Jacob J. Adashek , Shumei Kato , Jason K. Sicklick , Scott M. Lippman , Razelle Kurzrock
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引用次数: 0
Abstract
Cancer is traditionally diagnosed and treated on the basis of its organ of origin (e.g., lung or colon cancer). However, organ-of-origin diagnostics does not reveal the underlying oncogenic drivers. Fortunately, molecular diagnostics have advanced at a breathtaking pace, and it is increasingly apparent that cancer is a disease of the genome. Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). There are emerging targets as well, including but not limited to ALK, BRCA and/or homologous repair deficiency, ERBB2 (HER2), IDH1/2, KIT, KRASG12C, NRG1, and VHL. Many tissue-agnostic approvals center on rare/ultra-rare biomarkers (often < 1 % of cancers), necessitating screening hundreds of tumors to find a single one harboring the cognate molecular alteration. Approval has generally been based on small single-arm studies (<30–100 patients) with high response rates (>30 % to > 75 %) of remarkable durability. Because of biomarker rarity, single-gene testing is not practical; next generation sequencing of hundreds of genes must be performed to obtain timely answers. Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.
期刊介绍:
Cancer Treatment Reviews
Journal Overview:
International journal focused on developments in cancer treatment research
Publishes state-of-the-art, authoritative reviews to keep clinicians and researchers informed
Regular Sections in Each Issue:
Comments on Controversy
Tumor Reviews
Anti-tumor Treatments
New Drugs
Complications of Treatment
General and Supportive Care
Laboratory/Clinic Interface
Submission and Editorial System:
Online submission and editorial system for Cancer Treatment Reviews