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

Miguel Córdova-Delgado ,Rocío Artigas,Matías Freire,Javiera Torres,Matías Muñoz-Medel,Betzabé Cisternas,Carolina Ibáñez,Fernando Crovari,Nathaly De La Jara,Bruno Nervi,Jorge Madrid,Enrique Norero,Ricardo Armisén,Liliana Ramos,Valentina Gárate-Calderón,Javier Cáceres,Manuel Espinoza,Gareth I Owen,José Peña,Ignacio N Retamal,Yuwei Liao,Francisco Acevedo,Gonzalo Sepúlveda-Hermosilla,Mauricio P Pinto,Diego Romero,Marcelo Garrido,Rodrigo Lizana,Sebastián Mondaca,María Loreto Bravo,María Florencia Fernández ,Héctor Galindo ,Alejandro Corvalán ,César Sánchez ,Catalina Balmaceda ,María J Maturana ,Érica Koch ,Chi Kong Li

doi:10.3390/cancers11091275

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.

Highlights

Worldwide, stomach or gastric cancer (GC) currently ranks as the fifth most common malignancy and the third leading cause of cancer mortality [1]
We found that 28.9% of patients in our cohort were PDL1+ (by combined positive score (CPS) ≥ 10); 13% were classified as MMR-deficient
A better patient stratification based on molecular profiling obtained from different geographical areas might contribute to rationalize the use of targeted therapies, improving patient survival

Summary

Introduction

Stomach or gastric cancer (GC) currently ranks as the fifth most common malignancy and the third leading cause of cancer mortality [1]. Studies demonstrate GC incidence and mortality rates display wide regional/geographical heterogeneity. Over half of the new GC cases are diagnosed in developing countries. High-risk areas include East Asian, Eastern Europe, Central and South. Southern Asia, North and East Africa, North America, Australia, and New Zealand are low-risk areas. Mortality/survival rates exhibit a wide geographical heterogeneity. Within South America, mortality rates range from 3.6 to 23.6 per 100,000/year. In Chile, GC is the leading cause of cancer death with 25.1 and 13.2 per 100,000/year for men and women, respectively [2,3]. Several factors may explain this scenario, most studies suggest that high mortality rate can be attributed to late diagnosis, due to slow-growing asymptomatic tumors

Methods

Discussion

Conclusion