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Background: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting.Methods: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out.Results: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062).Conclusions: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer.Clinical Trial Registration: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.Methods: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.Results: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025).Conclusions: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.Clinical Trial Registration: Clinical Trial Registration: UMIN-CTR as UMIN000007074. [ABSTRACT FROM AUTHOR]

PURPOSE: In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians. PATIENTS AND METHODS: Of 666 enrolled postmenopausal women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety. RESULTS: Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] v 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.48; 95% CI, 0.27 to 0.87; P =.007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% v 76.8%; grade 3/4, 89.2% v 62.5%), leukopenia (43.1% v 38.3%; 32.3% v 23.5%), and thrombocytopenia (27.7% v 13.5%; 4.6% v 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer–specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 v –0.069; P =.0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 v 61.7 ng/mL). CONCLUSION: Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL. [ABSTRACT FROM AUTHOR]

PURPOSE: In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians. PATIENTS AND METHODS: Of 666 enrolled postmenopausal women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety. RESULTS: Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] v 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.49; 95% CI, 0.27 to 0.87; P =.007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% v 76.8%; grade 3/4, 89.2% v 62.5%), leukopenia (43.1% v 38.3%; 32.3% v 23.5%), and thrombocytopenia (27.7% v 13.5%; 4.6% v 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer–specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 v –0.069; P =.0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 v 61.7 ng/mL). CONCLUSION: Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL. [ABSTRACT FROM AUTHOR]

Background: NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer.Methods: Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215.Results: A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001).Conclusions: The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX.Clinical Trial Registration: ClinicalTrials.gov: NCT01644890. [ABSTRACT FROM AUTHOR]

Background: In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2.Methods: In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n = 46) was conducted to compare results with those of the overall population.Results: At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6‒not estimable) with palbociclib-letrozole vs 13.8 months (5.6‒22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26−1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians.Conclusions: These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2‒ ABC. ClinicalTrials.gov: NCT01740427. [ABSTRACT FROM AUTHOR]

Purpose: This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC).Methods: In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide.Results: Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C max and AUC (0-t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t last) increased 2.5-fold after both doses under fed conditions.Conclusions: Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients. [ABSTRACT FROM AUTHOR]

Objective: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. Methods: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. Results: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocolrecommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. Conclusion: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting.Methods: We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416).Findings: Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group.Interpretation: S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer.Funding: Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho. [ABSTRACT FROM AUTHOR]

Background: We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. Methods: Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. Results: In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63). Conclusions: In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583. [ABSTRACT FROM AUTHOR]

Purpose: This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.Methods: Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m(2) weekly.Results: Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug-drug interactions.Conclusions: Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients. [ABSTRACT FROM AUTHOR]

Objective: Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial. Methods: HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes. Results: The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer. Conclusion: Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Methods: Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Results: Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m every 3 weeks was selected as the MTD in Japanese patients. Conclusions: The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations. [ABSTRACT FROM AUTHOR]

Objective: To explore the possibility of nonsurgical treatment of primary breast cancers by a sequential treatment of chemotherapy and radiotherapy. Methods: We conducted a safety and efficacy trial of chemotherapy and radiation therapy sequentially as primary therapy in patients with stage I-IIIA breast cancer. All patients underwent mastectomy or lumpectomy 12-16 weeks after the completion of radiation therapy to maximize the effect of radiation therapy. The primary endpoint was the pathological complete response (pCR) rate. Results: Between June 2004 and April 2005, one hundred eight patients were enrolled. Thirty six percent of the entire population achieved a pCR, which could not reject the null hypothesis. The pCR rate was 57% in patients with hormone receptor (HR)-negative/HER-2-positive tumors and 52% in patients with triple-negative tumors. While 7% of the HR-negative/HER2-positive patients recurred, a higher incidence of recurrence (24%) was observed in triple-negative tumors in a follow-up of 4.5 years. The rate of breast-conserving surgery was 88.9% (96/108). Conclusion: The pCR rate was not high enough, even though preoperative sequential chemoradiation therapy did not increase the risk of operative complications and could achieve a high rate of breast-conserving surgery. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim Radical cystectomy plus platinum-based perioperative chemotherapy is a standard treatment for patients with clinically localized muscle-invasive bladder cancer. The standard perioperative chemotherapy is methotrexate, vinblastine, doxorubicin and cisplatin ( MVAC). However, no prospective randomized trial has been published that compares neoadjuvant and adjuvant chemotherapy for bladder cancer. Moreover, the efficacy of perioperative chemotherapy with gemcitabine plus cisplatin ( GC) has not been clarified. In this study we have compared the clinical outcomes between neoadjuvant and adjuvant chemotherapy in patients receiving GC. Methods We retrospectively reviewed the records of patients who were scheduled to be treated with a radical cystectomy plus perioperative chemotherapy with GC from 2005 to 2010 at our institution. The primary outcome measure was recurrence-free survival ( RFS). Results A total of 42 patients received perioperative chemotherapy with GC (25 neoadjuvant, 17 adjuvant). The median number of cycles of GC administered to the two groups was not significantly different. The median duration of follow up was 28.6 months. During the follow-up period, recurrence was observed in nine and three patients in the neoadjuvant and adjuvant groups, respectively. The RFS rate at median follow up was 67 and 76% in the neoadjuvant and adjuvant groups, respectively. No significant difference in RFS at median follow up was observed between the two groups ( P = 0.124). Conclusion Our results showed no statistically significant difference in RFS between neoadjuvant and adjuvant GC chemotherapy for muscle-invasive bladder cancer. We expect to validate these findings in a prospective randomized trial. [ABSTRACT FROM AUTHOR]

Objective: Identifying factors that predispose patients to central nervous system (CNS) metastases may hasten disease detection and improve treatment outcomes. Methods: We reviewed the records of patients who were diagnosed with clinical stage I-III primary breast cancer at the National Cancer Center Hospital East from 2003 to 2005. Cox proportional hazard models were fitted to reveal risk factors for CNS metastases. Results: The median follow-up period after the operation was 53.5 months. Among the 591 identified patients with breast cancer, 76 experienced a relapse. Seventeen patients developed CNS metastases. Multivariate analysis indicated that the triple negative (TN) subtype (hazard ratio = 5.5) and a high Ki67 labeling index (LI; hazard ratio = 3.9) were associated with a higher risk for CNS metastases. At 4 years, the TN subtype was associated with significantly worse overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with hormone receptor-positive/ human epidermal growth factor receptor-2-negative tumors. Breast cancers with a Ki67 LI ≥30% were also associated with lower overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with cancers with a Ki67 LI <30%. Conclusion: TN or Ki67-overexpressing breast cancer produced earlier CNS metastases and lower disease-free and overall survival rates. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Ki-67 overexpression has been reported to be related to a poor prognosis for early stage breast cancer. We analyzed whether Ki-67 has a prognostic impact on risk subgroups based on the recommendations at St. Gallen in 2007. Methods: To determine the impact of Ki-67 on each risk group, a retrospective analysis was performed in patients with breast cancer who underwent curative surgery. Ki-67 was examined by immunohistochemistry with a predefined cutoff level of 10%. Results: A total of 1,166 patients were eligible for this analysis. During the follow-up period, distant metastasis was observed in 164 patients (14.1%), and 80 patients (6.9%) died. Ki-67 overexpression (Ki-67 ≥10%) was identified as an independent prognostic factor for distant-metastatic-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis. In the intermediate-risk group, the difference between Ki-67 overexpression and no overexpression was statistically significant in 5-year DFS (90.9 vs. 83.4%, p = 0.002) and OS (98.1 vs. 95.8%, p = 0.002). However, in both the low- and high-risk groups, Ki-67 overexpression was not an independent prognostic factor for either 5-year DFS or OS. Conclusions: Ki-67 overexpression indicates an unfavorable prognostic impact for DFS and OS. However, this impact is restricted only to those patients classified at intermediate risk. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Primary unknown cancer (PUC) is not rare neoplasm. The clinical features and survival time of these patients are heterogeneous. We analyzed cases that were referred to the National Cancer Center Hospital East with preliminary diagnosed PUC to evaluate the natural history and clinical features. Methods: We retrospectively reviewed medical records of PUC patients who were referred to our institution between August 2005 and December 2008. Results: One hundred and twenty-six patients with preliminary diagnoses of PUC were referred to the National Cancer Center Hospital East from community hospitals. The median age was 63 years (range 31-89 years). Almost all patients (85.7%) had good performance status (0-1). The mean interval between the first visit to a community hospital and referral to our hospital was 3.66 months (range 0-60 months). In 41 patients (32.5%), primary malignancies were identified by immunohistochemical studies and radiographical workup after referral to our hospital. Twenty-eight patients (22.2%) were defined as belonging to favorable subsets. About 50% of patients with unfavorable subsets received chemotherapy. None of the patients were autopsied. Conclusion: In about half of the patients with preliminary diagnosed PUC, the primary origin could be identified, or it was possible to distinguish subsets with favorable prognosis. [ABSTRACT FROM AUTHOR]

HER2-positive tumors account for approximately 18–20% of all breast cancers. These tumors tend to be more aggressive than HER2-negative tumors and are associated with a poorer prognosis. HER2 overexpression, as determined by either 3+ immunohistochemical staining for HER2 protein or HER2 gene amplification by fluorescence in situ hybridization, should be used to select patients for anti-HER2 therapy. Trastuzumab-containing regimens as first-line therapy should be recommended to women with HER2-positive metastatic breast cancer. The continuation of trastuzumab plus capecitabine provided a significant clinical benefit compared with capecitabine alone in women who experienced progression during trastuzumab treatment. An adjuvant trastuzumab-containing regimen should be also recommended to all intermediate- or high-risk women with HER2-positive early breast cancer. Cardiac function should be serially monitored during this treatment. Many anti-HER2 drugs against breast cancer are being developed. The basic mechanisms of their action and resistance emergence are being clarified step by step. Over the mid- or long term, clinical trials comparing these drugs will be conducted until drugs that are clinically effective and easy to use in the true sense survive. Biomarkers are being aggressively searched for concerning individual drugs under development. A position of the “proper drug for the proper patient” will be more firmly established. [ABSTRACT FROM AUTHOR]

Recently, randomized trials revealed that trastuzumab as adjuvant treatment was effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Safety information on adjuvant trastuzumab use in Japanese patients, especially cardiac toxicity data, is needed. We retrospectively reviewed 48 patients with early-stage HER2-positive breast cancer who were treated with curative surgery and adjuvant trastuzumab at the National Cancer Center Hospital East (Kashiwa, Japan). The cardiac safety as well as the short-term efficacy of trastuzumab were evaluated. The median age of the patients was 54 years. All patients received adjuvant or neoadjuvant cytotoxic chemotherapy. Twenty-seven patients (56%) received adjuvant radiation therapy. Forty-four patients (92%) received trastuzumab without concurrent cytotoxic chemotherapy and 4 patients (8%) on taxanes received trastuzumab concurrently. Twenty-five patients completed 1 year of trastuzumab treatment and 5 patients completed 2 years of trastuzumab treatment. Nine patients discontinued trastuzumab treatment, because of progressive disease (1 patient), decrease in left ventricular ejection fraction (LVEF; 2 patients), patient’s refusal (4 patients), and other reasons (2 patients). There were five cardiac events. A decrease in LVEF to less than 50% was seen in 2 patients. The relationship between trastuzumab treatment and the cardiac events was unclear in 3 patients. The median follow-up time was 21.2 months. The disease-free survival (DFS) was 97.5% at 1 year and 92.9% at 2 years. The incidence of cardiac events caused by trastuzumab treatment was low in our analysis. Adjuvant trastuzumab treatment for up to at least 1 year should be safe for Japanese breast cancer patients. [ABSTRACT FROM AUTHOR]

Background Two global phase 3 trials (301 trial of first- or second-line eribulin, EMBRACE of third- or later-line eribulin) were carried out during development of eribulin for breast cancer treatment. In this post marketing observation study in Japan, efficacy and safety of eribulin in metastatic breast cancer patients were examined. Additionally, the results were compared with that of phase 3 trials. Method We conducted a prospective study in patients with inoperable or recurrent HER2-negative breast cancer. We enrolled a similar number of patients receiving eribulin as first- or second-line therapy (early line) and those receiving eribulin as third- or later line therapy (later line), and followed the patients for two years (ClinicalTrials.gov Number: NCT02371174). For the overall survival and time to treatment failure, the estimated value of them were calculated by the Kaplan Meier method. The severity of adverse drug events was determined by CTCAE v 4.0. Results During September 2014 to February 2016, 651cases were registered at 182 facilities. In analysis set, 637 patients (319 patients of early line/317 patients of late line/1 patient of unknown) was median age of 62.7 (30 - 85) years. Performance status 0/1/2/3/4 was seen in 360/234/38/5/0 patients, respectively. Dose reduction were required in 33% of patients. The median overall survival (early line/late line) was 18.8 months/12.6 months, respectively, and median time to treatment failure was 4.4 months/3.8 months, respectively. Major side effects (early line/late line) were neutropenia (51%/56%), leucopenia (55%/57%), peripheral neuropathy (32%/22%). Grade 3≤ peripheral neuropathy was 2%. Conclusion The results of overall survival (18.8 months in early line, 12.6 months in later line) in this study is comparable to those of large phase 3 study (15.9 months in 301 trial, 13.1 months in EMBRACE). The incidence of Grade 3≤ peripheral neuropathy was lower than that of phase 3 trials. [ABSTRACT FROM AUTHOR]

Two global phase 3 trials (301 trial of first- or second-line eribulin, EMBRACE of third- or later-line eribulin) were carried out during development of eribulin for breast cancer treatment. In this post marketing observation study in Japan, efficacy and safety of eribulin in metastatic breast cancer patients were examined. Additionally, the results were compared with that of phase 3 trials. We conducted a prospective study in patients with inoperable or recurrent HER2-negative breast cancer. We enrolled a similar number of patients receiving eribulin as first- or second-line therapy (early line) and those receiving eribulin as third- or later line therapy (later line), and followed the patients for two years (ClinicalTrials.gov Number: NCT02371174). For the overall survival and time to treatment failure, the estimated value of them were calculated by the Kaplan Meier method. The severity of adverse drug events was determined by CTCAE v 4.0. During September 2014 to February 2016, 651cases were registered at 182 facilities. In analysis set, 637 patients (319 patients of early line/317 patients of late line/1 patient of unknown) was median age of 62.7 (30 - 85) years. Performance status 0/1/2/3/4 was seen in 360/234/38/5/0 patients, respectively. Dose reduction were required in 33% of patients. The median overall survival (early line/late line) was 18.8 months/12.6 months, respectively, and median time to treatment failure was 4.4 months/3.8 months, respectively. Major side effects (early line/late line) were neutropenia (51%/56%), leucopenia (55%/57%), peripheral neuropathy (32%/22%). Grade 3≤ peripheral neuropathy was 2%. The results of overall survival (18.8 months in early line, 12.6 months in later line) in this study is comparable to those of large phase 3 study (15.9 months in 301 trial, 13.1 months in EMBRACE). The incidence of Grade 3≤ peripheral neuropathy was lower than that of phase 3 trials. [ABSTRACT FROM AUTHOR]

Background: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). Methods: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. Results: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02–1.03) per 1.0-µg/mL increase in baseline D-dimer level. Conclusions: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage. [ABSTRACT FROM AUTHOR]

Subsequent treatments can result in a difficulty in interpretation of the overall survival results in confirmatory oncology clinical trials. To complement the intention‐to‐treat (ITT) analysis affected by subsequent treatment patterns unintentional in the trial protocol, several causal methods targeting the per‐protocol effect have been proposed. When two or more types of subsequent treatments are allowed in the trial protocol, however, these methods cannot answer clinical questions such as how sensitive the ITT analysis result is to higher or lower proportions of each subsequent treatment allowed in the trial protocol than observed, and to what extent ITT analysis result is generalizable to subsequent treatment patterns other than observed one. To answer these clinical questions, we propose a sensitivity analysis method for subsequent treatments using the inverse probability of treatment weighting method for stochastic dynamic treatment regimes (DTRs). We formulate oncology clinical trials with subsequent treatments as two‐stage designs in which initial treatments are randomized, but subsequent treatments are observational. In this formulation, we use stochastic DTRs to simulate specific proportions of each subsequent treatment and compare an initial experimental treatment with an initial control treatment under various proportions of each subsequent treatment. We applied our proposed method to a motivating randomized noninferiority trial for metastatic breast cancer. Simulation results are also reported to show the usefulness of the proposed method. [ABSTRACT FROM AUTHOR]

Background: The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. Methods: Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. Results: Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. Conclusions: Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET. [ABSTRACT FROM AUTHOR]

PURPOSE: This systematic review aimed to investigate the efficacy of telemedicine (TM) using videoconferencing systems in outpatient care for patients with cancer. METHODS: We searched six electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, ICTRP, and ClinicalTrials.gov) through June 2021 to identify randomized controlled trials that evaluated the use of TM using videoconferencing systems compared with usual face-to-face care in outpatient care for patients with cancer. We assessed the certainty of evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation. RESULTS: From the 2,400 articles screened, six randomized controlled trials were eligible for this study. Two studies evaluated the use of TM in cancer follow-up and four investigated psychotherapy for cancer. TM using videoconferencing systems may result in no differences in primary outcomes such as patient satisfaction (standardized mean difference, 0.11; 95% CI, –0.18 to 0.40) and outpatient attendance complete proportion (risk difference, 0.02%; 95% CI, –0.04 to 0.09), and secondary outcomes such as medical professional satisfaction, time devoted to outpatient care, and depression score. The certainty of evidence for these outcomes was low. Although the average money spent on outpatient visit was a primary outcome, the level of evidence was uncertain. CONCLUSION: Our results suggest that TM using videoconferencing systems in outpatient care for patients with cancer may be as effective as usual face-to-face care. Use of TM more frequently may be considered for patients with cancer who are expected to obtain benefit from TM using videoconference systems. Telemedicine using videoconferencing in outpatient care for patients with cancer may be as effective as usual care. [ABSTRACT FROM AUTHOR]

Purpose: Identifying factors associated with treatment alteration (treatment discontinuation and dose reduction) may help to attain the treatment goals for metastatic breast cancer. The value of changes in the quality of life (QOL) in predicting treatment alteration remained unclear. This study aimed to examine the relationship between changes in the QOL and treatment alteration of first-line chemotherapy for metastatic breast cancer.Methods: We merged data from two randomized clinical trials in Japan, conducted from 2006 to 2017, that included patients who were diagnosed with human epidermal growth factor receptor 2-negative and endocrine treatment-resistant breast cancer, with metastatic disease at presentation or recurrence after surgery. The European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 was used to assess QOL. The association between change in time-dependent QOL (worsening by 10-point or not) and time to treatment alteration was assessed using the Cox regression models controlling for patient characteristics (age, liver metastasis, hormone status, and treatment regimen) and baseline QOL.Results: Worsening physical functioning, global health status, and dyspnea were significantly associated with treatment discontinuation. Worsening role functioning, global health status, and fatigue were significantly associated with dose reduction. The threshold for defining worsening did not have a significant impact on the relationship.Conclusion: Changes in QOL are associated with the probability of treatment alteration among metastatic breast cancer patients. Physical functioning, role functioning, global health status, dyspnea, and fatigue should be prioritized for symptom management in patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. Methods: The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. Results: We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from − 7 to − 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from − 5 to − 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. Conclusion: We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30. [ABSTRACT FROM AUTHOR]

Although many publications have reported the incidence of venous thromboembolism (VTE) in patients with cancer from Western countries, to date, no prospective East Asian studies have been published, and potential racial differences remain unclear. The multicenter, prospective, observational Cancer-VTE Registry aimed to clarify the incidence of VTE and bleeding and identify risk factors in Japanese patients with solid tumors after one year of follow-up. Patients with colorectal, lung, stomach, pancreatic, breast, or gynecologic cancer were enrolled after VTE screening and before starting cancer treatment. The follow-up period was one year. The main outcomes were the incidences of symptomatic VTE, bleeding events (major or clinically relevant non-major), and all-cause death, evaluated according to VTE presence/absence at baseline. Multivariate analyses were conducted to identify risk factors for events. Among 9630 patients, the one-year cumulative incidences of symptomatic VTE, bleeding events, and all-cause death were 0.5%, 1.4%, and 12.2%, respectively. The majority of VTEs identified at baseline were asymptomatic distal deep vein thromboses; however, affected patients had higher event rates during the follow-up period. The most important independent risk factor for developing symptomatic VTE, bleeding events, and death during the follow-up period was the presence of symptomatic or asymptomatic VTE at baseline. These data have revealed the incidence of symptomatic VTE in Japanese patients with solid tumors during one year of follow-up. The presence of any VTE before initiating cancer treatment was an independent risk factor for symptomatic VTE, bleeding events, and death during subsequent treatment. [ABSTRACT FROM AUTHOR]

Background and Objective: Trastuzumab is a standard care as adjuvant chemotherapy (AdjCT) for patients with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer (BC) in Japan. However, no reports have evaluated its economics for patients with HER2-positive BC over 70 years of age. The objective of this study was to evaluate the cost-effectiveness of HER2-targeted trastuzumab + chemotherapy in Japan, comparing it with trastuzumab monotherapy. Methods: A three-state-partitioned survival model was developed to evaluate the cost-effectiveness of trastuzumab + chemotherapy versus trastuzumab monotherapy for AdjCT in elderly patients with HER2-positive BC. We derived the efficacy data, utilities, and costs of both arms from individual patient data in the RESPECT trial (NCT01104935) and published studies. The costs and quality-adjusted life years (QALYs) were discounted at 2% per annum using a payer perspective. The respective cost estimates were reported in 2019 Japanese Yen (JPY) or US dollars (US$). The primary outcome was the incremental cost-effectiveness ratio (ICER). We assured robustness with deterministic and probabilistic sensitivity analyses. Results: The cost per patient for trastuzumab + chemotherapy was JPY 14.6 million (US$137,000), and their QALYs were 9.308, compared with JPY 14.2 million (US$131,000) and 9.101, respectively, for trastuzumab monotherapy. The ICER of trastuzumab + chemotherapy versus trastuzumab monotherapy was JPY 2.7 milllion/QALY (US$17,200/QALY). The ICER for trastuzumab with chemotherapy varied from "Dominant" to "Dominated" in one-way sensitivity analysis. Conclusions: The base-case analysis suggests that AdjCT with trastuzumab + chemotherapy is likely to be a cost-effective choice for patients with HER2-positive BC aged 70 years or older. However, the sensitivity analysis suggested uncertainty regarding the cost-effectiveness of trastuzumab + chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural effusion is a common and devastating complication of metastatic breast cancer. This occurs in about 30% of patients with metastatic breast cancer during the clinical course, and chemical pleurodesis is sometimes performed to relieve dyspnea. However, the long-term outcome of pleurodesis and factors affecting successful pleurodesis have not been clarified. Objectives: The aim of this analysis is to evaluate the long-term outcome of pleurodesis and to identify risk factors associated with success. Methods: Data on 75 patients who had undergone chemical pleurodesis with OK-432 for pleural effusion due to metastatic breast cancer were reviewed retrospectively. The primary outcomes were success rate and pleural progression-free survival (PPFS) rate. Results: The median duration of follow-up was 134 days (range 8-975 days). During this period, 22 patients re-accumulated pleural fluid. The overall success rate was 70.5%. The 4-, 8- and 12-week PPFS rates were 88.0, 84.0 and 78.7% respectively. Multivariate analysis identified three unfavorable factors that were independently associated with unsuccessful pleurodesis, including estrogen-receptor negative status, a 24-h drainage volume of more than 100 mL before extubation and NSAID use. The PPFS rate at median follow-up was 93.5% in the low-risk group ( n = 41, 0 or 1 unfavorable factor) and 55.1% in the high-risk group ( n = 34, 2 or 3 unfavorable factors). The difference between the PPFS curves of the two risk groups was statistically significant ( P < 0.001). Conclusions: Pleurodesis for metastatic breast cancer was efficacious in controlling malignant pleural effusion. Our simple new risk model warrants further studies. [ABSTRACT FROM AUTHOR]

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE.Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months.Results: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial.Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses.Trial Registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ). [ABSTRACT FROM AUTHOR]

Background: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.Findings: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.Interpretation: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.Funding: Public Health Research Foundation (Japan), Taiho Pharmaceutical. [ABSTRACT FROM AUTHOR]

Intestinal perforation is a rare adverse event of antineoplastic therapy. However, once it occurs, it is potentially fatal. This report describes a case of intestinal perforation caused by bevacizumab in a patient with ovarian cancer who concurrently developed neutropenic enterocolitis. A 66-year-old woman diagnosed with metastatic ovarian cancer received combination chemotherapy with carboplatin, gemcitabine, and bevacizumab. On day 14, she developed grade 4 pancytopenia and febrile neutropenia, which resulted in neutropenic enterocolitis and intestinal perforation. Emergency surgery was performed, and an intestinal perforation found in the ascending colon was closed. Postoperatively, she developed an intra-abdominal abscess requiring peritoneal drainage. She was discharged from the hospital on recovery. [ABSTRACT FROM AUTHOR]

Background: In the double-blind, phase 3 PALOMA-3 study, palbociclib-fulvestrant significantly prolonged progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3.Methods: Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/day; 3 weeks on/1 week off; n = 347) or placebo (n = 174). Prespecified exploratory analyses compared the efficacy (data cutoff: October 23, 2015), safety, and pharmacokinetics (data cutoff: December 5, 2014) in Japanese women versus the overall population.Results: A total of 35 Japanese women were randomized to palbociclib-fulvestrant (n = 27) or placebo-fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5-not estimable) in the Japanese palbociclib-fulvestrant group and 11.2 months (95% CI, 5.6-not estimable) in the placebo-fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively).Conclusion(s): The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135). [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy.Methods: We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL.Results: Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia.Conclusions: We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses.Trial Registration Number: C000000416. [ABSTRACT FROM AUTHOR]

Background: In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide (AC) followed by a taxane is a standard regimen. In the current study, the authors examined whether AC could be safely omitted, and compared the effectiveness of paclitaxel versus docetaxel.Methods: Female postoperative patients with axillary lymph node-positive breast cancer were eligible for enrollment in this phase 3, open-label, randomized controlled trial at 84 centers in Japan. Patients were randomized to 4 cycles of doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) followed by 4 cycles of paclitaxel at a dose of 175 mg/m2 (ACpT) or AC followed by 4 cycles of docetaxel at a dose of 75 mg/m2 (ACdT), or 8 cycles of paclitaxel (PTx) or docetaxel (DTx) every 3 weeks. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival adverse events. The authors adopted a 2 × 2 factorial design to examine the AC containing-regimens (ACpT and ACdT) versus the AC free-regimens (PTx and DTx), and the paclitaxel-containing regimens (ACpT and PTx) versus the docetaxel-containing regimens (ACdT and DTx).Results: Of 1060 patients, 1049 were treated and included in the intention-to-treat population. The DFS results did not demonstrate noninferiority between the AC-containing and the AC-free regimens (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 0.982-1.448 [Pnoninferiority  = .30]). Better outcomes were noted in patients treated with the docetaxel-containing regimens compared with the paclitaxel-containing regimens with respect to DFS (HR, 0.72; 95% CI, 0.589-0.875 [P = .0008]) and overall survival (HR, 0.75; 95% CI, 0.574-0.980 [P = .035]). Neutropenia, nausea, and vomiting were found to occur more often in the AC-containing arms, whereas the incidence of edema was greater in the docetaxel-containing treatment arms.Conclusions: Noninferiority in DFS was not demonstrated between the AC-containing and AC-free regimens. Compared with a similar regimen of paclitaxel, docetaxel appeared to increase the DFS. Cancer 2017;123:759-68. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to measure adherence rate to the quality indicators (QI) in clinical practice to evaluate the quality of care for breast cancer patients in Japan.Design: A retrospective record review.Setting: Two hundred twenty-four designated breast cancer care hospitals throughout Japan.Participants: A total of 15 227 patients diagnosed with breast cancer in 2005.Main Outcome Measures: The adherence rate of seven items that correspond to QIs of medical care, which were developed using an adaptation of RAND/UCLA (University of California, Los Angeles) appropriateness method.Results: The lowest quality score was the drug therapy adherence to the St. Gallen consensus recommendations, for which the overall quality score 52.8%. The highest quality score was the adherence rate of hormone receptor testing, for which overall quality score was 97.8%. The greatest variations across facilities were for HER-2 testing and for radiation therapy after breast-conserving surgery. The least variation was for hormone receptor testing.Conclusions: There was a range of measurements for the adherence rate to each QI, suggesting that the desired standards of care had not necessarily pervaded all facilities. It is necessary to strive for widespread implementation of QIs and realization of the significance of measuring the medical care quality among physicians treating breast cancer. [ABSTRACT FROM AUTHOR]

Background Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor–positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. Methods Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. Results Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). Conclusion These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor–positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy. [ABSTRACT FROM PUBLISHER]

Background: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. Methods: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). Results: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2–p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. Conclusions: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP. [ABSTRACT FROM AUTHOR]

To evaluate the effects of genetic polymorphisms of drug metabolizing enzymes on the pharmacokinetics of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide, and on the pharmacodynamics.One hundred and three Japanese patients with malignant lymphoma or breast cancer treated with cyclophosphamide (500-750 mg/m2) participated in this study. The plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. The genotypes of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, GST genes were determined by allele-specific polymerase chain reaction or polymerase chain reaction-restriction-fragment length polymorphism.A large interindividual difference (54-fold) was observed in the area under the curve ratio of 4-hydroxycyclophosphamide/cyclophosphamide calculated as the metabolic index. We first proved that leukocytopenia and neutropenia were significantly (P<0.01) related to the area under the curve of 4-hydroxycyclophosphamide. We found that the homozygotes of CYP2B6∗6 (Q172H and K262R) showed significantly (P<0.05) higher clearance and shorter half-life of cyclophosphamide than heterozygotes and homozygotes of CYP2B6∗1. The small sample size, however, limited the impact. On the other hand, it was clearly demonstrated that the patients possessing the single nucleotide polymorphisms of the CYP2B6 gene, g.-2320T>C, g.-750T>C (5′-flanking region), g.15582C>T (intron 3), or g.18492T>C (intron 5), had significantly lower area under the curve ratios of 4-hydroxycyclophosphamide/cyclophosphamide, indicating a decreased cyclophosphamide 4-hydroxylation. Of particular importance was the finding that leukocytopenia was significantly related to the single nucleotide polymorphisms g.-2320T>C, g.-750T>C, and g.18492T>C in CYP2B6 gene, which are highly linked. No relationship was observed between the pharmacokinetics of cyclophosphamide or 4-hydroxycyclophosphamide and genetic polymorphisms of the other enzymes.We clarified that the single nucleotide polymorphisms in the promoter region or introns in the CYP2B6 affect the potency of cyclophosphamide activation to 4-hydroxycyclophosphamide. This information would be valuable for predicting adverse reactions and the clinical efficacy of cyclophosphamide. [ABSTRACT FROM AUTHOR]

Background: Olfactory neuroblastoma is a rare sino-nasal tumor arising from the olfactory epithelium and is often characterized by local invasion or metastasis. The role of chemotherapy in the treatment of this tumor is unclear. The purpose of this study was to review our institution’s experience of chemotherapy for advanced or recurrent olfactory neuroblastoma. Methods: Twenty-one patients with histologically proven olfactory neuroblastoma were treated at our institution between 1992 and 2002. Twelve of these patients received chemotherapy in the setting of unresectable or recurrent disease and were retrospectively reviewed for clinical characteristics, treatment outcome or survival. Results: Eight patients of the 12 patients received cisplatin-based chemotherapy and the remaining four patients received chemotherapy consisting of docetaxel plus irinotecan (three patients) or cyclophosphamide, doxorubicin, and vincristine (1 patient). A partial response was achieved in five patients, with an overall response rate of 42%, although the chemotherapeutic regimens were heterogeneous. Two partial responses were obtained among the three patients who received docetaxel plus irinotecan. The response rate to chemotherapy was 83% in the younger age group (<40 years), as opposed to 0% in the older age group (≥40 years), and the difference between the two groups was statistically significant ( P = 0.02). Conclusion: Our study indicated that olfactory neuroblastoma would be sensitive to chemotherapy, especially with young patients. Docetaxel plus irinotecan has the possibility of showing favorable response, and warrants further investigation. [ABSTRACT FROM AUTHOR]

HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified HSD17B4 methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only HSD17B4 methylation was significantly different. The HSD17B4 methylation was at the transcriptional start site of its major variant, and was associated with its silencing. HSD17B4 was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and HSD17B4 methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy, HSD17B4 methylation was the most reliable marker to monitor response to the therapy. These results showed that HSD17B4 methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy. [ABSTRACT FROM AUTHOR]

While pertuzumab was added to adjuvant therapy for high-risk HER2-positive breast cancer according to APHINY trial, definition of "high risk of recurrence" is still unclear. Because neoadjuvant chemotherapy (NAC) including anti-HER2 drugs showed potent efficacy to achieve pCR and better survival, one lymph node metastases may show survival outcomes equivalent to node-negative cases. Hence, we examined the risk factors of recurrence in HER2-positive breast cancer and determined whether one lymph node metastasis after NAC is true predictor of recurrence. From May 1993 to March 2017, patients who underwent radical mastectomy/partial mastectomy after NAC for breast cancer in our institution were retrospectively examined. Among those patients, HER2-positive patients were 253, 23% of all patients. Breast cancer recurrence occurred in 46 (18.2%) of HER2-positive patients who underwent NAC and radical mastectomy. Multivariate analysis was performed on tumor size, lymph node metastasis, hormone receptor, Ki-67, preoperative chemotherapy regimen for recurrence risk factor. The risk of recurrence was significantly higher in one lymph node metastasis group than in the node-negative group (HR 6.157, p=.0006, 95%CI 2.175-17.435). Likewise, the risk of recurrence was significantly higher in the group with two or more lymph node metastases than in the node-negative group (HR 3.877, p=.0107, 95%CI 1.370-10.972). The presence of even one lymph node metastasis was suggested as a risk factor of recurrence, likely representing metastatic potential of the disease. [ABSTRACT FROM AUTHOR]

Background Eribulin demonstrated longer overall survival for pretreated metastatic breast cancer. Several factors are reported to be associated with their survival outcomes of breast cancer patients, and scarce of predictors are determined for each agent. Previous reports have demonstrated that high neutrophil to lymphocyte ratio (NLR) is related to poor survival outcomes of cancer. We hypothesized that low NLR is predictor of longer survival of breast cancer patients. We investigated whether baseline NLR before chemotherapy is associated with overall survival, and explored possible mechanism of better survival in patients with metastatic breast cancer. Methods We extracted female patients with metastatic breast cancer who received Eribulin for metastatic disease at NCCHE. We included HER2-negative disease, and those treated with standard chemotherapy including eribulin. We retrieved patient and disease characteristics; age, disease location, de novo stage IV or recurrent disease, hormone receptor status. Result We identified 135 patients between July 2012 and December 2018 with a median age of 57.9 (34-77), of which 106 (78.5%) had HR positive disease, 104 (77.0%) had recurrent disease, and 114 (84.4%) had visceral disease. Log rank test showed hormone receptor status and visceral disease were significant variable for candidate for multivariate analysis. COX regression model demonstrated that decreasing of NLR was associated with better OS [HR = 1.145, 95% confidence interval (95% CI)=1.073-1.223]. We showed low NLR at the administration of eribulin was independent predictor of OS [HR = 1.048, 95% confidence interval (95% CI)=1.004-1.093]. Conclusion We showed low NLR is better prognostic factor of any chemotherapy for metastatic breast cancer. Our exploratory research also showed low NLR at eribulin administraton was suspected to be better OS indicator regardless of pretreated chemotherapy. [ABSTRACT FROM AUTHOR]

While pertuzumab was added to adjuvant therapy for high-risk HER2-positive breast cancer according to APHINY trial, definition of "high risk of recurrence" is still unclear. Because neoadjuvant chemotherapy (NAC) including anti-HER2 drugs showed potent efficacy to achieve pCR and better survival, one lymph node metastases may show survival outcomes equivalent to node-negative cases. Hence, we examined the risk factors of recurrence in HER2-positive breast cancer and determined whether one lymph node metastasis after NAC is true predictor of recurrence. From May 1993 to March 2017, patients who underwent radical mastectomy/partial mastectomy after NAC for breast cancer in our institution were retrospectively examined. Among those patients, HER2-positive patients were 253, 23% of all patients. Breast cancer recurrence occurred in 46 (18.2%) of HER2-positive patients who underwent NAC and radical mastectomy. Multivariate analysis was performed on tumor size, lymph node metastasis, hormone receptor, Ki-67, preoperative chemotherapy regimen for recurrence risk factor. The risk of recurrence was significantly higher in one lymph node metastasis group than in the node-negative group (HR 6.157, p=.0006, 95%CI 2.175-17.435). Likewise, the risk of recurrence was significantly higher in the group with two or more lymph node metastases than in the node-negative group (HR 3.877, p=.0107, 95%CI 1.370-10.972). The presence of even one lymph node metastasis was suggested as a risk factor of recurrence, likely representing metastatic potential of the disease. [ABSTRACT FROM AUTHOR]

Eribulin demonstrated longer overall survival for pretreated metastatic breast cancer. Several factors are reported to be associated with their survival outcomes of breast cancer patients, and scarce of predictors are determined for each agent. Previous reports have demonstrated that high neutrophil to lymphocyte ratio (NLR) is related to poor survival outcomes of cancer. We hypothesized that low NLR is predictor of longer survival of breast cancer patients. We investigated whether baseline NLR before chemotherapy is associated with overall survival, and explored possible mechanism of better survival in patients with metastatic breast cancer. We extracted female patients with metastatic breast cancer who received Eribulin for metastatic disease at NCCHE. We included HER2-negative disease, and those treated with standard chemotherapy including eribulin. We retrieved patient and disease characteristics; age, disease location, de novo stage IV or recurrent disease, hormone receptor status. We identified 135 patients between July 2012 and December 2018 with a median age of 57.9 (34-77), of which 106 (78.5%) had HR positive disease, 104 (77.0%) had recurrent disease, and 114 (84.4%) had visceral disease. Log rank test showed hormone receptor status and visceral disease were significant variable for candidate for multivariate analysis. COX regression model demonstrated that decreasing of NLR was associated with better OS [HR = 1.145, 95% confidence interval (95% CI)=1.073-1.223]. We showed low NLR at the administration of eribulin was independent predictor of OS [HR = 1.048, 95% confidence interval (95% CI)=1.004-1.093]. We showed low NLR is better prognostic factor of any chemotherapy for metastatic breast cancer. Our exploratory research also showed low NLR at eribulin administraton was suspected to be better OS indicator regardless of pretreated chemotherapy. [ABSTRACT FROM AUTHOR]