Fukino Satomi

Human endoplasmic reticulum oxidoreductin 1-α is a novel predictor for poor prognosis of breast cancer.

Human endoplasmic reticulum oxidoreductin 1‐α (hERO1‐α) is an oxidizing enzyme that exists in the endoplasmic reticulum and its expression is augmented under hypoxia. It regulates a redox state of various kinds of protein through reoxidation of “client” protein disulfide isomerase. Interestingly, although the expression of hERO1‐α in normal tissues was comparatively limited, various types of cancer cells expressed it in large amounts. Therefore, we examined the role of ERO1‐α in tumor growth using murine breast cancer line 4T1 and found that knockdown of murine ERO1‐α inhibited in vivo tumor growth and decreased lung metastasis compared with wild‐type 4T1. Moreover, we investigated the relationship between expression of hERO1‐α and prognosis in breast cancer patients. Seventy‐one patients with breast cancer who underwent surgery between 2005 and 2006 in Sapporo Medical University Hospital (Sapporo, Japan) were analyzed in this study. Significant differences were found between the hERO1‐α‐positive group (n = 33) and hERO1‐α‐negative group (n = 38) in nuclear grade (P < 0.001) and intrinsic subtype (P = 0.021) in univariate analysis. More importantly, in multivariate analysis of disease‐free survival by Cox regression, expression of hERO1‐α was the only independent prognosis factor (P = 0.035). Finally, in univariate survival analysis, patients positive for hERO1‐α had significantly shorter disease‐free survival and overall survival than those patients negative for hERO1‐α. These findings indicate that the expression of hERO1‐α in cancer cells is associated with poorer prognosis and thus can be a prognostic factor for patients with breast cancer.

Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis?

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.

Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer; a Prospective Multicenter Study.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy. Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.

Use of the dye-guided sentinel lymph node biopsy method alone for breast cancer metastasis to avoid unnecessary axillary lymph node dissection

For sentinel lymph node biopsy (SLNB), a combination of dye-guided and γ-probe-guided methods is the most commonly used technique. However, the number of institutes in which the γ-probe-guided method is able to be performed is limited, since special equipment is required for the method. In this study, SLNB with the dye-guided method alone was evaluated, and the clinicopathological characteristics were analyzed to identify any factors that were predictive of whether the follow-up axillary lymph node dissection (ALND) was able to be omitted. A total of 374 patients who underwent SLNB between 1999 and 2009 were studied. The SLN identification rate was analyzed, in addition to the false-positive and false-negative rates and the correlation between the clinicopathological characteristics and axillary lymph node metastases. The SLN was identified in 96.8% of cases, and, out of the patients who had SLN metastasis, 63.0% did not exhibit metastasis elsewhere. The sensitivity was 96.4% and the specificity was 100%. The false-negative rate was 3.6%. Univariate analyses revealed significant differences in the lymph vessel invasion (ly) status, nuclear grade (NG), maximum tumor size and the percentage of the area occupied by the tumor cells in the SLN (SLN occupation ratio) between the patients with and without non-SLN metastasis, indicating that these factors may be predictive of axillary lymph node metastasis. Multivariate analysis revealed that ly status was an independent risk factor for non-SLN metastasis. In conclusion, SLN with the dye-guided method alone provided a high detection rate. The study identified a predictive factor for axillary lymph node metastasis that may improve the patients’ quality of life.

Risk of node metastasis of sentinel lymph nodes detected in level II/III of the axilla by single‑photon emission computed tomography/computed tomography

In breast cancer, single-photon emission computed tomography/computed tomography (SPECT/CT) shows the exact anatomical location of sentinel nodes (SN). SPECT/CT mainly exposes axilla and partly exposes atypical sites of extra-axillary lymphatic drainage. The mechanism of how the atypical hot nodes are involved in lymphatic metastasis was retrospectively investigated in the present study, particularly at the level II/III region. SPECT/CT was performed in 92 clinical stage 0-IIA breast cancer patients. Sentinel lymph nodes are depicted as hot nodes in SPECT/CT. Patients were divided into two groups: With or without hot node in level II/III on SPECT/CT. The existence of metastasis in level II/III was investigated and the risk factors were identified. A total of 12 patients were sentinel lymph node biopsy metastasis positive and axillary lymph node dissection (ALND) was performed. These patients were divided into two groups: With and without SN in level II/III, and nodes in level II/III were pathologically proven. In 11 of the 92 patients, hot nodes were detected in level II/III. There was a significant difference in node metastasis depending on whether there were hot nodes in level II/III (P=0.0319). Multivariate analysis indicated that the hot nodes in level II/III and lymphatic invasion were independent factors associated with node metastasis. There were 12 SN-positive patients followed by ALND. In four of the 12 patients, hot nodes were observed in level II/III. Two of the four patients with hot nodes depicted by SPECT/CT and metastatic nodes were pathologically evident in the same lesion. Therefore, the present study indicated that the hot node in level II/III as depicted by SPECT/CT may be a risk of SN metastasis, including deeper nodes.

Phase I Clinical Study of Survivin-Derived Peptide Vaccine for Patients with Advanced Gastrointestinal Cancers

Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family. It is expressed in fetal tissues but not in normal adult tissues. Since Survivin is over expressed in various types of tumor tissues as well as tumor cell lines, it is considered to be suitable as a target antigen for cancer vaccine therapy. We identified an HLA-A24-restricted antigenic peptide, SVN-2B (AYACNTSTL), derived from a splicing variant of Survivin-2B. In the present study, we carried out a phase I clinical study assessing the safety and efficacy of vaccination with the peptide in patients having advanced gastrointestinal cancer. Vaccinations with 0.1mg, 1.0mg, or 3.0mg doses of the SVN-2B peptide were given subcutaneously four times at 14-day intervals. In 20 patients who received at least one vaccination, grade 1 and grade 2 treatment-related adverse events were observed, including injection site extravasation (grade 2), injection site reaction (grade 1), skin induration (grade 1) and fever (grade 1). No severe adverse event was observed in any patient. Based on tumor size evaluated by computed tomography, eight of the 15 patients who completed the vaccination schedule were considered to have stable disease as assessed by the RECIST criteria. Analysis of peripheral blood lymphocytes using HLA-A24/ peptide tetramers revealed the highest increase of SVN-2B-specific cytotoxic T lymphocyte frequency in the 1.0mg dose group. The present clinical study indicates that SVN-2B peptide vaccination is safe and can be considered a potent immunotherapy for HLA-A24positive gastrointestinal cancer patients.

Lymph node shape in computed tomography imaging as a predictor for axillary lymph node metastasis in patients with breast cancer

The aim of the present study was to evaluate whether preoperative computed tomography (CT) is a useful modality for the diagnosis of axillary lymph node metastasis. The axillary lymph node status was examined in patients with primary breast cancer who had undergone surgery. In total, 75 patients were analyzed with preoperative contrast CT images, following which the patients underwent an intraoperative sentinel lymph node biopsy to determine possible predictors of axillary lymph node metastasis. The lymph node shape was classified into three groups, which included fat-, clear-and obscure-types. Multivariate analysis revealed that clear-type lymph nodes in preoperative contrast CT imaging may be an independent predictor of lymph node metastasis (odds ratio, 15; P=0.003). Therefore, the results indicated that preoperative CT examination is useful to predict axillary lymph node metastasis.

A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study

Purpose Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. Experimental design We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. Results The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10−6, 1.64 x 10−5, and 9.77 x 10−6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10−12), suggesting the cumulative effect of the three SNPs. Conclusion We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

Comparison of surgical outcomes and complications between the Harmonic FOCUS and conventional surgery for open thyroidectomy

The aim of the present study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in thyroid surgery. Patients with resectable thyroid cancer and Basedows disease were assigned to ultrasonic scalpel or conventional technique (knot-tying and electrocoagulation). The present study used the Harmonic FOCUS® (HF) as an ultrasonic scalpel. Between February 2013 and May 2016, 45 patients were enrolled into the study. Duration of the surgery was significantly decreased in the HF group compared with the conventional surgery (CS) group (median 142 vs. 151 min; P=0.0406). Intraoperative blood loss and total volume of drainage fluid were significantly decreased in the HF group compared with the CS group (median 40 vs. 125 ml; P=0.0054, and median 120 vs. 175.5 ml; P=0.0490). Duration of drain placement and length of hospitalization stay were similar in the two groups. Furthermore, the overall incidence of postoperative complications did not differ between the two groups. Overall, the present study suggests that open thyroidectomy using the HF is safe and effective and not associated with any increase in complications.

Abstract 2031: Association between CYP2D6 genotype and response to tamoxifen in a prospective multicenter study in Japan

Purpose: CYP2D6 is key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen”. We previously reported that reduced- or null-function alleles of CYP2D6 were significantly associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are still discrepant reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we carried out prospective multicenter studies to evaluate the value of CYP2D6 genotyping in tamoxifen therapy. Patients and Methods: We studied 279 patients with hormone receptor-positive and Her-2 negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 - 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker of response to tamoxifen. We investigated the effects of allelic variants of CYP2D6 on Ki-67 change in breast cancer tissues, histological response, breast conservative operation and hot flash. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy for 14-28 days (P = 0.00000000024). Moreover, proportion of estrogen receptor positive cells in breast cancer tissues were significantly associated with Ki-67 change after tamoxifen therapy (P = 0.0099). CYP2D6 variants were not significantly associated with histological response, breast conservative operation and hot flash (P = 0.25, P = 0.28 and P = 0.34, respectively). However, CYP2D6 variants were significantly associated with Ki-67 decrease after the preoperative tamoxifen therapy (P = 0.000014; in patients with two variant alleles v patients carrying one or two wild-type alleles). Conclusion: Our result suggest that genetic variation in CYP2D6 is a key predictor for the prognosis of patients with breast cancer treated with tamoxifen. Citation Format: Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi-Tanaka, Takashi Kuwayama, Chie Watanabe, Tomoko Takamaru, Hiroyuki Takei, Kana Miyahara, Hiroshi Matsumoto, Yoshie Hasegawa, Goro Kutomi, Hiroaki Shima, Fukino Satomi, Hideki Maeda, Minoru Okazaki, Hisamitsu Zaha, Mai Onomura, Ayami Matsukata, Yasuaki Sagara, Shinichi Baba, Akimitsu Yamada, Kazuhiro Shimada, Daisuke Shimizu, Koichiro Tsugawa, Arata Shimo, Tan Ern Yu, Mikael Hartman, Chan Ching Wang, Soo Chin Lee, Yusuke Nakamura. Association between CYP2D6 genotype and response to tamoxifen in a prospective multicenter study in Japan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2031.