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Summary: Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8–17.6), 22.8 (17.3–31.0), 16.3 (12.4–19.9), and 12.6 (11.2–15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7–4.4), 5.2 (3.7–5.9), 4.2 (3.7–5.1), and 3.8 (3.5–4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan. [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]

Background: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus‐induced oral mucositis. Materials and Methods: This randomized, multicenter, open‐label, phase III study evaluated the efficacy of POC in preventing everolimus‐induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8‐week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2‐sided type I error rate of 5% and 80% power to detect 25% risk reduction. Results: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p =.034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p =.015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction. Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT 02069093. Implications for Practice: The Oral Care‐BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor‐positive, HER2‐negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus. Oral mucositis is a clinically significant complication of mucotoxic cancer therapy. This article focuses on the effect of dental intervention, before everolimus treatment, on oral mucositis. [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 This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings. [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]

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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]

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]

Eribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m. Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886). [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]

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]