Oligo-Metastatic Cancers: Putative Biomarkers, Emerging Challenges and New Perspectives

Abstract

Some cancer patients display a less aggressive form of metastatic disease, characterized by a low tumor burden and involving a smaller number of sites, which is referred to as "oligometastatic disease" (OMD). This review discusses new biomarkers, as well as methodological challenges and perspectives characterizing OMD. Recent studies have revealed that specific microRNA profiles, chromosome patterns, driver gene mutations (ERBB2, PBRM1, SETD2, KRAS, PIK3CA, SMAD4), polymorphisms (TCF7L2), and levels of immune cell infiltration into metastases, depending on the tumor type, are associated with an oligometastatic behavior. This suggests that OMD could be a distinct disease with specific biological and molecular characteristics. Therefore, the heterogeneity of initial tumor burden and inclusion of OMD patients in clinical trials pose a crucial methodological question that requires responses in the near future. Additionally, a solid understanding of the molecular and biological features of OMD will be necessary to support and complete the clinical staging systems, enabling a better distinction of metastatic behavior and tailored treatments.

Keywords: biomarkers; genetics; metastases; oligo-metastatic; prognosis; radiotherapy.

Figure 1

Literature analysis (number per year) of articles dealing with OMD (until January 2023).

Figure 2

The figure shows two patients (A₁,B₁) who have the same onset of de novo OMD. Both patients receive radical excision of all lesions (primary tumor and single liver metastases). Patient A₁ is disease-free at the 3-year follow-up (A₂) (“true” OMD). Patient B₁ develops poly-metastatic disease (“false” OMD) within 1 year of follow-up (B₂). The markers that clearly differentiate these two clinical entities that apparently have the same onset are unknown. Previous evidence suggests that the dynamic study of the primary tumor and metastases (C₁ vs. C₂ and D₁ vs. D₂) could provide important prognostic indications. High infiltrates of cytotoxic granzyme-b positive (GrzB+) CD8+ T cells and the regression of key-driver mutation clones could be the basis for true OMD. The cellular composition of the tumor mass is shown in the figure (C₁,C_2,D₁,D₂) to focus on these two last concepts. Some types of cells that make up the tumor microenvironment, such as neutrophils, mast cells, fibroblasts, regulatory cells, etc., have been omitted.