Interaction between intratumoral ERCC1 expression and adjuvant treatment with S-1 on the survival of patients enrolled in the ACTS-GC study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 53-53 ◽  
Author(s):  
Koji Kitada ◽  
Atsushi Ochiai ◽  
Wataru Ichikawa ◽  
Masanori Terashima ◽  
Issei Kurahashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Adjuvant Treatment ◽  
Excision Repair ◽  
Predictive Marker ◽  
Phase Iii ◽  
Biomarker Analysis ◽  
The Difference ◽  
Ercc1 Expression ◽  
Gastric Cancer Patients

53 Background: Excision repair cross-complementing group 1 (ERCC1) is thought to be involved in resistance to platinum-based therapy. Recently, expression of this gene was shown to be associated with the outcome in patients with gastric cancer. Biomarker analysis was conducted to evaluate the influence of this gene expression on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007). Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. ERCC1 expression was measured by RT-PCR in the macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression of ERCC1 was categorized into low and high values at the median. Results: The ERCC1 expression level was quantifiable in 97% of the 829 specimens and the distribution was balanced across the arms. In the S-1 group, overall survival (OS) tended to be longer in the high ERCC1 expression group than in the low ERCC1 expression group (HR, 0.698; 95% CI, 0.469-1.040; p= 0.076). On the contrary, in the surgery group, the OS was shorter in the high ERCC1 expression group than in the low ERCC1 expression group (HR, 1.216; 95% CI, 0.881-1.679; p= 0.232), although the difference was not statistically significant. The HR for OS of S-1 to surgery alone was smaller in the high-ERCC1 (HR, 0.465; 95% CI, 0.320-0.678) than in the low-ERCC1 group (HR, 0.805; 95% CI, 0.568-1.141). Significant interaction between the S-1 group and ERCC1 expression was observed (p= 0.033). Conclusions: This large biomarker study showed that intratumoral ERCC1 gene expression may be a predictive marker in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.

scholarly journals Proliferation Cycle Transcriptomic Signatures are Strongly associated With Gastric Cancer Patient Survival

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianwen Hu ◽  
Yanpeng Yang ◽  
Yongchen Ma ◽  
Yingze Ning ◽  
Guowei Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Treatment Options ◽  
Disease Diagnosis ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Transcriptome Data ◽  
Genomic Changes ◽  
The Difference ◽  
Gastric Cancer Patients

Gastric cancer is one of the most heterogeneous tumors with multi-level molecular disturbances. Sustaining proliferative signaling and evading growth suppressors are two important hallmarks that enable the cancer cells to become tumorigenic and ultimately malignant, which enable tumor growth. Discovering and understanding the difference in tumor proliferation cycle phenotypes can be used to better classify tumors, and provide classification schemes for disease diagnosis and treatment options, which are more in line with the requirements of today’s precision medicine. We collected 691 eligible samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, combined with transcriptome data, to explore different heterogeneous proliferation cycle phenotypes, and further study the potential genomic changes that may lead to these different phenotypes in this study. Interestingly, two subtypes with different clinical and biological characteristics were identified through cluster analysis of gastric cancer transcriptome data. The repeatability of the classification was confirmed in an independent Gene Expression Omnibus validation cohort, and consistent phenotypes were observed. These two phenotypes showed different clinical outcomes, and tumor mutation burden. This classification helped us to better classify gastric cancer patients and provide targeted treatment based on specific transcriptome data.

Impact of the gene expressions of thymidylate synthase and dihydropyrimidine dehydrogenase on survival in patients enrolled in the ACTS-GC study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 52-52 ◽  
Author(s):  
Mitsuru Sasako ◽  
Masanori Terashima ◽  
Wataru Ichikawa ◽  
Atsushi Ochiai ◽  
Koji Kitada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Thymidylate Synthase ◽  
Statistical Significance ◽  
Dihydropyrimidine Dehydrogenase ◽  
Phase Iii ◽  
P Value ◽  
Gene Expressions ◽  
Biomarker Analysis ◽  
Formalin Fixed Paraffin Embedded ◽  
Gastric Cancer Patients

52 Background: The efficacy of 5-FU-based therapy is basically related to the expression of enzymes involved in pyrimidine metabolism, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT). Biomarker analysis was conducted to evaluate the influence of these expressions on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007) Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. Expressions of TS, DPD, TP and OPRT were measured by RT-PCR in macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression levels of each gene were categorized as low or high at the 33.3rd or 66.7th percentile. If the p-value of the interaction was less than 0.1, statistical significance was assumed. Results: Expressions of the 4 genes were quantifiable in 97% of the 829 specimens and the distributions were balanced across the arms. The hazard ratio (HR) for overall survival (OS) of S-1 to surgery alone was smaller in the high-TS (highest one-third) (HR, 0.370; 95%CI, 0.221-0.619) than in the low-TS group (lower two-thirds) (HR, 0.757; 95%CI, 0.563-1.018). This interaction between TS expression and OS was statistically significant (p=0.015). Similarly, the HR for OS of S-1 to surgery alone was smaller in the high-DPD (higher two-thirds) (HR, 0.520; 95%CI, 0.376-0.720) than in the low-DPD group (lowest one-third) (HR, 0.848; 95%CI, 0.563-1.276). This interaction (p=0.065) was also statistically significant. There was no interaction between the TP or OPRT expression and OS. Conclusions: This large biomarker study showed that intratumoral TS and DPD gene expressions may be predictive markers of the efficacy of S-1 in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.

Polymorphism of nucleotide excision repair genes as predictors for clinical outcome in advanced gastric cancer patients treated with oxaliplatin-based chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4565-4565
Author(s):  
H. Hur ◽  
K. Song ◽  
C. Park ◽  
Y. Hong ◽  
H. Chun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Cancer Patients ◽  
Excision Repair ◽  
Predictive Marker ◽  
Hematologic Toxicity ◽  
Nucleotide Excision ◽  
Grade 3 ◽  
Gastric Cancer Patients ◽  
Repair Genes

4565 Background: The individual variations in treatment response and the toxicity of combination regimen of oxaliplatin and 5-fluorouracil with leucovorin (FOLFOX) for advanced gastric cancer patients have been reported. The aim of this study is to evaluate the influence of polymorphism of nucleotide excision repair genes that are involved in the metabolism of cisplatin on the clinical outcomes of gastric cancer patients treated with modified FOLFOX-6 chemotherapy. Methods: From March 2006 to December 2007, eighty-two patients with advanced gastric cancer were treated with modified FOLFOX-6 as the primary chemotherapy in our institution. Of these patients, 55 patients who were available for peripheral blood sampling before starting chemotherapy were enrolled in this study. Genomic DNA was extracted from mononuclear cells of patients’ blood. Four polymorphisms were investigated in three genes, ERCC, GSTP and XRCC. Results: The overall response rate (RR) was 40.0%. Median time to progression (TTP) and overall survival (OS) was 6 months (C.I.: 5.0 - 7.0 months) and 15.0 months (C.I.: 9.7 - 20.3 months). Grade 3 or 4 hematologic toxicities were presented in 17 patients (30.9%), gastrointestinal toxicities in 5 patients (9.1%), peripheral neuropathy in 5 patients (9.1%) and hepato-toxicity in 4 patients (7.3%). Most common types of polymorphism were G/G (67.3%) in XRCC1 Arg399Gln, A/A (74.5%) in GSTP1 Ile105Val, C/C (60.0%) in ERCC1 Asn118Asn and C/A (49.1%) in ERCC1 C8092A. The RR was significantly lower in patients with C/C type in ERCC1 C8092A gene than those with other type (25.0% vs 51.6%, p=0.046). However, there were no differences of TTP and OS among the polymorphisms in three genes. The rate of grade 3 or 4 hematologic toxicity was higher in patients with C/T or T/T in ERCC1 codon 118 gene than those with C/C type (45.5% vs 21.2%, p=0.057). Conclusions: We demonstrated that modified FOLFOX-6 chemotherapy was effective and tolerable. The polymorphism of C/C type in ERCC1 C8092A gene was found to be a predictive marker of the poor response and C/C type in ERCC1 Asn118Asn gene was to be a predictive marker of the hematologic toxicity. No significant financial relationships to disclose.

Multicenter Phase II Trial of S-1 Plus Cisplatin in Patients With Untreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

2006 ◽  
Vol 24 (4) ◽  
pp. 663-667 ◽  
Author(s):  
Jaffer A. Ajani ◽  
Fa-Chyi Lee ◽  
Deepti A. Singh ◽  
Daniel G. Haller ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Median Number ◽  
Phase Iii ◽  
Highly Active ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Gastric Cancer Patients

Purpose S-1 plus cisplatin is considered highly active in Japanese gastric cancer patients. We conducted a phase II multi-institutional trial, in the West, in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma to evaluate activity and safety of this combination. Methods Patients received cisplatin intravenously at 75 mg/m2 on day 1 and S-1 orally at 25 mg/m2/dose bid (50 mg/m2/d) on days 1 to 21, repeated every 28 days. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with a Karnofsky performance status (KPS) of ≥ 70% and near-normal organ function were eligible. All patients provided a written informed consent. To observe a 45% confirmed overall response rate (ORR), 41 assessable patients were needed. Results All 47 patients were assessed for safety and survival, and 41 patients were assessed for ORR. The median age was 56 years and median KPS was 80%. The median number of chemotherapy cycles was four. The confirmed ORR was 51% (95% CI, 35% to 67%) and it was 49% by an independent review. At the 6-month interval, 71% of patients were alive, with a median survival time of 10.9 months. Frequent grade 3 or 4 toxicities included fatigue (26%), neutropenia (26%), vomiting (17%), diarrhea (15%), and nausea (15%); however, stomatitis (2%) and febrile neutropenia (2%) were uncommon. There was one (2%) treatment-related death. Conclusion S-1 plus cisplatin is active against gastric cancer and has a favorable toxicity profile. A global phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin currently is accruing patients.

Effect of baseline sarcopenia on adjuvant treatment for D2 dissected gastric cancer: Analysis of the ARTIST phase III trial

2020 ◽  
Vol 152 ◽  
pp. 19-25
Author(s):  
Jeong Il Yu ◽  
Changhoon Choi ◽  
Jeeyun Lee ◽  
Won Ki Kang ◽  
Se Hoon Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Adjuvant Treatment ◽  
Phase Iii ◽  
Phase Iii Trial

scholarly journals Neoantigens Derived from Recurrently Mutated Genes as Potential Immunotherapy Targets for Gastric Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Zhou ◽  
Wenyi Zhao ◽  
Jingcheng Wu ◽  
Jun Lu ◽  
Yongfeng Ding ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Sequencing Data ◽  
Driver Genes ◽  
Cell Immunotherapy ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Gastric Cancer Patients

Neoantigens are optimal tumor-specific targets for T-cell based immunotherapy, especially for patients with “undruggable” mutated driver genes. T-cell immunotherapy can be a “universal” treatment for HLA genotype patients sharing same oncogenic mutations. To identify potential neoantigens for therapy in gastric cancer, 32 gastric cancer patients were enrolled in our study. Whole exome sequencing data from these patients was processed by TSNAD software to detect cancer somatic mutations and predict neoantigens. The somatic mutations between different patients suggested a high interpatient heterogeneity. C>A and C>T substitutions are common, suggesting an active nucleotide excision repair. The number of predicted neoantigens was significantly higher in patients at stage T1a compared to in patients at T2 or T4b. Six genes (PIK3CA, FAT4, BRCA2, GNAQ, LRP1B, and PREX2) were found as recurrently mutated driver genes in our study. Combining with highly frequent HLA alleles, several neoantigens derived from six recurrently mutated genes were considered as potential targets for further immunotherapy.

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