Pan-Cancer Molecular Biomarkers: Practical Considerations for the Surgical Pathologist

Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with NTRK fusions, and combined dabrafenib-trametinib for BRAF V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (FGFR), RET, and ROS1 fusions; ERBB2 amplification; and mutations in the AKT1/2/3, NF1, RAS pathway and (mitogen-activated protein kinase (MAPK) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of “when” than “if.” In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.