Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study.

Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m2) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings.

Dose Reduction versus Dose-interval Prolongation in Eribulin Mesilate Monotherapy in Patients with Metastatic Breast Cancer: A Retrospective Comparative Study.

It is often necessary to modify the dose or schedule of eribulin mesilate (Eri) because of adverse events. Therefore, we retrospectively investigated the optimal approach for Eri dose adjustment and/or dosage interval adjustment. Patients who received Eri at the institutions affiliated with the Division of Oncology of the Aichi Prefectural Society of Hospital Pharmacists between July 2011 and November 2013 were enrolled in this study. We compared the group that underwent dose reduction without changes to their dosage interval (dose reduction group) with the group that had a change in their dosage interval (dose-interval prolongation group). The primary end-point was time to treatment failure (TTF), and the secondary end-points were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and adverse events. The TTF and OS of the dose reduction group were approximately two times longer than those of the dose-interval prolongation group. In addition, the dose reduction group had significantly improved ORR and CBR, which together indicate an antitumor effect (p=0.013 and 0.002, respectively). Although peripheral neuropathy occurred significantly more frequently in the patients in the dose reduction group (p=0.026), it was grade 1 and controllable in most of the cases. There were no differences in the occurrence of other adverse effects between the two groups. Therefore, we suggest that dose reduction with maintenance of the dosage interval is the preferred treatment approach in cases where Eri dose or schedule modification is necessary.

The efficacy and safety of FSK0808, filgrastim biosimilar: a multicenter, non-randomized study in Japanese patients with breast cancer.

OBJECTIVE: FSK0808 is a filgrastim biosimilar. This study assessed the efficacy and safety of FSK0808 in patients with breast cancer. METHODS: One hundred and four breast cancer patients undergoing chemotherapy were enrolled in the study. FSK0808 was used to treat the neutropenia experienced by the patients in the course of their chemotherapy. Efficacy was evaluated by the recovery of absolute neutrophil count following FSK0808 administration based on the duration of neutropenia in patients who received pre- or postoperative chemotherapy containing fluorouracil, epirubicin and cyclophosphamide. Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events version 3.0. The incidence of febrile neutropenia and generation of an anti-granulocyte colony-stimulating factor antibody were also evaluated. RESULTS: The average duration of neutropenia in Cycle 2 was 2.2 days with a standard deviation of 1.5 days. The upper limit of the 97.5% one-sided confidence interval was 2.5 days and was confirmed not to exceed 3.0 days, which was defined as the threshold value of absolute neutrophil count recovery. The incidence of febrile neutropenia across all treatment cycles was 34.6%. Observed adverse drug reactions with an incidence of > 5% were back pain (60.6%), bone pain (9.6%), alanine aminotransferase increase (8.7%), aspartate aminotransferase increase (5.8%) and arthralgia (5.8%). Production of the anti-granulocyte colony-stimulating factor antibody was not observed in any patient during the study. CONCLUSIONS: FSK0808 was safe and well tolerated in breast cancer patients undergoing chemotherapy and effectively stimulated neutrophil recovery.

A phase III open-label study to assess safety and efficacy of palonosetron for preventing chemotherapy-induced nausea and vomiting (CINV) in repeated cycles of emetogenic chemotherapy.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is of great importance for the completion of multiple cycles of cancer chemotherapy. Palonosetron is a second-generation 5-HT(3) receptor antagonist with proven efficacy for both acute and delayed CINV. This study was designed to assess the safety and efficacy of 0.75 mg palonosetron in repeated cycles of highly emetogenic chemotherapy or anthracycline-cyclophosphamide combination (AC/EC). METHODS: We gave 0.75 mg palonosetron to 538 patients 30 min prior to ≥ 50 mg/m(2) cisplatin or AC/EC on day 1. Prophylactic dexamethasone was administered on days 1-3. The primary endpoint was the incidence rate of adverse events (AEs). The secondary endpoint was complete response rate (CR, defined as no emesis and no rescue medication) throughout the study period. RESULTS: Treatment-related AEs were seen in 44% (237 of 538 patients). Serious AEs were seen in 4% (23 of 538 patients), all considered unrelated or unlikely to be related to palonosetron. Only one patient discontinued the study due to a treatment-related AE. No trend toward worsening of AEs was observed in subsequent cycles of chemotherapy. Complete response rates were maintained throughout repeated cycles. CONCLUSION: The extraordinary safety profile and maintenance of efficacy of 0.75 mg palonosetron combined with dexamethasone were demonstrated throughout repeated chemotherapy cycles.

Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group.

We evaluated the efficacy and safety of sequential therapy with trastuzumab monotherapy (H-mono) followed by H plus docetaxel (D) after disease progression (H --> H + D) versus combination therapy with H + D as first-line therapy. Patients with human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer (MBC) and left ventricular ejection fraction >50% were randomly assigned to either (a) H --> H + D [H, once weekly 2 mg/kg (loading dose, 4 mg/kg); D, once every 3 weeks 60 mg/m(2)] or (b) H + D. Primary endpoints were progression-free survival (PFS) for the H-mono stage of the H --> H + D group and H + D group and overall survival (OS) for both groups. Secondary endpoints were overall response rate, time to treatment failure, second PFS and safety. The planned number of patients was 160 patients in total. Of 112 patients enrolled, 107 were eligible. After 112 patients were enrolled, the Independent Data Monitoring Committee recommended stopping enrollment because PFS and OS were greater in the H + D group than the H --> H + D group. Median PFS was 445 days in the H + D group versus 114 days for H-mono in the H --> H + D group [hazard ratio (HR), 4.24; P < 0.01]. OS was significantly longer in the H + D group (HR, 2.72; P = 0.04). H + D therapy is significantly superior to H --> H + D therapy as first-line therapy in patients with HER2-positive MBC, especially in terms of OS.

A case of invasive micropapillary carcinoma of the breast.

BACKGROUND: Invasive micropapillary carcinoma (IMP) of the breast is uncommon and has only recently been characterized. Knowing the cytological appearance of IMP is important to enable early diagnosis by fine needle aspiration cytology (FNAC). We describe a case of IMP diagnosed by preoperative FNAC. CASE: A 48-year-old menopausal woman presented in 2003 with a mass in her left breast. Mammogram and ultrasound findings indicated that the tumor was malignant. Cytological examination showed papillary clusters of hyperchromatic cells with irregular and crowded nuclei, but lacking papillary cores. No myoepithelial cells were seen. Based on the cytological findings, invasive micropapillary carcinoma was diagnosed. Microscopic findings showed cancer cells with moderate atypia in abundant micropapillary cancer nests without a fibrovascular core. These cancer nests were morula-like, surrounded by empty, clear spaces lined with delicate strands of fibrocollagenous stroma. The polarity of each cancer nest was reversed, with the secretion border facing fibrocollagenous stroma. These pathological features occupied the invasive part of the primary tumor. CONCLUSION: The cytologic features of IMP are distinctive and correlate with histology. FNAC of IMP is important role to confirm the diagnosis.

Low expression of the snail gene is a good prognostic factor in node-negative invasive ductal carcinomas.

BACKGROUND: While Snail is a zinc-finger transcription factor that triggers the epithelial-mesenchymal transition, it has also been reported to be indirectly regulated by estrogen receptor alpha (ERalpha) and to be involved in the transcriptional repression of the aromatase gene. The aim of the present study was to examine the role of Snail expression in node-negative invasive ductal carcinomas. METHODS: We analyzed Snail mRNA expression levels in 86 node-negative invasive ductal carcinomas by real-time quantitative RT-PCR and studied whether Snail mRNA expression correlates with clinicopathological factors. RESULTS: No correlation was found between Snail mRNA expression and ERalpha protein expression levels. However, we observed that none of the 34 patients showing low Snail mRNA expression developed distant metastasis while 6 of 52 (12%) showing high expression of Snail mRNA did. The level of Snail mRNA expression was not found to be significantly correlated with clinicopathological factors. No inverse correlation was found between the Snail and aromatase mRNA expression levels in our series. CONCLUSION: Our data show that low expression of Snail mRNA is a good prognostic factor in node-negative invasive ductal carcinomas. Snail expression is suggested to be involved in distant metastasis in node-negative invasive ductal carcinomas.

Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer.

BACKGROUND: The association between breast cancer risk and genetic polymorphisms of p53 at codon 72 (Arg72Pro) has been investigated by several studies, but the results are not consistent. The aim of this case-control study conducted in Nagoya, Japan, was to reconfirm the results of prior studies of polymorphisms of p53 Arg72Pro, and to test if polymorphisms of p73 G4C14-to-A4T14 at exon 2 (G4A) were also associated with breast cancer risk. METHODS: The cases were 200 breast cancer patients who visited Aichi Cancer Center Hospital. The controls were 282 local citizens who underwent a health check-up. All cases and controls were recruited from Chubu Japan. Genotyping was carried out by polymerase chain reaction with confronting two-pair primers. RESULTS: The p53 genotype distribution was 40.4% for Arg72 homozygous, 48.9% for heterozygous, and 10.7% for Pro72 homozygous in controls, and 32.0%, 50.0%, and 18.0% in cases, respectively. A comparison between cases and controls indicated a significantly increased risk for Pro72 homozygosity in cases (odds ratio=2.14; 95% confidence interval=1.21-3.79). The genotypic frequencies for p73 G4A were 54.3% for G/G, 39.7% for G/A, and 6.0% for A/A in controls; and 59.0%, 32.0%, and 9.0% in cases, respectively. There were no significant differences in p73 G4A frequency between cases and controls. CONCLUSIONS: This study implies an association of breast cancer risk with the p53 polymorphism Arg72Pro, but not with p73 G4A.

Transforming growth factor B1 T29C polymorphism and breast cancer risk in Japanese women.

BACKGROUND: A cohort study for Caucasians aged 65 years or older demonstrated a marked breast cancer risk reduction for those with the CC genotype of transforming growth factor B1 (TGF B1) T29C polymorphism. This is a prevalent case-control study to examine the reported risk reduction for Japanese women. PATIENTS AND METHODS: A total of 232 histologically diagnosed breast cancer patients who visited Aichi Cancer Center Hospital between June 1999 and March 2000 were enrolled. The controls were 172 female outpatients without cancer at the same hospital. DNA was extracted from peripheral blood, and TGF B1 genotype was determined by PCR-CTPP. RESULTS: The genotype frequency was 23.7% for TT, 49.2% for TC, and 27.1% for CC among controls, and 28.9%, 46.1%, and 25.0%, respectively, among cases. Age-adjusted odds ratio (OR) relative to the TT genotype was 0.81 (95% confidence interval, 0.50-1.31) for the TC genotype and 0.77 (0.45-1.34) for the CC genotype. For premenopausal women, the CC genotype was significantly associated with reduced risk of breast cancer in comparison with the TT genotype (OR=0.45, 0.20-0.98). The association was not observed for postmenopausal women (OR=1.40, 0.64-3.08). CONCLUSION: The present study showed risk reduction for Japanese premenopausal women with the CC genotype, but not for postmenopausal Japanese women.

Combination of subareolar blue dye and peritumoral RI for sentinel lymph node biopsy.

BACKGROUND: The identification rate of sentinel lymph nodes (SLNs) is variable because numerous different methods employing different tracers have been used for sentinel lymph node detection. The aim of this study was to determine the optimal technique for sentinel lymph node biopsy (SLNB). METHODS: From May 1999 to December 2001, SLNB was performed for 376 patients with T1-3 and N0-1 primary breast cancer using blue dye alone, radioisotope (RI) alone and combination of RI and blue dye. Two hundred sixty-eight patients underwent SLNB using blue dye alone. They were divided into 4 groups (Group A: n=50; peritumoral injection, Group B: n=83; the first half to receive subareolar injection, Group C: n=83; the second half to receive subareolar injection, and Group D: n=52; small incision according to an axillary skin landmark). One hundred eight patients underwent SLNB using RI. Tin colloid was used in 49 cases (Tin Colloid Group) and phytate in 59 cases (Phytate Group). Among them, 29 patients underwent injection of RI alone and 79 patients received a combination of RI and blue dye. RESULTS: The identification rates of SLN using blue dye alone were 60%, 82%, 92% and 79% in Groups A, B, C and D, respectively. The identification rates of SLN in patients receiving RI alone and in those receiving combination of RI and blue dye were 40% and 89%, respectively, in Tin Colloid Group, and 92% and 94%, respectively, in Phytate Group. CONCLUSION: When using blue dye alone, subareolar injection provided a better identification rate than peritumoral injection. The combination of peritumoral phytate and subareolar blue dye provided the best identification rate (94%) in all the groups. The combination of intraparenchymal phytate and subareolar blue dye was the most efficient technique for sentinel node biopsy in breast cancer patients.

Significant reduction in breast cancer risk for Japanese women with interleukin 1B -31 CT/TT relative to CC genotype.

OBJECTIVE: The present case-control study aimed to examine the associations between breast cancer risk and three functional polymorphisms (Interleukin (IL) -1A C-889T, IL-1B C-31T and IL-1RN 86-bp variable number tandem repeat) related to expression of IL-1beta, which combines estrogen receptor. METHODS: Cases were 231 patients with breast cancer who had been diagnosed 1 month to 6 years before their enrollment in 1999-2000 at Aichi Cancer Center Hospital. Controls were 186 non-cancer outpatients recruited during the same period at the digestive tract, breast surgery and gynecology clinics. RESULTS: There were no differences in the genotype distributions of the IL-1A and IL-1RN polymorphisms, but individuals harboring a IL-1B C-31T T allele (high expression allele) were less frequent among cases (74.3%) than among controls (84.9%). The age-adjusted odds ratio (OR) relative to CC genotype was 0.52 (95% confidence interval, 0.30-0.88) for CT genotype, 0.58 (0.32-1.02) for TT genotype and 0.54 (0.33-0.90) for CT/TT genotype. Subgroup analysis showed that the preventive effect was significantly stronger for postmenopausal women than for premenopausal women (interaction 0.30, 0.11-0.84). CONCLUSIONS: Although this is the first report on the association between breast cancer risk and IL-1B C-31T, the observed association seems plausible in a biological sense.