When Genomic Scars Outlive Genomic Vulnerability: Dynamic DNA Damage Repair in Cancer Evolution and Therapeutic Resistance

Genomic biomarkers are increasingly used to identify therapeutically exploitable defects in DNA damage repair (DDR). However, genomic alterations and mutational scars largely represent the evolutionary history of a tumor, whereas therapeutic sensitivity depends on its current functional state. This distinction becomes particularly relevant during cancer progression and treatment, when selective pressure may reshape DNA repair capacity without erasing the genomic footprints generated by previous repair deficiency. Here, we examine the emerging concept of genomic scar-functional state discordance, whereby persistent genomic evidence of defective DNA repair may coexist with partial or complete restoration of repair competence. Multiple mechanisms may contribute to this transition, including secondary or reversion mutations, restoration of homologous recombination, replication fork stabilization, compensatory pathway activation, clonal selection, and epigenetic reprogramming. Conversely, initially repair-proficient tumors may acquire new DDR vulnerabilities during evolution, emphasizing the bidirectional and dynamic nature of genome maintenance. These processes challenge the assumption that a single genomic assessment can reliably define a stable therapeutic vulnerability throughout the disease course. We discuss how longitudinal approaches integrating tumor genomics, circulating tumor DNA, mutational signatures, epigenomic information, and functional measures of DNA repair could distinguish historical genomic damage from active biological dependency. Particular attention is given to gastrointestinal malignancies, including pancreatic, colorectal, gastric, and biliary tract cancers, in which DDR alterations are increasingly investigated but their predictive interpretation remains heterogeneous. We propose that precision oncology should progressively move from the concept of a static genomic biomarker toward that of a dynamic genomic state, in which therapeutic vulnerabilities are periodically reassessed as tumors evolve under treatment pressure.