出版者・発行元：IJC Heart and Vasculature  

Background: The impact of coronary bifurcation angle (BA) on incomplete stent apposition (ISA) after crossover stenting followed by side branch (SB) intervention has not been established. Methods: A total of 100 crossover stentings randomly treated with proximal optimization technique followed by short balloon dilation in the SB (POT-SBD group, 48 patients) and final kissing balloon technique (KBT group, 52 patients) were analyzed in the PROPOT trial. Major ISA with maximum distance > 400 μm and its location was determined using optical coherence tomography before SB intervention and at the final procedure. The BA was defined as the angle between the distal main vessel and SB. Optimal POT was determined when the difference in stent volume index between the proximal and distal bifurcation was greater than the median value (0.86 mm3/mm) before SB intervention. Result: Major ISA was more frequently observed in the POT-SBD than in the KBT group (35% versus 17%, p < 0.05). In the POT-SBD group, worsening ISA after SBD was prominent at the distal bifurcation. The BA was an independent predictor of major ISA (odds ratio 1.04, 95% confidence interval 1.00–1.07, p < 0.05) with a cut-off value of 59.5° (p < 0.05). However, the cases treated with optimal POT in the short BA (<60°) indicated the lowest incidence of major ISA. In the KBT group, BA had no significant impact. Conclusion: A wide BA has a potential risk for the occurrence of major ISA after POT followed by SBD in coronary bifurcation stenting.

DOI： 10.1016/j.ijcha.2023.101265

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記述言語：英語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: Metastatic breast cancer (MBC) is usually incurable; treatment aims to maximize patients’ function and quality of life (QOL). Eribulin is a standard treatment in patients with MBC pretreated with anthracycline and taxane; however, the best administration schedule is unknown. Methods: In this prospective phase II trial of patients with luminal MBC, we administered biweekly eribulin to patients who completed a three-cycle induction treatment. Results: Sixty patients with hormone-receptor-positive and HER2-negative MBC were enrolled; 40 obtained stable disease (SD) or better efficacy after induction therapy, after which they were switched to biweekly maintenance administration. The median progression-free survival (PFS) in patients who switched to maintenance therapy was 15.21 weeks (95% CI 9.71–22.14), starting on the first day of maintenance therapy. Overall survival (OS) in patients who switched to maintenance therapy was 21.39 months (95% CI 18.89–32.89). PFS and OS in the whole population starting from the registration date were 19.00 weeks (95% CI 17.00–25.00) and 21.52 months (95% CI 16.23–24.25), respectively. PFS from the enrollment date for patients who received maintenance therapy was 25.29 weeks (95% CI 19.14–32.14). Patients who achieved complete response or partial response during induction therapy had significantly longer PFS compared to patients with SD. Conclusion: The efficacy of biweekly administration of eribulin at maintenance was nonsignificant. However, less frequent visits are convenient, and reduced dose intensity improves safety. Biweekly administration, besides dose reduction, could be an acceptable option for patients who are unable to maintain a standard regimen.

DOI： 10.1007/s10549-023-07030-x

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記述言語：英語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups. Methods: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated. Results: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33–0.78) and 29% (HR: 0.71, 95% CI 0.49–1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29–0.74). Conclusions: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

DOI： 10.1007/s10549-023-07099-4

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記述言語：英語   出版者・発行元：Journal for immunotherapy of cancer  

BACKGROUND: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. METHODS: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers. RESULTS: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy. CONCLUSIONS: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs. TRIAL REGISTRATION NUMBER: JapicCTI-194782, jRCT2080224706, UMIN000036970.

DOI： 10.1136/jitc-2023-007126

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記述言語：英語   出版者・発行元：International Journal of Cancer  

In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.

DOI： 10.1002/ijc.34525

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記述言語：英語   出版者・発行元：BMC Medicine  

Background: There is increasing interest in the use of liquid biopsies, but data on longitudinal analyses of circulating tumor DNA (ctDNA) remain relatively limited. Here, we report a longitudinal ctDNA analysis of MONALEESASIA, a phase Ib trial evaluating the efficacy and safety of ribociclib plus endocrine therapy (ET) in Asian patients with hormone receptor–positive, human epidermal growth factor receptor-2–negative advanced breast cancer. Methods: MONALEESASIA enrolled premenopausal and postmenopausal Japanese and postmenopausal non-Japanese Asian patients. All patients received ribociclib with ET (letrozole, fulvestrant, or tamoxifen with goserelin). ctDNA was analyzed using a targeted next-generation sequencing panel of 572 cancer-related genes and correlated by best overall response (BOR). Results: Five hundred seventy-four cell-free DNA samples from 87 patients were tested. The most frequently altered genes at baseline included PIK3CA (29%) and TP53 (22%). Treatment with ribociclib plus ET decreased ctDNA in most patients at the first on-treatment time point, regardless of dose or ET partner. Patients with partial response and stable disease had lower ctDNA at baseline that remained low until data cutoff if no progressive disease occurred. Most patients with progressive disease as the best response had higher ctDNA at baseline that remained high at the end of treatment. For patients with partial response and stable disease with subsequent progression, ctDNA increased towards the end of treatment in most patients, with a median lead time of 83 days (14–309 days). In some patients with BOR of partial response who experienced disease progression later, specific gene alterations and total ctDNA fraction increased; this was sometimes observed concurrently with the development of new lesions without a change in target lesion size. Patients with alterations in PIK3CA and TP53 at baseline had shorter median progression-free survival compared with patients with wild-type PIK3CA and TP53, 12.7 and 7.3 months vs 19.2 and 19.4 months, respectively (P =.016 and P =.0001, respectively). Conclusions: Higher ctDNA levels and PIK3CA and TP53 alterations detected at baseline were associated with inferior outcomes. On-treatment ctDNA levels were associated with different patterns based on BOR. Longitudinal tracking of ctDNA may be useful for monitoring tumor status and detection of alterations with treatment implications. Trial registration: ClinicalTrials.gov NCT02333370 . Registered on January 7, 2015.

DOI： 10.1186/s12916-023-03017-z

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記述言語：英語   出版者・発行元：Cancer Medicine  

Background: The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear. Methods: We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. Results: The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. Conclusions: In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes.

DOI： 10.1002/cam4.6390

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記述言語：英語   出版者・発行元：Breast Cancer  

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2− mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis. Methods: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2− mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0–100) = − 0.45 × estrogen receptor (ER) (%) − 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38). Results: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients. Conclusions: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2− mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

DOI： 10.1007/s12282-023-01485-y

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. Patients and methods: Patients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). Results: In the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67–1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33–0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. Conclusions: OS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.

DOI： 10.1016/j.ejca.2023.01.031

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記述言語：英語   出版者・発行元：Cancer Medicine  

Pembrolizumab plus chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE-355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine–carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD-L1 CPS ≥10, PD-L1 CPS ≥1, and the intention-to-treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty-seven patients were randomized in Japan (pembrolizumab plus chemotherapy, n = 61; placebo plus chemotherapy, n = 26), 66 (76%) had PD-L1 CPS ≥1, and 28 (32%) had PD-L1 CPS ≥10. Median time from randomization to data cutoff (June 15, 2021) was 44.7 (range, 37.2–52.9) months in the ITT population. Hazard ratios (HRs; 95% CI) for OS were 0.36 (0.14–0.89), 0.52 (0.30–0.91), and 0.46 (0.28–0.77) in the PD-L1 CPS ≥10, PD-L1 CPS ≥1, and ITT populations, respectively. HRs (95% CI) for PFS were 0.52 (0.20–1.34), 0.61 (0.35–1.06), and 0.64 (0.39–1.05). Grade 3 or 4 treatment-related adverse events occurred in 85% of patients in each group (no grade 5 events). Consistent with the global population, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy in Japanese patients and supports this combination in this setting.

DOI： 10.1002/cam4.5757

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET. Methods: In this international, randomised, double-blind, placebo-controlled, phase 3 trial, women aged 18 years or older with stage 1–3c (amended to stage 2–3c) HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Randomisation was stratified according to hormone receptor (HR) status (HR-positive vs. HR-negative), nodal status (0, 1–3 or 4+), and trastuzumab regimen (sequentially vs. concurrently with chemotherapy). Overall survival was analysed by intention to treat. ExteNET is registered (Clinicaltrials.gov: NCT00878709) and is complete. Results: Between July 9, 2009, and October 24, 2011, 2840 women received neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 8.1 (IQR, 7.0–8.8) years, 127 patients (8.9%) in the neratinib group and 137 patients (9.6%) in the placebo group in the intention-to-treat population had died. Eight-year overall survival rates were 90.1% (95% CI 88.3–91.6) with neratinib and 90.2% (95% CI 88.4–91.7) with placebo (stratified hazard ratio 0.95; 95% CI 0.75–1.21; p = 0.6914). Conclusions: Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.

DOI： 10.1016/j.ejca.2023.02.002

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記述言語：英語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy is a standard treatment for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC); however, their toxicities and financial burden are major issues, especially for prolonged treatment. We investigated fulvestrant plus palbociclib in patients with HR-positive MBC resistant to fulvestrant monotherapy. Methods: Patients who initially received fulvestrant as their first- or second-line endocrine therapy were assigned to group A. Patients with disease progression during fulvestrant monotherapy who subsequently received fulvestrant plus palbociclib were assigned to group B. The primary endpoint was progression-free survival (PFS1) in group B. We set the threshold median PFS of 5 months (null hypothesis). Results: Between January 2018 and February 2020 we enrolled 167 patients in group A (January 2018–February 2020) from 55 institutions, of whom 72 subsequently received fulvestrant plus palbociclib and were enrolled in group B. The median follow-up was 23.8 and 8.9 months in groups A and B, respectively. The median PFS in group B (combination therapy) was 9.4 (90% confidence interval [CI]: 6.9–11.2) months (p < 0.001). This was 25.7 (90% CI: 21.2–30.3) months in group A (fulvestrant monotherapy). The TTF in group B was 7.2 (90% CI: 5.5–10.4) months. In the post-hoc analysis, the median PFS1 in group B among patients with longer-duration fulvestrant monotherapy (> 1 year) was longer than that of patients with shorter-duration monotherapy (≤ 1 year) (11.3 vs. 7.6 months). No new toxicities were observed. Conclusion: Our findings suggest that palbociclib plus fulvestrant after disease progression despite fulvestrant monotherapy is potentially safe and effective in patients with HR-positive/HER2-negative advanced MBC.

DOI： 10.1007/s10549-023-06911-5

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記述言語：英語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: Neoadjuvant endocrine therapy (NET) is a treatment option for estrogen receptor-positive (ER+) postmenopausal early breast cancer (EBC). This phase III trial evaluated the prognosis of EBC patients treated with/without chemotherapy (CT) following NET. Methods: ER+/HER2−, T1c-2, and clinically node-negative EBC patients were enrolled in 2008–2013 and treated with endocrine therapy (ET) in weeks 24–28. All patients, excluding those with progressive disease (PD) during NET or ≥ 4 positive lymph nodes after surgery, were randomized to ET for 4.5–5 years with/without CT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant DFS (DDFS), overall survival (OS), and DFS/DDFS/OS according to clinical response to NET. Results: Of 904 patients, 669 were randomized to CT+ET (n = 333) or ET alone (n = 336). The median follow-up was 7.8 years. DFS (CT+ET, 47 events; ET alone, 70 events) and DDFS did not reach the planned numbers of events. Eight-year DFS/DDFS rates were 86%/93% and 83%/92%, respectively. DFS was significantly better in CT+ET than ET alone in subgroups aged < 60 years (P = 0.016), T2 (P = 0.013), or Ki67 > 20% (P = 0.026). Progesterone receptor and histological grade were predictive markers for clinical responses to NET. Conclusion: NET may be used as standard treatment for patients with ER+EBC. Although it is difficult to decide whether to administer adjuvant CT based solely on the effect of NET, the response to NET may help to inform this decision. Trial registration: This study was registered at the UMIN Clinical Trials Registry under UMIN000001090 (registered 20 March 2008).

DOI： 10.1007/s10549-023-06874-7

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記述言語：英語   出版者・発行元：Japanese Journal of Clinical Oncology  

Background: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment. Methods: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate. Results: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer. Conclusion: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

DOI： 10.1093/jjco/hyac184

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出版者・発行元：南江堂  

DOI： 10.1093/jjco/hyac166

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記述言語：英語   出版者・発行元：Breast Cancer  

Background: Breast-conserving surgery with radiotherapy is one of standard treatments for early breast cancer. However, it is regarded as an option to treat elderly patients with small hormone receptor-positive breast cancer with breast-conserving surgery and hormone therapy without radiotherapy. We conducted two sequential prospective studies to examine the feasibility of breast-conserving surgery without radiotherapy since 2002 and present the results. Patients and methods: Primary female breast cancer patients who fulfilled the strict eligibility criteria were prospectively enrolled in two sequential studies named WORTH 1 and 2. The surgical materials were sliced in 5-mm intervals and all slices were examined microscopically. Postoperative radiotherapy was not allowed, but tamoxifen or anastrozole was administered for 5 years. Ipsilateral breast tumor recurrence (IBTR)-free survival was the primary outcome. Results: The data of the two studies were combined (N = 321). The median follow-up period for IBTR was 94 months (4–192 months). Only three patients were treated with adjuvant chemotherapy. The 5- and 10-year IBTR-free rates were 97.0% and 90.5%, respectively. The age at operation and PR status affected IBTR rates independently. When we calculated IBTR-free rates of patients who were 65 years of age or older at the time of surgery and had PR-positive tumors, the 5- and 10-year IBTR rates were both 98.4%. Conclusions: Our “5-mm-thick slice and 5-mm free-margin” method may be effective to select patients who can be treated by breast-conserving surgery and hormone therapy without radiotherapy.

DOI： 10.1007/s12282-022-01406-5

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記述言語：英語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: The aim was to understand real-world cyclin-dependent kinase (CDK) 4 and 6 inhibitor use in Japan. Methods: This retrospective observational study used a Japanese administrative claims database and included patients with presumptive hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) prescribed CDK4 and 6 inhibitor therapy between December 2017 and March 2021. Patient characteristics, treatment patterns, and selected clinical and safety outcomes were descriptively summarized. Time to discontinuation (TTD) and chemotherapy-free survival (CFS) were examined using Kaplan–Meier estimates. Results: The study cohort (N = 6442) was predominantly female (99.4%; median [range] age 64 [26–99] years) with records of metastases (79.6%) within 1 year prior to initiating CDK4 and 6 inhibitor therapy. In total, 4463 (69.3%) and 1979 (30.7%) were prescribed palbociclib and abemaciclib, respectively, as their first CDK4 and 6 inhibitor, most commonly in combination with fulvestrant (n = 3801; 59.0%). Overall, 3756 patients initiated a subsequent anticancer treatment, of whom 748 (19.9%) initiated a different CDK4 and 6 inhibitor in combination with the same or different endocrine therapy. Median TTD (95% confidence interval) was 9.7 (9.3, 10.1) months for the first CDK4 and 6 inhibitor therapy. Median CFS was 26.1 (24.6, 27.8) months. Incidence of clinically relevant diarrhea was higher after abemaciclib initiation (9.8%) than after palbociclib initiation (1.5%). More patients experienced dose reduction with palbociclib (69.3%) than with abemaciclib (53.0%). Conclusion: The data provide insights into current clinical practices for CDK4 and 6 inhibitor use in Japan that could help establish future treatment strategies for ABC.

DOI： 10.1007/s10549-022-06816-9

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記述言語：英語   出版者・発行元：Cancer Medicine  

Background: In this open-label, Phase 1 study, we explore the safety and efficacy of E7389-LF (liposomal formulation of eribulin) in Japanese patients with advanced solid tumors. Methods: This open-label, Phase 1 study enrolled Japanese adult patients to receive E7389-LF for the treatment of advanced solid tumors. Treatment with E7389-LF 2.0 mg/m2 every 3 weeks (previously determined maximum tolerated dose) was tested for the treatment of adenoid cystic carcinoma, gastric cancer, esophageal cancer, or small lung cell cancer in the expansion part of this study. Secondary endpoints included safety, objective response rate, best overall response, and progression-free survival. Results: As of October 16, 2020, 43 patients were enrolled (adenoid cystic carcinoma, n = 12; gastric cancer, n = 10; esophageal cancer, n = 11; small cell lung cancer, n = 10). Thirty-three patients experienced a Grade ≥3 treatment-related treatment-emergent adverse event, most commonly neutropenia (53.5%). Additionally, the incidence of hypersensitivity did not appear to change with a reduced number of infusion steps (2 vs. 4) and patients who were administered prophylactic pegylated granulocyte-colony stimulating factor had a noticeably lower incidence of Grade 3–4 neutropenia (although this did not have a proper control). The overall objective response rate was 11.6% (95% confidence interval: 3.9–25.1), corresponding to two partial responses in patients with adenoid cystic carcinoma, two partial responses in gastric cancer, and one partial response in esophageal cancer. Median progression-free survival was longer in the adenoid cystic carcinoma population (16.6 months) than in others. Conclusions: E7389-LF 2.0 mg/m2 every 3 weeks was well tolerated for the treatment of several different tumor types, and larger studies in these populations are warranted.

DOI： 10.1002/cam4.4996

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出版者・発行元：日本乳腺甲状腺超音波医学会（JABTS）  

記述言語：英語   出版者・発行元：Journal of Contemporary Brachytherapy  

Purpose: We investigated the long-term oncological outcome of high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) for adjuvant accelerated partial breast irradiation (APBI) after breast conserving surgery in Japanese patients. Material and methods: Between June 2002 and October 2011, 86 breast cancer patients were treated at National Hospital Organization Osaka National Hospital (trial number of the local institutional review board, 0329). Median age was 48 years (range, 26-73 years). Eighty patients had invasive and 6 patients non-invasive ductal carcinoma. Tumor stage distribution was pT0 in 2, pTis in 6, pT1 in 55, pT2 in 22, and pT3 in one patient, respectively. Twenty-seven patients had close/positive resection margins. Total physical HDR dose was 36-42 Gy in 6-7 fractions. Results: At a median follow-up of 119 months (range, 13-189 months), the 10-year local control (LC) and overall survival rate was 93% and 88%, respectively. Concerning the 2009 Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology risk stratification scheme, the 10-year LC rate was 100%, 100%, and 91% for patients considered as low-risk, intermediate-risk, and high-risk, respectively. According to the 2018 American Brachytherapy Society risk stratification scheme, the 10-year LC rate was 100% and 90% for patients ‘acceptable’ and ‘unacceptable’ for APBI, respectively. Wound complications were observed in 7 patients (8%). Risk factors for wound complications were the omission of prophylactic antibiotics during MIB, open cavity implantation, and V100 ≥ 190 cc. No grade ≥ 3 late complications (CTCVE version 4.0) were observed. Conclusions: Adjuvant APBI using MIB is associated with favorable long-term oncological outcomes in Japanese patients for low-risk, intermediate-risk, and acceptable groups of patients.

DOI： 10.5114/jcb.2023.125579

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出版者・発行元：Gan to kagaku ryoho. Cancer &amp; chemotherapy  

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出版者・発行元：Gan to kagaku ryoho. Cancer &amp; chemotherapy  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語  

DOI： 10.1016/j.dib.2022.108558

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記述言語：英語   出版者・発行元：Breast Cancer  

Background: Talazoparib, a poly(ADP-ribose) polymerase enzyme inhibitor, is approved for the treatment of patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative advanced breast cancer. This two-part study, a recently published dose-escalation part followed by the dose-expansion part reported here, evaluated the efficacy and safety of talazoparib in Japanese patients with gBRCA1/2-mutated advanced breast cancer. Methods: In this open-label, multicenter phase 1 study (NCT03343054), the primary endpoint of the dose-expansion part was confirmed objective response rate (ORR), determined by investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Patients received the recommended phase 2 dose (1 mg/day; 0.75 mg/day moderate renal impairment). Results: Nineteen Japanese patients with gBRCA1/2-mutated locally advanced or metastatic breast cancer were enrolled. Confirmed ORR was 57.9% (11/19; 90% confidence interval [CI] 36.8–77.0). Stable disease was observed in 36.8% (7/19) of patients. Per investigator assessment, median PFS was 7.2 months (95% CI 4.1–not estimable) and 12-month OS rate was 84.7% (90% CI 57.5–95.1). Median OS was not reached; 17/19 patients were alive and censored at 12 months. All patients experienced treatment-related adverse events (AEs); the majority were hematologic. The most common treatment-related AE was anemia (68.4%; [13/19]). Grade 3/4 treatment-related AEs were observed in 52.6% (10/19) of patients. During the safety period, there were no grade 5 treatment-emergent AEs, treatment-related serious AEs, or deaths. Conclusions: In Japanese patients with gBRCA mutations and locally advanced or metastatic breast cancer, talazoparib monotherapy was generally well tolerated and resulted in clinically meaningful ORRs. Clinicaltrials.gov identifier: NCT03343054.

DOI： 10.1007/s12282-022-01390-w

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DOI： 10.1093/jjco/hyac098

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記述言語：英語   出版者・発行元：Journal of Clinical Endocrinology and Metabolism  

Background: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. Methods: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. Results: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. Conclusion: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

DOI： 10.1210/clinem/dgac467

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記述言語：英語   出版者・発行元：Cancer Science  

No standard options existed for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer that progresses after second-line trastuzumab emtansine therapy before 2020. The purpose of this study was to examine the efficacy of pertuzumab retreatment after disease progression following pertuzumab-containing therapy for HER2-positive locally advanced or metastatic breast cancer for the first time. This randomized, open-label, multicenter phase III trial was undertaken in 93 sites in Japan. Eligible patients with HER2-positive breast cancer who had received pertuzumab, trastuzumab, and chemotherapy as first- and/or second-line therapy were randomly assigned (1:1) to: (i) pertuzumab, trastuzumab, and physician's choice chemotherapy (PTC), or (ii) trastuzumab and physician's choice chemotherapy (TC). The primary end-point was investigator-assessed progression-free survival (PFS). Between August 1, 2015 and December 31, 2018, 219 patients were randomized to PTC (n = 110) or TC (n = 109). Median follow-up was 14.2 months (interquartile range, 9.0–22.2), and median PFS was 5.3 months (95% confidence interval [CI], 4.0–6.6) with PTC and 4.2 months (95% CI, 3.2–4.8) with TC (stratified hazard ratio 0.76 [95% CI upper limit 0.967]; p = 0.022). Progression-free survival was improved by adding pertuzumab in all prespecified subgroups. The PTC arm showed a trend towards better overall survival and duration of response, but similar objective response and health-related quality of life. The incidence of treatment-related adverse events was similar between groups except for diarrhea. Pertuzumab retreatment contributes to disease control for HER2-positive locally advanced or metastatic breast cancer previously treated with pertuzumab-containing regimens.

DOI： 10.1111/cas.15474

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DOI： 10.1016/j.annonc.2022.07.267

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DOI： 10.1016/j.annonc.2022.07.295

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出版者・発行元：医歯薬出版  

記述言語：英語   出版者・発行元：Clinical Cancer Research  

Purpose: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA). Patients and Methods: Patients with hormone receptor–positive/ human epidermal growth factor receptor 2–negative (HRþ/HER2¯) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent. Results: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified. Conclusions: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HRþ/HER2¯ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

DOI： 10.1158/1078-0432.CCR-22-0305

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: Preclinical models revealed potential synergistic effects of programmed cell death-1 inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies. Therefore, we investigated the use of nivolumab, bevacizumab, and paclitaxel triple therapy for metastatic breast cancer. Methods: This phase 2, multicentre, single-arm study (NEWBEAT) investigated the safety and efficacy of first-line nivolumab, paclitaxel, and bevacizumab in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of programmed cell death-ligand 1 expression. The primary end-point was objective response rate. Key secondary end-points included progression-free survival, overall survival, and toxicities. A biomarker study evaluated tumour programmed cell death-ligand 1 expression and serum VEGF-A levels. Results: Between February 2018 and October 2018, 57 patients were enrolled. An objective response rate was seen in 39/56 patients (70%, 95% confidence interval [CI]: 55.9–81.2%), meeting the primary end-point. The objective response rate was 74% in patients with hormone receptor-positive breast cancer versus 59% in patients with triple-negative breast cancer. The median progression-free survival and overall survival were 14.0 (95% CI 11.0–16.3) and 32.5 (95% CI 26.0–not evaluable) months, respectively (median follow-up: 29.5 months). Grade 3/4 adverse drug reactions occurred in 33 of 57 patients (58%). There were no grade 5 adverse events. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3/4 events in eight patients (14%). Biomarker analysis showed that tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. Efficacy outcomes were similar between the serum VEGF-high and VEGF-low groups. Conclusions: First-line nivolumab, bevacizumab, and paclitaxel therapy showed promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.

DOI： 10.1016/j.ejca.2022.05.014

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記述言語：英語   出版者・発行元：New England Journal of Medicine  

BACKGROUND In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. METHODS We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. RESULTS A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P=0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P=0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. CONCLUSIONS Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone.

DOI： 10.1056/NEJMoa2202809

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Breast Cancer  

Background: We carried out the first multi-institutional prospective study on accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy in a shorter period for early breast cancer in Japan. Methods: Patient eligibility criteria included positive hormone receptors, tumors ≤ 3 cm and TNM stage pN0M0. After breast-conserving surgery (Japanese cylindrical resection) and histological confirmation of negative surgical margins and the absence of lymph node metastasis, applicator implantation was performed either postoperatively or intraoperatively. High-dose-rate brachytherapy of 36 Gy in 6 fractions was delivered. Results: Forty-six patients from six institutions received this treatment regimen, and the median follow-up time was 60 months (range 57–67 months). The median resected breast tissue volume was 81 cm3 (range 28–260 cm3). No Grade 4 late sequela, local recurrence nor death due to breast cancer were observed. Grade 2–3 sequelae such as rib fracture (2%), soft tissue necrosis (9%), fibrosis (20%), and breast pain (9%) were observed. The resected breast tissue volumes of the patients who had Grade ≥ 2 fibrosis and Grade < 2 fibrosis were 105.9 ± 32.3 cm3 and 76.3 ± 45.6 cm3, respectively, p = 0.02. The overall cosmetic outcome score of Excellent/Good was 74% at 60 months after APBI. Grade ≥ 1 fibrosis was observed in 44% and 92% of patients who scored Excellent/Good and Fair/Poor, respectively, p = 0.004. Conclusions: This study showed excellent local control and survival results with minimal late sequelae.

DOI： 10.1007/s12282-022-01339-z

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出版者・発行元：Breast Cancer  

Background: This retrospective observational study validated nuclear grading criteria developed to identify a high-risk group with recurrence rate ≥20-30% and local pathology diagnosis used in a previous multi-institutional randomized N·SAS-BC 01 trial, where the efficacy of adjuvant chemotherapy regimens was evaluated in 733 high-risk node-negative invasive breast cancer patients.Methods: Of 545 patients with long-term follow-up data (median 12.1 years), pathology slides, and local pathology diagnosis, 530 eligible patients were subjected to central pathology review (CPR) for histological type and nuclear grade (NG). Concordance in NGs was compared with local diagnosis. The 10/15-year recurrence-free survival (RFS) and overall survival (OS) rates stratified by NG and histological type were calculated.Results: Local diagnoses were invasive ductal carcinoma (IDC)-NG2, IDC-NG3, invasive lobular carcinoma (ILC), and metaplastic carcinoma (MC) in 158/327/38/7 patients, respectively. The 10/15-year RFS rates were 87.2/82.6% for IDC-NG2 and 81.8/75.0% for IDC-NG3 (p = 0.061), and OS rates were 95.0/92.8% for IDC-NG2 and 90.8/85.7% for IDC-NG3 (p = 0.042). CPR graded 485 locally diagnosed IDCs as IDC-NG1/NG2/NG3/unknown in 98/116/267/4 patients, respectively. No significant difference was found among survival curves for the three NG groups. Although the agreement level between local and CPR diagnoses was low (κ = 0.311), both diagnoses identified a patient group with a 15-year recurrence rate ≥ 20%. The 10/15-year RFS rates were 79.4/63.5% for ILC and 68.6%/unknown for MC.Conclusions: The N·SAS grading system identified a patient group with high-risk node-negative invasive breast cancer, suggesting that local diagnosis was performed efficiently in the N·SAS-BC 01 trial.Trial registration number: UMIN000022571. Date of registration: June 1, 2016.

DOI： 10.1007/s12282-022-01350-4

記述言語：英語   出版者・発行元：Breast Cancer  

In the original publication of the article, the affiliation of the co-author, Norikazu Masuda, should be changed from “National Hospital Organization Osaka National Hospital, Osaka, Japan” to “Nagoya University Graduate School of Medicine, Nagoya, Japan”.

DOI： 10.1007/s12282-022-01367-9

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DOI： 10.1016/j.annonc.2022.05.065

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DOI： 10.1016/j.ejca.2022.03.004

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DOI： 10.1016/j.annonc.2022.03.183

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出版者・発行元：篠原出版新社  

記述言語：英語   出版者・発行元：The Lancet Oncology  

Background: Anticancer treatment regimens typically cause unpleasant side-effects. We aimed to investigate the benefit of switch maintenance endocrine therapy plus bevacizumab after fixed cycles of first-line induction chemotherapy with weekly paclitaxel plus bevacizumab in patients with oestrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer. Methods: BOOSTER was a prospective, open-label, multicentre, randomised, controlled, phase 2 study done in 53 hospitals in Japan. Eligible patients were women aged 20–75 years, with an Eastern Cooperative Oncology Group performance status of 0–1, who had not received chemotherapy for ER-positive, HER2-negative advanced or metastatic breast cancer. All patients received four to six cycles (in which 4 weeks of treatment constitute one cycle) of weekly paclitaxel plus bevacizumab induction therapy (weekly paclitaxel 90 mg/m2, administered intravenously on days 1, 8, and 15 of each cycle, plus bevacizumab 10 mg/kg administered intravenously on days 1 and 15 of each cycle; first registration). Patients with a complete response, partial response, or stable disease after induction therapy (responders) were then randomly assigned (1:1) using the randomisation enrolment form to either continue weekly paclitaxel plus bevacizumab or switch to maintenance endocrine therapy (an aromatase inhibitor or fulvestrant with or without ovarian-function suppression) plus bevacizumab. Randomisation was stratified by induction therapy period, response to induction therapy, age, history of endocrine therapy, and study site. Patients could receive weekly paclitaxel plus bevacizumab reinduction if they had disease progression with maintenance endocrine therapy plus bevacizumab. The primary endpoint was time to failure of strategy (TFS). Efficacy and safety analyses were done in all treated patients (full analysis set). This study is registered with ClinicalTrials.gov, NCT01989780, and registration and follow-up are closed. Findings: Between Jan 1, 2014, and Dec 31, 2015, we enrolled 160 patients who began weekly paclitaxel plus bevacizumab induction therapy. 125 (78%) patients (responders) were randomly assigned to endocrine therapy plus bevacizumab (n=62; n=61 in the full analysis set) or weekly paclitaxel plus bevacizumab (n=63; n=63 in the full analysis set). Among 61 patients in the switch maintenance endocrine therapy plus bevacizumab group, 32 (52%) were reinitiated on weekly paclitaxel plus bevacizumab. At a median follow-up of 21·3 months (IQR 13·0–28·2), TFS was significantly longer in the endocrine therapy plus bevacizumab group than in the weekly paclitaxel plus bevacizumab group (median 16·8 months [95% CI 12·9–19·0] vs 8·9 months [5·7–13·8]; hazard ratio 0·51 [0·34–0·75]; p=0·0006). The most common grade 3–4 non-haematological adverse events after randomisation were proteinuria (in ten [16%] of 61 patients in the endocrine therapy plus bevacizumab group vs eight [13%] of 63 patients in the weekly paclitaxel plus bevacizumab group), hypertension (six [10%] vs six [10%]), and peripheral neuropathy (one [2%] vs six [10%]). One treatment-related death was reported in the weekly paclitaxel plus bevacizumab group (duodenal ulcer perforation). Interpretation: Switch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. Funding: Chugai Pharmaceutical. Translation: For the Japanese translation of the abstract see Supplementary Materials section.

DOI： 10.1016/S1470-2045(22)00196-6

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記述言語：英語   出版者・発行元：BMC Medicine  

Background: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC’s response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. Methods: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. Results: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). Conclusions: Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. Trial registration: UMIN000023162.

DOI： 10.1186/s12916-022-02332-1

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記述言語：英語  

DOI： 10.1093/jjco/hyac022

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出版者・発行元：Catheterization and Cardiovascular Interventions  

Objective: We investigated the effect of proximal optimization technique (POT) on coronary bifurcation stent failure (BSF) in cross-over stenting by comparing with the kissing balloon technique (KBT) in a multicenter randomized PROPOT trial. Background: POT is recommended due to increased certainty for optimal stent expansion and side branch (SB) wiring. Methods: We randomized 120 patients treated with crossover stenting into the POT group, which was followed by SB dilation (SBD), and the KBT group. Finally, 52 and 57 patients were analyzed by optical coherence tomography before SBD and at the final procedure, respectively. Composite BSF was defined as a maximal malapposition distance of >400 μm, or malapposed and SB-jailed strut rates of >5.95% and >21.4%, respectively. Results: Composite BSF before SBD in the POT and KBT groups was observed in 29% and 26% of patients, respectively. In the POT group, differences in stent volumetric index between the proximal and distal bifurcation (odds ratio [OR] 60.35, 95% confidential interval [CI] 0.13–0.93, p = 0.036) and between the proximal bifurcation and bifurcation core (OR: 3.68, 95% CI: 1.01–13.40, p = 0.048) were identified as independent risk factors. Composite BSF at final in 27% and 32%, and unplanned additional procedures in 38% and 25% were observed, respectively. Composite BSF before SBD was a risk factor for the former (OR: 6.33, 95% CI: 1.10–36.50, p = 0.039) and the latter (OR: 6.43, 95% CI: 1.25–33.10, p = 0.026) in the POT group. Conclusion: POT did not result in a favorable trend in BSF. Insufficient expansion of the bifurcation core after POT was associated with BSF.

DOI： 10.1002/ccd.30120

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記述言語：英語   出版者・発行元：International Journal of Nanomedicine  

Background: NK105 is a paclitaxel (PTX)-incorporating “core-shell-type” polymeric micellar nanoparticle formulation composed of block copolymers (polyethylene glycol and a polyamino acid). The efficacy and safety of NK105 and paclitaxel in advanced or recurrent breast cancer have never been compared at equivalent dose levels. Patients and Methods: Patients were randomly assigned to either NK105 or PTX in a 1:1 ratio. The study drug was administered on Day 1, 8, and 15 of a 28-day cycle with 80 mg/m2. The primary endpoint was overall response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 123 patients (NK105, n=62; PTX, n=61) received one of the two drugs. There was no significant difference in ORR, the median PFS, or OS (NK105 group: 41.9%, 9.1, and 27.5 months, respectively; PTX group: 45.9%, 7.8, and 32.4 months, respectively). Neutropenia occurred more frequently in the NK105 group, but most patients did not require granulocyte-colony stimulating factor or dose-reduction. The median time to onset of peripheral sensory neuropathy (PSN) in the NK105 group was significantly longer than that in the PTX group (p=0.001), and PSN (≥ grade 3) was not observed in the NK105 group. Conclusion: Weekly NK105 administration was well-tolerated. Efficacy was similar in both groups. The PSN profile was better in the NK105 group.

DOI： 10.2147/IJN.S372477

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記述言語：英語   出版者・発行元：Cancer Management and Research  

Purpose: Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and Methods: Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study. Results: In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3–4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3–4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3–4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/ or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%). Conclusion: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.

DOI： 10.2147/CMAR.S348591

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC. Methods: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2–3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative. Results: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%). Conclusion: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

DOI： 10.1007/s10549-021-06396-0

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語  

DOI： 10.1158/1078-0432.CCR-20-4685

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10549-021-06313-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12282-021-01239-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12282-021-01238-9

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-021-08504-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10147-021-01920-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Breast Cancer  

Background: We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS. Patients and methods: We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records. Results: We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2–2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2–2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2–2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2–2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm. Conclusion: We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.

DOI： 10.1007/s12282-021-01225-0

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記述言語：英語  

DOI： 10.1007/s10147-021-01940-w

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記述言語：英語  

DOI： 10.1002/onco.13782

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1200/JCO.20.01139

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14877

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12282-020-01162-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/onco.13691

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10637-020-00991-6

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2217/imt-2020-0242

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10549-020-06018-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Lancet Oncology  

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.

DOI： 10.1016/S1470-2045(20)30534-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/onco.13531

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10549-020-05921-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S0140-6736(20)32531-9

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記述言語：英語  

DOI： 10.1002/cam4.3528

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語  

DOI： 10.1200/JCO.20.00147

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記述言語：日本語   出版者・発行元：Cancer Science  

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.

DOI： 10.1111/cas.14554

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記述言語：英語  

DOI： 10.1002/cam4.3091

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記述言語：英語  

DOI： 10.1007/s12282-020-01057-4

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DOI： 10.1186/s13063-020-04408-w

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記述言語：英語  

DOI： 10.1038/s41598-020-63033-4

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DOI： 10.1186/s13063-020-04341-y

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DOI： 10.1007/s12282-019-01029-3

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記述言語：日本語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: Addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) has improved pathological complete response (pCR) rates in previous studies. We present long-term survival outcomes (disease-free survival [DFS], pre-planned secondary endpoint; overall survival [OS], post hoc exploratory endpoint) of our randomized study of the addition of CBDCA to NAC for HER2-negative breast cancer. Methods: Patients with stage II/III, HER2-negative breast cancer (N = 179) were randomly assigned to receive CP–CEF (four 3-week cycles of CBDCA [area under the curve, 5 mg/mL/min, day 1] and weekly paclitaxel [wPTX, 80 mg/m2, day 1, 8, 15] followed by four 3-week cycles of cyclophosphamide, epirubicin, and 5-fluorouracil [CEF, 500/100/500 mg/m2]) or P–CEF (four cycles of wPTX followed by four cycles of CEF) as NAC. DFS and OS were analyzed at each population of pCR status and assigned treatment arm. Results: Of 179 patients, 154 were available for long-term follow-up. At a median follow-up of 6.6 years (range, 0.7–8.0 years), patients who achieved pCR [n = 42, 23.5% (CP–CEF: n = 28, P–CEF: n = 16)] had longer DFS and OS than non-pCR patients [DFS; HR 0.15 (0.04–0.61), P = 0.008, OS; log-rank P = 0.003]. Addition of carboplatin to NAC significantly improved DFS and OS in the subset of patients with TNBC [DFS: HR, 0.22 (0.06–0.82), P = 0.015; OS: HR, 0.12 (0.01–0.96), P = 0.046], but not in the subset of patients with hormone receptor-positive disease or among all patients. Conclusions: Addition of carboplatin to neoadjuvant chemotherapy significantly improved DFS and OS in patients with TNBC but not in those with hormone receptor-positive, HER2-negative breast cancer.

DOI： 10.1007/s10549-020-05580-y

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記述言語：英語  

DOI： 10.1007/s10549-020-05590-w

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DOI： 10.1007/s12328-019-01035-0

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記述言語：英語  

DOI： 10.1186/s13058-020-01263-0

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記述言語：英語  

DOI： 10.1007/s10549-020-05524-6

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記述言語：英語  

DOI： 10.1093/jjco/hyz119

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記述言語：英語  

DOI： 10.1001/jamaoncol.2019.4782

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DOI： 10.1007/s12282-019-00997-w

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記述言語：英語  

DOI： 10.18632/oncotarget.27163

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記述言語：英語  

DOI： 10.1016/j.ejca.2019.06.023

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記述言語：英語  

DOI： 10.1016/j.tranon.2019.07.013

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DOI： 10.1038/s41598-019-50099-y

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DOI： 10.1007/s12282-019-00970-7

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DOI： 10.1007/s12282-019-00984-1

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記述言語：英語  

DOI： 10.1002/cam4.2423

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DOI： 10.2217/fon-2019-0143

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記述言語：英語  

DOI： 10.1200/JGO.18.00173

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DOI： 10.1007/s10147-018-1353-9

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DOI： 10.1016/j.ejca.2018.11.014

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DOI： 10.1007/s10147-018-1359-3

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記述言語：英語  

DOI： 10.3390/ijms20040984

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記述言語：日本語   出版者・発行元：Oncology Letters  

The value of assessing tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive/human epidermal growth factor receptor type 2 (HER2) negative breast cancer has yet to be determined. In the present study, a total of 184 cases with early distant recurrence detected within 5 years following the primary operation, 134 with late distant recurrence diagnosed following 5 years or longer and 321 controls without recurrence for >10 years following starting the initial treatment for ER-positive/HER2 negative breast cancer, registered in 9 institutions, were analyzed. The distributions of TILs and their clinical relevance were investigated. TIL distributions did not differ significantly among the early, late and no recurrence groups, employing a 30% cut-off point as a dichotomous variable. In those who had received adjuvant chemotherapy as well as endocrine therapy, a trend toward higher TIL proportions was detected when the early recurrence group was compared with the no recurrence group employing the 30% cut-off point (P=0.064). The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group). High TIL distributions also predicted shorter survival time following the detection of recurrence (P=0.026). However, these prognostic interactions were not significant in multivariate analysis (P=0.200). The present retrospective study demonstrated no significant interaction between TIL proportions and the timing of recurrence. However, higher TIL proportions were observed in breast cancer patients with aggressive biological phenotypes, which tended to be more responsive to chemotherapy. The clinical relevance of stromal TILs for identifying patients who would likely benefit from additional therapies merits further investigation in a larger patient population.

DOI： 10.3892/ol.2018.9853

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記述言語：日本語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. Methods: NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result, ESR1 and PGR single-gene scores, and ER gene-group score. Results: Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18–30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18–30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (p < 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (p < 0.001), ESR1 score (p = 0.049), PGR score (p < 0.001), and ER gene-group score (p < 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31, p = 0.010). Conclusion: The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer.

DOI： 10.1007/s10549-018-4964-y

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記述言語：英語  

DOI： 10.1136/esmoopen-2018-000476

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DOI： 10.1007/s10549-018-4958-9

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DOI： 10.1056/NEJMoa1810527

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DOI： 10.1016/j.ejca.2018.08.011

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DOI： 10.1016/j.ejca.2018.08.002

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記述言語：日本語   出版者・発行元：Japanese Journal of Clinical Oncology  

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic Breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

DOI： 10.1093/jjco/hyy097

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DOI： 10.1016/j.ejca.2018.05.017

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DOI： 10.1007/s12282-018-0843-y

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DOI： 10.1002/cam4.1600

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DOI： 10.5114/jcb.2018.76983

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DOI： 10.1002/cam4.1516

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DOI： 10.1007/s00280-018-3544-5

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記述言語：英語  

DOI： 10.1016/j.breast.2017.12.017

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DOI： 10.1111/cas.13507

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DOI： 10.1007/s12282-017-0798-4

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DOI： 10.1007/s10549-017-4489-9

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DOI： 10.1007/s12282-017-0815-7

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DOI： 10.1080/03007995.2017.1400426

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DOI： 10.1177/1178223418786243

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DOI： 10.1136/esmoopen-2017-000314

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記述言語：日本語   出版者・発行元：Respiratory Medicine Case Reports  

Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.

DOI： 10.1016/j.rmcr.2018.01.006

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記述言語：英語  

DOI： 10.18632/oncotarget.22990

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DOI： 10.18632/oncotarget.22110

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記述言語：英語  

DOI： 10.1200/JCO.2017.73.7585

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DOI： 10.1634/theoncologist.2017-0072

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記述言語：英語  

DOI： 10.1056/NEJMc1708487

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記述言語：英語  

DOI： 10.1056/NEJMoa1706450

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記述言語：英語  

DOI： 10.1200/JGO.2016.008318

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記述言語：日本語   出版者・発行元：Breast Cancer  

Unfortunately, in the original publication of this article, the P value of “ER (%), median (range)” was misplaced to previous row “Tumor grade 3” in Table 4. The original article was corrected.

DOI： 10.1007/s12282-017-0771-2

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記述言語：英語  

DOI： 10.1007/s11604-017-0640-0

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記述言語：英語  

DOI： 10.1016/S1470-2045(17)30376-5

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記述言語：英語  

DOI： 10.1056/NEJMoa1612645

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記述言語：英語  

DOI： 10.1016/j.humpath.2017.04.004

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記述言語：英語  

DOI： 10.3892/mco.2017.1233

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記述言語：英語  

DOI： 10.1093/jjco/hyx001

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記述言語：日本語   出版者・発行元：Breast Cancer  

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

DOI： 10.1007/s12282-016-0730-3

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記述言語：日本語   出版者・発行元：Cancer Science  

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

DOI： 10.1111/cas.13221

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記述言語：英語  

DOI： 10.21873/invivo.11088

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記述言語：英語  

DOI： 10.1007/s10549-017-4138-3

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記述言語：英語  

DOI： 10.1002/cncr.30421

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記述言語：英語  

DOI： 10.3892/ol.2016.5538

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記述言語：日本語   出版者・発行元：Annals of Oncology  

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35mg/m2 on days 1-3 every 3 weeks) or docetaxel (60mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P=0.54) and overall survival (14.6 versus 13.5 months; P=0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P=0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥ 3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥ 3 leukopenia occurred in 63.3% and 70.7%, and grade ≥ 3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel.

DOI： 10.1093/annonc/mdw621

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記述言語：英語  

DOI： 10.1007/s10549-016-4075-6

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記述言語：英語  

DOI： 10.1016/j.ejca.2016.09.024

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記述言語：英語  

DOI： 10.1159/000475879

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記述言語：英語  

DOI： 10.1093/jjco/hyw127

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記述言語：日本語   出版者・発行元：Breast Cancer  

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than 10 years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

DOI： 10.1007/s12282-015-0649-0

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DOI： 10.1007/s12282-015-0652-5

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記述言語：日本語   出版者・発行元：Breast Cancer Research  

Background: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. Methods: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. Results: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). Conclusions: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

DOI： 10.1186/s13058-016-0731-3

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記述言語：英語  

DOI： 10.1007/s00595-015-1236-x

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記述言語：英語  

DOI： 10.1093/jjco/hyw013

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記述言語：英語  

DOI： 10.1016/S1470-2045(15)00613-0

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記述言語：英語  

DOI： 10.1186/s12885-016-2270-9

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記述言語：英語  

DOI： 10.1016/S1470-2045(15)00551-3

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記述言語：英語  

DOI： 10.1200/JCO.2014.60.1971

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記述言語：英語  

DOI： 10.1245/s10434-015-4809-4

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記述言語：英語  

DOI： 10.1007/s12282-015-0640-9

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記述言語：英語  

DOI： 10.1159/000442192

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記述言語：英語  

DOI： 10.1007/s10147-015-0832-5

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記述言語：英語  

DOI： 10.1007/s12282-014-0524-4

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記述言語：英語  

DOI： 10.1097/NCC.0000000000000201

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記述言語：英語  

DOI： 10.1007/s00520-015-2654-4

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記述言語：日本語   出版者・発行元：Cancer Chemotherapy and Pharmacology  

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/m2 weekly. Results: Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m2) 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/m2 and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m2 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/m2 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.

DOI： 10.1007/s00280-015-2826-4

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記述言語：日本語   出版者・発行元：Japanese Journal of Clinical Oncology  

This Phase III trial aims to determine the superiority of intensive follow-up to standard follow-up in terms of overall survival in high-risk breast cancer patients, who are expected to have recurrence rates of over 30% within 5 years after surgery. Eligible patients are randomized either to the intensive follow-up group or to the standard follow-up group; the former will undergo physical examination, bone scintigraphy, chest computed tomography, abdominal computed tomography, brain magnetic resonance imaging/computed tomography and frequent tumor marker evaluations, whereas the latter will undergo physical examination at the same frequency and tumor markers will be evaluated once a year. Mammography once a year is planned for both groups. The primary endpoint is overall survival. Patient accrual was started in November 2013. A total of 1700 patients will be enrolled for 3 years and followed up for 7 years after closure of accrual. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012429.

DOI： 10.1093/jjco/hyv110

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DOI： 10.1007/s12282-013-0511-1

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DOI： 10.1007/s10147-015-0814-7

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DOI： 10.1007/s10147-015-0785-8

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記述言語：英語  

DOI： 10.1186/s13014-015-0430-8

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記述言語：英語  

DOI： 10.5301/jbm.5000136

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記述言語：英語  

DOI： 10.1007/s10147-014-0716-0

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記述言語：英語  

DOI： 10.1007/s00520-014-2597-1

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記述言語：英語  

DOI： 10.1007/s12282-013-0475-1

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DOI： 10.1007/s10549-014-3237-7

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記述言語：日本語  

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記述言語：英語  

DOI： 10.1016/j.canlet.2014.08.042

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記述言語：英語  

DOI： 10.1007/s12282-013-0454-6

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記述言語：英語  

DOI： 10.1007/s12282-013-0444-8

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記述言語：英語  

DOI： 10.1007/s12282-013-0466-2

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記述言語：日本語  

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記述言語：英語  

DOI： 10.1093/jjco/hyu090

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記述言語：日本語   出版者・発行元：International Journal of Clinical Oncology  

Background: The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer. Methods: Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline. Results: Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) (P = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014-0.721; P = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592-0.846). Conclusion: Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer. © 2013 Japan Society of Clinical Oncology.

DOI： 10.1007/s10147-013-0614-x

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記述言語：英語  

DOI： 10.1007/s10549-014-3090-8

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記述言語：日本語   出版者・発行元：Anticancer Research  

Aim: We undertook a prospective phase II study to evaluate the efficacy of S-1 plus trastuzumab combination regimen for human epidermal-growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: HER2-positive MBC patients received oral administration of S-1 (80 mg/m2/day, days 1 to 28, every 6 weeks) and intravenous weekly trastuzumab (2 mg/kg), according to the results of a prior Phase I trial of our group. Results: A total of 28 patients were enrolled and received a median of 3.5 (range 1-10) cycles of treatment. Overall response rate and clinical benefit rate were 53.6% and 75.0%, respectively. Progression-free survival was 30 weeks. With regard to grade 3 and 4 adverse effects, leucopenia, neutropenia, increase in serum alanine aminotransferase, and diarrhea were observed. Conclusion: Combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this trial.

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記述言語：日本語   出版者・発行元：Anticancer Research  

Aim: We undertook a prospective phase II study to evaluate the efficacy of S-1 plus trastuzumab combination regimen for human epidermal-growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: HER2-positive MBC patients received oral administration of S-1 (80 mg/m2/day, days 1 to 28, every 6 weeks) and intravenous weekly trastuzumab (2 mg/kg), according to the results of a prior Phase I trial of our group. Results: A total of 28 patients were enrolled and received a median of 3.5 (range 1-10) cycles of treatment. Overall response rate and clinical benefit rate were 53.6% and 75.0%, respectively. Progression-free survival was 30 weeks. With regard to grade 3 and 4 adverse effects, leucopenia, neutropenia, increase in serum alanine aminotransferase, and diarrhea were observed. Conclusion: Combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this trial.

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記述言語：日本語  

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DOI： 10.1007/s10549-014-2947-1

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DOI： 10.1016/S1470-2045(14)70138-X

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DOI： 10.1007/s12282-012-0394-6

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DOI： 10.1007/s10549-013-2814-5

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記述言語：英語  

DOI： 10.1155/2014/620876

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記述言語：日本語  

DOI： 10.1158/0008-5472.SABCS13-P4-16-11

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DOI： 10.1097/CAD.0000000000000016

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記述言語：日本語   出版者・発行元：Breast Cancer Research and Treatment  

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m2 on day 1; capecitabine: 1,650 mg/m2 on days 1-14 every 3 weeks) or docetaxel alone (75 mg/m2 on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10-20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014-1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer. © 2013 The Author(s).

DOI： 10.1007/s10549-013-2691-y

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記述言語：英語  

DOI： 10.1093/jjco/hyt091

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記述言語：英語  

DOI： 10.1007/s10147-012-0437-1

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記述言語：英語  

DOI： 10.2174/15734013113099990001

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記述言語：日本語   出版者・発行元：Breast Cancer Research and Treatment  

The aromatase inhibitors exemestane and anastrozole are approved in Japan for first-line treatment of postmenopausal patients with advanced, hormone-receptor-positive breast cancer. This phase 3, randomized, double-blind study directly compared time to progression (TTP) for exemestane and anastrozole therapy in this patient population. Eligible patients were randomized to receive exemestane 25 mg or anastrozole 1 mg, each once daily. The primary endpoint was TTP based on assessment by an expert radiologic images review committee (ERIRC). Secondary endpoints included investigator-assessed TTP, time to treatment failure, overall survival, objective response rate, clinical benefit rate, and safety. A total 298 patients were randomized to receive exemestane (n = 149; mean age 63.4 years) or anastrozole (n = 149; mean age 64.0 years). Median ERIRC-assessed TTP was 13.8 and 11.1 months (hazard ratio = 1.007; 95 % confidence interval [CI]: 0.771, 1.317) and median investigator-assessed TTP was 13.8 and 13.7 months (hazard ratio = 1.059; 95 % CI: 0.816, 1.374) in the exemestane and anastrozole arms, respectively. Median overall survival was 60.1 months in the anastrozole arm and was not reached in the exemestane arm at data cutoff. The objective response rate was 43.9 % (95 % CI: 35.3, 52.8) and 39.1 % (95 % CI: 30.6, 48.1) in the exemestane and anastrozole arms, respectively. Treatment-related adverse events grade ≥3 occurred in 9.4 and 6.0 % of patients, and treatment-related serious adverse events occurred in 4.0 and 3.4 % of patients in the exemestane and anastrozole arms, respectively. In this study, the efficacy and safety profiles of exemestane were similar to those of anastrozole in Japanese patients with advanced, hormone-receptor-positive breast cancer; however, TTP non-inferiority of exemestane versus anastrozole was not confirmed. © 2013 The Author(s).

DOI： 10.1007/s10549-013-2573-3

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DOI： 10.1007/s00280-013-2140-y

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DOI： 10.1245/s10434-012-2825-1

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記述言語：日本語   出版者・発行元：European Journal of Pharmacology  

Since the introduction of 2-aminoethoxydiphenylborate (2-APB) as a membrane permeable modulator of inositol (1,4,5)-trisphosphate receptors, subsequent studies have revealed additional actions of this chemical on multiple Ca 2+-permeable ionic channels in the plasma membrane. However, no reports have yet examined 2-APB as a modulator targeting contractile machinery in smooth muscle, independent of Ca2+ mobilization, namely Ca 2+ sensitization. Here, we assessed whether or not 2-APB affects intracellular signaling pathways of Ca2+ sensitization for contraction using α-toxin permeabilized human detrusor smooth muscle. Although contractions were induced by application of Ca2+-containing bath solutions, 2-APB had little effect on contractions induced by 1 μM Ca2+ alone but significantly reversed the carbachol-induced augmentation of Ca2+-induced contraction in the presence of guanosine triphosphate (carbachol-induced Ca2+ sensitization). The rho kinase inhibitor Y-27632 and protein kinase C inhibitor GF-109203X also reversed the carbachol-mediated Ca2+ sensitization. Additional application of 2-APB caused a small but significant further attenuation of the contraction in the presence of GF-109203X but not in the presence of Y-27632. Like carbachol, the rho kinase activator; sphingosylphosphorylcholine, protein kinase C activator; phorbol 12,13 dibutyrate, and myosin light chain phosphatase inhibitor; calyculin-A all induced Ca2+ sensitization. However, the inhibitory activity of 2-APB was limited with sphingosylphosphorylcholine- induced Ca2+ sensitization. This study revealed a novel inhibitory effect of 2-APB on smooth muscle contractility through inhibition of the rho kinase pathway. © 2013 Elsevier B.V.

DOI： 10.1016/j.ejphar.2013.03.006

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記述言語：日本語   出版者・発行元：Breast Cancer  

Background: A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy. Methods: Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m2 on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol. Results: Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred. Conclusions: This study demonstrated that biweekly administration of 150 mg/m2 irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes. © 2011 The Japanese Breast Cancer Society.

DOI： 10.1007/s12282-011-0316-z

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記述言語：日本語   出版者・発行元：Cancer Chemotherapy and Pharmacology  

Purpose: The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. The purpose of this phase II study was to evaluate the efficacy and safety of a monthly XP regimen in patients with metastatic breast cancer (MBC). Methods: Eligible patients had received one or fewer prior chemotherapy regimens for MBC. Patients received oral capecitabine of low dose (828 mg/m2 twice daily, days 1-21) plus paclitaxel (80 mg/m2, i.v., over 60 min, days 1, 8 and 15) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival (OS) and safety were secondary endpoints. An exploratory analysis of efficacy according to hormone receptor (HR) status was performed. Results: Forty-four patients were enrolled, and 43 patients were evaluable. ORR was 46.5 %. PFS and OS were 8.3 and 22.9 months, respectively. ORR was 45.5 % in patients with HR-positive tumors and 50 % in HR-negative cases. The most frequently observed grade 3/4 adverse events were neutropenia (27.9 %), leukopenia (11.6 %), hand-foot syndrome (HFS, 9.3 %) and fatigue (7.0 %). There were no discontinuations due to HFS. Conclusions: Monthly XP was an effective and well-tolerated regimen for the first- or second-line treatment for MBC. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00280-012-2068-7

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DOI： 10.1002/cncr.27818

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DOI： 10.1002/cncr.27789

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DOI： 10.1159/000355196

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DOI： 10.1093/jjco/hys120

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DOI： 10.1007/s00520-011-1239-0

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DOI： 10.1016/S1470-2045(11)70373-4

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DOI： 10.1016/j.clbc.2011.10.002

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記述言語：日本語   出版者・発行元：Breast  

Background: Some studies have shown that high body mass index (BMI) is associated with inferior outcome after adjuvant therapy with anastrozole in breast cancer patients. We aimed to investigate predictive effect of BMI on clinical response to neoadjuvant therapy with exemestane in postmenopausal patients with primary breast cancer. Patients and methods: The study group consisted of 109 patients from the JFMC 34-0601 neoadjuvant endocrine therapy trial. Patients were categorized into three groups according to BMI: low (BMI<22kg/m2), intermediate (22≤BMI<25kg/m2) and high (BMI≥25kg/m2). Statistical analyses were performed to explore the predictive effect of BMI on clinical response. Results: Higher BMI correlated with positive progesterone receptor status (p<0.01) and low Ki-67 index (p=0.03). Objective response rates (ORR) were 21.7% in low BMI, 56.0% in intermediate BMI and 60.6% in high BMI, respectively (p=0.01). In a multivariate analysis, low BMI was an independent negative predictor of clinical response. Conclusion: Low BMI was associated with a decreased ORR to neoadjuvant endocrine therapy with exemestane. Our results may suggest that the predictive effect of BMI varies according to the type of aromatase inhibitor and objective outcome. © 2011 Elsevier Ltd.

DOI： 10.1016/j.breast.2011.07.015

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DOI： 10.1155/2012/286210

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DOI： 10.1016/j.ijrobp.2010.07.035

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DOI： 10.1007/s10549-011-1685-x

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DOI： 10.1093/jjco/hyr081

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DOI： 10.3892/ijo.2011.926

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記述言語：日本語   出版者・発行元：Cancer Science  

Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stageII/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25mg/day was administered for 16weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24weeks of administration. The ORR was 47% (55/116) at Week16 and 51% (59/116) at Week24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated. © 2011 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2011.01867.x

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DOI： 10.1007/s00280-010-1371-4

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DOI： 10.1007/s10549-010-1332-y

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DOI： 10.1007/s00066-010-2134-1

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記述言語：日本語   出版者・発行元：Breast Cancer  

Background: Aromatase inhibitors (AIs) have been employed as adjuvant therapy or as treatment for recurrent cases. However, when AI treatment fails, it is unclear which endocrine therapy is the most appropriate to introduce at this point and how effective it will be. In this study, we investigated the efficacy and safety of toremifene (TOR, Fareston®), a selective estrogen receptor modulator (SERM). Methods: Patients with recurrent or advanced breast cancer who had measurable or evaluable lesions, and were diagnosed as having progressive disease during AI treatment and subsequently given TOR at 120 mg/day (TOR120) as endocrine therapy were selected and analyzed retrospectively in relation to their medical history. Results: Of a total of 83 cases examined, 80 were evaluable. The objective response rate (ORR) was 15.0% (12/80), the clinical benefit (CB) rate was 45.0% (36/80), and median time to failure (TTF) was 7.8 months. TOR120 was also effective in the progressive disease cases relapsed on AI treatment. When TOR120 was used, as a first-, second- or third-line treatment, the CB rate was 57% (32/56); this fell to 17% (4/24) when TOR120 was used as a fourth-line or later treatment. There was no response in the five estrogen receptor (ER)-negative cases, compared with an ORR of 15% (10/67) in ER-positive cases. In cases with a human epidermal growth factor receptor 2 (HER2) score of 0, 1+, and 2+, the ORR was 11% (7/61), while there was no response in the five cases with scores of 3+. TOR120 was effective in cases previously treated with tamoxifen (TAM), with an ORR and CB rate of 12 and 29%, respectively. The last AI used was anastrozole in 30 cases and examestane in 46; the response rates to TOR120 were similar in both groups. With regard to adverse effects, hot flushes and/or night sweating was observed in 10 and 12 cases, respectively, but all of them were categorized as grade 1, and the treatment was rated excellent in acceptability. Conclusions: TOR120 was rated excellent in acceptability, and high efficacy was observed when it was used up to third-line treatment for AI-failure cases, although this study may show some selection bias because of the retrospective study. In addition, it was also considered effective for TAM-failure cases. © 2009 The Japanese Breast Cancer Society.

DOI： 10.1007/s12282-009-0148-2

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DOI： 10.1093/jjco/hyq054

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DOI： 10.1002/cncr.25206

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DOI： 10.1093/jjco/hyq021

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DOI： 10.1007/s10549-010-0888-x

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記述言語：日本語   出版者・発行元：Cancer Chemotherapy and Pharmacology  

Purpose Although anthracycline is a key agent in breast cancer treatment, its use is associated with the risk of cardiotoxicity. Recently, the value of combination therapy with docetaxel and cyclophosphamide was reported. Because the characteristics of paclitaxel differ on weekly versus tri-weekly administration, such as in the induction of apoptosis and anti-angiogenic activity, establishment of a treatment regimen with a combination of paclitaxel and cyclophosphamide (PC) is warranted. We initiated a phase I study to determine the maximum tolerated dose (MTD) and recommended dose (RD) of combination therapy with PC for advanced or recurrent breast cancer. Patients and methods Eligible patients had advanced or recurrent breast cancer. Paclitaxel was given intravenously on days 1, 8, and 15 of every 3-week course, and cyclophosphamide on day 1, over a total of four courses. Paclitaxel was given at 80 mg/m2 for level 1 and 100 mg/m2 for level 2, and cyclophosphamide at 600 mg/m2 in both cases. Onset of dose-limiting toxicity was evaluated during the first course, and tolerability throughout the four courses. Results Four patients were enrolled in each of levels 1 and 2 from October 2006 to November 2007. The main toxicities were grade 3 neutropenia in four patients (50%) and sensory neuropathy in one (12.5%). An MTD was not attained, as neither a hematologic toxicity of grade 4 nor a non-hematologic toxicity of grade 3 or higher was observed during the first course at level 1 or 2. Response rate amongst assessable patients (one in level 1, two in level 2) was 66.7%. Conclusions Safety was well tolerated throughout the four courses at level 2, and this dosage level was therefore regarded as the RD. © Springer-Verlag 2009.

DOI： 10.1007/s00280-009-1137-z

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DOI： 10.1097/CAD.0b013e328336acb1

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DOI： 10.1007/s12282-009-0152-6

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DOI： 10.1186/1471-2407-10-56

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DOI： 10.1007/s10549-009-0498-7

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DOI： 10.1159/000318169

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記述言語：日本語   出版者・発行元：Chemotherapy  

Background: Capecitabine is an established therapy for metastatic breast cancer. In Japan, a 4 weekly regimen is often used, but data for this schedule in the first-line setting are lacking. Methods: Metastatic breast cancer patients who had received no chemotherapy for recurrent disease received capecitabine 825 mg/m2 twice daily, on days 1-21 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was response rate. Results: In 33 eligible patients, median age was 53 years (range 27-73). Prior adjuvant therapy included an anthracycline in 90% and a taxane in 40%. The response rate was 18%; a further 24% had stable disease for ≥6 months. Median progression-free and overall survival were 6.9 and 24.8 months, respectively. The only grade 3 events were neutropenia (6%) and hand-foot syndrome (15%). Conclusions: These preliminary results confirm previous data showing that a lower capecitabine dose is an active and well-tolerated first-line therapy for metastatic breast cancer. Copyright © 2010 S. Karger AG, Basel.

DOI： 10.1159/000313531

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DOI： 10.1007/s11604-009-0345-0

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DOI： 10.1093/jjco/hyp052

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DOI： 10.1007/s00520-008-0550-x

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DOI： 10.1016/j.acra.2008.12.009

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DOI： 10.1245/s10434-009-0465-x

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DOI： 10.1007/s00280-008-0882-8

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DOI： 10.1158/1078-0432.CCR-08-1881

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DOI： 10.1097/RCT.0b013e3181671ad2

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記述言語：日本語   出版者・発行元：Annals of Oncology  

Background: This is a randomized, double-blind, dose-ranging study in patients receiving highly emetogenic chemotherapy (HEC) to evaluate the safety, efficacy, and pharmacokinetics of palonosetron, in combination with dexamethasone. Materials and methods: We randomized 233 patients to receive palonosetron as a single i.v. bolus dose of 0.075, 0.25, or 0.75 mg before administration of HEC. Dexamethasone (12-16 mg i.v. on day 1, 8 mg i.v. on day 2, and 4-8 mg i.v. on day 3) was administered for prophylactic antiemesis. Pharmacokinetics of palonosetron was analyzed in 24 patients. Results: In this study, all patients were given ≥50 mg/m2 cisplatin, which was considered to be HEC. No significant differences in complete response (CR: no emesis and no rescue medication) rates were found in the first 24 h between the 0.075-, 0.25-, and 0.75-mg groups (77.6%, 81.8%, and 79.5%, respectively). In the 120-h period of overall observation, CR rates increased in a dose-dependent manner. In the 0.75-mg group, we observed a significantly longer time to treatment failure than in the 0.075-mg group (median time >120 versus 82.0 h, P = 0.038). Palonosetron was tolerated well and did not show any dose-related increase in adverse effects. Conclusions: Palonosetron at doses of 0.25 and 0.75 mg was shown to be effective in preventing chemotherapy-induced nausea and vomiting with high CR rates of patients treated with HEC in Japan. All tested doses of palonosetron were tolerated well. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

DOI： 10.1093/annonc/mdp195

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DOI： 10.1186/bcr2300

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記述言語：日本語   出版者・発行元：Breast Cancer Research and Treatment  

Purpose: This multicenter phase II study examined the impact of pathological effect on survival after preoperative chemotherapy in Japanese women with early stage breast cancer. Patients and methods: Prior to surgery, patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). Primary endpoint was 3 year disease free survival (DFS) stratified by the absence or presence of Quasi-pCR (QpCR; absence of invasive tumor or only focal residual tumor cells). Secondary endpoints were predictors for QpCR, clinical response, breast conservation rate, and safety. Results: Between June 2002 and June 2004, 202 women were enrolled. Among 191 assessable patients, 25% achieved QpCR. With 40 months median follow-up, 3 year DFS was estimated at 91% for all patients. 3 year DFS for patients with QpCR was 98% vs. 89% without QpCR (hazard ratio 0.38 [95% Confidence Interval 0.09-0.84], P = 0.0134). HER2 status and response to FEC were independent predictors of QpCR. The overall clinical response was 75%; 85% of patients achieved breast conservation. Grade 3/4 neutropenia was the most common adverse event, observed in 44% and 35% of patients during FEC and docetaxel, respectively. Treatment related side effects were manageable; there were no treatment related fatalities. Conclusion: FEC followed by docetaxel is an active and manageable preoperative regimen for women with early stage breast cancer. QpCR following preoperative chemotherapy predicts favorable DFS. HER2 overexpression and clinical response to FEC predict QpCR. © 2007 Springer Science+Business Media, LLC.

DOI： 10.1007/s10549-007-9744-z

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記述言語：日本語   出版者・発行元：Cancer Chemotherapy and Pharmacology  

Background: The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. Three-weekly XP regimens have demonstrated excellent efficacy in phase II and III trials in metastatic breast cancer. We conducted a dose-finding study to identify the recommended 4-weekly XP regimen in patients with inoperable or recurrent breast cancer for phase II evaluation. Methods: Eligible patients had inoperable or recurrent breast cancer previously treated with chemotherapy (but not capecitabine or paclitaxel) in the (neo)adjuvant or metastatic setting. Each 4-week treatment cycle consisted of escalating doses of capecitabine (628 or 829 mg/m2 twice daily [b.i.d.] on days 1-21) and paclitaxel (80 or 90 mg/m2 on days 1, 8, and 15). Dose-limiting toxicities (DLT) were evaluated during the first two cycles. Results: Nine patients were treated. At dose level 1 (capecitabine 628 mg/m2 b.i.d. plus paclitaxel 80 mg/m2), one patient experienced a DLT (grade 3 non-hematologic toxicity). There were no further DLTs at dose level 1 or 2. Although the MTD was not reached, dose level 2 (capecitabine 829 mg/m2 b.i.d., days 1-21, plus paclitaxel 80 mg/m2, days 1, 8, and 15, every 28 days) is recommended for phase II evaluation, taking into consideration the single-agent doses used in Japan and the doses identified in Western studies of 3-weekly XP. The overall response rate was 44%; all patients treated at dose level 2 achieved a partial response. Conclusions: This 4-weekly XP regimen was well tolerated, active in patients with pretreated advanced breast cancer, and could be given as outpatient treatment. These results are consistent with findings of phase II and III trials evaluating 3-weekly regimens, and indicate that further investigation of a 4-weekly XP regimen is warranted. © 2007 Springer-Verlag.

DOI： 10.1007/s00280-007-0555-z

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記述言語：日本語   出版者・発行元：Japanese Heart Journal  

Prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) continues to be a significant problem. Recent controlled studies have demonstrated that cilostazol suppresses restenosis after PTCA. The effects of ticlopidine, another antiplatelet agent, were compared in terms of outcomes of patients randomized for treatment with the two drugs after PTCA. A total of 35 patients (47 lesions) were assigned prospectively and randomly to ticlopidine (17 patients, 24 lesions) and cilostazol (18 patients, 23 lesions) groups. Minimal luminal diameter (MLD) and percentage of stenosis to reference diameter were estimated before PTCA, just after the procedure and after 4 months follow-up. All patients underwent 4 months angiographic follow-up, at the end of which MLD was 2.03 ± 0.71 mm in the ticlopidine group and 2.05 ± 0.68 mm in the cilostazol group (p = 0.95), and the percentage of stenosis to reference diameter was 31.4 ± 16.7% and 30.0 ± 17.0%, respectively (p = 0.78). The restenosis rate was 12.5% in the ticlopidine group and 17.4% in the cilostazol group (p = 0.69), relatively low as compared to the 20% to 30% reported in previous studies. Adverse drug reactions during the follow-up period were observed in two of the ticlopidine group and none of the cilostazol group. We conclude that both ticlopidine and cilostazol are effective for the prevention of restenosis after PTCA, however the former may be associated with slight side effects.

DOI： 10.1536/jhj.42.43

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出版者・発行元：Journal of the Neurological Sciences  

Somatic mosaicism of an expanded repeat is present in tissues of patients with triplet repeat diseases. Of the spinocerebellar ataxias associated with triplet repeat expansion, the most prominent heterogeneity of the expanded repeat is seen in dentatorubral-pallidoluysian atrophy (DRPLA). The common feature of this somatic mosaicism is the difference in the repeat numbers found in the cerebellum as compared to other tissues. The expanded allele in the cerebellum shows a smaller degree of expansion. We previously showed by microdissection analysis that the expanded allele in the granular layer in DRPLA cerebellum has less expansion than expanded alleles in the molecular layer and white matter. Whether this feature of lesser expansion in granule cells is common to other types of neurons is yet to be clarified. We used a newly developed excimer laser microdissection system to analyze somatic mosaicism in the brains of two patients, one with early- and another with late-onset DRPLA, and used single cell PCR to observe the cell-to-cell differences in repeat numbers. In the late onset patient, repeat expansion was more prominent in Purkinje cells than in granule cells, but less than that in the glial cells. In the early onset patient, repeat expansion in Purkinje cells was greater than in granule cells but did not differ from that in glial cells. These findings suggest that there is a difference in repeat expansion among neuronal subgroups and that the number of cell division cycles is not the only determinant of somatic mosaicism. © 2001 Published by Elsevier Science B.V.

DOI： 10.1016/S0022-510X(01)00596-2

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