Publications by authors named "Yoshiaki Nakamura"

105 Publications

SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: Path to the realization of biomarker-guided precision oncology in advanced solid tumors.

Cancer Sci 2021 Sep 12. Epub 2021 Sep 12.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Comprehensive genomic profiling enables the detection of genomic biomarkers in advanced solid tumors. However, efficient patient screening for the success of precision oncology remains challenging due to substantial barriers, such as genotyping costs and accessibility to matched therapies. To address these challenges, we launched GI-SCREEN, a nationwide gastrointestinal cancer genomic screening project within the SCRUM-Japan network in 2015 with the specific purpose of matching patients with a diverse portfolio of affiliated interventional targeted therapy trials. Subsequently, we initiated the molecular profiling projects GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2, which incorporate tissue and plasma multiomics approaches to accurately identify patients with advanced solid tumors who would benefit from matched therapies. These projects have led to a significant increase in patient participation in targeted clinical trials and the approval of several therapeutics and companion diagnostics. Additionally, clinicogenomic analyses utilizing the SCRUM-Japan database have provided new insights into the molecular mechanisms of advanced solid tumors. In this review, we describe the path to the realization of cancer precision medicine for patients with advanced solid tumors based on the SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN platforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15132DOI Listing
September 2021

Impact of serum vitamin D on the response and prognosis in breast cancer patients treated with neoadjuvant chemotherapy.

Breast Cancer 2021 Sep 6. Epub 2021 Sep 6.

Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan.

Background: Several studies have recently reported that the relationships between serum vitamin D and the prognosis or the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. However, there are no data regarding the clinical impacts of the vitamin D in Japanese breast cancer patients so far.

Patients And Methods: In the present study, a total of 250 patients with clinical Stage I-III primary breast cancer who were treated with NAC and subsequently underwent definitive surgery were included. Serum 25-hydroxvitamin D (25(OH)D) levels were evaluated using blood samples obtained before NAC.

Results: The serum 25(OH)D was positively associated with age, and the serum 25(OH)D was significantly higher in postmenopausal women than that in pre/peri-menopausal women. Serum 25(OH)D level was not associated with the achievement of pathological complete response (pCR) in this cohort. The low 25(OH)D levels were significantly associated with shorter time to distant recurrence (TTDR). According to the univariate analysis, high clinical stage before NAC (cStage III) and low serum 25(OH)D level were significantly associated with the shorter TTDR, and pCR was significantly associated with the longer TTDR. According to a multivariate analysis, low serum 25(OH)D level were independent poor prognostic factors for TTDR.

Conclusions: The low 25(OH)D levels were significantly associated with poorer prognosis in Japanese women with operable breast cancer patients treated with NAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12282-021-01292-3DOI Listing
September 2021

Circulating Tumor DNA Analysis Detects Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer.

Clin Cancer Res 2021 Aug 10. Epub 2021 Aug 10.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

Purpose: 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 amplification and co-occurring resistance mechanisms in advanced gastric cancer.

Experimental Design: We assessed genomic characteristics of -amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with -amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors.

Results: 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%). amplification profiling of paired tissue and plasma revealed that amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with and co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the copy number.

Conclusions: ctDNA sequencing identifies amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with -amplified advanced gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-1414DOI Listing
August 2021

Comparing GOZILA and COLOMATE: Ongoing Umbrella/Basket Trials Examining Genetic Testing in Gastrointestinal Malignancies.

Oncology (Williston Park) 2021 Jul 17;35(7):382-389. Epub 2021 Jul 17.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) assays have advantages over classic tissue-based analyses because of their low invasiveness and availability of repeated sampling. Because of the low incidence of target gene alterations such as HER2 or BRAF V600E in gastrointestinal cancers, very large screening platforms are needed to develop genome-based clinical trials. For those reasons, ctDNA-based screening studies are being actively conducted; among them are the GOZILA (Guardant Originates in Zipangu Liquid biopsy Arrival) study in Japan and the COLOMATE (COlorectal Cancer Liquid BiOpsy Screening Protocol for Molecularly Assigned ThErapy) study in the United States. Although only patients with metastatic colorectal cancer (mCRC) who had previously received standard chemotherapies are eligible for the COLOMATE study, patients with various types of solid tumors at any line of treatment are eligible for GOZILA. This broad coverage of the eligible population allows a target of 5000 patients. By contrast, effective screening of selected candidate patients for companion trials using rapid turnaround time by ctDNA-based NGS assay is the key for COLOMATE. The companion trials of targeted therapies in mCRC are similar between GOZILA and COLOMATE. Both studies have identified patients eligible for studies by examining ERBB2 (HER2), BRAF V600E, BRAF non-V600E, and FGFR alterations, as well as MET amplification and rechallenge with anti-EGFR antibodies. The existence of various companion trials for common alterations that can be potential therapy targets on the 2 platforms can lead to future international collaboration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.46883/ONC.2021.3507.0382DOI Listing
July 2021

Quantitative trait loci for growth-related traits in Japanese quail (Coturnix japonica) using restriction-site associated DNA sequencing.

Mol Genet Genomics 2021 Sep 12;296(5):1147-1159. Epub 2021 Jul 12.

Laboratory of Animal Breeding and Genetics, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, 739-8525, Japan.

This study aimed to identify quantitative trait loci (QTLs) for growth-related traits by constructing a genetic linkage map based on single nucleotide polymorphism (SNP) markers in Japanese quail. A QTL mapping population of 277 F birds was obtained from an intercross between a male of a large-sized strain and three females of a normal-sized strain. Body weight (BW) was measured weekly from hatching to 16 weeks of age. Non-linear regression growth models of Weibull, Logistic, Gompertz, Richards, and Brody were analyzed, and growth curve parameters of Richards was selected as the best model to describe the quail growth curve of the F birds. Restriction-site associated DNA sequencing developed 125 SNP markers that were informative between their parental strains. The SNP markers were distributed on 16 linkage groups that spanned 795.9 centiMorgan (cM) with an average marker interval of 7.3 cM. QTL analysis of phenotypic traits revealed four main-effect QTLs. Detected QTLs were located on chromosomes 1 and 3 and were associated with BW from 4 to 16 weeks of age and asymptotic weight of Richards model at genome-wide significant at 1% or 5% level. No QTL was detected for BW from 0 to 3 weeks of age. This is the first report identified QTLs for asymptotic weight of the Richards parameter in Japanese quail. These results highlight that the combination of QTL studies and the RAD-seq method will aid future breeding programs identify genes underlying the QTL and the application of marker-assisted selection in the poultry industry, particularly the Japanese quail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00438-021-01806-wDOI Listing
September 2021

REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer.

BMC Cancer 2021 Jun 7;21(1):674. Epub 2021 Jun 7.

Department of Colorectal Surgery, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan.

Background: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge.

Methods: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360).

Discussion: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative.

Trial Registration: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08395-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186219PMC
June 2021

Efficacy of pembrolizumab in microsatellite instability-high locally advanced cholangiocarcinoma: a case report.

Clin J Gastroenterol 2021 Oct 3;14(5):1459-1463. Epub 2021 Jun 3.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01458-8DOI Listing
October 2021

Mapping of Quantitative Trait Loci Controlling Egg-Quality and -Production Traits in Japanese Quail () Using Restriction-Site Associated DNA Sequencing.

Genes (Basel) 2021 05 13;12(5). Epub 2021 May 13.

Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8525, Japan.

This research was conducted to identify quantitative trait loci (QTL) associated with egg-related traits by constructing a genetic linkage map based on single nucleotide polymorphism (SNP) markers using restriction-site associated DNA sequencing (RAD-seq) in Japanese quail. A total of 138 F females were produced by full-sib mating of F birds derived from an intercross between a male of the large-sized strain with three females of the normal-sized strain. Eggs were investigated at two different stages: the beginning stage of egg-laying and at 12 weeks of age (second stage). Five eggs were analyzed for egg weight, lengths of the long and short axes, egg shell strength and weight, yolk weight and diameter, albumen weight, egg equator thickness, and yolk color (L*, a*, and b* values) at each stage. Moreover, the age at first egg, the cumulative number of eggs laid, and egg production rate were recorded. RAD-seq developed 118 SNP markers and mapped them to 13 linkage groups using the Map Manager QTX b20 software. Markers were spanned on 776.1 cM with an average spacing of 7.4 cM. Nine QTL were identified on chromosomes 2, 4, 6, 10, 12, and Z using the simple interval mapping method in the R/qtl package. The QTL detected affected 10 egg traits of egg weight, lengths of the long and short axes of egg, egg shell strength, yolk diameter and weight, albumen weight, and egg shell weight at the beginning stage, yellowness of the yolk color at the second stage, and age at first egg. This is the first report to perform a quail QTL analysis of egg-related traits using RAD-seq. These results highlight the effectiveness of RAD-seq associated with targeted QTL and the application of marker-assisted selection in the poultry industry, particularly in the Japanese quail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12050735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153160PMC
May 2021

Greater extent of blood-tumor TCR repertoire overlap is associated with favorable clinical responses to PD-1 blockade.

Cancer Sci 2021 Aug 22;112(8):2993-3004. Epub 2021 Jun 22.

Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda City, Japan.

With the widespread use of programmed death receptor-1 (PD-1) blockade therapy, sensitive and specific predictive biomarkers that guide patient selection are urgently needed. T-cell receptor (TCR) repertoire, which reflects antitumor T-cell responses based on antigen specificity, is expected as a novel biomarker for PD-1 blockade therapy. In the present study, the TCR repertoire of eight patients with gastrointestinal cancer treated with anti-PD-1 antibody (nivolumab) was analyzed. To analyze the tumor-associated T-cell clones in the blood and their mobilization into the tumor, we focused on T-cell clones that presented in both blood and tumor (blood-tumor overlapping clones). Responders to PD-1 blockade tended to exhibit a higher number of overlapping clones in the tumor and a higher total frequency in the blood. Moreover, a higher total frequency of overlapping clones in blood CD8 T cells before treatment was associated with a favorable clinical response. Collectively, these results suggest the possibility of blood-tumor TCR repertoire overlap to predict clinical response to PD-1 blockade and guide patient selection before the treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353913PMC
August 2021

The Right Treatment of the Right Patient: Integrating Genetic Profiling Into Clinical Decision Making in Advanced Gastric Cancer in Asia.

Am Soc Clin Oncol Educ Book 2021 Mar;41:1-8

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Gastric cancer is a major global health burden, especially when patients are diagnosed with recurrent or metastatic gastric cancer. Despite recent advances in treatment options with palliative chemotherapy, the median overall survival of patients with gastric cancer remains within 1 or 2 years after the diagnosis of metastatic disease. Gastric cancer is significantly more prevalent in eastern Asia (e.g., Japan and Korea). Next-generation sequencing (NGS) is rapidly being adopted as part of clinical practice in Korea and Japan, especially in patients with gastric cancer. Approximately 10% to 15% of the patients with gastric cancer who undergo NGS of their tumor specimen are allocated to target-matched clinical trials in Japan and Korea. In Japan and Korea, a cell-free DNA NGS panel is also actively being investigated as an alternative NGS test for patients with gastric cancer, which may reflect the tumor heterogeneity of gastric cancer. In Japan and Korea, multiple biomarkers, such as HER2, mismatch repair, Epstein-Barr virus, PD-L1 (combined positive score), EGFR, FGFR2, and CLDN18.2, are routinely assessed through immunohistochemistry or in situ hybridization before initiation of the first-line treatment in all patients with gastric cancer. Most tertiary cancer centers in Korea routinely perform HER2, mismatch repair, Epstein-Barr virus, and PD-L1 NGS before palliative chemotherapy in patients with gastric cancer. Biomarker evaluation for all patients with metastatic gastric cancer enables clinicians to identify available biomarker-based clinical trials early during the course of treatment, which expands treatment opportunities while patients are medically fit for clinical trials, if available. Comprehensive genomic profiling using a tissue or circulating tumor DNA NGS panel is considered necessary during second-line or subsequent treatment. It is hoped that a comprehensive molecular profiling strategy will facilitate greater use of precision medicine through molecularly targeted therapies for patients with gastric cancer in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/EDBK_321247DOI Listing
March 2021

Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study.

Ther Adv Med Oncol 2021 20;13:17588359211009143. Epub 2021 Apr 20.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background: The C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients with chemorefractory metastatic colorectal cancer (mCRC). However, there had been no direct comparative phase III trial to compare the efficacy between TAS102 plus BEV and standard therapy with either TAS102 or regorafenib monotherapy.

Methods: We retrospectively reviewed the medical records of patients with mCRC who received TAS102 plus BEV, TAS102 monotherapy, or regorafenib monotherapy after standard chemotherapies during 2013-2019.

Results: Patients received TAS102 plus BEV ( = 139), TAS102 monotherapy ( = 153), or regorafenib monotherapy ( = 133). With a median follow-up of 25.3 months, median overall survival (OS) was 11.5 months [95% confidence interval (CI), 9.9-13.9] for TAS102 plus BEV, 8.1 months (95% CI, 6.8-9.2) for TAS102 monotherapy, and 6.8 months (95% CI, 5.7-8.5) for regorafenib monotherapy. The hazard ratios were 0.67 (95% CI, 0.51-0.88) for TAS102 plus BEV TAS102 monotherapy and 0.71 (95% CI, 0.54-0.94) for TAS102 plus BEV regorafenib monotherapy. Median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-5.4) for TAS102 plus BEV, 2.5 months (95% CI, 1.6-2.3) for TAS102 monotherapy, and 2.1 months (95% CI, 1.6-2.3) for regorafenib monotherapy. The hazard ratios were 0.57 (95% CI, 0.45-0.73) for TAS102 plus BEV TAS102 monotherapy and 0.44 (95% CI, 0.34-0.58) for TAS102 plus BEV regorafenib monotherapy. On multivariate analysis, TAS102 plus BEV was independently correlated with better OS and PFS. No unexpected adverse events were observed in any group.

Conclusion: Our study shows that OS and PFS are longer in patients treated with TAS102 plus BEV than in those treated with TAS102 or regorafenib monotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/17588359211009143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064512PMC
April 2021

CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer.

Cancer Sci 2021 Jul 7;112(7):2915-2920. Epub 2021 Jun 7.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253296PMC
July 2021

A Growth Performance and Nonlinear Growth Curve Functions of Large- and Normal-Sized Japanese Quail ().

J Poult Sci 2021 Apr;58(2):88-96

Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8525, Japan.

This study aimed to evaluate the differences between the growth patterns of large- and normal-sized Japanese quail strains and their F progeny, by fitting their growth parameter values to five nonlinear regression growth models (Weibull, Logistic, Gompertz, Richards, and Brody). The Richards model presented the best fit for both sexes of the large-sized quail strain, whereas the Gompertz model presented the best fit for both sexes of the normal-sized quail strain, based on goodness-of-fit criteria (higher adjusted R and lower Akaike and Bayesian information criteria). Both sexes of F birds derived from the cross between normal-sized females and large-sized males were best fitted by the Richards model. In contrast, growth parameters of the F birds derived from the cross between large-sized females and normal-sized males were best fitted to the Gompertz model. The data could be fitted nearly as well to the Weibull and Logistic models as to the Richards and Gompertz models. The Brody model presented the poorest fit for the growth parameter values. The results indicated that the Richards and Gompertz models could best describe the growth characteristics of both large- and normal-sized quails. Moreover, the observed growth pattern of the F birds was likely inherited from the male parental strain. To the best of our knowledge, this is the first study comparing the growth curves of the reciprocal F generations with their parental strains in quails.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2141/jpsa.0200020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076622PMC
April 2021

A Low Tumor Mutational Burden and Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors.

Clin Cancer Res 2021 Jul 29;27(13):3714-3724. Epub 2021 Apr 29.

National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Purpose: This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade.

Experimental Design: Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC.

Results: Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type (21.4 vs. 54.8%; odds, 4.45; = 0.045). Compared with wild-type mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; < 0.001), lower intratumoral CD8 T-cell levels, higher intratumoral CD204 macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas mutations in the C2 domain were not.

Conclusions: Low TMBs and mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0401DOI Listing
July 2021

Transient suppression of transplanted spermatogonial stem cell differentiation restores fertility in mice.

Cell Stem Cell 2021 08 12;28(8):1443-1456.e7. Epub 2021 Apr 12.

Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8787, Japan. Electronic address:

A remarkable feature of tissue stem cells is their ability to regenerate the structure and function of host tissue following transplantation. However, the dynamics of donor stem cells during regeneration remains largely unknown. Here we conducted quantitative clonal fate studies of transplanted mouse spermatogonial stem cells in host seminiferous tubules. We found that, after a large population of donor spermatogonia settle in host testes, through stochastic fate choice, only a small fraction persist and regenerate over the long term, and the rest are lost through differentiation and cell death. Further, based on these insights, we showed how repopulation efficiency can be increased to a level where the fertility of infertile hosts is restored by transiently suppressing differentiation using a chemical inhibitor of retinoic acid synthesis. These findings unlock a range of potential applications of spermatogonial transplantation, from fertility restoration in individuals with cancer to conservation of biological diversity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351876PMC
August 2021

Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm.

Nat Rev Clin Oncol 2021 08 31;18(8):473-487. Epub 2021 Mar 31.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-021-00492-2DOI Listing
August 2021

Phonon transport in the nano-system of Si and SiGe films with Ge nanodots and approach to ultralow thermal conductivity.

Nanoscale 2021 Mar;13(9):4971-4977

Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka 560-8531, Japan.

Phonon transport in the nano-system has been studied using well-designed nanostructured materials to observe and control the interesting phonon behaviors like ballistic phonon transport. Recently, we observed drastic thermal conductivity reduction in the films containing well-controlled nanodots. Here, we investigate whether this comes from the interference effect in ballistic phonon transport by comparing the thermal properties of the Si or Si0.75Ge0.25 films containing Ge nanodots. The experimentally-obtained thermal resistance of the nanodot layer shows peculiar nanodot size dependence in the Si films and a constant value in the SiGe films. From the phonon simulation results, interestingly, it is clearly found that in the nanostructured Si film, phonons travel in a non-diffusive way (ballistic phonon transport). On the other hand, in the nanostructured SiGe film, although simple diffusive phonon transport occurs, extremely-low thermal conductivity (∼0.81 W m-1 K-1) close to that of amorphous Si0.7Ge0.3 (∼0.7 W m-1 K-1) is achieved due to the combination of the alloy phonon scattering and Ge nanodot scattering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0nr08499aDOI Listing
March 2021

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens.

Sci Rep 2021 01 11;11(1):341. Epub 2021 Jan 11.

Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan.

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-79385-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801605PMC
January 2021

ASO Author Reflections: Circulating Tumor DNA (ctDNA) as a Potentially Practice-Changing Innovation to Evolve "Precision Onco-Surgery" in Resectable Colorectal Liver Metastases.

Ann Surg Oncol 2021 Aug 4;28(8):4756-4757. Epub 2021 Jan 4.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 2770882, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09456-9DOI Listing
August 2021

Impact of Preoperative Circulating Tumor DNA Status on Survival Outcomes After Hepatectomy for Resectable Colorectal Liver Metastases.

Ann Surg Oncol 2021 Aug 3;28(8):4744-4755. Epub 2021 Jan 3.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Background: The optimal perioperative management of patients who undergo hepatectomy for resectable colorectal liver metastases (CRLM) remains unclear due to the lack of reliable methods to stratify the risk of recurrence.

Methods: A single-center retrospective study was performed to investigate the impact of preoperative circulating tumor DNA (ctDNA) on survival outcomes of patients who underwent initial hepatectomy for solitary resectable CRLM between January 2005 and December 2017 using the comprehensive genotyping platform Guardant360.

Results: Of 212 patients who underwent initial hepatectomy for solitary resectable CRLM, 40 patients for whom pre-hepatectomy plasma was available underwent ctDNA analysis. Among them, 32 (80%) had at least 1 somatic alteration in their ctDNA, while the other 8 (20%) had no detectable ctDNA. Among the patients with undetectable ctDNA, only one had recurrence and none died during a median follow-up period of 39.0 months. The recurrence-free survival was significantly shorter in patients who were positive for ctDNA than in those who were negative for ctDNA [median, 12.5 months vs not reached (NR); HR, 7.6; P = 0.02]. The overall survival also tended to be shorter in patients who were positive for ctDNA than those who were negative for ctDNA (median, 78.1 months vs NR; P = 0.14; HR not available).

Conclusions: In patients undergoing hepatectomy for solitary resectable CRLM, the absence of detectable preoperative ctDNA identified patients with a high chance for a cure. Risk stratification according to preoperative ctDNA analysis may be an effective tool that can improve the perioperative management of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09449-8DOI Listing
August 2021

Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2021 06 13;20(2):113-120.e1. Epub 2020 Nov 13.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address:

Background: The prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear.

Patients And Methods: This study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing.

Results: Between 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036).

Conclusion: HER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2020.11.002DOI Listing
June 2021

[Precision Medicine for Advanced Solid Malignancies Based on Circulating Tumor DNA Analysis].

Gan To Kagaku Ryoho 2020 Dec;47(12):1645-1652

Dept. of Gastrointestinal Oncology, National Cancer Center Hospital East.

Cancer precision medicine has become widespread in the world. In Japan, genomic profiling tumor tissues using next generation sequencing(NGS)has been reimbursed to enable simultaneous measurement of multiple biomarkers and genomic abnormalities in clinical practice. However, NGS analysis of tumor tissue has several problems, including long turnaround time, and difficulty in capturing heterogeneity and longitudinal genotyping. Liquid biopsy, an advanced technique that has been developed in recent years, can assess the status of tumors using samples of body fluids, such as blood and urine, without the use of tumor tissue. In particular, circulating tumor DNA(ctDNA), which is released from tumor cells into the blood by apoptosis and necrosis, can be used to select molecularly targeted therapies, monitor therapeutic efficacy, and determine risk of recurrence and select for adjuvant chemotherapy by assessment of minimal residual disease(MRD). In this review, we outline the usefulness, disadvantages and future perspectives of ctDNA analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2020

[Ⅱ.Diagnosis and Treatment of HER2-Positive Metastatic Colorectal Cancer].

Gan To Kagaku Ryoho 2020 Nov;47(11):1565-1569

Dept. of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East.

View Article and Find Full Text PDF

Download full-text PDF

Source
November 2020

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1).

Int J Clin Oncol 2021 Feb 29;26(2):233-283. Epub 2020 Nov 29.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published "Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment" in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made.

Methods: A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020.

Results: The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines.

Conclusion: We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-020-01831-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819967PMC
February 2021

FMS-like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer.

Cancer Sci 2021 Jan 20;112(1):314-322. Epub 2020 Nov 20.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

FMS-like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co-altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co-alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non-FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780005PMC
January 2021

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Nat Med 2020 12 5;26(12):1859-1864. Epub 2020 Oct 5.

Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1063-5DOI Listing
December 2020

Flexion Angles of Finger Joints in Two-Finger Tip Pinching Using 3D Bone Models Constructed from X-Ray Computed Tomography (CT) Images.

Appl Bionics Biomech 2020 10;2020:8883866. Epub 2020 Sep 10.

Department of Radiology School of Medicine, Jichi Medical University and Hospital, Tochigi 329-0498, Japan.

The motion analysis of two-finger tip pinching using the thumb and index finger provides crucial data for designing the motion mechanism of electric prosthetic hands. The purpose of this study is to determine the joints that have high mobility during two-finger tip pinching by measuring the flexion angle of each joint. Ten Japanese men with normal hand were selected. CT images were obtained while the hands adopted the following four postures: a basic posture not pinching a cylinder, and three postures pinching wooden cylinders with different diameters (2, 10, and 30 mm). Three-dimensional bone models of the thumb and index finger were created using the CT images and used to measure the flexion angles of the joints. The flexion angles of the proximal interphalangeal and metacarpophalangeal joints of the index finger significantly decreased as the diameter of the cylinder increased. However, even when the diameter of the cylinder changed, the flexion angle of the distal interphalangeal joint of the index finger, and the flexion and rotation angles of all of the thumb joints did not change. When pinching objects of different sizes with a two-finger tip pinch, the posture of the thumb is fixed, and only the posture of the index finger changes. When designing the two-finger tip pinch motion for an electric prosthetic hand, it is sufficient to drive the joints of the index finger only.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8883866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501542PMC
September 2020

Development of circulating tumour DNA analysis for gastrointestinal cancers.

ESMO Open 2020 01;5(Suppl 1):e000600

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address:

Comprehensive genomic profiling using next-generation sequencing (NGS) enables the identification of multiple genomic biomarkers established in advanced gastrointestinal (GI) cancers. However, tissue-based NGS has limitations, such as long turnaround time and failure to detect tumour heterogeneity. Recently, the analysis of circulating tumour DNA (ctDNA) using polymerase chain reaction-based or NGS-based methods has demonstrated the capability to detect genomic alterations with high accuracy compared with tumour tissue analysis with short turnaround time and identify heterogeneous resistance mechanisms. Furthermore, ctDNA analysis can be repeatedly performed on disease progression to clarify resistant clones. Clinical trials that test the outcome of a selected targeted therapy based on a ctDNA result are ongoing to prospectively evaluate the clinical utility of ctDNA analysis. Furthermore, the improvement of ctDNA analysis beyond current technical limits of mutation-based ctDNA detection methods has expanded the potential for detecting the presence of tumours in patients with no clinically evident disease, such as minimal residual disease and early cancer. Although a careful understanding of the advantages and limitations are required and further prospective studies are needed, the ctDNA analysis has the potential to overcome several challenges in the treatment of various types of cancers at all stages, including GI cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2019-000600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003376PMC
January 2020

Clinical and molecular factors for selection of nivolumab or irinotecan as third-line treatment for advanced gastric cancer.

Ther Adv Med Oncol 2020 17;12:1758835920942377. Epub 2020 Jul 17.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center, Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

Background: The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial.

Methods: This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS).

Results: A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 2.0 months) and OS (median 12.9 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 1.8 months) and a trend of longer OS (median 3.9 6.1 months) in patients with ⩾2 of these factors.

Conclusions: Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1758835920942377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370559PMC
July 2020
-->