Faculty Profiles - HOTTA Katsuyuki

Epidermal growth factor receptor mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma Reviewed

Shinichi Toyooka, Toshimi Takano, Takayuki Kosaka, Katsuyuki Hotta, Keitaro Matsuo, Shuji Ichihara, Yoshiro Fujiwara, Junichi Soh, Hiroki Otani, Katsuyuki Kiura, Keisuke Aoe, Yasushi Yatabe, Yuichiro Ohe, Tetsuya Mitsudomi, Hiroshi Date

CANCER SCIENCE 99 ( 2 ) 303 - 308 2008.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P < 0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma.

DOI： 10.1111/j.1349-7006.2007.00688.x

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib. Reviewed International journal

Yoshiro Fujiwara, Katsuyuki Kiura, Shinichi Toyooka, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Junichi Soh, Yasushi Tanimoto, Arihiko Kanehiro, Katsuya Kato, Hiroshi Date, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 59 ( 1 ) 81 - 7 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

PURPOSE: The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. PATIENTS AND METHODS: Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. RESULTS: The serum KL-6 levels ranged from 199 to 9080U/ml (median, 550U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p=0.040) as well as OS (hazard ratio: 4.858, p=0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p=0.0194). CONCLUSION: Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib.

DOI： 10.1016/j.lungcan.2007.07.018

How Can We Increase the Number of Participants in Lung Cancer Screening?(The 22nd Lung Cancer Mass Screening Seminar)

Masakage Mieko, Nishii Kenji, Hotta Katsuyuki, Tabata Masahiro, Takigawa Nagio, Kiura Katsuyuki, Ueoka Hiroshi

Japanese Journal of Lung Cancer 47 ( 6 ) 743 - 750 2007.10

Language：Japanese Publisher：The Japan Lung Cancer Society

Recently, the number of participants in lung cancer screening has been decreasing in Okayama Prefecture, which may lower the screening effects to improve lung cancer mortality and as a result many municipalities may stop lung cancer screening in the near future. In Japan, lung cancer screening has already been abandoned in 109 (5%) municipalities, since they considered that the effectiveness of lung cancer screening was inferior to that of screening programs for other cancers. In this report, we discussed the following issues in lung cancer screening today by analyzing questionnaires for bureaucrat responsible for lung cancer screening. Due to their insufficient knowledge about lung cancer, up-to-date information or cumulative knowledge was not efficiently used in screening. Though the bureaucrat understood the importance of quality control of screening, quality control was not included in the specification form for public bidding for selecting the screening agency. It was surprising that some officers understood neither the difference between tuberculosis screening and lung cancer screening nor the purpose of screening. These results indicate that these officers failed to explain the necessity of lung cancer screening for the community and emphasize the usefulness of selecting the appropriate agency with high accuracy for the financial manager. In conclusion, the bureaucrat responsible for lung cancer screening have to understand "cancer screening with high quality" in the nation's statement, and give equal opportunities for lung cancer screening to the community. The screening agency has the responsibility to increase the number of participation of individuals in lung cancer screening.

DOI： 10.2482/haigan.47.743

CiNii Article

CiNii Books

抗悪性腫瘍薬の至適投与法確立を目指して非小細胞肺癌(NSCLC)症例における、腫瘍EGFR遺伝子変異の殺細胞性抗癌剤治療効果への影響の検討

Other Link： http://search.jamas.or.jp/link/ui/2008089614

堀田勝幸, 木浦勝行, 豊岡伸一, 瀧川奈義夫, 宗淳一, 藤原義朗, 田端雅弘, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 450 - 450 2007.10

肺非小細胞癌における治療前血清KL-6値とゲフィチニブ単剤療法の治療効果の関連

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 629 - 629 2007.10

腰髄液腔・腹腔短絡術(LPシャント)とゲフィチニブ投与が著効した癌性髄膜炎

久保寿夫, 瀧川奈義夫, 木浦勝行, 梅村茂樹, 高田三郎, 堀田勝幸, 田端雅弘, 谷本光音, 豊岡伸一, 伊達洋至

肺癌 47 ( 5 ) 672 - 672 2007.10

Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer. Reviewed International journal

Junichi Soh, Shinichi Toyooka, Shuji Ichihara, Yoshiro Fujiwara, Katsuyuki Hotta, Hiroshi Suehisa, Naruyuki Kobayashi, Kouichi Ichimura, Keisuke Aoe, Motoi Aoe, Katsuyuki Kiura, Hiroshi Date

International journal of cancer 121 ( 5 ) 1162 - 7 2007.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

We previously examined the relationship between epidermal growth factor receptor (EGFR) status and clinical outcomes of nonsmall-cell lung cancer (NSCLC) patients treated with gefitinib. In our study, we additionally examined HER2 status and investigate the impact of genetic status as predictors in Japanese NSCLC patients treated with gefitinib. The HER2 copy number status was determined by fluorescence in situ hybridization assay and mutation of HER2 exon 20 was determined by direct sequencing in 74 patients to investigate the relationship between molecular statuses including HER2 and EGFR and the clinical outcomes of patients treated with gefitinib. The high HER2 copy number was identified in 32 (43.2%) of 74 NSCLC patients and no HER2 exon 20 mutations were found. The high HER2 copy number was significantly associated with the sensitivity to gefitinib (p = 0.0045) and a prolonged progression-free survival (PFS) (p = 0.0089) in a univariate analysis, but not in a multivariate analysis. Multivariate analyses exhibited that the drug-sensitive EGFR mutation was an independent predictive factor of a better sensitivity to gefitinib (OR = 41.9, p = 0.002), prolonged overall survival (HR = 0.32, p = 0.019) and PFS (HR = 0.31, p = 0.0045). The high EGFR copy number might have a weak association with better response and prognosis without statistical significance. In conclusion, the drug-sensitive EGFR mutation, rather than HER2 and EGFR copy numbers, is a determinant of favorable clinical outcomes in gefitinib-treated patients with NSCLC, although the high HER2 copy number, to some extent, may influence the gefitinib effect.

DOI： 10.1002/ijc.22818

Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung Reviewed

Hiroshi Suehisa, Shinichi Toyooka, Katsuyuki Hotta, Akiko Uchida, Junichi Soh, Yoshiro Fujiwara, Keitaro Matsuo, Mamoru Ouchida, Minoru Takata, Katsuyuki Kiura, Hiroshi Date

JOURNAL OF CLINICAL ONCOLOGY 25 ( 25 ) 3952 - 3957 2007.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose
Adjuvant chemotherapy with uracil- tegafur has been demonstrated to prolong survival among patients with resected lung adenocarcinomas. Epidermal growth factor receptor ( EGFR) mutations have been reported to be present in lung adenocarcinomas. The present study evaluated whether the EGFR status could be used as a biologic predictor of the outcome of adjuvant chemotherapy with uracil- tegafur.
Patients and Methods
The EGFR mutational status of 187 patients with resected lung adenocarcinomas was determined using a polymerase chain reaction - based assay for EGFR exons 19 and 21; the results were then correlated with the effect of adjuvant uracil- tegafur chemotherapy on survival. The antiproliferative effect of fluorouracil ( FU) on adenocarcinoma cell lines with EGFR wild-type or mutant type status was examined by measuring the inhibitory concentrations at 50% ( IC(50)s).
Results
Among the 187 patients, 68 received uracil- tegafur as adjuvant chemotherapy, and 119 were not treated with any chemotherapeutic agents. EGFR mutations were present in 79 patients ( 43%). Overall, the adjuvant chemotherapy with uracil- tegafur significantly prolonged survival compared with the control group ( hazard ratio = 0.38; P =.005). The survival benefit of adjuvant chemotherapy with uracil- tegafur was also examined after stratifying the patients according to EGFR mutation status. Adjuvant chemotherapy significantly prolonged survival among patients with EGFR wild- type tumors ( hazard ratio = 0.34; P =.013) but not among patients with EGFR mutant tumors. In an in vitro experiment, the IC(50)s of EGFR mutant cells to FU were higher than those of wild-type cells, indicating that EGFR wild- type cells are more sensitive to FU than mutant cells.
Conclusion
EGFR status influenced the effect of adjuvant chemotherapy with uracil- tegafur. Adjuvant chemotherapy could be customized based on EGFR status.

DOI： 10.1200/JCO.2007.11.8646

Other Link： http://orcid.org/0000-0003-1761-6314

Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer. Reviewed International journal

Katsuyuki Hotta, Katsuyuki Kiura, Shinichi Toyooka, Nagio Takigawa, Junichi Soh, Yoshiro Fujiwara, Masahiro Tabata, Hiroshi Date, Mitsune Tanimoto

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 ( 7 ) 632 - 7 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

INTRODUCTION: The relationship between the EGFR gene mutation status and clinical outcome has not fully been assessed in patients with non-small cell lung cancer (NSCLC) who received cytotoxic agents. The aim of this study was to clarify its association. We also examined whether this association could be affected by previous gefitinib treatment. METHODS: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy in their treatment course were included in this study. An EGFR mutation was determined in exons 19 and 21 by direct sequencing. RESULTS: Of 194 Japanese patients with advanced or relapsed NSCLC assessable for mutation analysis, 60 received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment courses. EGFR mutations significantly affected progression-free survival (PFS) in the first-line cytotoxic chemotherapy regimens in the multivariate analysis (hazard ratio for PFS = 0.422; p = 0.0422). In contrast, in 28 (47%) of the 60 patients who also received cytotoxic chemotherapy after the relapse to gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status, and its sensitivity was retained even in the second-line treatment setting in patients with EGFR mutations. CONCLUSIONS: EGFR mutations were therefore significantly associated with a better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, whereas gefitinib sensitivity was associated with an EGFR mutation even in the second-line or later treatment settings.

DOI： 10.1097/JTO.0b013e318074bc0d

EGFR変異とUFTによる肺腺癌術後補助療法の関連性についての検討

末久弘, 豊岡伸一, 堀田勝幸, 内田亜希子, 宗淳一, 木浦勝行, 浅野博昭, 藤原義朗, 松尾恵太郎, 青江基, 高田穣, 清水信義, 伊達洋至

日本呼吸器外科学会雑誌 21 ( 3 ) 404 - 404 2007.4

The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Reviewed International journal

Shuji Ichihara, Shinichi Toyooka, Yoshiro Fujiwara, Katsuyuki Hotta, Hisayuki Shigematsu, Masaki Tokumo, Junichi Soh, Hiroaki Asano, Kouichi Ichimura, Keisuke Aoe, Motoi Aoe, Katsuyuki Kiura, Kenji Shimizu, Hiroshi Date, Nobuyoshi Shimizu

International journal of cancer 120 ( 6 ) 1239 - 47 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (-216G/T and -191C/A), using a PCR-based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation.

DOI： 10.1002/ijc.22513