From Tissue-Agnostic to N-of-One Therapies: (R)Evolution of the Precision Paradigm

Abstract

Precision medicine has exploited next-generation sequencing (NGS) and gene/immune-targeted drug deployment to transform the outlook for several lethal cancers. For instance, there are now several FDA-approved medications that target the sequelae of aberrant genes in a tissue-agnostic approach: pembrolizumab [microsatellite instability and tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb)] and larotrectinib/entrectinib (NTRK fusions). Molecular interrogation further reveals the disruptive reality that metastatic cancers are tremendously complex and individually distinct. Therefore, optimized treatment often requires drug combinations (rather than monotherapy) and N-of-one customization. Early studies of this approach suggest feasibility, safety, and efficacy. Real-world data/master registry trials may also provide massive, clinically relevant datasets that further fuel the (r)evolution in oncology.

Keywords: cancer genes; cell-free DNA; circulating tumor DNA; next-generation sequencing; precision oncology.