Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3′ massive analysis of cDNA ends (3′MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-β-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/β-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.

Case Report Proteogenomic analysis in an early onset diffuse gastric cancer patient revealed alterations in PIK3R1, TP53, SMAD4 and a potential role of the PI3K-AKT and EGFR pathways: a case report Miguel Cordova-Delgado, Mauricio P. Pinto, Gonzalo Pizarro, Elard Koch, Cristian Vargas, Mauricio Hernández, Guillermo Nourdin, Pablo Saldivia, Maria Paz Rodriguez Z., Alejandro Berkovits, Patricio Manque, Juvenal A. Rios, Benjamin Garcia-Bloj, Marcelo Garrido

Major advances in sequencing technologies and targeted therapies have accelerated the incorporation of oncology into the era of precision medicine and “biomarker-driven” treatments. However, the impact of this approach on the everyday clinic has yet to be determined. Most precision oncology reports are based on developed countries and usually involve metastatic, hard-to-treat or incurable cancer patients. Moreover, in many cases race and ethnicity in these studies is commonly unreported and real-world evidence in this topic is scarce. Herein, we report data from a total of 202 Chilean advanced stage refractory cancer patients. Retrospectively, we collected patient data from NGS tests and IHC in order to determine the proportion of patients that would benefit from targeted treatments. Overall >20 tumor types were included in our cohort and 37% of patients (n = 74) displayed potentially actionable alterations, including on-label, off-label and immune checkpoint inhibitor recommendations. Our findings were in-line with previous reports such as the cancer genome atlas (TCGA). To our knowledge, this is the first report of its kind in Latin America delivering real-world evidence to estimate the percentage of refractory tumor patients that might benefit from precision oncology. Although this approach is still in its infancy in Chile, we strongly encourage the implementation of mutational tumor boards in our country in order to provide more therapeutic options for advanced stage refractory patients.

Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. Methods: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni’s multiple adjustment tests determined statistical differences between allele frequencies. Results: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031–0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. Conclusions: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.

Background: About 80–90% of gastrointestinal stromal tumor (GIST) patients harbor KIT proto-oncogene (KIT) and/or platelet-derived growth factor receptor alpha (PDGFRA) gain-of-function mutations. The KIT gene also encodes a tyrosine kinase receptor; therefore, KIT/PDGFRA alterations not only serve as hallmarks, but also as potential therapeutic targets. Previous reports have demonstrated that differences in the KIT/PDGFRA mutation rates are generally attributed to ethnic and/or technical factors. Herein, we report a molecular profiling of KIT/PDGFRA in a Latin American cohort of GIST patients. Methods: In this observational study, DNA samples were obtained from paraffin blocks in 42 GIST patients. We performed KIT/PDGFRA molecular profiling by Sanger sequencing. Patients’ clinical characteristics were obtained from their medical records. A single case was further analyzed with next-generation sequencing (NGS). Results: Patients were predominantly females (n=22; 52.4%). Median age at diagnosis was 53 years old. As expected, the stomach was the most frequent primary location (47.6%), and 38.1% of cases were metastatic. We detected KIT and PDGFRA alterations in 64.3% and 4.8% of patients, respectively. Within this subset (n=29), 82.8% had exon-11 KIT mutations, and 6.9% had exon 18 PDGFRA mutations. As predicted, KIT and PDGFRA mutations were mutually exclusive, and 31% (n=13) were wild-type KIT/PDGFRA. These results could be attributed to ethnic and methodological differences. Therefore, we presented a case of a metastatic patient analyzed by NGS to illustrate the clinical utility of an alternative screening strategy to Sanger sequencing. Conclusions: There were a high proportion of wild-type GISTs in this cohort. This could be attributed to technical/methodological and/or ethnic/genetic differences. Our findings also encourage the use of alternative techniques, such as NGS for KIT/PDGFRA screenings, particularly in the case of advanced-stage patients.