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. 2025 Feb:60:101111.
doi: 10.1016/j.neo.2024.101111. Epub 2024 Dec 21.

Clinical and genetic drivers of oligo-metastatic disease in colon cancer

Alessandro Ottaiano  1 , Mariachiara Santorsola  2 , Roberto Sirica  3 , Annabella Di Mauro  4 , Antonella Di Carlo  3 , Monica Ianniello  3 , Francesco Sabbatino  5 , Rosa Castiello  3 , Francesca Del Peschio  3 , Marco Cascella  6 , Francesco Perri  7 , Maurizio Capuozzo  8 , Nicola Martucci  9 , Edoardo Mercadante  9 , Valentina Borzillo  10 , Rossella Di Franco  10 , Francesco Izzo  11 , Vincenza Granata  12 , Carmine Picone  12 , Antonella Petrillo  12 , Massimiliano Berretta  13 , Salvatore Stilo  14 , Luca Tarotto  14 , Anna Chiara Carratù  2 , Gerardo Ferrara  4 , Madhura Tathode  15 , Alessia Maria Cossu  15 , Marco Bocchetti  15 , Michele Caraglia  15 , Guglielmo Nasti  2 , Giovanni Savarese  3
Affiliations

Clinical and genetic drivers of oligo-metastatic disease in colon cancer

Alessandro Ottaiano et al. Neoplasia. 2025 Feb.

Abstract

Background: Oligo-metastatic disease (OMD) in colon cancer patients exhibits distinct clinical behavior compared to poly-metastatic disease (PMD), with a more responsive and indolent course. This study aims to identify clinical and biological factors uniquely associated with oligo-metastatic behavior.

Methods: Metastatic colon cancer patients from an academic center underwent genetic characterization. OMD was defined as ≤3 lesions per organ, each with a total diameter <70 mm and none exceeding 25 mm. Tumor DNA sequencing by NGS utilized the TruSight Oncology 500 kit. Overall survival (OS) was determined from metastasis diagnosis until death using Kaplan-Meier analysis. Multivariate Cox regression examined prognostic links between clinicopathological and genetic factors. Associations with metastatic patterns were evaluated using Chi-square.

Results: The analysis involved 104 patients (44 with OMD, 60 with PMD). OMD was more prevalent in males (P = 0.0299) and with single organ involvement (P = 0.0226). Multivariate analysis adjusted for age (>70 vs. <70 years), gender (male vs. female), tumor side (right vs. left), metastatic involvement (more than one site vs. one site), response to first-line therapy (disease control vs. no disease control), and RAS/BRAF variants (wild-type vs. mutated) identified OMD vs. PMD as the strongest independent predictor of survival (HR: 0.14; 95 % CI: 0.06-0.33; P<0.0001). OMD patients exhibited distinct molecular characteristics, including lower frequencies of BRAF p.V600E (P=0.0315) and KRAS mutations (P=0.0456), as well as a higher frequency of high tumor mutational burden (P=0.0127). Additionally, by integrating data from public datasets and our case study, we hypothesize that some gene alterations (i.e.: BRAF, SMAD4, RAF1, and mTOR) may prevent OMD occurrence.

Conclusion: OMD, characterized by male predominance, single-site involvement, and distinct molecular features in colon cancer, suggests the need for tailored management strategies.

Keywords: BRAF; KRAS; Next generations sequencing; Oligo-metastatic disease; Prognosis; Tumor mutational burden.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the paper entitled “Clinical and genetic drivers of oligo-metastatic disease in colon cancer.”

Figures

Fig 1
Fig. 1
Flowchart depicting the process of patient inclusion and exclusion in the analyzed cohort.
Fig 2
Fig. 2
Kaplan-Meier survival curves, stratified by metastatic pattern as defined in the Methods section, demonstrate distinct outcomes. Patients with oligo-metastatic disease exhibit clear divergence in survival curves compared to those with poly-metastatic disease, with median survivals of 88.0 versus 29.0 months, respectively (P<0.0001 by Log Rank test). The number at risk is reported below the figure.
Fig 3
Fig. 3
Prioritization of genes involved in worsening the prognosis of colon cancer and being not altered in oligo-metastatic patients was performed using the Phenolyzer tool. In the upper section (A), the Phenolyzer score, ranging from 0 to 1, is displayed. A higher score indicates a stronger association between the gene and the disease. The lower panel (B) features a network visualization tool that illustrates gene–gene and gene–disease relationships (see Materials and Methods for further details).
See this image and copyright information in PMC

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