|Ahead of print
Eribulin monotherapy in heavily pretreated metastatic breast cancer patients in real life
Murat Sari, Pınar Saip
Department of Internal Medicine, Istanbul University, Istanbul Medical Faculty, Division of Medical Oncology, Capa, Fatih/Istanbul, Turkey
Department of Internal Medicine, Istanbul University, Istanbul Medical Faculty, Division of Medical Oncology, Capa, Fatih/Istanbul
Source of Support: None, Conflict of Interest: None
BACKGROUND AND AIM: Our retrospective, single-center study aimed at evaluating the efficacy and safety of eribulin in heavily pretreated metastatic breast cancer (MBC) in routine clinical practice.
SUBJECTS AND METHODS: Twenty-eight patients treated with eribulin for MBC between May 2014 and November 2017 were included in our study. Clinical and biological assessment of toxicity was controlled at each visit. Tumor response was evaluated every three cycles of treatment.
RESULTS: Median age at eribulin treatment was 52.5-year. Tumors were hormone receptor positive (71.4%), HER2-positive (10.7%), and triple negative (TN) (25%). Most of the patients (92.8%) presented with visceral metastases, mainly in the lymph nodes (57.1%) and liver (53.6%). Median previous metastatic chemotherapy line was 4 [1–7]. Median number of metastatic sites were 3 (1–4). Median number of eribulin cycles was 4. At the end of follow-up period, 36% of the patients were still alive. Eighteen patients died due to disease progression. The objective response rate was 21.5% with a 42.9% clinical benefit rate. Median progression-free survival and overall survival (OS) were 4 (95% CI: 2.7–5.2) and 14 (95% CI: 11.8–16.1) months, respectively. Treatment was well tolerated. None of the patients discontinued eribulin treatment due to toxicity. The most commonly reported toxicities were asthenia (71.4%), peripheral neuropathy (67.9%), and neutropenia (46.4%).
CONCLUSION: Eribulin is an effective new treatment option in heavily pretreated MBC, with a manageable toxicity profile. Our results confirm that treatment with eribulin is feasible and safe in real-world patients.
Keywords: Efficacy, eribulin, metastatic breast cancer, safety
| » Introduction|| |
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among females worldwide. Also, breast cancer is the most common type of cancer in Turkish women (age-standardized incidence rate is 43.8/100.000 female person) as in the world. One in four women diagnosed with cancer has breast cancer. With respect to stage, 11.5% of the cases are diagnosed in the metastatic phase at presentation which is above the world average (~5%). Despite advances in primary and adjuvant treatment for local breast cancer, many patients will experience metastatic disease. Also, up to 30%of women with early-stage, nonmetastatic breast cancer at diagnosis will develop distant metastatic disease. Although patients with metastatic breast cancer (MBC) are unlikely to be cured of their disease, survival has improved significantly over time due to improved options for treatment.
The goals of treatment of MBC are to prolong survival and improve quality of life by reducing cancer-related symptoms. Due to the availability of many agents to treat MBC, no ideal sequence of treatments that can be applied to all patients exist in the guidelines. Anthracycline- and taxane-based regimens remain the standard chemotherapy options for neoadjuvant/adjuvant and/or first-line treatment for MBC, and after progression under these drugs, many therapeutic options are available now. The preferred agents, based on their efficacy and toxicity profile, are capecitabine, gemcitabine, vinorelbine, and eribulin. The latter is one of the few agents to provide a survival gain, although small (2.5 months) in a heavily pretreated population of MBC patients.
The microtubule polymerization inhibitor, eribulin, is an analog of halichondrin B, which is derived from the sea sponge Halichondria okadai. It restricts the growth phase of microtubule and sequesters tubulin into nonproductive aggregates and finally induces G2/M cell-cycle block, mitotic spindle disruption, and finally apoptotic cell death after prolonged mitotic blockage.
There is currently no standard therapy for patients with recurrent breast cancer after multiple chemotherapies. To date, little is known about the real-life routine use of eribulin in patients outside of clinical trials. Recent reports indicate efficacy and safety comparable to the randomized trials, with response rates ranging from 18% to 30%.,,, In Turkey, eribulin is approved for treatment in locally advanced or MBC patients who have progressed after an anthracycline, taxane, capecitabine, vinorelbine, and gemcitabine regimens for advanced disease. Here, we present a retrospective analysis of the first 28 patients with MBC treated with eribulin at a single-center, Istanbul University, Institute of Oncology in Istanbul, Turkey.
| » Subjects and Methods|| |
The medical records of 28 Turkish women with MBC patients treated with eribulin at the Istanbul University Institute of Oncology between May 2014 and November 2017 were retrospectively analyzed. Patients who were metastatic at the initial presentation or became metastatic after adjuvant treatment were included in this study. All patients received at least one cycle of eribulin. The follow-up and data collection were completed in June 2018. Eribulin was administrated at a dose of 1.4 mg/m2 intravenously over 2–5 min on days 1 and 8 of a 21-day chemotherapy cycle according to the product guidelines. Primary granulocyte colony-stimulating factor (G-CSF) was not given routinely except for patients who developed grade 3–4 neutropenia. Dose reduction was done depending on patients' grade 3–4 toxicity. Patient data including demographics, clinical, and pathological characteristics of disease and number of previous chemotherapy treatment line, eribulin dosage, and number of received eribulin cycles were retrospectively collected using the patient records. Radiology reports and clinical and laboratory assessments of the treating medical oncologist were used for efficacy evaluations. Imaging assessments were repeated with 3-month intervals and the same modality used at baseline was consistently used for future evaluations of response. Treatment response was determined as such: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Objective response rate (ORR) was defined as the sum of the obtained PR and CR and the clinical benefit rate (CBR) was the sum of PR, CR and SD maintained for at least 3 months. Adverse events were registered retrospectively by searching the physician's reports as well as the relevant laboratory values and were quantified by the investigators according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Local institutional ethic committee approval obtained. Patient identifier data were anonymized to preserve patient confidentiality.
OS and PFS were the primary efficacy endpoints. OS was defined as the time from first course of eribulin until death from any cause or last follow-up and PFS as the time from first course of eribulin until tumor progression or death. Patients still alive and without progression at last follow-up were censored for the purpose of OS and PFS analysis. Survival estimates were calculated using the Kaplan–Meier method. Primary taxane sensitivity as defined by CR, PR, or SD >3 months under taxane treatment in metastatic setting. Categorical covariates analyses were as follows: ECOG performance status (0–1 vs. 2–3), hormone receptors (HR− vs. HR+), age (≤50 vs. >50 years), HER2+ overexpression (no/yes), number of prior chemotherapy (≤4 vs. >4 lines), and different metastasis localization (visceral metastases, liver, bone, lymph nodes, lung, brain, serous or skin metastases) and taxane sensitivity. Significant factors in the univariate analyses were included in a multivariate analysis to identify independent predictor and prognostic factors of the clinical benefit. All statistical analyses were calculated using SPSS Software v25.0 (SPSS Inc., Chicago, IL, USA) and in all assessments, a P value <0.05 was considered as statistically significant.
| » Results|| |
Main clinicopathological characteristics of the breast tumors as well as the previous chemotherapy treatments are presented in [Table 1]. Median age at breast cancer diagnosis and at eribulin initiation was 42.5 (27–67) and 52.5 (29–72) years old, respectively. All of the patients had metastatic disease at the start of treatment: 92.8% of the patients presented with visceral metastases, mainly in the lymph nodes (57.1%) and liver (53.6%). The majority of the patients (89.3%) had previously received adjuvant and/or neoadjuvant chemotherapy before they were diagnosed with metastases. Most patients were heavily pretreated with a median of 4 (range 1–7) metastatic chemotherapy lines prior to eribulin treatment. All patients had previously received anthracycline- and/or taxane-based treatments (89.3% of the patients had previously received anthracycline and 100% taxane regimen in neoadjuvant/adjuvant and/or metastatic chemotherapy settings). The majority (57.6%) of patients pretreated with taxanes showed primary taxane sensitivity. Median number of metastatic sites were 3 (1–4). Brain metastases were present in 28.6% (n = 8) of the patients.
At the end of the follow-up period (June 2018), all patients who had been treated at least two cycles of eribulin received a median of four courses of eribulin (range 2–37), whereas four patients were still on eribulin. About 36% of the patients were still alive. Eighteen patients died due to disease progression. Any significant relationship for overall survival on the basis of hormone-positive/HER2/neu-positive and TNBC could not be shown in [Figure 1]. One patient had a complete response. Five patients showed a partial response yielding an ORR of 21.5% and six patients showed stable response with a CBR of 42.9%. Median PFS was 4 (95% CI: 2.7-–.2) months and median OS was 14 (95% CI: 11.8–16.1) months [Table 2].
|Figure 1: Kaplan–Meier curves for overall survival on the basis of hormone-positive/HER2/neu-positive and TNBC|
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No significant OS or PFS difference was demonstrated in patients who received ≤3 chemotherapy lines to >3 lines and had metastatic site ≤2 to >2. The TN subgroup had significantly worse OS than non-TN group (respectively, 10 vs. 14 months, P < 0.05; HR [95% CI] = 3.1 [1,03–9.3]). But significantly higher OS was detected in the TN subgroup in regard of chemotherapy lines ≤3 to >3 (10 vs. 4 months, P < 0.05).
Using the Cox regression model, a difference was detected regarding OS in univariate analysis; TN status, prior use of an anthracycline-based regimen in metastatic period, and PFS on immediately preceding therapy <3 months were significantly associated with a shorter OS. However, in multivariate analysis, TN status and prior use of an anthracycline-based regimen in metastatic period were the only two independent prognostic factors of this population. Also, the presence of lung metastases and duration of eribulin treatment < median eribulin treatment time (129.5 days) were significantly associated with shorter PFS in univariate analysis. But no significant prognostic factor associated with PFS was detected in multivariate analysis [Table 3].
Eribulin treatment was globally well tolerated. None of the patients discontinued eribulin treatment due to toxicity. Adverse events (AEs) of any type and grade were reported in 85.7% (n = 24) of patients. The most commonly reported toxicities were asthenia (71.4%), peripheral neuropathy (67.9%, mostly grad 1–2), and neutropenia (46.4%). Most AEs were grades 1 and 2. Major toxicities were of grade 3 (32.1%) and grade 4 (10.7%) as follows: grade 3/4 neutropenia (28.6%) and grade 3/4 peripheral neuropathy (3.6%) [Table 4]. Four patients were admitted to hospital during the eribulin treatment due to febrile neutropenia. Dose reductions were necessary in 11 patients due to mainly hematological toxicity (77.8%). Three patients received reduced dose of eribulin prior to treatment due to neutropenia and two of these patients received full dose of eribulin later on.
| » Discussion|| |
MBC is usually considered lethal and the main goal of treatment is to prolong survival and palliate the symptoms. In this retrospective analysis, we evaluated the clinical efficacy and safety of eribulin in heavily pretreated patients after it became available in our country. Microtubule inhibitor, eribulin, showed survival benefit and acceptable toxicity in heavily pretreated MBC patients in phase III trials.,, The phase III EMBRACE trial  comparing eribulin with the treating physician's choice (TPC) in heavily pretreated MBC patients who had been treated previously with an anthracycline and a taxane were enrolled. Patients had received three to five previous chemotherapy lines including an anthracycline and a taxane, and found that patients treated with eribulin experienced a significant survival benefit with a manageable toxicity. The results of the EMBRACE study led to the approval of eribulin by European Medical Agency in 2011 for the treatment of patients with MBC who have progressed after at least two chemotherapeutic regimens for advanced disease. In a second phase III trial, the safety and efficacy of eribulin versus capecitabine in patients with locally advanced or MBC in earlier-line treatment was analyzed as first- or second-line therapy; there were no major differences between the drugs in efficacy with respect to OS or PFS but a different toxicity profile. A pooled analysis of these two phase III trials  showed the beneficial effects of eribulin in terms of survival in patient subgroups, including women with HER2 and TN disease.
Patients treated in clinical trials with favorable features are often not representative of the general population treated in routine practice, so we wanted to evaluate the reproducibility of the results of the two phase III trials , in real life. Here, we present the results from a single center.
Our real-life results in this unselected population are consistent with EMBRACE  in terms of both efficacy and safety [Table 4]. The median age of patients at the initiation of eribulin treatment was 52.5 years and similar with phase III trials and retrospective studies.,,,,,,, Median prior metastatic chemotherapy line of our patients and the proportion of metastatic organs were similar with EMBRACE. Median PFS was 4 months, compared with 3.7 months in EMBRACE  and 4.1 months in study 301, so it was in line with reported phase III trials and approved the efficacy of eribulin in clinical practice. ORR and CBR were higher (21.4% and 42.9%) compared with 14.9% and 30.9% in EMBRACE  respectively, probably due to the response evaluation in our study was based on evaluation of the treating physician and thus was less strict than protocol of randomized trials. Median OS also was slightly higher 14 months compared with 13.1 months in the EMBRACE  and lower to study 301 (15.9 months) probably due to unselected population in contrast to randomized trials. The proportion of HR+ tumors was higher in our study compared with EMBRACE (71.4% vs. 64%). All patients had previously been treated with hormone therapy. This favorable prognostic value could explain slightly better OS results despite expected lower survival rates of retrospective studies. HR+ and non-TN tumors had better survival than TN tumors [Figure 2]. These poor results in TN group may be due to the fact that our patients received eribulin at a later phase, because we detected significantly longer OS rates in TN patients in univariate and multivariate analyses when they received eribulin at an earlier stage (≤3 chemotherapy lines) [Figure 3]. In our study, capecitabine pretreatment rate was greater in our study (85.7%) compared with EMBRACE (73%). Our patients had relatively aggressive disease because most of the patients had progressed rapidly on prior therapy (67.9% within 3 months). But interesting relationship was detected between OS and PFS of preceding therapy. PFS on immediately preceding therapy >3 months were significantly associated with a longer OS in univariate analysis.
|Figure 2: Kaplan–Meier curves for overall survival of triple-negative patients|
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|Figure 3: Kaplan–Meier curves for overall survival of triple-negative patients in regard of chemotherapy line of treatment|
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In contrast with that reported by Garrone et al., patients exposed to a rechallange with taxanes could not obtain a benefit in terms of response in our study. We cannot prognosticate that previous sensibility to taxanes could be predictive marker for eribulin sensibility as they are both microtubule inhibitor. But our results show efficacy of eribulin in patients progressing under prior treatment with two microtubule inhibitors: taxanes and vinorelbine.
This analysis could not show that patients with more than two metastatic involved organs gain survival benefit in contrast to phase III studies.,
The tolerability of eribulin in this unselected population was comparable and in line with EMBRACE [Table 4]. Adverse events occurred in 99% of the patients in the EMBRACE study compared to 85.7% in our study. Asthenia (the most common both in EMBRACE and in our study), neutropenia, and neuropathy were the most common side effects. Grade 3/4 neutropenia was less commonly seen mostly due to prophylactic G-CSF usage in our study. There were four patients requiring hospitalization due to febrile neutropenia. We had to make eribulin dose reduction during treatment period due to myelotoxicity.
Our study has some limitations. First, it was a retrospective study including a heterogenous group of patients. Many items are not described according to a predefined study protocol and there is missing information for some patients about disease characteristics in the patient records. Second, patient number was not enough to assess the effectiveness of eribulin in terms of variables like molecular subtypes of breast cancer. Third, the efficacy analysis of our study could be challenged because all patients were not evaluated homogeneously. But evaluation of all patients for efficacy by the same treating physician and the usage of same imaging modality for disease evaluation could be accepted as an advantage.
This retrospective study let the inclusion of a heterogenous group of patients unlike randomized trials with strict inclusion criteria. So, these findings may provide a realistic picture of what is observed in routine clinical practice.
| » Conclusion|| |
We present data on eribulin treatment in unselected, heavily pretreated MBC patients from a single-center university hospital. In summary, this retrospective analysis supports the efficacy and safety of eribulin in heavily pretreated MBC patients, with a population exposed to a median of four prior lines of chemotherapy. The survival benefit of eribulin was regardless of the number of metastatic organs, previous treatment regimens, or lines of treatment. Low- and manageable toxicity profile, shorter duration of administration with no premedication, and efficacy in heavily pretreated patients make eribulin a preferable regimen. However, further validation of the current findings should be performed in a larger study.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]