A predictive signature for oxaliplatin and 5-fluorouracil based chemotherapy in locally advanced gastric cancer

Abstract

Adjuvant chemotherapy(AC) plays a substantial role in the treatment of locally advanced gastric cancer (LAGC), but the response remains poor. We aims to improve its efficacy in LAGC. Therefore, we identified the expression of eight genes closely associated with platinum and fluorouracil metabolism ( RRM1 , RRM2 , RRM2B , POLH , DUT , TYMS , TYMP , MKI67 ) in the discovery cohort (N=291). And we further validated the findings in TCGA (N=279) and GEO. Overall survival (OS) was used as an endpoint. Univariate and multivariate Cox models were applied. A multivariate Cox regression model was simulated to predict the OS. In the discovery cohort, the univariate Cox model indicated that AC was beneficial to high-RRM1, high-DUT, low-RRM2, low-RRM2B, low-POLH, low-KI67, low-TYMS or low-TYMP patients, the results were validated in the TCGA cohort. The multivariate Cox model showed consistent results. Cumulative analysis indicated that patients with low C-Score respond poorly to the AC, whereas the high and medium C-Score patients significantly benefit from AC. A risk model based on the above variables successfully predicted the OS in both cohorts (AUC=0.75 and 0.67, respectively). Further validation in a panel of gastric cancer cell (GC) lines (N=37) indicated that C-Score is significantly associated with IC50 value to fluorouracil. Mutation profiling showed that C-Score was associated with the number and types of mutations. In conclusion, we successfully simulated a predictive signature for the efficacy of AC in LAGC patients and further explored the potential mechanisms. Our findings could promote precision medicine and improve the prognosis of LAGC patients.

Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy

“…DUT RNA expression was also associated with shorter disease-free survival in colorectal cancer patients undergoing adjuvant chemotherapy with 5-FU (67). In gastric tumor patients, positive expression of DUT at the protein level was associated with high grade and younger age at diagnosis (68). Our study revealed for the first time the association of DUT expression with the presence of distant metastases, which are a sign of worse prognosis in EOC patients.…”

Transcriptome-based stemness indices analysis reveals platinum-based chemo-theraputic response indicators in advanced-stage serous ovarian cancer

“…However, the underlying mechanism of how the genes impacted OS and PFS in a reverse pattern still needed to be further illuminated. Among the PFS-associated genes, AURKA [ 22 , 39 ], CDK1 [ 40 ], and RRM2 [ 12 ] had been validated correlating to the platinum response by experimental methods. These reports partially verified that identifying platinum-response indicators among stemness-associated genes according to mRNAsi was reliable and worthwhile.…”

“…The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed and visualized by clusterProfiler R package, enrichplot, and ggplot2 [ 12 ]. The candidate key genes were eventually selected according to the enriched pathways.…”

Neoadjuvant Chemotherapy with S-1 and Oxaliplatin followed by Laparoscopic D2 Gastrectomy for Clinical Stage III Gastric Cancer: Primary Results of Phase II nacG-SOX130 Study

“…In the clinical setting, the AIO-FLOT4 study demonstrated that the replacement of cisplatin to oxaliplatin in combination with epirubicin to docetaxel, did show a higher rate of curative resection (84% versus77%, p=0.01), and prolonged OS [HR 0.77 (0.63-0.94), p=0.012] [19]. More recently, oxaliplatin-specific signatures based on tumor biology are rigorously sought after in gastric cancer [20]. In order to clarify these confusing understandings about neoadjuvant chemotherapy for resectable gastric cancer, it is necessary to plan a new study targeting the pure neoadjuvant population of Stage III patients with a regimen containing oxaliplatin instead of cisplatin, and also with the latest non-invasive radical D2 surgery.…”