Yu Sunakawa | Showa University (original) (raw)

Papers by Yu Sunakawa

Frontiers in Oncology

BackgroundGeriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to ... more BackgroundGeriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to predict overall survival (OS) or risk of serious adverse events (SAEs) in older cancer patients. However, the clinical utility is relatively unknown in older patients suffering malnutrition with gastrointestinal (GI) cancer, including gastric cancer (GC) and pancreatic cancer (PC).Materials and methodsWe retrospectively included patients aged ≥65 years with GC, PC, and colorectal cancer (CRC) who received a G8 questionnaire at first visit from April 2018 to March 2020. The associations between G8/IADL and safety or OS were assessed in patients with advanced/unresectable tumors.ResultsOf 207 patients (median age: 75 years), the median G8 score was 10.5 and normal G8 score rate was 6.8%. Both the median G8 score and normal G8 (>14) score rate numerically increased in the order of GC < PC < CRC. There was no clear association between the G8 standard cutoff value of 14 and SAEs or O...

Journal of Clinical Oncology

109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has be... more 109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEEPER trial (JACCRO CC-13)[NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus...

Targeted Oncology

Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased av... more Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased availability of targeted therapies. However, in patients with gastrointestinal (GI) cancers, the utility of genomic profiling is unclear because of common non-druggable alterations and rapid disease progression that prevent a sufficient time period to seek targets. The aim of this study was to determine the utility of genomic profiling tests in patients with GI cancers. The subjects of this retrospective study were patients with GI cancers and patients with non-GI cancers who underwent tissue-based genomic profiling at a single institution from April 2017 to October 2020. The profile of gene alterations, frequency of tumor mutational burden-high (≥ 10 Muts/Mb), and accessibility of recommended molecular targeted therapy were compared between patients with GI cancers and patients with non-GI cancers. In all, 133 patients with GI cancers and 63 patients with non-GI cancers were included. The genomic profiles of GI cancers showed the highest frequencies of TP53, KRAS, and APC mutations and a significantly lower frequency of PIK3CA mutations than those of non-GI cancers. Tumor mutational burden-high was significantly less prevalent in GI cancers (4% vs 20%, p = 0.008). Twenty-nine patients with GI cancers (40%) and 35 patients with non-GI cancers (56%) were recommended for targeted therapies based on the findings. Among them, seven patients each with GI cancers and non-GI cancers received the recommended therapy on their genomic findings, which showed similar treatment accessibility between the GI and non-GI cancer groups (10% vs 11%, p = 0.791). HER2-targeted and BRAF-targeted therapies were the primary treatments administered to patients with GI cancers. Although their genomic profiles revealed fewer druggable sites, patients with GI cancers accessed targeted therapies similarly to patients with non-GI cancers. The utility of genomic profile testing in patients with GI cancers was highlighted to determine if patients can receive specific treatments, such as HER2-targeted and BRAF-targeted therapies.

Clinical Cancer Research, 2021

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its... more Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA...

Gastric Cancer, 2021

Background There is no large real-world data regarding efficacy and safety of immunotherapy in ga... more Background There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC. Methods A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety. Results Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29–7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71–1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3–18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25–2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72–1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS. Conclusions Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.

Journal of Clinical Oncology, 2020

4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor ti... more 4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor tissue testing in terms of enrollment to matched clinical trials across a wide range of GI cancers (Nakamura Y, et al. ASCO-GI 2020). Here, we investigated the utility of ctDNA genotyping in mCRC in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue genotyping was performed using a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In GOZILA, NGS-based ctDNA genotyping was performed using Guardant360 since Feb 2018. All tests were conducted centrally in a CLIA-certified and CAP-accredited laboratory. Patients with actionable alterations were enrolled into matched company-sponsored or investigator-initiated interventional clinical trials. Results: As of Apr 2019, 2,791 mCRC patients (2,754 eligible for analysis) in GI-SCREEN and 470 (464 eligible for analysis) in GOZILA were enrolled. There were no significant di...

Journal of Clinical Oncology, 2016

3595Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system... more 3595Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system via ADCC (antibody-dependent cell-mediated cytotoxicity). Immune response through T-cell activation...

Annals of Oncology, 2019

Background FOLFOXIRI plus bevacizumab (bev) is one of preferred 1st-line regimens for RAS mutant ... more Background FOLFOXIRI plus bevacizumab (bev) is one of preferred 1st-line regimens for RAS mutant metastatic colorectal cancer (mCRC); however, the original dosage is slightly toxic for Japanese patients (pts) due to frequent febrile neutropenia. We have reported that modified (m)-FOLFOXIRI (IRI 150mg/m2, OHP 85mg/m2, levofolinate 200mg/m2, and 5-FU 2400mg/m2 for 46-h continuous, up to 12 cycles followed by maintenance with 5-FU/levofolinate) plus bev has good objective response rate (ORR) of 76% as well as tolerability in Japanese pts with RAS mutant mCRC [Satake H, et al. Oncotarget 2018]. However, the follow-up time was short; therefore, clinical data was immature. Methods The primary endpoint was ORR. Progression-free survival (PFS), overall survival (OS), early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. The tumor shrinkage was evaluated every 8 weeks by the external review board. Pre-planned updated analysis was performed in January 2019...

Future Oncology, 2019

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; ... more Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

Journal of Clinical Oncology, 2015

4039 Background: A recent genome-wide association study reported associations between risk of Bar... more 4039 Background: A recent genome-wide association study reported associations between risk of Barrett’s esophageal and esophageal adenocarcinoma and seven single-nucleotide polymorphisms (SNPs) in ...

Journal of Clinical Oncology, 2014

4018 Background: Multiple tumor immune checkpoint receptors and ligands, some of which are select... more 4018 Background: Multiple tumor immune checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumors, play a role as an antitumor immune suppressor. The pot...

Journal of Clinical Oncology, 2014

3571 Background: Epidermal growth factor receptor (EGFR) turnover is a highly regulated process c... more 3571 Background: Epidermal growth factor receptor (EGFR) turnover is a highly regulated process controlling the amount of receptor proteins available for antibody binding. The ubiquitin proteasome system (UPS) is responsible for EGFR degradation. The single nucleotide polymorphism (SNP) rs895374 is located in UbcH7, an E2 ligase conducting neddylation of HECT E3 ligases involved in EGFR degradation. Neddylation activates E3 ligases and switches the balance between degradation and recycling towards degradation. We have previously reported that rs895374 correlates with progression free survival (PFS) in patients (n=108) treated with cetuximab in two phase II studies of further-line treatment. The aim of this study was to validate the predictive value of rs895374 in an independent cohort of cetuximab treated patients with a cetuximab-free chemotherapy arm serving as negative control. Methods: Genomic DNA was isolated from tissue samples of 455 patients (median age 64 years, male 64.2%) treated in first-line ...

Journal of Clinical Oncology, 2014

e14512 Background: Recurrence after liver resection in patients with colorectal liver metastases ... more e14512 Background: Recurrence after liver resection in patients with colorectal liver metastases (CLM) is frequent, despite the chance of cure and long-term survival. The mechanisms of recurrence are not well understood. Tumor dormancy has been described as a state of hibernation until eventual outgrowth playing a critical role in tumor recurrence. In this study we investigated genetic variations within genes that are associated with tumor dormancy and their association with recurrence and outcome in patients with CLM. Methods: Genomic DNA was extracted from resected bevacizumab-pretreated CLM (FFPE) from 149 patients (median age 62 years, 58.4% male, median follow-up 3.9 years). Single nucleotide polymorphisms (SNP) in 13 genes associated with dormancy (TCF7L2, AXIN2, CD44, LGR5, ALDH1A1, uPA, uPAR, ITGA5, ITGB1, EGF, EGFR, Dll4, NOTCH3) were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS) and overall survival (OS). Results: In univariate analysis, rs10...

Japanese Journal of Clinical Oncology, 2018

In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in... more In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in conferring survival benefit. For the last three decades, great progress has been achieved in adjuvant and palliative chemotherapy. Powerful combination regimens using doublet or triplet cytotoxic agents have been developed and new molecular targeted drugs, including trastuzumab and ramucirumab, have been introduced in clinical practice. These advances have resulted from the accumulation of many clinical trials. A well-designed phase III trial can change standard treatment; however, such a trial is hard to complete due to its huge cost and need to recruit many patients. Some cooperative groups have actively made efforts at fundraising and patient recruitment, which can make implementation of high-quality and large-scale phase III trials possible. This review summarizes the development of chemotherapy for gastric cancer with focus on cooperative groups around the world, considering effective treatment developments in gastric cancer. We studied 11 active cooperative groups, including six in Europe, two in the United States, and three in Japan, that have completed one or more phase III trials cited in the major guidelines. Each cooperative group had its own characteristics and contributed to the establishment of standard treatment in each region. International collaboration in the development of gastric cancer treatment may be difficult due to regional differences in standards of care, particularly for resectable gastric cancer. Whereas, intergroup collaboration within each region is a reasonable method to effectively develop treatments for resectable and advanced gastric cancer.

Journal of Clinical Oncology, 2014

611 Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrat... more 611 Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrated the prolonged progression-free survival (PFS) with higher response rate (RR) in the OPUS study. To evaluate the clinical efficacy and safety of the cet plus mFOLFOX6, we conducted a multi-center phase II study of Japanese pts. Methods: In this trial, pts with KRAS wild type tumor and receiving no prior chemotherapy for mCRC were treated with cet (initial dose 400, and 250 mg/m2 weekly) followed by mFOLFOX6 (oxaliplatin 85mg/m2, l-leucovorin 200 mg/m2, fluorouracil, as 400mg/m2 intravenous bolus then 2,400mg/m246-hour continuous infusion). The treatment was repeated every 2 weeks. The primary endpoint was RR evaluated by the external review board according to RECIST v1.1. Secondary endpoints included PFS, OS, % chronological change at the base line and safety. Results: A total of 57 pts were enrolled from August 2010 to September 2011. The median age was 60 years, 65% of pts were male,...

Journal of Clinical Oncology, 2014

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC.... more 571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was res...

Journal of Clinical Oncology, 2015

621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angioge... more 621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS...

Frontiers in Oncology

BackgroundGeriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to ... more BackgroundGeriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to predict overall survival (OS) or risk of serious adverse events (SAEs) in older cancer patients. However, the clinical utility is relatively unknown in older patients suffering malnutrition with gastrointestinal (GI) cancer, including gastric cancer (GC) and pancreatic cancer (PC).Materials and methodsWe retrospectively included patients aged ≥65 years with GC, PC, and colorectal cancer (CRC) who received a G8 questionnaire at first visit from April 2018 to March 2020. The associations between G8/IADL and safety or OS were assessed in patients with advanced/unresectable tumors.ResultsOf 207 patients (median age: 75 years), the median G8 score was 10.5 and normal G8 score rate was 6.8%. Both the median G8 score and normal G8 (>14) score rate numerically increased in the order of GC < PC < CRC. There was no clear association between the G8 standard cutoff value of 14 and SAEs or O...

Journal of Clinical Oncology

109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has be... more 109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEEPER trial (JACCRO CC-13)[NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus...

Targeted Oncology

Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased av... more Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased availability of targeted therapies. However, in patients with gastrointestinal (GI) cancers, the utility of genomic profiling is unclear because of common non-druggable alterations and rapid disease progression that prevent a sufficient time period to seek targets. The aim of this study was to determine the utility of genomic profiling tests in patients with GI cancers. The subjects of this retrospective study were patients with GI cancers and patients with non-GI cancers who underwent tissue-based genomic profiling at a single institution from April 2017 to October 2020. The profile of gene alterations, frequency of tumor mutational burden-high (≥ 10 Muts/Mb), and accessibility of recommended molecular targeted therapy were compared between patients with GI cancers and patients with non-GI cancers. In all, 133 patients with GI cancers and 63 patients with non-GI cancers were included. The genomic profiles of GI cancers showed the highest frequencies of TP53, KRAS, and APC mutations and a significantly lower frequency of PIK3CA mutations than those of non-GI cancers. Tumor mutational burden-high was significantly less prevalent in GI cancers (4% vs 20%, p = 0.008). Twenty-nine patients with GI cancers (40%) and 35 patients with non-GI cancers (56%) were recommended for targeted therapies based on the findings. Among them, seven patients each with GI cancers and non-GI cancers received the recommended therapy on their genomic findings, which showed similar treatment accessibility between the GI and non-GI cancer groups (10% vs 11%, p = 0.791). HER2-targeted and BRAF-targeted therapies were the primary treatments administered to patients with GI cancers. Although their genomic profiles revealed fewer druggable sites, patients with GI cancers accessed targeted therapies similarly to patients with non-GI cancers. The utility of genomic profile testing in patients with GI cancers was highlighted to determine if patients can receive specific treatments, such as HER2-targeted and BRAF-targeted therapies.

Clinical Cancer Research, 2021

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its... more Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA...

Gastric Cancer, 2021

Background There is no large real-world data regarding efficacy and safety of immunotherapy in ga... more Background There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC. Methods A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety. Results Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29–7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71–1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3–18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25–2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72–1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS. Conclusions Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.

Journal of Clinical Oncology, 2020

4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor ti... more 4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor tissue testing in terms of enrollment to matched clinical trials across a wide range of GI cancers (Nakamura Y, et al. ASCO-GI 2020). Here, we investigated the utility of ctDNA genotyping in mCRC in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue genotyping was performed using a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In GOZILA, NGS-based ctDNA genotyping was performed using Guardant360 since Feb 2018. All tests were conducted centrally in a CLIA-certified and CAP-accredited laboratory. Patients with actionable alterations were enrolled into matched company-sponsored or investigator-initiated interventional clinical trials. Results: As of Apr 2019, 2,791 mCRC patients (2,754 eligible for analysis) in GI-SCREEN and 470 (464 eligible for analysis) in GOZILA were enrolled. There were no significant di...

Journal of Clinical Oncology, 2016

3595Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system... more 3595Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system via ADCC (antibody-dependent cell-mediated cytotoxicity). Immune response through T-cell activation...

Annals of Oncology, 2019

Background FOLFOXIRI plus bevacizumab (bev) is one of preferred 1st-line regimens for RAS mutant ... more Background FOLFOXIRI plus bevacizumab (bev) is one of preferred 1st-line regimens for RAS mutant metastatic colorectal cancer (mCRC); however, the original dosage is slightly toxic for Japanese patients (pts) due to frequent febrile neutropenia. We have reported that modified (m)-FOLFOXIRI (IRI 150mg/m2, OHP 85mg/m2, levofolinate 200mg/m2, and 5-FU 2400mg/m2 for 46-h continuous, up to 12 cycles followed by maintenance with 5-FU/levofolinate) plus bev has good objective response rate (ORR) of 76% as well as tolerability in Japanese pts with RAS mutant mCRC [Satake H, et al. Oncotarget 2018]. However, the follow-up time was short; therefore, clinical data was immature. Methods The primary endpoint was ORR. Progression-free survival (PFS), overall survival (OS), early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. The tumor shrinkage was evaluated every 8 weeks by the external review board. Pre-planned updated analysis was performed in January 2019...

Future Oncology, 2019

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; ... more Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

Journal of Clinical Oncology, 2015

4039 Background: A recent genome-wide association study reported associations between risk of Bar... more 4039 Background: A recent genome-wide association study reported associations between risk of Barrett’s esophageal and esophageal adenocarcinoma and seven single-nucleotide polymorphisms (SNPs) in ...

Journal of Clinical Oncology, 2014

4018 Background: Multiple tumor immune checkpoint receptors and ligands, some of which are select... more 4018 Background: Multiple tumor immune checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumors, play a role as an antitumor immune suppressor. The pot...

Journal of Clinical Oncology, 2014

3571 Background: Epidermal growth factor receptor (EGFR) turnover is a highly regulated process c... more 3571 Background: Epidermal growth factor receptor (EGFR) turnover is a highly regulated process controlling the amount of receptor proteins available for antibody binding. The ubiquitin proteasome system (UPS) is responsible for EGFR degradation. The single nucleotide polymorphism (SNP) rs895374 is located in UbcH7, an E2 ligase conducting neddylation of HECT E3 ligases involved in EGFR degradation. Neddylation activates E3 ligases and switches the balance between degradation and recycling towards degradation. We have previously reported that rs895374 correlates with progression free survival (PFS) in patients (n=108) treated with cetuximab in two phase II studies of further-line treatment. The aim of this study was to validate the predictive value of rs895374 in an independent cohort of cetuximab treated patients with a cetuximab-free chemotherapy arm serving as negative control. Methods: Genomic DNA was isolated from tissue samples of 455 patients (median age 64 years, male 64.2%) treated in first-line ...

Journal of Clinical Oncology, 2014

e14512 Background: Recurrence after liver resection in patients with colorectal liver metastases ... more e14512 Background: Recurrence after liver resection in patients with colorectal liver metastases (CLM) is frequent, despite the chance of cure and long-term survival. The mechanisms of recurrence are not well understood. Tumor dormancy has been described as a state of hibernation until eventual outgrowth playing a critical role in tumor recurrence. In this study we investigated genetic variations within genes that are associated with tumor dormancy and their association with recurrence and outcome in patients with CLM. Methods: Genomic DNA was extracted from resected bevacizumab-pretreated CLM (FFPE) from 149 patients (median age 62 years, 58.4% male, median follow-up 3.9 years). Single nucleotide polymorphisms (SNP) in 13 genes associated with dormancy (TCF7L2, AXIN2, CD44, LGR5, ALDH1A1, uPA, uPAR, ITGA5, ITGB1, EGF, EGFR, Dll4, NOTCH3) were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS) and overall survival (OS). Results: In univariate analysis, rs10...

Japanese Journal of Clinical Oncology, 2018

In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in... more In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in conferring survival benefit. For the last three decades, great progress has been achieved in adjuvant and palliative chemotherapy. Powerful combination regimens using doublet or triplet cytotoxic agents have been developed and new molecular targeted drugs, including trastuzumab and ramucirumab, have been introduced in clinical practice. These advances have resulted from the accumulation of many clinical trials. A well-designed phase III trial can change standard treatment; however, such a trial is hard to complete due to its huge cost and need to recruit many patients. Some cooperative groups have actively made efforts at fundraising and patient recruitment, which can make implementation of high-quality and large-scale phase III trials possible. This review summarizes the development of chemotherapy for gastric cancer with focus on cooperative groups around the world, considering effective treatment developments in gastric cancer. We studied 11 active cooperative groups, including six in Europe, two in the United States, and three in Japan, that have completed one or more phase III trials cited in the major guidelines. Each cooperative group had its own characteristics and contributed to the establishment of standard treatment in each region. International collaboration in the development of gastric cancer treatment may be difficult due to regional differences in standards of care, particularly for resectable gastric cancer. Whereas, intergroup collaboration within each region is a reasonable method to effectively develop treatments for resectable and advanced gastric cancer.

Journal of Clinical Oncology, 2014

611 Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrat... more 611 Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrated the prolonged progression-free survival (PFS) with higher response rate (RR) in the OPUS study. To evaluate the clinical efficacy and safety of the cet plus mFOLFOX6, we conducted a multi-center phase II study of Japanese pts. Methods: In this trial, pts with KRAS wild type tumor and receiving no prior chemotherapy for mCRC were treated with cet (initial dose 400, and 250 mg/m2 weekly) followed by mFOLFOX6 (oxaliplatin 85mg/m2, l-leucovorin 200 mg/m2, fluorouracil, as 400mg/m2 intravenous bolus then 2,400mg/m246-hour continuous infusion). The treatment was repeated every 2 weeks. The primary endpoint was RR evaluated by the external review board according to RECIST v1.1. Secondary endpoints included PFS, OS, % chronological change at the base line and safety. Results: A total of 57 pts were enrolled from August 2010 to September 2011. The median age was 60 years, 65% of pts were male,...

Journal of Clinical Oncology, 2014

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC.... more 571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was res...

Journal of Clinical Oncology, 2015

621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angioge... more 621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS...