Adjuvant chemotherapy after surgery improves survival of patients with stage II–III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, ...suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II–III gastric cancer.
In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II–III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival.
We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2–92·0), 74·8% (69·9–80·1), and 66·0% (60·1–72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% 95% CI 73·5–87·1 vs 64·5% 56·8–73·3; univariate hazard ratio 0·47 95% CI 0·30–0·75, p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% 66·5–79·9 in patients who received chemotherapy plus surgery vs 72·5% 65·8–79·9 in patients who only had surgery; 0·93 0·62–1·38, p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort.
The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II–III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted.
Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.
Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in ...gastric cancer are lacking. In this retrospective analysis, we use our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identify four molecular subtypes that are prognostic for survival. We then built a support vector machine with linear kernel to generate a risk score that is prognostic for five-year overall survival and validate the risk score using three independent datasets. We also find that the molecular subtypes predict response to adjuvant 5-fluorouracil and platinum therapy after gastrectomy and to immune checkpoint inhibitors in patients with metastatic or recurrent disease. In sum, we show that the 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated using large patient cohorts in a prospective manner.
The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular ...targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial ...phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.
This study investigated whether MSI status can be used as a prognostic biomarker and whether it is helpful for predicting which patients will benefit from 5‐FU based adjuvant chemotherapy. Between ...2005 and 2008, an MSI status examination was performed in 1,990 gastric cancer patients who had undergone curative gastrectomy for gastric adenocarcinoma. MSI was analyzed by PCR amplification with fluorescent dye‐labeled primers of mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D5S346, D2S123 and D17S250) specific to the microsatellite loci. Patients with MSI‐H tumors accounted for 8.5% (n = 170) of the total study population. They tended to be older and female and to have distal tumor location, lower tumor stage, intestinal type of Lauren classification and differentiated histological type. The disease‐free survival curves showed no significant differences between MSS/MSI‐L and MSI‐H patients at each stage of I, II, III and IV. In gastric cancer patients with stage II and III, 5‐FU‐based adjuvant chemotherapy showed better disease‐free survival in the MSS/MSI‐L group, but showed no benefits in the MSI‐H group. By multivariate analysis, patients with MSS/MSI‐L tumors benefited from 5‐FU‐based adjuvant chemotherapy in terms of tumor disease‐free survival. MSI status in gastric cancer is not itself a prognostic indicator. However, it appears to be a possible guidance for the use of 5‐FU‐based chemotherapy in stage II and III gastric cancers after R0 resection.
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Through whole-exome and transcriptome analyses ...of 191 spontaneous canine mammary tumors (CMTs) that exhibit the archetypal features of human breast cancers, we found a striking resemblance of genomic characteristics including frequent PIK3CA mutations (43.1%), aberrations of the PI3K-Akt pathway (61.7%), and key genes involved in cancer initiation and progression. We also identified three gene expression-based CMT subtypes, one of which segregated with basal-like human breast cancer subtypes with activated epithelial-to-mesenchymal transition, low claudin expression, and unfavorable disease prognosis. A relative lack of ERBB2 amplification and Her2-enrichment subtype in CMT denoted species-specific molecular mechanisms. Taken together, our results elucidate cross-species oncogenic signatures for a better understanding of universal and context-dependent mechanisms in breast cancer development and provide a basis for precision diagnostics and therapeutics for domestic dogs.
In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable ...gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.
We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery
surgery) with MSI.
MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio HR, 1.88; 95% CI, 1.28 to 2.76;
< .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73;
= .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).
In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
Accurate prediction of treatment response for cancer patients is essential for overcoming intrinsic therapy resistance that results from genetic heterogeneity, varying tumor growth kinetics, and the ...complex tumor microenvironment. To achieve this goal, there is an urgent need for effective preclinical in vitro models that recapitulate the molecular–pathologic features and intricate ecology of native tumors for precision medicine. In this study, a vascularized organoid model (VOM) composed of patient‐derived gastric cancer organoids (PDOs), perfusable endothelium, and stomach decellularized extracellular matrix is presented that enables the prediction of clinical response to VEGFR2‐targeted therapy in gastric cancer patients. The results indicate that VOMs are dependent on the PDO molecular subtype. Moreover, VOMs accurately reproduce the clinically observed responses of patients treated with VEGFR2 inhibitor. Therefore, VOMs represent a valuable platform for providing clinical predictions for personalized testing and potential discovery of therapeutic drugs in various cancers that lack standardized regimens.
The Vascularized Organoid Model (VOM) accurately reproduces the drug response observed in patients in a clinic by providing a highly biomimetic cancer system to PDOs. The system is composed of stomach‐specific and collagen‐enriched materials, interstitial‐like tissue, and a perfusable blood vessel that enables drug delivery through vessels to the organoids instead of direct exposure.
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