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Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities.

Tumor-Agnostic Biomarkers: Heed Caution, and Why Cell of Origin Still Matters