior therapies. Furthermore, pre-specified exploratory analyses suggest that particular patient subgroups may have greater therapeutic benefit with eribulin, and may warrant further study to explore the potential mechanisms behind these differences.
In addition, several classes of new cytotoxic chemotherapeutic agents are currently being evaluated in clinical trials and these promising agents may offer solutions to the difficult issues surrounding breast cancer. Considering the high efficacy of taxanes in breast cancer, new antimicrotubule agents including eribulin are expected to achieve the primary goals of systemic therapy, which are to prolong survival and improve quality of life, thereby realizing the wish of patients with an incurable disease to live longer and better.
The original concept of this review was initiated by the author and he takes full responsibility for the intellectual content of this manuscript. The author would like to thank Sheridan Henness, PhD, and Simone Boniface of inScience Communications, Springer Healthcare, who provided medical writing assistance. This medical writing assistance was funded by Eisai Co. Ltd.
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