Impact of Eribulin Monotherapy on Post-Progression Survival in Patients with HER 2-Negative Advanced or Metastatic Breast Cancer

C l i n M e d International Library Citation: Kotake T, Kikawa Y, Takahara S, Tsuyuki S, Yoshibayashi H, et al. (2016) Impact of Eribulin Monotherapy on Post-Progression Survival in Patients with HER2-Negative Advanced or Metastatic Breast Cancer. Int J Cancer Clin Res 3:061 Received: June 16, 2016: Accepted: July 22, 2016: Published: July 25, 2016 Copyright: © 2016 Kotake T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Kotake et al. Int J Cancer Clin Res 2016, 3:061


Introduction
While survival outcomes of early breast cancer cases have been improved remarkably in recent years, still many patients develop metastases and require the treatment against the relapsed disease.breast cancer (A/MBC) is yet in the low level around 5%, despite the probability of disease silencing differs depending upon tumor subtype [1,2].
Chemotherapy regimens for HER2-negative A/MBC commonly comprise antineoplastic agents such as anthracycline or taxane [3], which provide limited survival advantages.Eribulin is a novel chemotherapeutic agent that inhibits microtubule movement through a site of action different from that of taxanes.Eribulin monotherapy significantly prolonged the overall survival of patients with metastatic breast cancer when compared with the treatment provided by the attending physician, in a phase III study (EMBRACE study) [4].A randomized trial with capecitabine (301 study) showed a tendency of better overall survival (OS) in patients treated with eribulin.
Based on these findings, eribulin is currently used, for many patients in the clinical practice, as a one of the option in 2 nd or 3 rd line chemotherapy for HER2-negative A/MBC.It is worth noting that these the aforementioned clinical studies demonstrated prolonged overall survival or a tendency thereof in eribulin-treated patients with no extension in progression-free survival [5].It was suggested that the treatment with eribulin may reduced occurrence of lethal new metastases such as those in the brain, lung, and liver, and prolong new metastasis-free survival the possible causes [6].However, the exact underlying mechanisms involved remain largely unknown.
Taking into account from the above, we conducted a multicenter observational retrospective study aiming at assessing the efficacy of eribulin on post-treatment in real-world clinical settings (KBCRN-R01 study).

Study population
Cases in which eribulin therapy was introduced for patients with HER2-negative A/MBC, between April 2011 and August 2014, were included in this study.The eribulin-treated cases were retrospectively collected from 12 Kyoto Breast Cancer Research Network (KBCRN) institutions in Japan.
The patients included in the study were histological diagnosed with breast cancer.The tumors were classified as recurrent, locally advanced, metastatic breast cancer using the American Joint Committee on Cancer (7 th edition) guidelines.The patients had undergone at least two courses of eribulin therapy, and presented with adequate organ as well as bone marrow functions.Patients were excluded if they had other malignancies or severe complication.
In principle, a 3-week treatment course comprised the administration of eribulin on day 1 and day 8, at a starting dose of 1.4 mg/m 2 .Depending on patient conditions, the drug was administered at a reduced dose or interrupted at the discretion of the attending physician.Treatment was continued until disease progression, occurrence of a serious toxic reaction, or patient's request for discontinuation.Attending physicians were allowed to change the method of administration at their discretion when toxic reactions emerged, and administration schedules that allowed for continuation of the treatment were collected.Tumor responses were assessed via CT, their periods depended on the patient's condition.Data on clinical outcome and toxicity were collected based on retrospective evaluation of the medical records, for the descriptive analyses.
This study was conducted under the approval of the ethics committee from principal institution, taking due care in protecting personal information.

Evaluation of efficacy and safety
Progression free survival (PFS) refers to the period from the start of eribulin administration to progression or death by any cause.Overall survival (OS) is the period from the start of eribulin administration to death, or the last follow-up day.Post-progression survival (PPS) is the period from progression that occurred after eribulin was administered to death, or the last follow-up day.This is the endpoint to evaluate the post-study therapy with eribulin.Overall response rate (ORR) is the proportion of patients for whom complete response (CR) or partial response (PR) was obtained.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4) were used for toxicity evaluation, while the conventional Response Evaluation Criteria In Solid Tumors (RECIST) criteria were used to assess the therapeutic effects.

Statistical analysis
Descriptive statistics were computed for demographic, clinicopathologic factors.Pearson χ 2 -test and Fisher's exact test were used for comparison of individual variables.Survival data were analyzed using three endpoints (OS, PFS, and PPS), and Kaplan-Meier analysis was performed for each of these subgroups using the log-rank test.Association between risk factors and survival data was examined using the COX proportional-hazards analysis.All statistical analyses were carried out using a computer software (SPSS version, SPSS inc.; Chicago, IL, USA), with p value of ≤ 0.05 considered significant.

Patient characteristics
A total of 110 patients with A/MBC underwent eribulin therapy

Discussion
The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines generally recommend the continuous administration of a single drug chemotherapy for HER2-negative A/MBC patients [7,8].However, although anthracycline-and taxane-based anti-cancer agents have been shown to be efficacious [9,10], still it is unclear about the magnitude of therapeutic impact on OS [11][12][13].Eribulin monotherapy is one of the few chemotherapy regimens that have been proven to prolong the OS.In the EMBRACE study, median PFS and OS were 3.7 months and 13.2 months, respectively [4].In the present study, the median PFS and OS were 4.0 months (95% CI, 3.2-4.7)and 16.8 months (95% CI, 8.8-24.7),respectively.Thus, major therapeutic outcomes of the this study reproduced or even compared favorably with the results from the EMBRACE study.
The essential aims of the treatment for A/MBC patients are to improve survival outcomes and maintain quality of life (QOL).To this end, it is important to manage drug toxicity, which, as a result, contributes not only to improvement in QOL but also to treatment continuity.In this study, 8 out of 110 cases (7.3%)where eribulin was discontinued due to the toxicity.In a retrospective study conducted by Dranitsaris et al., the rate of toxicity-caused discontinuation with eribulin was 8.9%, which was lower than that reported for other drugs [14].These findings indicate that eribulin can be safely and effectively administered to breast cancer patients.
The two previous studies (EMBRACE and 301) showed a unique property of eribulin treatment where PFS was not improved by the treatment but OS was significantly.The OS prolongation effect of eribulin was also reported in the treatment of progressive soft-tissue sarcomas.A phase III study, showed a similar trend that OS was significantly better in the eribulin-treated group compared with the standard treatment group, while no significant difference of PFS was detected between these two groups [15].Perez et al. have reported that, in the 301 study that compared capecitabine with eribulin, lethal organ metastases, such as those in the liver, the lung and the central nervous system, occurred at a lower frequency and after a longer period of time in the eribulin group [6].Further, Yoshida et al. have shown in an experimental setting that eribulin suppresses metastasis of breast cancer cells by inducing the conversion of epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) (appendix equation) [16].EMT is an essential cell function for tissue construction during normal developmental [17] and is also observed during cancer progression; it is considered to promote invasion and metastasis by enhancing the motility of cancer cells and degradation of extracellular matrix [18].
In the present study, total dose of eribulin and appearance of a new lesion or metastasis (HR, 0.26; p = 0.001, HR, 2.84; p = 0.006, respectively) were factors that showed statistically significant correlations with PPS in the multivariate analysis.This suggests that eribulin may suppress new lesions and lead to improved prognosis.However, such a prognosisimproving effect of eribulin should be compared with other anti-cancer agents, and is just a speculation at this point of time.Further investigations on the OS-improving effect of eribulin through prospective studies and translational research are expected.

Conclusion
The present study indicates the total dose of eribulin and appearance of a new lesion were correlated with the PPS.Suppression of new lesions may lead to the OS-improving effect of eribulin.Further studies are merited to evaluate the effects of this drug on post-treatment.

Figure 2 :
Figure 2: A Kaplan-Meier curves of post-progression survival (PPS) stratified by PD in 88 patients who had visceral disease when eribulin therapy was started.Increase in the size of pre-existing lesion (IPEL) vs. Appearance of a new lesion or metastasis (NM).

6.
EA Perez (2013) New metastasis versus increase in size of pre-existing lesion and its correlation with overall survival in patients with MBC treated with eribulin of capecitabine in Study 301, a Phase III randomized trial.ECC, 1911.

Number of prior chemotherapy for advanced disease
ER: estrogen receptor; PgR: progesterone receptor • Page 3 of 5 • ISSN: 2378-3419 Kotake et al.Int J Cancer Clin Res 2016, 3:061 at 12 participating institutions in Japan between April 2011 and August 2014.Table1illustrates the background of the patients included in the study.The patients with A/MBC received a median of 3 chemotherapy lines, wherein 86 (78.2%) and 104 (94.5%) of them had been previously treated with anthracycline-and taxane-based anti-cancer agents, respectively.

Table 2 :
Characterisics of patients with tumor progression following eribulin treatment.

Table 3 :
Univariate and multivariable cox regression analyses of PPS.