Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study
Authors: Ottaiano Alessandro , De Luca Antonella , Santorsola Mariachiara , Scognamiglio Giosuè , Di Mauro Annabella , Chiodini Paolo , Lambiase Matilde , Sacco Alessandra , Petrillo Antonella , Granata Vincenza , Fusco Roberta , Mercadante Edoardo , Martucci Nicola , De Luca Giuseppe , Rocca Antonello La , Celentano Egidio , Crispo Anna , Di Gennaro Piergiacomo , Tatangelo Fabiana , Ferrara Gerardo , Izzo Francesco , Belli Andrea , Patrone Renato , Delrio Paolo , Rega Daniela , De Franciscis Silvia , Muto Paolo , Ravo Vincenzo , Di Franco Rossella , Borzillo Valentina , Santagata Sara , Rea Giuseppina , Castaldo Daniela , Pace Ugo , De Feo Gianfranco , Scala Stefania , Nasti Guglielmo , Normanno Nicola 
Published: October 2023

Abstract
Background
Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as “oligo-metastatic disease” (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies.

Methods
The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients.

Discussion
Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment.

Trial registration
ClinicalTrials.gov ID NCT05806151.