Adjusting the dosing schedule of eribulin to every 4 weeks (twice, on day 1 and day 8) improved overall survival in patients with human epidermal growth factor receptor 2-negative metastatic and advanced breast cancer

Adjusting the dosing schedule of eribulin to every 4 weeks (twice, on day 1 and day 8) improved overall survival in patients with human epidermal growth factor receptor 2-negative metastatic and advanced breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adjusting the dosing schedule of eribulin to every 4 weeks (twice, on day 1 and day 8) improved overall survival in patients with human epidermal growth factor receptor 2-negative metastatic and advanced breast cancer Yutaka Mizuno, Chihiro Toyoda, Yoshimi Shimizu, Takahiro Ichikawa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5819643/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Eribulin, a non-taxane microtubule inhibitor, is often unsustainable on the standard dosing schedule (days 1 and 8 every 3 weeks, Q3W) owing to severe hematological toxicities. We compared overall survival (OS) between this schedule and a modified one (days 1 and 8 every 4 weeks, Q4W). Methods: This single-center prospective cohort study compared objective response rate (ORR), progression-free survival (PFS), PFS2, OS, and safety in patients with breast cancer receiving eribulin on either a Q3W dosing schedule ( n = 47) or a Q4W dosing schedule ( n = 31). Results : The median PFS was 5.5 months for the Q3W group and 9.0 months for the Q4W group ( p = 0.065). The median PFS2 was 8.9 months for Q3W and 19.3 monthsfor Q4W ( p = 0.098). In contrast, the median OS was 15.0 months for Q3W and 26.7 months for Q4W ( p = 0.040). The median OS was longer in patients with a baseline absolute lymphocyte count ( ALC) of ≥1500/μL ( p = 0.007) and in the Q4W group ( p = 0.001). Multivariable analyses identified baseline ALC and dosing schedule as independent OS predictors ( p = 0.022 and p = 0.006). The frequency and severityof hematologic toxicities, including leukopenia and neutropenia, were similar between groups. Conclusion: Adjusting the eribulin dosing schedule from Q3W to Q4W improved the OS of patients with human epidermal growth factor receptor 2-negative advanced and metastatic breast cancer who showed a neutrophil count of <1500 mm³ on day 1 of the next cycle. Absolute lymphocyte count Breast cancer Dosing schedule Eribulin Overall survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The goal of metastatic breast cancer (MBC) treatment is to preserve the quality of life and improve the overall survival (OS) of patients; some guidelines have recommended drug treatment strategies to best manage patients with advanced breast cancer (ABC) and MBC [1, 2]. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, has shown unique antineoplastic effects on breast cancer cells, including vascular remodeling and epithelial-mesenchymal transition [3]. Decreased expression of transforming growth factor-beta (TGF-β), a potent immunosuppressive factor, has been observed in eribulin-treated patients with breast cancer [4, 5]. In the phase 3 EMBRACE study, eribulin monotherapy significantly improved OS compared to treatment of physician’s choice (TPC) in anthracycline- and taxane-refractory human epidermal growth factor receptor 2 (HER2)-negative MBC [6]. In Japan, the JBCRG-19 study concluded that eribulin improved progression-free survival (PFS) and time to treatment failure compared to TPC in first- or second-line chemotherapy, though without statistical significance [7]. The Japanese Breast Cancer Society Clinical Practice Guidelines for Systemic Treatment 2022 weakly recommend eribulin for patients previously treated with anthracycline- and taxane-based chemotherapy, including neoadjuvant and adjuvant therapy [8]. Despite these benefits, 99% of patients in the EMBRACE study experienced adverse events, leading to treatment discontinuation [6]. Neutropenia was the most common grade 3 or 4 adverse event, occurring in 21% and 24% of patients, respectively [6]. In the 301 study, grade 3 or 4 hematologic toxicities, primarily neutropenia, were more common in the eribulin arm than in the capecitabine arm (65% vs. 9%, respectively) [9]. Two postmarketing observational studies in Japan reported that grade ≥ 3 neutropenia occurred in 49.5% and 59.8% of patients [10, 11]. In the EMBRACE study, a few patients discontinued eribulin due to hematologic toxicities, with 18% receiving granulocyte colony-stimulating factor (G-CSF) [6]. Conversely, in the 301 study, neutropenia was the primary cause of eribulin discontinuation (1.7%), and 14.6% received G-CSF [9]. Effective management of neutropenia is crucial for continuing eribulin treatment, as using G-CSF to maintain chemotherapy dose intensity is not recommended in MBC. As a result, alternative dosing schedules for eribulin that may reduce neutropenia have been explored. In Japan, two phase II trials (the JUST and JACCRO BC-03 studies) showed that eribulin given biweekly from the second (cycle 2) or fourth cycle (cycle 4) was well tolerated in patients who could not tolerate the standard schedule, maintaining equivalent efficacy [12, 13]. However, thus far, no studies have compared the efficacy of standard and altered dosing schedules of eribulin for prolonging OS. Thus, in the present study, we aimed to evaluate the OS of patients with ABC and MBC who received eribulin on a new altered dosing schedule (days 1 and 8, every 4 weeks; Q4W), stratified according to the standard dosing schedule (days 1 and 8, every 3 weeks; Q3W) and the Q4W schedule; we also assessed the safety of this altered eribulin dosing schedule. Patients and Methods Patient eligibility This single-center prospective cohort study was conducted at Yokkaichi Municipal Hospital (Mie, Japan). In the EMBRACE study, the OS of eribulin was reported to be 13.1 months [6]. Therefore, we expected an OS of 20 months after changing the dosing schedule from Q3W. Assuming an entry period of 24 months and a follow-up period of 36 months, a total of 82 patients were required for the detection of the OS gain with a two-sided alpha of 0.05 and a power of 75%. The inclusion criteria were women aged ≥20 years with histologically confirmed HER2-negative metastatic or advanced breast cancer, prior treatment with anthracycline or taxane chemotherapy, an Eastern Cooperative Oncology Group performance status of 0–2, at least one measurable lesion according to RECIST ver. 1.1, and preserved function of major organs (bone marrow, liver, kidneys, and lungs). The exclusion criteria were as follows: presence of active infection, uncontrolled ischemic heart disease, interstitial pneumonia or pulmonary fibrosis, large pleural effusions or ascites requiring drainage, uncontrolled diabetes, active other malignancy, or symptomatic brain metastases; we also excluded pregnant women or women of childbearing potential. This study adhered to the Declaration of Helsinki of the World Medical Association. The protocol was approved by the institutional review board of Yokkaichi Municipal Hospital (No. 2014-12), and written informed consent was obtained from all patients. Treatment procedures and evaluation of outcome All patients were initially assigned to the Q3W dosing schedule of eribulin (1.4 mg/m²) for the first cycle. Figure 1 illustrates the subsequent patient assignments. For example, if a patient’s neutrophil count was ≤ 1500 mm³ and ≥ 1000 mm³ on day 1 of any cycle, the dosing schedule was adjusted to Q4W and maintained thereafter. Eribulin treatment was discontinued upon disease progression, intolerable adverse events, or death. The objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) were assessed according to RECIST ver. 1.1. PFS was defined as the time from treatment initiation to disease progression or death. PFS2 was defined as the time from the start of eribulin treatment until disease progression or death after the second treatment. OS was defined as the time from treatment initiation until death from any cause. Measurement of the neutrophil count and absolute lymphocyte count (ALC) Blood samples were collected before each cycle of eribulin administration, and the neutrophil count and ALC were measured using a Sysmex XN-9000 hematology analyzer (Kobe, Japan) at Yokkaichi Municipal Hospital. Statistical analyses PFS, PFS2, and OS were analyzed using the Kaplan–Meier method, with survival curves compared between the treatment groups using the log-rank test. Multivariate regression analysis for OS was performed using the Cox proportional hazards model to calculate the hazard ratio (HR) and 95% confidence interval (95% CI). A p -value < 0.05 was considered statistically significant. All statistical analyses were performed using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Results Patient characteristics Seventy-eight patients were evaluated in this study, and their characteristics are summarized in Table 1. Forty-seven (60.3%) patients continued Q3W eribulin therapy, while 31 (39.7%) were switched to the Q4W dosing schedule. Before transitioning to Q4W, the median cycle was 2 (range: 2–6) cycles. The median age at enrollment was 67 (range: 39–90) years, with the median age in the Q4W group significantly higher than in the Q3W group ( p = 0.008). Of the 78 patients, 51 (65.4%) were estrogen receptor (ER)- or progesterone receptor (PgR)-positive. Eribulin was administered as first- or second-line chemotherapy to 59 (76%) patients, and 36 (46%) had previously received anthracyclines and taxanes. The median number of metastatic organs was 2 (range: 1–3), with bone lesions the most common (48.7%). The baseline ALC was similar between the Q3W and Q4W groups ( p = 0.834), while the baseline neutrophil count was significantly lower in the Q4W group ( p = 0.025). Overall r esponse rate The overall ORR was 7.6%, with it being 6.3% in the Q3W group and 9.6% in the Q4W group. The DCR was 28.2%, with it being 25.5% in the Q3W group and 33.3% in the Q4W group. The proportion of patients with stable disease for over 6 months was 40.4% in the Q3W group and 61.2% in the Q4W group, while the CBR was 46.8% and 70.9% in the Q3W and Q4W groups, respectively. PFS and OS in Q3W and Q4W groups The results for PFS and OS are shown in Figures 2a and 2b, respectively. The median PFS was 5.5 months in the Q3W group and 9.0 months in the Q4W group (HR: 0.640; 95% CI: 0.398–1.030; p = 0.065). The median PFS was longer in the Q4W group, although the difference was insignificant. In contrast, the median OS was 15.0 months in the Q3W group and 26.7 months in the Q4W group, with a significantly prolonged OS in the Q4W group (HR: 0.535; 95% CI: 0.294–0.971; p = 0.040). Subsequent therapies after eribulin treatment At the data cut-off, 31/47 (65.9%) patients in the Q3W and 19/31 (61.2%) in the Q4W groups underwent subsequent therapy, respectively. The most common regimen after eribulin treatment was bevacizumab (Bev) + paclitaxel (PTX) in 11/31 (35%) patients in the Q3W group and in 7/19 (36%) in the Q4W group. PFS2 in the Q3W and Q4W groups The results for PFS2 are shown in Figure 3; the median PFS2 was 8.9 months in the Q3W group and 19.3 months in the Q4W group (HR: 0.655; 95% CI: 0.397–1.082; p = 0.098). There was a strong trend toward improved median PFS2 in the Q4W group. Subgroup analyses for OS in different baseline ALC and different dosing schedules The OS results for patients with different baseline ALCs are shown in Figure 4. The median OS stratified by a baseline ALC of ≥ 1500/μL and < 1500/μL was 26.1 and 20.7 months, respectively, with no significant difference (HR: 0.628; 95% CI: 0.332–1.188; p = 0.152). In the Q4W group, the median OS for an ALC of ≥ 1500/μL and < 1500/μL was 26.1 and 26.0 months, respectively. In contrast, the median OS in the Q3W group stratified by a baseline ALC of ≥ 1500/μL and < 1500/μL was 28.1 and 13.0 months, respectively. OS was significantly prolonged in the baseline ALC ≥ 1500/μL group (HR: 0.329; 95% CI: 0.146–0.739; p = 0.007) and Q4W group (HR: 0.314; 95% CI: 0.152–0.678; p = 0.001). Univariable and multivariable analyses for OS Univariable and multivariable analyses revealed that a baseline ALC of ≥ 1500/μL and Q4W dosing schedule were independent predictors of longer OS ( p = 0.022 and p = 0.006, respectively) (Table 2). Safety The frequency and grade of hematologic toxicities, including leukopenia and neutropenia, were similar in both groups (Table 3). No new safety signals were observed. Discussion This is the first report demonstrating significantly prolonged OS in patients with ABC and MBC when the eribulin schedule was adjusted from Q3W to Q4W after a neutrophil count of < 1500 mm³ on day 1 post-cycle 2. Additionally, this study identified the Q4W dosing schedule as a predictor of OS. Three phase II clinical trials have evaluated biweekly eribulin administration. The JUST study (n = 88) investigated eribulin schedule modification in Japanese patients with HER2-negative MBC previously treated with anthracycline, taxane, and ≤ 3 prior regimens for MBC [12]. The JUST study modified the dosing schedule to biweekly if an adverse event occurred before eribulin administration on day 8 of cycle 1 or day 1 of cycle 2. In the biweekly dosing groups, the ORR was 21.4%, the CBR was 31.0%, the median time to treatment failure was 81.5 days, and the median OS was 523 days. The JACCRO BC-03 study (n = 40) is a phase II trial evaluating biweekly eribulin administration after the third cycle of induction therapy in hormone receptor-positive, HER2-negative Japanese patients with MBC [13]. The ORR was 17.5%, and the DCR was 100%. The median PFS was 15.21 weeks (95% CI: 9.71–22.14), and the median OS was 21.39 months (95% CI: 17.00–25.00). Smith et al. conducted a phase II study of biweekly eribulin in patients with HER2-negative MBC [14], with treatment starting from cycle 1, unlike the JUST and JACCRO BC-03 studies. The ORR was 12% (95% CI: 5–24%), the DCR was 65% (95% CI: 51–77%), and the CBR was 30% (95% CI: 18–43%). The median PFS was 3.6 months (95% CI: 2.9–4.1), and the median OS was 13.2 months (95% CI: 10.6–not evaluable). Our study showed an ORR of 9.6%, a DCR of 33.3%, and a CBR of 70.9% in patients receiving eribulin in the Q4W group. The median PFS was 9.0 months, and the median OS was 26.7 months. The higher CBR in our study likely reflects the greater proportion of patients with stable disease for over 6.0 months compared to the Q3W group. This outcome may stem from the flexibility of the dosing schedule after cycle 2. In contrast, the JUST study implemented biweekly dosing after cycle 2, the JACCRO BC-03 study after cycle 4, and the Smith et al. study from cycle 1. The median PFS in the Q4W group was longer than that in the Q3W group. Furthermore, the median OS was significantly longer in the Q4W group (26.7 months) than in the Q3W group (15.0 months). In the present study, 31 (65.9%) patients in the Q3W group and 19 (61.2%) in the Q4W group received subsequent treatment after eribulin. Additionally, the median PFS2 was longer in the Q4W group (19.3 months) than in the Q3W group (8.9 months). Recently, PFS2 has been considered in randomized controlled trials (RCTs) for recurrent breast cancer (e.g., OlympiAD and DESTINY-Breast03 trials) [15, 16]. A meta-analysis of 38 RCTs assessing the correlation of OS with PFS, ORR, and PFS2 revealed a moderate correlation between PFS2 and OS (r = 0.67; 95% CI: 0.08–0.69). This correlation was also observed across subgroup analyses for various parameters, including immunotherapy versus non-immunotherapy, survival after progression (<12 vs. ≥12 months), and treatment continuation after third-line therapy (<50% vs. ≥50%) [17]. Eribulin exhibits antitumor effects on breast cancer cells and appears to induce vascular remodeling and epithelial–mesenchymal transition [3]. Furthermore, treatment with eribulin has been associated with the decreased expression of TGF-β, a potent immunosuppressive factor [4, 5]. These morphological and immunological changes enhance the efficacy of subsequent treatment after eribulin. We speculate that the increased duration of OS in the Q4W group may be attributed to the eribulin-associated increase in PFS2, despite this increase not being statistically significant. The incidences of grade 3/4 neutropenia with the Q3W dosing schedule of eribulin ranged from 22.2% to 59.8% in previous studies (EMBRACE study: 45%, 301 study: 45.5%, JBCRG-19 study: 22.2%, postmarketing observational study in Japan: 49.5–59.8%). For biweekly dosing, incidences ranged from 31.0% to 88.1% (JUST study: 88.1%, JACCRO BC-03 study: 50.0%, Smith et al.: 31.0%) [6, 7, 9-13]. The incidence of febrile neutropenia with a Q3W dosing schedule of eribulin ranged from 2.1% to 7.7% (301 study: 2.1%, postmarketing observational study in Japan: 3.5–7.7%). With a biweekly dosing schedule, the incidence ranged from 0% to 11.9% (JUST study: 11.9%, JACCRO BC-03 study and Smith et al.: 0%) [7, 9-13]. Our study found that the incidence of grade 3/4 neutropenia was 31.9% in the Q3W group and 32.2% in the Q4W group, lower than the rates reported in the JUST and JACCRO BC-03 studies. Smith et al. reported that over 50% of patients received G-CSF (pegfilgrastim or filgrastim). Conversely, most patients with febrile neutropenia in our study did not receive pegfilgrastim or filgrastim but were treated with prophylactic antibiotics. Kawamura et al. used a mechanistic pharmacodynamic model to describe changes in neutrophil counts over time based on post-marketing real-world data of neutropenic profiles in patients with MBC treated with eribulin [18]. The study concluded that low serum albumin levels and baseline neutrophil count were associated with severe neutropenia. Virtual simulations using the pharmacodynamic model predicted the probability of grade ≥ 3 neutropenia to be 69%, 27%, and 27% for patients on the standard, biweekly, and triweekly eribulin treatment schedules, respectively. In the Q4W dosing schedule, eribulin is administered on day 1 of the next cycle once the neutrophil count has sufficiently recovered between days 8 and 29 to maintain baseline levels. This approach may also prolong the time to treatment failure. Our study showed that the median OS for patients with a baseline ALC of ≥ 1500/μL and < 1500/μL was 26.7 and 17.9 months, respectively, with a longer median OS in patients with a baseline ALC of ≥ 1500/μL. Based on the EMBRACE data, Miyoshi et al. reported that a high baseline ALC of ≥ 1500/μL was a significant and independent predictor of longer OS in patients treated with eribulin [19]. In a post hoc analysis of data from a postmarketing observational study of eribulin in Japan, Takahashi et al. reported that the median OS was significantly longer in patients with a baseline ALC of ≥ 1500/μL than those with an ALC of < 1500/μL [20]. Recent reports have indicated that baseline ALC and the pattern of disease progression (progression by pre-existing disease versus new metastases) are associated with OS in patients treated with eribulin [21]. Additionally, dynamic changes in the neutrophil-to-lymphocyte ratio at 3 or 6 months after initiating eribulin have been linked to OS [22]. This study analyzed the subgroup OS of eribulin-treated patients stratified by dosing schedule and baseline ALC. The median OS in the Q4W group, stratified by a baseline ALC of ≥ 1500/µL and < 1500/µL, was 26.1 months and 26.0 months, respectively. Conversely, the median OS for a baseline ALC of ≥ 1500/μL and < 1500/μL in the Q3W group was 28.1 and 13.0 months, respectively. The median OS was prolonged in the baseline ALC ≥ 1500/μL and Q4W groups. Multivariate analysis, adjusted for other potential confounders, confirmed that baseline ALC and dosing schedule were predictors of OS. This study had some limitations. It was a prospective cohort analysis with a small sample size, and patient backgrounds, including age, varied between the Q3W and Q4W groups. The efficacy and safety of the Q3W and Q4W dosing schedules from cycle 1 should be further investigated in RCTs. In conclusion, our results showed that adjusting eribulin administration from the Q3W to the Q4W dosing schedule significantly prolonged OS in patients with HER2-negative ABC and MBC. Specifically, when patients on the Q3W dosing schedule have a neutrophil count of < 1500 mm³ on day 1 of the next cycle, adjusting to the Q4W schedule can improve outcomes in patients with HER2-negative ABC and MBC. Abbreviations ABC Advanced breast cancer ALC Absolute lymphocyte count CBR Clinical benefit rate DCR Disease control rate HER2 Human epidermal growth factor receptor 2 G-CSF Granulocyte colony-stimulating factor MBC Metastatic breast cancer ORR Objective response rate OS Overall survival PFS Progression-free survival RCT Randomized controlled trial Declarations Acknowledgments We thank the patients and their families who participated in this study and Professor Junichiro Watanabe from Juntendo University (Tokyo, Japan) for his insightful suggestions. Funding This study was not sponsored. Conflicts of interest YM reports honoraria from Eisai, Pfizer, Eli Lilly, Diichi-Sankyo, Chugai, Kyowa Kirin, and AstraZeneca. CT, YS, TI, and MS have no conflicts of interest to disclose. Author Contributions Conceptualization: Yutaka Mizuno; Data curation: Yutaka Mizuno, Chihiro Toyoda, Yoshimi Shimizu, Takahiro Ichikawa; Methodology: Yutaka Mizuno; Formal analysis and investigation: Yutaka Mizuno; Writing - original draft preparation: Yutaka Mizuno, Writing - review and editing: Masahiro Shibata. Data availability The participants did not give written consent for their data to be shared publicly; therefore, due to the sensitive nature of the research, supporting data are unavailable. Compliance with Ethical Standards Ethics approval All procedures involving human participants were conducted under the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was approved by the institutional review board of Yokkaichi Municipal Hospital (No. 2014-12). Consent to participate Written informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that human research participants provided informed consent for the publication of all tables and figures. References Cardoso F, Paluch-Shimon S, Schumacher-Wulf E et al (2024) 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast 76:103756. https://doi.org/10.1016/j.breast.103756 Im SA, Gennari A, Park YH et al (2023) Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer. 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World J Surg Oncol 19:324. https://doi.org/10.1186/s12957-021-02441-w Su MX, Lin HW, Nguyen HTH et al (2024) Monitoring trends in the absolute lymphocyte count and the neutrophil-to-lymphocyte ratio in patients with breast cancer receiving eribulin. BMC Cancer 24:195. https://doi.org/10.1186/s12885-024-11923-5 Tables Table 1. Characteristics of all patients and those treated with eribulin on Q3W and Q4W dosing schedules Overall (n = 78) Q3W (n = 47) Q4W (n = 31) p -value* Median age (range), years 67 (39–90) 65 (39–82) 70 (45–90) 0.008 * Advanced breast cancer, n (%) 21 (27) 15 (32) 6 (19) 0.299 Metastatic breast cancer, n (%) 57 (73) 32 (68) 25 (81) ER/PgR positive, n (%) 51 (65) 34 (72) 17 (55) 0.146 ER/PgR negative, n (%) 27 (35) 13 (28) 14 (45) No. of prior chemotherapy regimens for advanced/metastatic diseases, n (%) 0.797 0 25 (32) 14 (30) 11 (35) 1 34 (44) 22 (47) 12 (39) ≥ 2 19 (24) 11 (23) 8 (26) Prior anticancer therapy, n (%) Endocrine therapy 51 (65) 34 (72) 17 (55) 0.146 CDK4/6 inhibitor 20 (26) 15 (32) 5 (16) 0.185 Anthracycline only 40 (51) 25 (53) 15 (48) 0.817 Taxane only 57 (73) 37 (78) 20 (65) 0.198 Anthracycline and taxane 36 (46) 23 (49) 12 (39) 0.486 Metastatic sites, n (%) 0.084 Bone 38 (49) 23 (49) 15 (48) Liver 31 (40) 20 (43) 11 (35) Lymph nodes 30 (38) 20 (43) 10 (32) Lung 26 (33) 12 (26) 14 (45) Pleura 12 (15) 9 (19) 3 (10) Brain 7 (9) 4 (9) 3 (10) Peritoneum 5 (6) 4 (9) 1 (3) Ovary 1 (1) 1 (2) 0 No. of metastatic sites, median (range) 2 (1–3) 2 (1–3) 2 (1–3) 0.987 Baseline ALC, median (μL, range) 1221 (177–3918) 1253 (448–2512) 1208 (177–3918) 0.557 Pre-Q4W ALC, median (μL, range) 1240 (672–2891) 0.834 Baseline neutrophil count, median (μL, range) 3729 (1443–8732) 3804 (1443–8490) 3476 (1561–8731) 0.679 Pre-Q4W neutrophil count, median (μL, range) 3150 (1151–5989) 0.025 * ALC: absolute lymphocyte count; CDK: cyclin-dependent kinase; ER: estrogen receptor; PgR: progesterone receptor; Q4W: quaque four weeks. Table 2. Factors predicting overall survival in patients with breast cancer by univariate and multivariate analysis Univariate Multivariate Variable HR 95%CI p -value* HR 95%CI p -value* Baseline ALC (< 1500/μL vs ≥ 1500/μL) 0.666 0.352–1.262 0.212 0.396 0.180–0.880 0.022* Dosing schedule (Q3W vs Q4W) 0.519 0.285–0.944 0.031 * 0.382 0.191–0.765 0.006* Age (< 65 vs ≥ 65 years) 0.804 0.458–1.410 0.447 0.973 0.502–1.888 0.937 Disease setting (ABC vs MBC) 0.737 0.394–1.382 0.342 1.078 0.448–2.592 0.866 Subtype (ER/PgR-positive vs -negative) 0.982 0.544–1.774 0.954 1.276 0.665–2.483 0.472 Refractory to anthracyclines (yes vs no) 1.372 0.771–2.440 0.281 1.434 0.638–3.225 0.382 Refractory to taxanes (yes vs no) 1.040 0.549–1.970 0.904 1.305 0.618–2.755 0.485 ABC: advanced breast cancer; ALC: absolute lymphocyte count; CI: confidence interval; ER: estrogen receptor; HR: hazard ratio; MBC: metastatic breast cancer; PgR: progesterone receptor. Table 3. Adverse events in all patients and those treated with eribulin on a Q3W and a Q4W dosing schedule Overall (n = 78) Q3W (n = 47) Q4W (n = 31) p -value* Adverse event Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4 Hematologic toxicities, n (%) Leukopenia 40 (51.2) 23 (29.5) 20 (42.5) 14 (29.7) 20 (64.5) 9 (29.0) 0.942 Neutropenia 33 (42.3) 25 (32.1) 19 (40.4) 15 (31.9) 14 (45.1) 10 (32.2) 0.731 Anemia 34 (43.6) 10 (12.8) 17 (36.1) 4 (8.5) 17 (54.8) 6 (19.3) 0.207 AST increased 12 (15.4) 2 (2.6) 9 (19.1) 2 (4.2) 3 (9.6) 0 0.485 ALT increased 12 (15.4) 2 (2.6) 9 (19.1) 2 (4.2) 3 (9.6) 0 0.593 Febrile neutropenia 20 (25.6) 20 (25.6) 12 (25.5) 12 (25.5) 8 (25.8) 8 (25.8) 1 Non–hematologic toxicities, n (%) Nausea 10 (12.8) 4 (5.1) 6 (12.7) 2 (4.2) 4 (12.9) 2 (6.4) 1 Stomatitis 9 (11.5) 1 (1.3) 3 (6.3) 1 (2.1) 6 (19.3) 0 0.053 Vomiting 5 (6.4) 5 (6.4) 3 (6.3) 3 (6.3) 2 (6.4) 2 (6.4) 1 Fatigue 6 (7.7) 4 (5.1) 6 (12.7) 4 (8.5) 0 0 0.238 Malaise 11 (14.1) 0 10 (21.2) 0 1 (3.2) 0 0.044 * Anorexia 13 (16.7) 0 9 (19.1) 0 4 (12.9) 0 0.275 Dysgeusia 19 (24.3) 0 9 (19.1) 0 10 (32.2) 0 0.309 Peripheral sensory neuropathy 16 (20.5) 3 (3.8) 8 (17.0) 1 (2.1) 8 (25.8) 2 (6.4) 0.559 Alopecia 6 (7.7) 0 4 (8.5) 0 2 (6.4) 0 0.286 ALT: alanine aminotransferase; AST: aspartate aminotransferase. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5819643","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":418788972,"identity":"6dfef932-01f2-4924-9655-2f31d27067f7","order_by":0,"name":"Yutaka Mizuno","email":"data:image/png;base64,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","orcid":"","institution":"Yokkaichi Municipal Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"Mizuno","suffix":""},{"id":418788973,"identity":"ccbb4ef2-c34b-4949-b69a-c83e565ecb29","order_by":1,"name":"Chihiro Toyoda","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Toyoda","suffix":""},{"id":418788974,"identity":"d9107ff6-c6e4-46fa-bbaa-e6ada226002e","order_by":2,"name":"Yoshimi Shimizu","email":"","orcid":"","institution":"Yokkaichi Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshimi","middleName":"","lastName":"Shimizu","suffix":""},{"id":418788975,"identity":"711c860d-9f8c-40c0-82b6-6b57c9b76c1f","order_by":3,"name":"Takahiro Ichikawa","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Ichikawa","suffix":""},{"id":418788976,"identity":"2defabea-4ac5-45c4-a7f4-c1df42827a2b","order_by":4,"name":"Masahiro Shibata","email":"","orcid":"","institution":"Nagoya Ekisaikai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Shibata","suffix":""}],"badges":[],"createdAt":"2025-01-13 11:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5819643/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5819643/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77331586,"identity":"659477de-f139-4582-b625-a28181554fc8","added_by":"auto","created_at":"2025-02-27 13:31:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84230,"visible":true,"origin":"","legend":"\u003cp\u003eFlow of dosing schedule modification of eribulin: Eribulin treatment was initiated on a standard schedule (Q3W) and continued if the neutrophil count was \u0026gt; 1500 mm³ on day 1 after the second cycle (open arrow). If the neutrophil count was \u0026lt; 1500 mm³ and \u0026gt; 1000 mm³ on day 1 after the second cycle, the schedule was changed to Q4W, and the Q4W dosing schedule was maintained (closed arrow)\u003c/p\u003e","description":"","filename":"Fig120250113.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5819643/v1/91bdefe31f0e6313b0204ae2.jpg"},{"id":77331237,"identity":"b0f027b7-240d-48f5-8a09-c4b527cbe1de","added_by":"auto","created_at":"2025-02-27 13:23:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":99793,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival (PFS) (a) and overall survival (OS) (b) in patients with breast cancer receiving Q3W and Q4W dosing schedules. The median OS was significantly longer in the Q4W group compared to the Q3W group.\u003c/p\u003e\n\u003cp\u003eHR: hazard ratio; CI: confidence interval\u003c/p\u003e","description":"","filename":"Fig220250113.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5819643/v1/d303bf817096c1fd8de6e399.jpg"},{"id":77331235,"identity":"d22a31bf-31d8-42d2-8bfd-cad334bba805","added_by":"auto","created_at":"2025-02-27 13:23:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63024,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival 2 (PFS2) in patients with breast cancer receiving Q3W and Q4W of eribulin. The median PFS2 was longer in the Q4W group than in the Q3W group.\u003c/p\u003e\n\u003cp\u003eHR: hazard ratio; CI: confidence interval\u003c/p\u003e","description":"","filename":"Fig320250113.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5819643/v1/19dc87209638012e8d832fdd.jpg"},{"id":77331236,"identity":"6a29c7d7-a45d-4a3e-9817-bb7409f95608","added_by":"auto","created_at":"2025-02-27 13:23:58","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":105564,"visible":true,"origin":"","legend":"\u003cp\u003ePatients’ overall survival (OS) based on baseline absolute lymphocyte count (ALC) and eribulin dosing schedule. The median OS was longer in the baseline ALC ≥ 1500/μL and Q4W groups.\u003c/p\u003e\n\u003cp\u003eHR: hazard ratio; CI: confidence interval; NA: not available\u003c/p\u003e","description":"","filename":"Fig420250113.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5819643/v1/8aeb16ae1c8dda120b8cdf1d.jpg"},{"id":77331591,"identity":"734c8273-7afa-4d59-bbcf-6a83f3321773","added_by":"auto","created_at":"2025-02-27 13:32:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1288849,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5819643/v1/e12c4a41-f086-4a7c-9f3f-f28650c2b933.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adjusting the dosing schedule of eribulin to every 4 weeks (twice, on day 1 and day 8) improved overall survival in patients with human epidermal growth factor receptor 2-negative metastatic and advanced breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe goal of metastatic breast cancer (MBC) treatment is to preserve the quality of life and improve the overall survival (OS) of patients; some guidelines have recommended drug treatment strategies to best manage patients with advanced breast cancer (ABC) and MBC [1, 2]. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, has shown unique antineoplastic effects on breast cancer cells, including vascular remodeling and epithelial-mesenchymal transition [3]. Decreased expression of transforming growth factor-beta (TGF-\u0026beta;), a potent immunosuppressive factor, has been observed in eribulin-treated patients with breast cancer [4, 5]. In the phase 3 EMBRACE study, eribulin monotherapy significantly improved OS compared to treatment of physician\u0026rsquo;s choice (TPC) in anthracycline- and taxane-refractory human epidermal growth factor receptor 2 (HER2)-negative MBC [6]. In Japan, the JBCRG-19 study concluded that eribulin improved progression-free survival (PFS) and time to treatment failure compared to TPC in first- or second-line chemotherapy, though without statistical significance [7]. The Japanese Breast Cancer Society Clinical Practice Guidelines for Systemic Treatment 2022 weakly recommend eribulin for patients previously treated with anthracycline- and taxane-based chemotherapy, including neoadjuvant and adjuvant therapy [8].\u003c/p\u003e\n\u003cp\u003eDespite these benefits, 99% of patients in the EMBRACE study experienced adverse events, leading to treatment discontinuation [6]. Neutropenia was the most common grade 3 or 4 adverse event, occurring in 21% and 24% of patients, respectively [6]. In the 301 study, grade 3 or 4 hematologic toxicities, primarily neutropenia, were more common in the eribulin arm than in the capecitabine arm (65%\u0026nbsp;vs. 9%, respectively)\u0026nbsp;[9]. Two\u0026nbsp;postmarketing\u0026nbsp;observational studies\u0026nbsp;in Japan\u0026nbsp;reported\u0026nbsp;that grade \u0026ge; 3 neutropenia\u0026nbsp;occurred in 49.5% and 59.8%\u0026nbsp;of patients [10, 11].\u0026nbsp;In the EMBRACE study, a few patients discontinued eribulin due to hematologic toxicities, with 18% receiving granulocyte colony-stimulating factor (G-CSF) [6]. Conversely, in the 301 study, neutropenia was the primary cause of eribulin discontinuation (1.7%), and 14.6% received G-CSF\u0026nbsp;[9]. Effective management of neutropenia is crucial for continuing eribulin treatment, as using G-CSF to maintain chemotherapy dose intensity is not recommended in MBC. As a result, alternative dosing schedules for eribulin that may reduce neutropenia have been explored. In Japan, two phase II trials (the JUST and JACCRO BC-03 studies) showed that eribulin given biweekly from the second (cycle 2) or fourth cycle (cycle 4) was well tolerated in patients who could not tolerate the standard schedule, maintaining equivalent efficacy\u0026nbsp;[12, 13]. However, thus far, no studies have compared the efficacy of standard and altered dosing schedules of eribulin for prolonging OS.\u003c/p\u003e\n\u003cp\u003eThus, in the present study, we aimed to evaluate the OS of patients with\u0026nbsp;ABC and MBC who received eribulin on a new altered dosing schedule (days 1 and 8, every 4 weeks; Q4W), stratified according to the standard dosing schedule (days 1 and 8, every 3 weeks; Q3W) and the Q4W schedule; we also assessed the safety of this altered eribulin dosing schedule.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient eligibility\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-center prospective cohort study was conducted at Yokkaichi Municipal Hospital (Mie, Japan). In the EMBRACE study, the OS of eribulin was reported to be 13.1 months [6]. Therefore, we expected an OS of 20 months after changing the dosing schedule from Q3W. Assuming an entry period of 24 months and a follow-up period of 36 months, a total of 82 patients were required for the detection of the OS gain with a two-sided alpha of 0.05 and a power of 75%. The inclusion criteria were women aged \u0026ge;20 years with histologically confirmed HER2-negative metastatic or advanced breast cancer, prior treatment with anthracycline or taxane chemotherapy, an Eastern Cooperative Oncology Group performance status of 0\u0026ndash;2, at least one measurable lesion according to RECIST ver. 1.1, and preserved function of major organs (bone marrow, liver, kidneys, and lungs). The exclusion criteria were as follows: presence of active infection, uncontrolled ischemic heart disease, interstitial pneumonia or pulmonary fibrosis, large pleural effusions or ascites requiring drainage, uncontrolled diabetes, active other malignancy, or symptomatic brain metastases; we also excluded pregnant women or women of childbearing potential. This study adhered to the Declaration of Helsinki of the World Medical Association. The protocol was approved by the institutional review board of Yokkaichi Municipal Hospital (No. 2014-12), and written informed consent was obtained from all patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment procedures and evaluation of outcome\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were initially assigned to the Q3W dosing schedule of eribulin (1.4 mg/m\u0026sup2;) for the first cycle. Figure 1 illustrates the subsequent patient assignments. For example, if a patient\u0026rsquo;s neutrophil count was \u0026le; 1500 mm\u0026sup3; and \u0026ge; 1000 mm\u0026sup3; on day 1 of any cycle, the dosing schedule was adjusted to Q4W and maintained thereafter. Eribulin treatment was discontinued upon disease progression, intolerable adverse events, or death. The objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) were assessed according to RECIST ver. 1.1. PFS was defined as the time from treatment initiation to disease progression or death. PFS2 was defined as the time from the start of eribulin treatment until disease progression or death after the second treatment. OS was defined as the time from treatment initiation until death from any cause.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMeasurement of the\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eneutrophil count\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;and absolute lymphocyte count (ALC)\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood samples were collected before each cycle of eribulin administration, and\u0026nbsp;the neutrophil count and ALC\u0026nbsp;were measured using a Sysmex XN-9000 hematology analyzer (Kobe, Japan) at Yokkaichi Municipal Hospital.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePFS, PFS2, and OS were analyzed using the Kaplan\u0026ndash;Meier method, with survival curves compared between the treatment groups using the log-rank test. Multivariate regression analysis for OS was performed using the Cox proportional hazards model to calculate the hazard ratio (HR) and 95% confidence interval (95% CI). A \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 was considered statistically significant. All statistical analyses were performed using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient characteristics\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeventy-eight patients were evaluated in this study, and their characteristics are summarized in Table 1. Forty-seven (60.3%) patients continued Q3W eribulin therapy, while 31 (39.7%) were switched to the Q4W dosing schedule.\u0026nbsp;Before transitioning to Q4W, the\u0026nbsp;median cycle\u0026nbsp;was 2 (range: 2\u0026ndash;6)\u0026nbsp;cycles.\u0026nbsp;The median age at enrollment was 67 (range: 39\u0026ndash;90) years, with the median age in the Q4W group significantly higher than in the Q3W group (\u003cem\u003ep\u003c/em\u003e = 0.008). Of the 78 patients, 51 (65.4%) were estrogen receptor (ER)- or progesterone receptor (PgR)-positive. Eribulin was administered as first- or second-line chemotherapy to 59 (76%) patients, and 36 (46%) had previously received anthracyclines and taxanes. The median number of metastatic organs was 2 (range: 1\u0026ndash;3), with bone lesions the most common (48.7%). The baseline ALC was similar between the Q3W and Q4W groups (\u003cem\u003ep\u003c/em\u003e = 0.834), while the baseline neutrophil count was significantly lower in the Q4W group (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e=\u0026nbsp;0.025).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOverall r\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eesponse rate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall ORR was 7.6%, with it being 6.3% in the Q3W group and 9.6% in the Q4W group. The DCR was 28.2%, with it being 25.5% in the Q3W group and 33.3% in the Q4W group. The proportion of patients with stable disease for over 6 months was 40.4% in the Q3W group and 61.2% in the Q4W group, while the CBR was 46.8% and 70.9% in the Q3W and Q4W groups, respectively.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePFS and OS in Q3W and Q4W groups\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results for PFS and OS are shown in Figures 2a and 2b, respectively. The median PFS was 5.5 months in the Q3W group and 9.0 months in the Q4W group (HR: 0.640; 95% CI: 0.398\u0026ndash;1.030; \u003cem\u003ep\u003c/em\u003e = 0.065). The median PFS was longer in the Q4W group, although the difference was insignificant. In contrast, the median OS was 15.0 months in the Q3W group and 26.7 months in the Q4W group, with a significantly prolonged OS in the Q4W group (HR: 0.535; 95% CI: 0.294\u0026ndash;0.971; \u003cem\u003ep\u003c/em\u003e = 0.040).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubsequent therapies after eribulin treatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the data cut-off, 31/47 (65.9%) patients in the Q3W and 19/31 (61.2%) in the Q4W groups underwent subsequent therapy, respectively. The most common regimen after eribulin treatment was bevacizumab (Bev) + paclitaxel (PTX) in 11/31 (35%) patients in the Q3W group and in 7/19 (36%) in the Q4W group. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePFS2 in the Q3W and Q4W groups\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results for PFS2 are shown in Figure 3; the median PFS2 was 8.9 months in the Q3W group and 19.3 months in the Q4W group (HR: 0.655; 95% CI: 0.397\u0026ndash;1.082; \u003cem\u003ep\u003c/em\u003e = 0.098). There was a strong trend toward improved median PFS2 in the Q4W group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubgroup analyses for OS in different baseline ALC and different dosing schedules\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe OS results for patients with different baseline ALCs are shown in Figure 4. The median OS stratified by a baseline ALC of \u0026ge; 1500/\u0026mu;L and \u0026lt; 1500/\u0026mu;L was 26.1 and 20.7 months, respectively, with no significant difference (HR: 0.628; 95% CI: 0.332\u0026ndash;1.188; \u003cem\u003ep\u003c/em\u003e = 0.152). In the Q4W group, the median OS for an ALC of \u0026ge; 1500/\u0026mu;L and \u0026lt; 1500/\u0026mu;L was 26.1 and 26.0 months, respectively. In contrast, the median OS in the Q3W group stratified by a baseline ALC of \u0026ge; 1500/\u0026mu;L and \u0026lt; 1500/\u0026mu;L was 28.1 and 13.0 months, respectively. OS was significantly prolonged in the baseline ALC \u0026ge; 1500/\u0026mu;L group (HR: 0.329; 95% CI: 0.146\u0026ndash;0.739; \u003cem\u003ep\u003c/em\u003e = 0.007) and Q4W group (HR: 0.314; 95% CI: 0.152\u0026ndash;0.678; \u003cem\u003ep\u003c/em\u003e = 0.001).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eUnivariable and multivariable analyses for OS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariable and multivariable analyses revealed that a baseline ALC of \u0026ge; 1500/\u0026mu;L and Q4W dosing schedule were independent predictors of longer OS (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.022 and \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.006, respectively) (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe frequency and grade of hematologic toxicities, including leukopenia and neutropenia, were similar in both groups (Table 3). No new safety signals were observed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first report demonstrating significantly prolonged OS in patients with ABC and MBC when the eribulin schedule was adjusted from Q3W to Q4W after a neutrophil count of \u0026lt; 1500 mm\u0026sup3; on day 1 post-cycle 2. Additionally, this study identified the Q4W dosing schedule as a predictor of OS. Three phase II clinical trials have evaluated biweekly eribulin administration.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe JUST study (n = 88) investigated eribulin schedule modification in Japanese patients with HER2-negative MBC previously treated with anthracycline, taxane, and \u0026le; 3 prior regimens for MBC [12]. The JUST study modified the dosing schedule to biweekly if an adverse event occurred before eribulin administration on day 8 of cycle 1 or day 1 of cycle 2. In the biweekly dosing groups, the ORR was 21.4%, the CBR was 31.0%, the median time to treatment failure was 81.5 days, and the median OS was 523 days. The JACCRO BC-03 study (n = 40) is a phase II trial evaluating biweekly eribulin administration after the third cycle of induction therapy in hormone receptor-positive, HER2-negative Japanese patients with MBC [13]. The ORR was 17.5%, and the DCR was 100%. The median PFS was 15.21 weeks (95% CI: 9.71\u0026ndash;22.14), and the median OS was 21.39 months (95% CI: 17.00\u0026ndash;25.00). Smith et\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eal. conducted a phase II study of biweekly eribulin in patients with HER2-negative MBC [14], with treatment starting from cycle 1, unlike the JUST and JACCRO BC-03 studies. The ORR was 12% (95% CI: 5\u0026ndash;24%), the DCR was 65% (95% CI: 51\u0026ndash;77%), and the CBR was 30% (95% CI: 18\u0026ndash;43%). The median PFS was 3.6 months (95% CI: 2.9\u0026ndash;4.1), and the median OS was 13.2 months (95% CI: 10.6\u0026ndash;not evaluable). Our study showed an ORR of 9.6%, a DCR of 33.3%, and a CBR of 70.9% in patients receiving eribulin in the Q4W group. The median PFS was 9.0 months, and the median OS was 26.7 months. The higher CBR in our study likely reflects the greater proportion of patients with stable disease for over 6.0 months compared to the Q3W group. This outcome may stem from the flexibility of the dosing schedule after cycle 2. In contrast, the JUST study implemented biweekly dosing after cycle 2, the JACCRO BC-03 study after cycle 4, and the Smith et al. study from cycle 1.\u003c/p\u003e\n\u003cp\u003eThe median PFS in the Q4W group was longer than that in the Q3W group. Furthermore, the median OS was significantly longer in the Q4W group (26.7 months) than in the Q3W group (15.0 months). In the present study, 31 (65.9%) patients in the Q3W group and 19 (61.2%) in the Q4W group received subsequent treatment after eribulin. Additionally, the median PFS2 was longer in the Q4W group (19.3 months) than in the Q3W group (8.9 months). Recently, PFS2 has been considered in randomized controlled trials (RCTs) for recurrent breast cancer (e.g., OlympiAD and DESTINY-Breast03 trials) [15,\u0026nbsp;16]. A meta-analysis of 38 RCTs assessing the correlation of OS with PFS, ORR, and PFS2 revealed a moderate correlation between PFS2 and OS (r = 0.67; 95% CI: 0.08\u0026ndash;0.69). This correlation was also observed across subgroup analyses for various parameters, including immunotherapy versus non-immunotherapy, survival after progression (\u0026lt;12 vs. \u0026ge;12 months), and treatment continuation after third-line therapy (\u0026lt;50% vs. \u0026ge;50%)\u0026nbsp;[17]. Eribulin exhibits antitumor effects on breast cancer cells and appears to induce vascular remodeling and epithelial\u0026ndash;mesenchymal transition [3]. Furthermore, treatment with eribulin has been associated with the decreased expression of TGF-\u0026beta;, a potent immunosuppressive factor [4, 5].\u0026nbsp;These morphological and immunological changes enhance the efficacy of subsequent\u0026nbsp;treatment after eribulin. We speculate that the increased duration of OS in the Q4W group may be attributed to the eribulin-associated increase in PFS2, despite this increase not being statistically significant.\u003c/p\u003e\n\u003cp\u003eThe incidences of grade 3/4 neutropenia with the Q3W dosing schedule of eribulin ranged from 22.2% to 59.8% in previous studies (EMBRACE study: 45%, 301 study: 45.5%, JBCRG-19 study: 22.2%, postmarketing observational study in Japan: 49.5\u0026ndash;59.8%). For biweekly dosing, incidences ranged from 31.0% to 88.1% (JUST study: 88.1%, JACCRO BC-03 study: 50.0%, Smith et al.: 31.0%) [6, 7, 9-13]. The incidence of febrile neutropenia with a Q3W dosing schedule of eribulin ranged from 2.1% to 7.7% (301 study: 2.1%, postmarketing\u0026nbsp;observational study in Japan: 3.5\u0026ndash;7.7%). With a biweekly dosing schedule, the incidence ranged from 0% to 11.9% (JUST study: 11.9%, JACCRO BC-03 study and Smith et al.: 0%) [7, 9-13]. Our study found that the incidence of grade 3/4 neutropenia was 31.9% in the Q3W group and 32.2% in the Q4W group, lower than the rates reported in the JUST and JACCRO BC-03 studies. Smith et al. reported that over 50% of patients received G-CSF (pegfilgrastim or filgrastim). Conversely, most patients with febrile neutropenia in our study did not receive pegfilgrastim or filgrastim but were treated with prophylactic antibiotics. Kawamura et al. used a mechanistic pharmacodynamic model to describe changes in neutrophil counts over time based on post-marketing real-world data of neutropenic profiles in patients with MBC treated with eribulin [18]. The study concluded that low serum albumin levels and baseline neutrophil count were associated with severe neutropenia. Virtual simulations using the pharmacodynamic model predicted the probability of grade \u0026ge; 3 neutropenia to be 69%, 27%, and 27% for patients on the standard, biweekly, and triweekly eribulin treatment schedules, respectively. In the Q4W dosing schedule, eribulin is administered on day 1 of the next cycle once the neutrophil count has sufficiently recovered between days 8 and 29 to maintain baseline levels. This approach may also prolong the time to treatment failure.\u003c/p\u003e\n\u003cp\u003eOur study showed that the median OS for patients with a baseline ALC of \u0026ge; 1500/\u0026mu;L and \u0026lt; 1500/\u0026mu;L was 26.7 and 17.9 months, respectively, with a longer\u0026nbsp;median OS in patients with a baseline ALC of \u0026ge; 1500/\u0026mu;L. Based on the EMBRACE data, Miyoshi et al. reported that a high baseline ALC of \u0026ge; 1500/\u0026mu;L was a significant and independent predictor of longer OS in patients treated with eribulin [19]. In a \u003cem\u003epost hoc\u003c/em\u003e analysis of data from a postmarketing observational study of eribulin in Japan, Takahashi et al. reported that the median OS was significantly longer in patients with a baseline ALC of \u0026ge; 1500/\u0026mu;L than those with an ALC of \u0026lt; 1500/\u0026mu;L [20]. Recent reports have indicated\u0026nbsp;that\u0026nbsp;baseline ALC and\u0026nbsp;the\u0026nbsp;pattern of disease\u0026nbsp;progression (progression by pre-existing disease versus new metastases) are associated with OS in patients treated with eribulin\u0026nbsp;[21]. Additionally, dynamic changes in the neutrophil-to-lymphocyte ratio at 3 or 6 months after initiating eribulin have been linked to OS [22]. This study analyzed the subgroup OS of eribulin-treated patients stratified by dosing schedule and baseline ALC. The median OS in the Q4W group, stratified by a baseline ALC of \u0026ge; 1500/\u0026micro;L and \u0026lt; 1500/\u0026micro;L, was 26.1 months and 26.0 months, respectively. Conversely, the median OS for a baseline ALC of \u0026ge; 1500/\u0026mu;L and \u0026lt; 1500/\u0026mu;L in the Q3W group was 28.1 and 13.0 months, respectively. The median OS was prolonged in the baseline ALC \u0026ge; 1500/\u0026mu;L and Q4W groups. Multivariate analysis, adjusted for other potential confounders, confirmed that baseline ALC and dosing schedule were predictors of OS.\u003c/p\u003e\n\u003cp\u003eThis study had some limitations. It was a prospective cohort analysis with a small sample size, and patient backgrounds, including age, varied between the Q3W and Q4W groups. The efficacy and safety of the Q3W and Q4W dosing schedules from cycle 1 should be further investigated in RCTs.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our results showed that adjusting eribulin administration from the Q3W to the Q4W dosing schedule significantly prolonged OS in patients with HER2-negative ABC and MBC. Specifically, when patients on the Q3W dosing schedule have a neutrophil count of \u0026lt; 1500 mm\u0026sup3; on day 1 of the next cycle, adjusting to the Q4W schedule can improve outcomes in patients with HER2-negative ABC and MBC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eABC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eAdvanced breast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eALC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eAbsolute lymphocyte count\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eCBR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eClinical benefit rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eDisease control rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eHER2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eHuman epidermal growth factor receptor 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eG-CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eGranulocyte colony-stimulating factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eMBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eMetastatic breast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eObjective response rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eProgression-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eRandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients and their families who participated in this study and Professor Junichiro Watanabe from Juntendo University (Tokyo, Japan) for his insightful suggestions.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not sponsored.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYM reports honoraria from Eisai, Pfizer, Eli Lilly, Diichi-Sankyo, Chugai, Kyowa Kirin, and AstraZeneca. CT, YS, TI, and MS have no conflicts of interest to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Yutaka Mizuno; Data curation: Yutaka Mizuno, Chihiro Toyoda, Yoshimi Shimizu, Takahiro Ichikawa; Methodology: Yutaka Mizuno; Formal analysis and investigation: Yutaka Mizuno; Writing - original draft preparation: Yutaka Mizuno, Writing - review and editing: Masahiro Shibata.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eavailability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants did not give written consent for their data to be shared publicly; therefore, due to the sensitive nature of the research, supporting data are unavailable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures involving human participants were conducted under the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was approved by the institutional review board of Yokkaichi Municipal Hospital (No. 2014-12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all individual participants included in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that human research participants provided informed consent for the publication of all tables and figures.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCardoso F, Paluch-Shimon S, Schumacher-Wulf E et al (2024) 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast 76:103756. \u003cu\u003ehttps://doi.org/10.1016/j.breast.103756\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eIm SA, Gennari A, Park YH et al (2023) Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer. ESMO Open 8:101541. https://doi.org/10.1016/j.esmoop. 101541\u003c/li\u003e\n\u003cli\u003eKashiwagi S, Asano Y, Goto W et al (2018) Mesenchymal-epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. Anticancer Res 38:401-410.https://doi.org/10.21873/anticanres.12236\u003c/li\u003e\n\u003cli\u003eGoto W, Kashiwagi S, Asano Y et al (2018) Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. Anticancer Res 38:2929-2938. https://doi.org/10.21873/anticanres.12541\u003c/li\u003e\n\u003cli\u003eKashiwagi S, Asano Y, Goto W et al (2020) Validation of systemic and local tumour immune response to eribulin chemotherapy in the treatment of breast cancer. Anticancer Res 40:3345-3354. https://doi.org/10.21873/anticanres.14317\u003c/li\u003e\n\u003cli\u003eCortes J, O\u0026rsquo;Shaughnessy J, Loesch D et al (2011) Eribulin monotherapy versus treatment of physician\u0026rsquo;s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377:914-923.https://doi.org/10.1016/S0140-6736(11)60070-6\u003c/li\u003e\n\u003cli\u003eAogi K, Watanabe K, Kitada M et al (2021) Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19). Int J Clin Oncol 26:1229-1236. https://doi.org/10.1007/s10147-021-01920-0\u003c/li\u003e\n\u003cli\u003eTerada M, Ito A, Kikawa Y et al (2023) The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition. Breast Cancer 30:872-884.https://doi.org/10.1007/s12282-023-01505-x\u003c/li\u003e\n\u003cli\u003eKaufman PA, Awada A, Twelves C et al (2015) Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601.https://doi.org/10.1200/JCO.2013.52.4892\u003c/li\u003e\n\u003cli\u003eWatanabe J, Ito Y, Ohsumi S et al (2017) Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study. Investig New Drugs 35:791-799.https://doi.org/10.1007/s10637-017-0486-4\u003c/li\u003e\n\u003cli\u003eInoue K, Takahashi M, Mukai H et al (2020) Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting. Investig New Drugs 38:1540-1549.https://doi.org/10.1007/s10637-019-00890-5\u003c/li\u003e\n\u003cli\u003eOhtani S, Nakayama T, Yoshinami T et al (2018) Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY). Breast Cancer 25:438-446.https://doi.org/10.1007/s12282-018-0843-y\u003c/li\u003e\n\u003cli\u003eKobayashi K, Masuda N, Mizuno T et al (2023) Phase II trial of biweekly administration with eribulin after three cycles of induction therapy in hormone receptor-positive, HER2-negative metastatic breast cancer (JACCRO BC-03). Breast Cancer Res Treat 201:409-415.https://doi.org/10.1007/s10549-023-07030-x\u003c/li\u003e\n\u003cli\u003eSmith J 2nd, Irwin A, Jensen L et al (2020) Phase II study of eribulin mesylate administered biweekly in patients with human epidermal growth factor receptor-2-negative metastatic breast cancer. Clin Breast Cancer 20:160-167.https://doi.org/10.1016/j.clbc.2019.09.007\u003c/li\u003e\n\u003cli\u003eRobson ME, Tung N, Conte P et al (2019) OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician\u0026apos;s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 30:558-566.https://doi.org/10.1093/annonc/mdz012\u003c/li\u003e\n\u003cli\u003eHurvitz SA, Hegg R, Chung WP et al (2023) Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401:105-117.https://doi.org/10.1016/s0140-6736(22)02420-5\u003c/li\u003e\n\u003cli\u003eWoodford RG, Zhou DD, Kok PS et al (2022) The validity of progression-free survival 2 as a surrogate trial end point for overall survival.\u003csup\u003e \u003c/sup\u003eCancer 128: 1449-1457.https://doi.org/10.1002/cncr.34085\u003c/li\u003e\n\u003cli\u003eKawamura T, Kasai H, Fermanelli V et al (2018) Pharmacodynamic analysis of eribulin safety in breast cancer patients using real‐world postmarketing surveillance data. Cancer Sci 109:2822-2829.https://doi.org/10.1111/cas.13708\u003c/li\u003e\n\u003cli\u003eMiyoshi Y, Yoshimura Y, Saito K et al (2020) High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician\u0026rsquo;s choice-in the EMBRACE study. Breast Cancer 27:706-715.https://doi.org/10.1007/s12282-020-01067-2\u003c/li\u003e\n\u003cli\u003eTakahashi M, Inoue K, Mukai H et al (2021) Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan. Breast Cancer 28:945-955.https://doi.org/10.1007/s12282-021-01232-1\u003c/li\u003e\n\u003cli\u003eMorisaki T, Kashiwagi S, Asano Y et al (2021) Prediction of survival after eribulin chemotherapy for breast cancer by absolute lymphocyte counts and progression types. World J Surg Oncol 19:324. https://doi.org/10.1186/s12957-021-02441-w\u003c/li\u003e\n\u003cli\u003eSu MX, Lin HW, Nguyen HTH et al (2024) Monitoring trends in the absolute lymphocyte count and the neutrophil-to-lymphocyte ratio in patients with breast cancer receiving eribulin. BMC Cancer 24:195. https://doi.org/10.1186/s12885-024-11923-5\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Characteristics of all patients and those treated with eribulin on Q3W and Q4W dosing schedules\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003e(n = 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003eQ3W\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003eQ4W\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eMedian age (range), years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e67 (39\u0026ndash;90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e65 (39\u0026ndash;82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e70 (45\u0026ndash;90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eAdvanced breast cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e21 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e15 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e6 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eMetastatic breast cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e57 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e32 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e25 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eER/PgR positive, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e51 (65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e34 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e17 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eER/PgR negative, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e27 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e13 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e14 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eNo. of prior chemotherapy regimens for advanced/metastatic diseases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e25 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e14 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e11 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e34 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e22 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e12 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026ge; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e19 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e11 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e8 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003ePrior anticancer therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Endocrine therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e51 (65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e34 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e17 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;CDK4/6 inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e20 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e15 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e5 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.185\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Anthracycline only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e40 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e25 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e15 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.817\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Taxane only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e57 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e37 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e20 (65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; Anthracycline and taxane\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e36 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e23 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e12 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.486\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eMetastatic sites, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e38 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e23 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e15 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e31 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e20 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e11 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e30 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e20 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e10 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e26 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e12 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e14 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pleura\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e12 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e9 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e3 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e7 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e4 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e3 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Peritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e5 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e4 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Ovary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eNo. of metastatic sites, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.987\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eBaseline ALC, median (\u0026mu;L, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e1221 (177\u0026ndash;3918)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e1253 (448\u0026ndash;2512)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e1208 (177\u0026ndash;3918)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.557\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003ePre-Q4W ALC, median (\u0026mu;L, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e1240 (672\u0026ndash;2891)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.834\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003eBaseline neutrophil count, median (\u0026mu;L, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e3729 (1443\u0026ndash;8732)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e3804 (1443\u0026ndash;8490)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e3476 (1561\u0026ndash;8731)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e0.679\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36.0825%;\"\u003e\n \u003cp\u003ePre-Q4W neutrophil count, median (\u0026mu;L, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.5258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e3150 (1151\u0026ndash;5989)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.4639%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.025\u003c/strong\u003e\u003cstrong\u003e*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eALC: absolute lymphocyte count; CDK: cyclin-dependent kinase; ER: estrogen receptor; PgR: progesterone receptor; Q4W: quaque four weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Factors predicting overall survival in patients with breast cancer by univariate and multivariate analysis\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eBaseline ALC (\u0026lt; 1500/\u0026mu;L vs \u0026ge; 1500/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.666\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.352\u0026ndash;1.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.180\u0026ndash;0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.022*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eDosing schedule (Q3W vs Q4W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.285\u0026ndash;0.944\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003cstrong\u003e*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.191\u0026ndash;0.765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eAge (\u0026lt; 65 vs \u0026ge; 65 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.804\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.458\u0026ndash;1.410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.973\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.502\u0026ndash;1.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.937\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eDisease setting (ABC vs MBC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.394\u0026ndash;1.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.342\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.448\u0026ndash;2.592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.866\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eSubtype (ER/PgR-positive vs -negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.544\u0026ndash;1.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.665\u0026ndash;2.483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eRefractory to anthracyclines (yes vs no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.771\u0026ndash;2.440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.638\u0026ndash;3.225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 209px;\"\u003e\n \u003cp\u003eRefractory to taxanes (yes vs no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.549\u0026ndash;1.970\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.618\u0026ndash;2.755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.485\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eABC: advanced breast cancer; ALC: absolute lymphocyte count; CI: confidence interval; ER: estrogen receptor; HR: hazard ratio; MBC: metastatic breast cancer; PgR: progesterone receptor. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Adverse events in all patients and those treated with eribulin on a Q3W and a Q4W dosing schedule\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eQ3W\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eQ4W\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGrade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGrade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGrade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHematologic toxicities, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Leukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (29.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (64.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.942\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33 (42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19 (40.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15 (31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (45.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.731\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e34 (43.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (36.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (54.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; AST increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.485\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; ALT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Febrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon\u0026ndash;hematologic toxicities, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Nausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Stomatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.238\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Malaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Anorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.275\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Dysgeusia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19 (24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Peripheral sensory neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.559\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Alopecia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.286\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eALT: alanine aminotransferase; AST: aspartate aminotransferase.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Absolute lymphocyte count, Breast cancer, Dosing schedule, Eribulin, Overall survival","lastPublishedDoi":"10.21203/rs.3.rs-5819643/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5819643/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003e\u003c/em\u003eEribulin, a non-taxane microtubule inhibitor, is often unsustainable on the standard dosing schedule (days 1 and 8 every 3 weeks, Q3W) owing to severe hematological toxicities. We compared overall survival (OS) between this schedule and a modified one (days 1 and 8 every 4 weeks, Q4W).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e\u003c/em\u003eThis single-center prospective cohort study compared objective response rate (ORR), progression-free survival (PFS), PFS2, OS, and safety in patients with breast cancer receiving eribulin on either a Q3W dosing schedule (\u003cem\u003en\u003c/em\u003e = 47) or a Q4W dosing schedule (\u003cem\u003en\u003c/em\u003e = 31).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e: The median PFS was 5.5 months for the Q3W group and 9.0 months for the Q4W group (\u003cem\u003ep\u003c/em\u003e = 0.065). The median PFS2 was 8.9 months for Q3W and 19.3 monthsfor Q4W (\u003cem\u003ep\u003c/em\u003e= 0.098). In contrast, the median OS was 15.0 months for Q3W and 26.7 months for Q4W (\u003cem\u003ep\u003c/em\u003e = 0.040). The median OS was longer in patients with a baseline absolute lymphocyte count\u003cstrong\u003e (\u003c/strong\u003eALC) of ≥1500/μL (\u003cem\u003ep\u003c/em\u003e = 0.007) and in the Q4W group (\u003cem\u003ep\u003c/em\u003e = 0.001). Multivariable analyses identified baseline ALC and dosing schedule as independent OS predictors (\u003cem\u003ep\u003c/em\u003e = 0.022 and \u003cem\u003ep\u003c/em\u003e = 0.006). The frequency and severityof hematologic toxicities, including leukopenia and neutropenia, were similar between groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003e\u003c/em\u003eAdjusting the eribulin dosing schedule from Q3W to Q4W improved the OS of patients with human epidermal growth factor receptor 2-negative advanced and metastatic breast cancer who showed a neutrophil count of \u0026lt;1500 mm³ on day 1 of the next cycle.\u003c/p\u003e","manuscriptTitle":"Adjusting the dosing schedule of eribulin to every 4 weeks (twice, on day 1 and day 8) improved overall survival in patients with human epidermal growth factor receptor 2-negative metastatic and advanced breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-27 13:23:52","doi":"10.21203/rs.3.rs-5819643/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"60c6b347-e621-4521-82a7-1827b9022093","owner":[],"postedDate":"February 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-27T13:23:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-27 13:23:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5819643","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5819643","identity":"rs-5819643","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}