Yoshimasa Kosaka

Phase III placebo-controlled, double-blind, randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide chemotherapy

PurposePegfilgrastim is a pegylated form of filgrastim, a recombinant protein of granulocyte colony-stimulating factor, that is used to reduce the risk of febrile neutropenia (FN). Here, we report the results of a phase III trial of pegfilgrastim in breast cancer patients receiving docetaxel and cyclophosphamide (TC) chemotherapy.MethodsWe conducted a double-blind, placebo-controlled, randomized trial to determine the efficacy of pegfilgrastim in reducing the risk of FN in early-stage breast cancer patients. A total of 351 women (177 in the pegfilgrastim group and 174 in the placebo group) between 20 and 69xa0years of age with stage I–III invasive breast carcinoma who were to receive TC chemotherapy (docetaxel 75xa0mg/m2 and cyclophosphamide 600xa0mg/m2 every 3xa0weeks) as either neoadjuvant or adjuvant therapy were enrolled; 346 of these patients were treated with either pegfilgrastim (nu2009=u2009173) or placebo (nu2009=u2009173).ResultsThe incidence of FN was significantly lower in the pegfilgrastim group than in the placebo group (1.2 vs. 68.8xa0%, respectively; Pu2009<u20090.001). In addition, patients in the pegfilgrastim group required less hospitalization and antibiotics for FN. Most adverse events were consistent with those expected for breast cancer subjects receiving TC chemotherapy.ConclusionsPegfilgrastim is safe and significantly reduces the incidence of FN in breast cancer patients.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study)

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87xa0% [95xa0% confidence interval (CI) 85–90]. The pathologic complete response (pCR: ypT0/isxa0+xa0ypN0) rate was 51xa0%. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36xa0%, Pxa0<xa00.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82xa0%, Pxa0<xa00.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95xa0% CI 1.36–5.21, Pxa0=xa00.004 for cN2–3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95xa0% CI 1.15–2.91, Pxa0=xa00.011), and non-pCR (HR 1.98, 95xa0% CI 1.22–3.24, Pxa0=xa00.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95xa0% CI 1.43–4.90, Pxa0=xa00.002) and clinical tumor stage (HR 2.20, 95xa0% CI 1.16–4.20, Pxa0=xa00.017 for cT3–4 vs. cT1–2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95xa0% CI 1.48–6.62, Pxa0=xa00.003), clinical nodal stage (HR 4.26, 95xa0% CI 1.53–13.14, Pxa0=xa00.005 for cN2–3 vs. cN0), and young age (HR 2.40, 95xa0% CI 1.12–4.94, Pxa0=xa00.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0xa0+xa0ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95xa0% CI 1.31–5.97, Pxa0=xa00.006 and HR 3.86, 95xa0% CI 1.13–24.21, Pxa0=xa00.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Prognostic Significance of Promoter DNA Hypermethylation of cysteine dioxygenase 1 (CDO1) Gene in Primary Breast Cancer.

Using pharmacological unmasking microarray, we identified promoter DNA methylation of cysteine dioxygenase 1 (CDO1) gene in human cancer. In this study, we assessed the clinicopathological significance of CDO1 methylation in primary breast cancer (BC) with no prior chemotherapy. The CDO1 DNA methylation was quantified by TaqMan methylation specific PCR (Q-MSP) in 7 BC cell lines and 172 primary BC patients with no prior chemotherapy. Promoter DNA of the CDO1 gene was hypermethylated in 6 BC cell lines except SK-BR3, and CDO1 gene expression was all silenced at mRNA level in the 7 BC cell lines. Quantification of CDO1 methylation was developed using Q-MSP, and assessed in primary BC. Among the clinicopathologic factors, CDO1 methylation level was not statistically significantly associated with any prognostic factors. The log-rank plot analysis elucidated that the higher methylation the tumors harbored, the poorer prognosis the patients exhibited. Using the median value of 58.0 as a cut-off one, disease specific survival in BC patients with CDO1 hypermethylation showed significantly poorer prognosis than those with hypomethylation (p = 0.004). Multivariate Cox proportional hazards model identified that CDO1 hypermethylation was prognostic factor as well as Ki-67 and hormone receptor status. The most intriguingly, CDO1 hypermethylation was of robust prognostic relevance in triple negative BC (p = 0.007). Promoter DNA methylation of CDO1 gene was robust prognostic indicator in primary BC patients with no prior chemotherapy. Prognostic relevance of the CDO1 promoter DNA methylation is worthy of being paid attention in triple negative BC cancer.

Epigenetic silencing of HOPX contributes to cancer aggressiveness in breast cancer

Epigenetic silencing of HOPX has been shown to be frequent and specific in human cancers. HOPX is thought as a tumor suppressor gene and its promoter methylation is the main mechanism of down-regulation. In non-hereditary breast cancer, since roles of epigenetic modifications are more critical than in other cancers, the aim of this study is to seek into the roles and clinical relevance of epigenetic silencing of HOPX. Down-regulation of HOPX was observed in all human breast cancer cell lines tested. The promoter methylation was found in six of seven cell lines, and demethylating agents restored HOPX expression. The promoter methylation was cancer-specific in human breast tissues. Forced expression of HOPX attenuated anchorage-independent growth inxa0vitro. HOPX promoter methylation independently predicted worse prognosis of breast cancer patients. Of note, HOPX promoter methylation was significantly associated with HER2 positivity as well as advanced lymph node metastasis. HOPX promoter methylation is not only frequent and cancer-specific but also associated with aggressive phenotype in breast cancer. Epigenetic silencing of HOPX may have clinical potential as a biomarker in the treatment strategy of breast cancer patients.

Phase II randomized, controlled trial of 1 day versus 3 days of dexamethasone combined with palonosetron and aprepitant to prevent nausea and vomiting in Japanese breast cancer patients receiving anthracycline-based chemotherapy.

PurposeDexamethasone, plus a 5-HT3 receptor antagonist and an NK-1 receptor antagonist are recommended for controlling the chemotherapy-induced nausea and vomiting (CINV) of highly emetogenic chemotherapy. Several days of dexamethasone are effective for CINV; however, dexamethasone also has side effects. The purpose of this trial was to investigate whether the use of a second-generation 5-HT3 receptor antagonist and an NK-1 receptor antagonist could allow a reduced dose of dexamethasone for breast cancer patients receiving highly emetogenic chemotherapy.MethodsEighty breast cancer patients who received an anthracycline-cyclophosphamide combination regimen were enrolled. The patients were randomized to arm A (dexamethasone days 1–3) and arm B (dexamethasone day 1). The primary endpoint was complete response (CR) (no emetic episodes and no rescue medication) during the overall phase (days 1–5). The secondary endpoints were the CR during the delayed phase (days 2–5), complete control (CC) (no emetic episodes, no rescue medication, and no more than mild nausea) during the overall phase, and the safety of this antiemetic therapy.ResultsThere were no significant differences in the rates of CR and CC between arm A and B as follows: CR overall phase—arm A: 82.9xa0%, 90xa0% confidence interval [CI] 71.3–90.5xa0% vs arm B: 82.1xa0%, 90xa0% CI 70.0–90.0xa0%; pu2009=u20091.00; CR delayed phase—arm A: 87.8xa0%, 90xa0% CI 77.0–93.9xa0% vs arm B: 94.9xa0%, 90xa0% CI 85.6–98.3xa0%; pu2009=u20090.43; CC overall phase—arm A: 48.8xa0%, 90xa0% CI 36.4–61.3xa0% vs arm B: 61.5xa0%, 90xa0% CI 48.4–73.2xa0%; pu2009=u20090.27. There were very few adverse events and no severe adverse events associated with this antiemetic therapy.ConclusionsThe results suggest that the antiemetic effect provided by dexamethasone administered for 3xa0days can be obtained by dexamethasone administered for 1xa0day.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

SUMMARY RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

Abstract P3-09-03: Final result of randomised controlled phase II study of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3

Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute / delayed CINV. However, it has not been determined the medication schedule for DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. This is final result of current study. Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2013. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days). Eighty patients were estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting. Results: Eighty two patients were enrolled in this study. There was not inferiority about CR rate of five days after chemotherapy (81.1% of group A, 82.1% of group B). CC rate of group A (62.2%) was better than that of group B (46.2%). However, CC rate was no significant difference between group A and B. There was no significant difference about any level of nausea between group A and B. Conclusions: One day of dexamethasone with Palonosetron and Aprepitant treatment is enough to control the emesis of high emetogenic chemotherapeutic agents. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-03.

Optimized lymph node dissection range during progression of lower thoracic esophageal squamous cell carcinoma in the latest therapeutic surgical strategy: A retrospective analysis

The distribution of lymph node metastases, including recurrences, remains elusive in lower thoracic esophageal squamous cell carcinoma (LtESCC). The present study was a retrospective investigation into the optimized lymph node dissection range during LtESCC. Esophagectomies were performed on 163 patients with ESCC between 2009 and 2016, among whom 41 patients with LtESCC were examined. The rates of pathological and potential (including recurrences) metastases to lymph nodes and the prognosis (median, 34 months) were determined. Preoperative Docetaxel, Cisplatin and 5-fluorouracil chemotherapy was administered in >60% of cStage II/III LtESCC. During stage progression, abdominal lymph node metastasis rapidly becomes aggressive in LtESCC and lymph node metastases to the para-aortic area were more dominant than cervical and recurrent laryngeal nerve (RLN) areas. There were few control failures of regional lymph node metastases in LtESCC with surgery, if 1 unique case with cStage III who had metastases and recurrences of multiple lymph nodes during the clinical course was excluded. Defective lymph node dissection around the RLN did not worsen LtESCC prognosis with no RLN palsy. In the context of the potent preoperative chemotherapy and esophagectomy, lymph node dissection of cervical, para-aortic and RLN areas are putatively not mandatory to all LtESCC patients.

Carcinosarcoma of the esophagus: A report of 6 cases associated with zinc finger E‑box‑binding homeobox 1 expression

Esophageal carcinosarcoma (ECS) has been suggested to result from an epithelial mesenchymal transition (EMT) phenomenon. However, knowledge on its underlying molecular features is limited. The clinical and pathological features, and the prognosis of ECS require further investigation. In the present study, a total of 325 patients with esophageal tumors were observed between January 2004 and December 2014, of which 6 patients were diagnosed pathologically with ECS. The clinicopathological features were compared with those of corresponding cases with the identical pathological T stage (pT) of esophageal squamous cell carcinoma (ESCC). In terms of the clinical T stage (cT), the 6 cases were composed of cT1, cT2, cT3 and cT4 in 1, 1, 3 and 1 case, respectively. Nevertheless, pT was eventually diagnosed as pT1 in all cases. There was a large discrepancy between clinically diagnosed depth of tumor invasion prior to surgery and depth of tumor invasion following surgery. Zinc finger E-box-binding homeobox 1 (ZEB1), an EMT-associated transcription factor, was expressed only in the sarcoma component in all 6 cases of ECS. The ECS cases had a significantly poorer prognosis compared with the 115 pT1 ESCC cases. The present study suggests that the depth of invasion of ECS lesions does not correspond with their respective size, and the EMT of the carcinoma component may affect the prognosis by overexpression of the ZEB1 gene.

Lymph node metastasis and high serum CEA are important prognostic factors in hormone receptor positive and HER2 negative breast cancer

In recent years, treatment options for breast cancer have increased, and prognosis has improved since the 1990s. The present study examined the prognosis for recurrence of breast cancer between 2006 and 2009, in comparison with the results of past treatments, and sought to guide future treatment strategies by elucidating present prognostic factors. A total of 662 patients with breast cancer stage 0-III who underwent surgery at Kitasato University Hospital between January 2006 and March 2009 were included. Cases were classified into four subtypes, based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2 (HER2). Factors associated with recurrence and prognosis were then examined. The 5-year recurrence-free survival (RFS) was 94.9% and the 5-year disease-specific survival (DSS) was 98.4%. Factors related to RFS were pathological lymph node (pN) positive [hazard ratio (HR)=2.85, P=0.001], clinical lymph node (cN) positive (HR=2.28, P<0.01), and hormone receptor negative (HR=1.83, P<0.05). Factors associated with DSS were cN positive (HR=4.55, P<0.01), pN positive (HR=3.40, P<0.05), higher preoperative serum carcinoembryonic antigen (CEA) (HR=3.04, P<0.05), and hormone receptor negative (HR=2.32, P<0.05). In the hormone receptor positive HER2 negative, cN-positive/pN-positive breast cancer group, RFS and DSS were poorer compared with the other groups. In this group, preoperative high CEA level was a poor prognostic factor. The prognosis for hormone receptor positive HER2-negative breast cancer has improved significantly since the 1990s. On the other hand, the prognosis for cN-positive/pN-positive breast cancer was poor. Pre-treatment serum CEA positive cases exhibited a particularly poor prognosis.