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Background Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS). Patients and methods Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin. Result Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6–11.6) in the control group and 14.0 months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; P

Background Bone is a metastatic site for various types of cancer. Cancer patients in whom bone metastases progress often have skeletal-related events (SREs). Denosumab and zoledronic acid are both bone-modifying agents that prevent the occurrence of SREs. Denosumab has been shown to be superior to zoledronic acid in delaying SREs in various types of cancer, such as breast cancer, lung cancer, and multiple myeloma. However, it is still uncertain whether denosumab is superior to zoledronic acid in delaying the time to SREs in other types of cancers, including gastrointestinal cancer, pancreas-biliary system cancer, and other rare cancers. Patients and methods This retrospective study was conducted based on medical records from 2009 to 2015. Eligible patients who had been diagnosed with bone metastases from gastrointestinal cancer, pancreas-biliary system cancer, and rare cancers were included. Patients were assigned to a denosumab group, zoledronic acid group, or group without bone-modifying agent treatment (no-treatment group). Results The study included 168 patients. The times to SREs in the denosumab, zoledronic acid, and no-treatment groups were 186 days [95% confidence interval (CI), 96–323 days], 79 days (95% CI, 45–118 days), and 31 days (95% CI, 13–76 days), respectively. Although, a few patients had grade 3 or 4 adverse events in the denosumab and zoledronic acid groups, the bone-modifying agent treatment was not terminated. Conclusion From the perspective of the efficacy and safety of denosumab for delaying the time to SREs, denosumab should be used to prevent SREs in patients with bone metastases from gastrointestinal cancer, pancreas-biliary system cancer, and other rare cancers.

The breast and ovarian cancer-specific tumor suppressor BRCA1, along with its heterodimer partner BRCA1-associated RING domain protein (BARD1), plays important roles in DNA repair, centrosome regulation, and transcription. To explore further functions of BRCA1/BARD1, we performed mass spectrometry analysis and identified Obg-like ATPase 1 (OLA1) as a protein that interacts with the carboxy-terminal region of BARD1. OLA1 directly bound to the amino-terminal region of BRCA1 and γ-tubulin. OLA1 localized to centrosomes in interphase and to the spindle pole in mitotic phase, and its knockdown resulted in centrosome amplification and the activation of microtubule aster formation. OLA1 with a mutation observed in breast cancer cell line, E168Q, failed to bind BRCA1 and rescue the OLA1 knockdown-induced centrosome amplification. BRCA1 variant I42V also abrogated the binding of BRCA1 to OLA1. These findings suggest that OLA1 plays an important role in centrosome regulation together with BRCA1.

Background Anti-EGFR antibody is one of the options for treatment of RAS wild-type metastatic colorectal cancer (mCRC), especially when the primary tumor site locates in the left sided large intestine. We have shown that methylation status evaluated by genome-wide DNA methylation test correlates with clinical outcomes of anti-EGFR treatment in RAS wild-type mCRC. Here, we report about the development of novel in vitro diagnostics (IVD) based on DNA methylation status of selected CpG sites. Method We retrospectively collected KRAS wild-type mCRC cases who received anti-EGFR treatment in salvage line. DNA methylation status was measured for 16 CpG sites by our novel IVD using real-time PCR method for each case. Based on DNA methylation status, they were classified into 2 groups. Highly-methylated colorectal cancer (HMCC) was defined when 8 or more sites among 16 sites were methylated and low-methylated colorectal cancer (LMCC) was classified when it was less than 8 sites. We compared the clinical outcomes between the 2 groups, and the predictive accuracy of the DNA methylation status by the new diagnostic method was examined. Results A total of 83 cases were collected, with 20 cases classified as HMCC and 63 cases classified as LMCC. The response rate of the anti-EGFR treatment was 5.0% (1/20 cases) in HMCC and 30.2% (19/63 cases) in LMCC, respectively (p = 0.032). The median progression-free survival were 2.8 months and 5.3 months, respectively (p Conclusion DNA methylation status of the 16 CpG sites measured by our novel IVD was significantly correlated with the therapeutic effect of anti-EGFR treatment for KRAS wild-type mCRC. Currently, extended analysis is in progress using the data of more than 200 cases. We will report the results including the analysis of RAS status and primary tumor site.

Recent developments of cancer genomic medicine increase importance of diagnosis and treatment of hereditary cancer syndrome. Currently, for diagnosis of hereditary cancer, we often perform sequencing analysis for single or couple of genes after screening by clinical diagnosis. As a result, some individuals with segregation of cancer in their families harbor no pathological mutations, while, other individuals without obvious segregation of cancer in their families harbor germline mutations. Therefore, only single gene analysis or clinical information including family history is insufficient to identify some proportion of hereditary cancer individuals. Genetic tests that can comprehensively analyze multiple genes enable us to diagnose hereditary cancer more efficiently and to improve treatment strategies more effectively. In Tohoku University Hospital, a multi-gene panel testing for hereditary cancer "CancerNext" developed by Ambry Genetics Inc. have been adopted since March 1, 2019. This test covers 34 genes associated with increased risks for at least one of 8 major cancers (breast cancer, ovarian cancer, colorectal cancer, uterine cancer, pancreatic cancer, prostate cancer, gastric cancer and melanoma). We have already performed somatic multi-gene panel testing for cancer as Designated Core Hospitals for Cancer Genomic Medicine. Results of the "CancerNext" test are provided to the individuals after the discussion by tumor molecular board. We will report the actual situation of proceeding the test and the test result of five patients or more.

Background Diagnostic tests based on gene expression signatures identified by transcriptome analyses have been developed and these have been used for predicting prognosis, recurrence and/or effect of anticancer drugs including endocrine therapies in clinical practice of breast cancer, ahead of other cancer types. We have previously reported that TP53 signature, which has the ability to determine TP53 mutation status, are an independent prognostic factor of breast cancer, and also shown that the TP53 signature has better predictability of prognosis and efficacy on chemotherapies than the TP53 mutation status and other known clinic-pathological factors. Objects The aim of this study is to develop the diagnostic kit for in vitro diagnostics based on the TP53 signature. Methods We adopted an nCounter system (NanoString) because it has robust ability to analyze a gene expression signature of the TP53 signature from a small amount of RNA derived from archival FFPE tissues. Results We have designed a specific probe set for IVD of the TP53 signature and programed a new algorithm to determine the status of TP53 signature from the identified expression data. The algorithm has the characteristic that is hard to be affected by the outliers than previous algorithm (the algorithm cannot be disclosed). Using this method, we determined status of TP53 signature of 220 stage I-II breast cancers. The predictability of recurrence by the IVD of the TP53 signature will be shown in this study. We are also conducting a retrospective-prospective analysis of over 500 breast cancers as the validation study of the IVD under cooperation of JBCRG, OOTR. From this study, the predictability of the pathological CR (pCR) after neoadjuvant chemotherapies and the prognosis by the IVD will be also shown. Conclusion The TP53 signature diagnostic kit is expected to be a clinically useful biomarker for prediction of prognosis, recurrence and efficacy of perioperative chemotherapy in breast cancer.

Dissemination of glioblastomas is often observed, but the underlying mechanism is not well clarified especially from the genetic viewpoints. The present study examined whether PTEN gene mutations and MIB-1 labeling index (LI) correlate with the dissemination in 39 consecutive patients with glioblastomas. Dissemination was defined as leptomenigeal enhancement by magnetic resonance imaging performed in all patients every 2–3 months. We examined PTEN mutations in 26 patients using cDNA-based direct sequencing and MIB-1 LI in 38 patients. Median survival time of the 39 patients was 16.2 months. Dissemination was found in 17 of 39 patients (43.6%). PTEN mutation was significantly associated with dissemination (P=0.0140), and higher MIB-1 LI (⩾35%) resulted in earlier dissemination (P=0.0156). Kaplan–Meier survival plots showed a significantly poorer survival for patients with PTEN mutation (P=0.0012). The results indicate that the evaluation of PTEN mutation and MIB-1 LI are useful to predict dissemination and prognosis of glioblastomas.

Temperature-sensitive (ts) mutations have been used as a genetic and molecular tool to study the functions of many gene products. Each ts mutant protein may contain a temperature-dependent intramolecular mechanism such as ts conformational change. To identify key ts structural elements controlling the protein function, we screened ts p53 mutants from a comprehensive mutation library consisting of 2,314 p53 missense mutations for their sequence-specific transactivity through p53-binding sequences in Saccharomyces cerevisiae. We isolated 142 ts p53 mutants, including 131 unreported ts mutants. These mutants clustered in beta-strands in the DNA-binding domain, particularly in one of the two beta-sheets of the protein, and 15 residues (Thr155, Arg158, Met160, Ala161, Val172, His214, Ser215, Pro223, Thr231, Thr253, Ile254, Thr256, Ser269, Glu271, and Glu285) were ts hot spots. Among the 142 mutants, 54 were examined further in human osteosarcoma Saos-2 cells, and it was confirmed that 89% of the mutants were also ts in mammalian cells. The ts mutants represented distinct ts transactivities for the p53 binding sequences and a distinct epitope expression pattern for conformation-specific anti-p53 antibodies. These results indicated that the intramolecular beta-sheet in the core DNA-binding domain of p53 was a key structural element controlling the protein function and provided a clue for finding a molecular mechanism that enables the rescue of the mutant p53 function.

The carboxy-terminal portion of the p53 protein contains the tetramerization domain, and the introduction of multiple missense mutations in this domain disrupts the formation of p53 tetramers, resulting in the production of dimeric or monomeric forms of p53. It has recently been shown that a single missense or nonsense mutation in this domain affects the functional properties of p53 both in yeast and in mammalian cells. In this study, we tested the oligomerization of p53 with mutations in the oligomerization domain, when expressed in a human osteosarcoma cell line, Saos-2, in vivo. We found that single point mutations, including two missense and two nonsense mutations, in the α-helix of the oligomerization domain disrupted the oligomerization of p53, but that p53 still retained its ability to inhibit colony formation of cells to some degree. These results suggest that oligomerization and the carboxy-terminal basic domain are not prerequisite for p53-dependent tumor suppression, and this may explain why few of the tumor-derived p53 mutations that have been examined so far are carboxy-terminal mutations.

Methods We found the gene set to predict TP53 status in previous study. We made the multiplex RT-PCR system to predict TP53 status. The gene set for this system consists of 30 genes, 25 genes from TP53 predictive genes and 5 internal control genes were selected. A total of 103 breast cancer samples operated from September 2007 to November 2009 were examined in this study. The relationship between the result of TP53 status by multiplex RT-PCR, functional assay, clinicopathological factors and prognosis (recurrence) were analyzed. Results The TP53 status by the multiplex RT-PCR was well correlated with the result of functional assay. ER (P = 4.34E-06), PR (P = 7.90E-05), HER2 (P = 8.00E-4) and mitotic counts (P = 4.82E-06) status were different in TP53 status. Although the observation period was short (median 2.6 years), more recurrence was observed in patients with mutant TP53. Conclusion We developed the system to predict TP53 status using expression profile. The TP53 status diagnosed by this system could be one of the prognostic biomarker of breast cancer. The advantage of this multiplex RT-PCR system is its convenience and low cost. At present, we have been developing the same diagnostic system using formalin fixed paraffin embedded (FFPE) tissue samples. Gene expression profiles are now featured for biomarkers of breast cancer. MammaPrint and Oncotype DX had been available in clinical, but these were very expensive for common use and not popular in Japan. TP53 status has been known to correlate with the prognosis of breast cancer. The aim of this study is to develop a prognostic biomarker using expression profile about TP53 status.

Background: “Hospitals designated as specialist centers for treating cancer in regional areas” (designated hospitals) are located in bigger cities. As a result many cancer patients go to designated hospitals located outside their residential areas. Methods: This research was performed in three designated hospitals and two regional core hospitals in Miyagi, Japan, from September 2012 to December 2013. Requests to patients to participate in the survey were made during their chemotherapy appointments. We sought to evaluate patients' burden in commuting to the designated hospitals. We assessed the quality of cancer care using the Care Evaluation Scale (CES) and also recorded patients' satisfaction scores. This study was approved by the institutional review boards of all hospitals. Results: In total, 231 patients provided verbal consent and we collected 229 questionnaires. 70 patients commuted from outside of the medical care areas to the designated hospitals (group A) whilst 130 patients lived in the same area as the designated hospitals (group B). Group A required longer commuting time (P = 0.01) and more expensive transportation expenses (P = 0.01), and the patients suffered from the burden of commuting (P = 0.05). However group A's reported overall satisfaction scores were not different from group B's. CES scores showed no difference between group A and B. Group A considered there to be many patients with the same cancers attending the designated hospitals (p = 0.01). We are going to report detailed results from the study in the conference. Conclusion: Patients who commuted from outside of the medical care areas to the designated hospitals valued the quality of cancer care over and above their burden in travelling and were satisfied with the care given in the designated hospitals. When attending distant patients, however, an important issue remains how to establish a system for providing proper and immediate medical care in an oncologic emergency.

Background: We have reported that status of the TP53 mutation is predictable by expression profile of 33 genes (TP53 signature) in breast cancer and that the TP53 signature can predict overall survival and recurrent free survival of early breast cancer (Cancer Sci. 99: 324-32, 2008). The aim of this study is to determine whether the TP53 signature can also predict both the efficacy of NAC and the recurrence after surgery in breast cancer. Methods: An NAC cohort (E-GEOD-25066) that contains 508 patients with HER2 negative breast cancer is used. Among the genes previously used TP53 signature, 20 up-regulated and 5 down-regulated genes in breast cancer with TP53 mutation were selected and the TP53 status was determined by the ratio of the sum of expression values of 20 up-regulated genes to that of the 5 down-regulated genes. If the ratio (down / up) was less than 0.325, the tumor was determined as aTP53 mutant. If it was greater than or equal to 0.325, the tumor was determined aTP53 wild. Results: Fifty percent (255 of 508) of tumors was determined as a TP53 mutant. The pathological CR (pCR) rate is significantly higher in TP53 mutant tumor than in TP53 wild-type tumor (34.7% vs 5.4%). In Stage I and II patients (n = 280), recurrence free survival (RFS) was significantly better in patients with TP53 wild type tumor (P = 0.0018). Patients with TP53 mutant tumor not leading to pCR (mt / non-pCR) showed significantly worse RFS than the other patients (P Conclusions: TP53 signature has the ability to predict the efficacy of NAC and recurrence after surgery in breast cancer. The TP53 signature was especially useful to predict the recurrence in combination with pCR status. Our data suggests that patients with TP53 mutant tumor not leading to pCR after NAC may need adjuvant chemotherapy after surgery to improve prognosis of these patients.

Background: A recent phase III trial PALETTE has shown that pazopanib significantly prolonged progression-free survival compared with placebo for patients with previously-treated soft tissue sarcoma. The aim of the present study was to clarify whether the efficacy and safety by pazopanib treatment in Japanese population are similar to those reported in the previous study. Methods: We retrospectively analyzed best overall responses, durations of therapy and adverse events (AE) for 9 patients with soft tissue sarcoma treated with pazopanib in Tohoku University Hospital. The patients had taken pazopanib orally between December, 2012 and November, 2013. Results: The median age of patients was 52.8 years, and 5 were male. The histological subtypes includes 3 alveolar soft part sarcoma, 2 malignant peripheral nerve sheath tumor, 2 myxofibrosarcoma, 2 liposarcoma, and one undifferentiated sarcoma. The metastatic sites were lung (n = 5), peritoneum (n = 1), and brain (n = 1). Median treatment duration was 2.5 months. Best overall response was PR for 2, SD for 3, and PD for 3 patients. The all AE were observed in 89%; hypertension, anorexia, and fatigue (n = 5), hand-and-foot syndrome, diarrhea and hair color changes (n = 3), and epistaxis and liver enzyme elevation (n = 2). Grade 3 /4 AE were found in 67%; anorexia (n = 4), fatigue and diarrhea (n = 2), and AST and ALT increase (n = 1). Of them, 6 patients continued pazopanib treatment after its dose reduction. In addition, a fatal duodenal perforation and hemorrhage occurred in one patient. Conclusion: The effect of pazopanib in our cohort was equivalent to that reported in the PALETTE study and the AE were generally tolerable, which support its usefulness for Japanese patients with unresectable soft tissue sarcoma as well. Nonetheless, our study suggests that physicians should pay enough attention to angiogenesis inhibitor-specific toxicities by pazopanib treatment, including gastrointestinal hemorrhage.

Regoragenib is a novel oral multi-kinase inhibitor, which was approved by Japanese Ministry of Health, Labor and Welfare in March 2013. The purpose of this study was to verify the efficacy and safety of regorafenib in Japanese patients with colorectal cancer. We retrospectively analyzed 14 patients with chemo-refractory colorectal cancer, who had taken regorafenib orally in Tohoku University Hospital between June 1, 2013 and January 30, 2014. Mean age of the patients was 62.4 years old and 8 patients were male. Twelve patients had colon cancer and 2 patients had rectal cancer. Ten patients had liver metastasis, 3 had abdominal dissemination. Nine patients (64%) had KRAS mutation. Median time to failure was 48 days and the mean number of therapeutic course was 2.8. Among the patients who had measurable lesions, the best overall response was stable disease in 3 patients, and progressive disease in 3. Because of adverse events, the therapy was discontinued in 4 patients before the first response evaluation. Four patients had not yet had the first evaluation for the response until January 1, 2014. Major adverse events (≥ grade 2) were observed in 11 patients (79%), including elevation of liver enzyme (n = 8), hand-foot skin reaction (n = 7), and anorexia (n = 5). Severe adverse events (≥ grade 3) were seen in 8 patients (57%), including elevation of liver enzyme (n = 5), hand-foot skin reaction (n = 1), fatigue (n = 1), hypertension (n = 1), anorexia (n = 1), aspiration (n = 1) and rhabdomyolysis (n = 1). These treatment effects and toxic profiles by regorafenib treatment were consistent with those reported in previous other studies. In conclusion, our data support the notion that regorafenib is one of well-tolerated treatment option for chemo-refractory, progressive or recurrent colorectal cancer in Japanse populations as well. We also report a case of rhabdomyolysis which had never been reported as an adverse event of regorafenib therapy before its approval.

Aim: The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been widely observed in human colorectal cancer (CRC). However, the effect of CIMP status on the efficacy of standard chemotherapy is not fully known. Although CIMP-positive status is known to be associated with BRAF mutation, the relationship between CIMP and mutations in other genes in the epidermal growth factor receptor (EGFR) associated signal transduction such as PIK3CA, NRAS, and AKT1 have not been clarified. Then, we analyzed the relationship among CIMP, EGFR related gene mutation, and the response to chemotherapies Methods: In 125 metastatic colorectal cancer (mCRC) patients, we analyzed the relationship between CIMP status detected by methylaton-specific PCR in the five locus (CACNAG, IGF2, NEUROG1, RUNX3, and SOCS1) and clinical outcome of the standard chemotherapies, genetic status in 5 EGFR- related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) detected by direct sequencing in the hotspot mutation regions. Results: CIMP-positive status was significantly associated with proximal tumor location, lung and peritoneum metastasis (all p values Conclusions: Sequential irinotecan-based regimen followed by FOLFOX is more favorable for CIMP-positive tumors than the reverse sequence. However, the sequential order of chemotherapies did not make difference in CIMP-negative tumors. In addition, CIMP-positive tumors have high frequency of mutation in EGFR related genes. Disclosure: All authors have declared no conflicts of interest.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

For the elimination of cancer-care disparities, it is essential to improve the standard of cancer medical care in the general hospitals, as well as regional core cancer hospitals. Supported by Health Labour Sciences Research Grant, we carried out questionnaire survey for current situation on chemotherapy service of hospitals and extracted the underlying issues. One hundred fifty-three general hospitals, including the regional core cancer hospitals in Tohoku district, were subjected for the questionnaire with six major topics: (i) hospital scale and facilities; (ii) management system of chemotherapy regimens; (iii) operational status of chemotherapy; (iv) status of the clinical-path about chemotherapy; (v) implementation system of clinical trials; and (vi) training of professional medical care stuff. The answers were recovered from 61 hospitals, including 23 regional core cancer hospitals (total recovery rate 39.8%). Registration system of chemotherapy regimen and manuals for adverse events had been developed in almost all regional core cancer hospitals and about half of general hospitals. Providing common chemotherapy regimens and manuals of specialized facilities were general demands from general hospitals. Case conferences are held regularly at more than 90% of regional core cancer hospitals and about 40% of general hospitals. Although 75% of regional core cancer hospitals participated in clinical trials, there is a lack of information of clinical trials and of clinical research coordinators who support medical staffs. To improve these issues, the Tohoku Clinical Oncology Research and Education Group (T-CORE), supported by Health Labour Sciences Research Grant, is addressing the following tasks: publication and disclosure of common chemotherapy regimens, development of the regimen review system, and case conference by a tumor board on the Web.

Background Biological classification of colorectal cancer (CRC) by gene expression analysis can elucidate the heterogeneous background of the disease. But most of previous studies used fresh frozen samples that were difficult to obtain, store and handle. The purpose of this study was to classify CRC based on gene expression profiles using formalin-fixed, paraffin-embedded tissues (FFPE) and to correlate subgroups of CRC with biological features and clinical outcomes. Methods One hundred FFPE samples were obtained from CRC patients with unresectable metastasis or local recurrence who underwent surgical resection of primary tumor previously. RNA extracted from FFPE was subjected to gene expression microarray. Mutation analysis was carried out by direct DNA sequencing. Results CRC was stratified into four subgroups by unsupervised hierarchical clustering. By principle component analysis (PCA), CRC was divided into clusters A and B by component 1 and was divided into clusters 1 and 2 by component 2. Cluster B was significantly enriched in patients with KRAS mutation. After anti-EGFR therapy, cluster A patients showed better PFS than cluster B patients although the difference was not significant (P = 0.12). Cluster 2 patients exhibited worse PFS after first line chemotherapy with l-OHP or CPT-11 (P = 0.04). Conclusions We showed that gene expression profiles of CRC allowed stratification into four subgroups that had different biological features and clinical outcomes. Furthermore, we showed that the efficacies of anti-EGFR therapy and chemotherapy correlate with two distinct axes. Gene expression profile using FFPE may explain the heterogeneity of CRC and aid the identification of new biomarkers for anticancer therapy of metastatic CRC.

Background Activating mutation of the KRAS gene is a predictive biomarker for the loss of efficacy to Anti-EGFR antibody therapy. However, this was mainly established by the evidences of Caucasian studies. Then, this prospective study investigated the role of KRAS and other EGFR-related gene mutations on efficacy and safety to cetuximab plus irinotecan in Japanese patients with metastatic colorectal cancer (mCRC). Method We conducted a prospective study to analyze objective response to cetuximab plus irinotecan in molecularly defined KRAS wild-type (WT) or mutant subgroups of chemotherapy–refractory mCRC. KRAS mutations were detected by direct sequence on DNA from formalin-fixed, paraffin-embedded tissue of patients treated in 11 centers in Japan. Additional EGFR-related genes such as BRAF, PIK3CA, NRAS and AKT1 were examined. Results Forty-three patients were enrolled. KRAS mutations were found in 31.7% of 41 eligible patients. Response rate (RR) to cetuximab plus irinotecan, the primary end point of the study, was 17.9% and 0% for the WT KRAS patients and mutant KRAS patients, respectively. Progression-free survivals were 3.7 months versus 1.6 months (P = 0.0039); overall survivals were 7.7 months versus 4.4 months (P = 0.0005) for the WT KRAS patients and mutant KRAS patients, respectively. No significant differences in toxicity were observed between the WT and mutant KRAS groups. The combination of five genes analysis made the difference of clinical outcomes wider between all WT group and any mutant group. Conclusion We confirmed that the KRAS status is a useful predictive maker for the efficacy to cetuximab plus irinotecan therapy in Japanese mCRC patients, even though the response rate in the KRAS WT group was lower than expected. The combination of analysis in EGFR-related genes possibly contributes to the better prediction of the response.

Overall cancer treatment should be coordinated among a radiation oncologist, surgeon, and medical oncologist, where appropriate. Unfortunately, there were few medical oncologists in Japan mainly because of lack of the academic society like JSMO and divisions in medical schools and hospitals for medical oncology. Therefore, the multidisciplinary approach in treating cancers was inappropriate. Since 2006, more than 700 cancer drug therapy specialists (diplomates, Subspecialty Board of Medical oncology, JSMO) were fostered in Japan, and the medical oncologists with the diplomate are gradually distributed in local cancer core hospitals. The current role of the medical oncologists in the hospitals is diverse and it includes treatment and management of cancer chemotherapy, such as treatment of both common and rare advanced cancers, management of outpatient chemotherapy center, organization of the regimen review committee and tumor board, education of their medical staffs and patients etc. The expanding role of the medical oncologists in the management of cancer patients may contribute to the spread of standard cancer chemotherapy. However, the number of medical oncologist is still limited. Many challenges still exist, both within the hospital and in translating oncological, technological and societal change into the context of local medical society. Because the number of cancer patient is increasing in Japan, wide spread advances in oncology by oncology specialists is urgent matter. In this symposium, current and future roles of the medical oncologists in local cancer core hospitals and their role in medical oncology education should be discussed.

Tohoku University Hospital (TUH) Cancer Treatment Information Window (CTIW) had tried to support cancer patients who were affected by Higashi-Nihon Earthquake. First, CIW informed people in the area affected by the Earthquake by distributing leaflets with the information to the each evacuation center, by telop information on TV, as well as giving information on the web. Specifically, information of CTIW of TUH, such as telephone number, could be so helpful that the consultations to CTIW by telephone rapidly increased mainly from Ishinomaki area. Majority of consultations from patients after the Earthquake was anxiety for interruption of cancer treatments or diagnostic examinations, and CTIW of TUH could solve these troubles by hospitalizing patients to TUH or by referring to the other cancer-specialized hospitals without any damage in Miyagi prefecture. From these experiences, we propose to strengthen of cooperative partnership between the cancer-specialized hospitals, especially through such consultation and support services as CTIW, because each CTIW has already constructed the cooperative network to each department within hospital as well as to CTIW in other cancer-specialized hospitals. We emphasize that CTIW and its own hospital network with each clinical department and with other cancer-specialized hospitals will play an important role even in disasters in the future to save cancer patients in the affected area.

Cancer drug development for Japanese patients by Western Pharmaceutical Companies carries two main challenges. First, many new agents still offer incremental benefits over existing therapies or are hampered by acquired drug resistance and, secondly, they reach Japanese patients with an ∼2–3 year delay after their regulatory approvals in the European Union and the United States. This is based on the mechanisms of traditional cancer drug development where new agents are either tested as monotherapies or are placed in the context of moderately effective standards-of-care often based on regulatory considerations rather than science. Furthermore, Western cancer medicines are not formally investigated in Japanese patients until late in their development causing a delay for the additional investigations needed to address potential biologic differences in Japanese patients. Greater benefits and faster access for Japanese patients may be achieved through combined progress in cancer genetics, drug development and regulation. The introduction of precision medicine utilizing biomarker-driven patient selection for molecularly targeted agents has been a first step toward greater patient benefit in defined populations. In addition, new treatment modalities such as immunotherapy have become available to induce greater long-term effects. The next wave of innovation to overcome drug resistance and substantially improve patient outcomes may now require co-development of science-driven drug combinations within and across defined pathways within the cancer and the host. Furthermore, integrated drug development strategies are needed to achieve simultaneous availability of new medicines for Western and Japanese patients. This will require investigation of drug dosing, pharmacokinetics and pharmacodynamics in Western and Japanese patients as part of a global development program, which enables us to understand and address differences in cancer genetics, host genetics as well as disease prevalence. Such programs should be accompanied by earlier and more frequent regulatory interactions as well as Japanese regulations supporting effective execution of global programs and co-development of novel drugs. Overall, close collaboration between all stakeholders on the pharmaceutical, academic and regulatory side is needed to accomplish the goal of bringing greater benefit and faster access of Western-developed anti-cancer drugs to Japanese patients.