High Proportion of Potential Candidates for Immunotherapy in a Chilean Cohort of Gastric Cancer Patients: Results of the FORCE1 Study

Abstract

Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA; n = 90) and next generation sequencing (NGS; n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.

A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability

“…In particular, the percentage of EBV+ in our study is markedly higher (13%) versus the abovementioned studies (5%, 7%, or 9%, respectively). However, this is a characteristic of the Chilean population that has been reported previously [18,19]. Regarding the percentage of the MMR-D subtype (12%), this is fairly close to the 14% commonly observed in the routine clinic and reported by similar studies [20].…”

“…Patient inclusion criteria were age ≥18, diagnosed with confirmed GC, with ≥3 months of clinical follow-up, and able and willing to sign an informed consent. A subset of these patients were previously characterized as part of the FORCE1 study [19]. All participants signed a consent form to publish.…”

“…EBV status was determined using paraffin block sections obtained from FFPE samples. EBER1 expression was detected by a chromogenic in situ hybridization (CISH) method described previously [18,19]. MMR status was determined using a set of 4 biomarkers assessed by IHC [19].…”

“…EBER1 expression was detected by a chromogenic in situ hybridization (CISH) method described previously [18,19]. MMR status was determined using a set of 4 biomarkers assessed by IHC [19]. These are DNA repair enzymes coded by the MLH1, PMS2, MSH2, and MSH6 genes.…”

Molecular Classification of Gastric Cancer among Alaska Native People

“…In this study, we sought to gain a deeper understanding of the molecular features of gastric cancer in the AN population. Our analysis of a targeted 50 somatic gene mutation panel confirmed 60.6% of the patients had one or more gene mutations with the TP53 gene being the most frequently altered among AN patients, which was similar but lower in frequency, 36% when compared to other populations, 46-49% [13,[22][23][24]. Other genes that were commonly mutated in AN gastric cancer patients were PIK3CA, PTEN, KRAS, APC, and CTNN1B, which were comparable to the TCGA study (Table 3) [13].…”