Variant allele frequency: a decision-making tool in precision oncology?

Precision oncology requires additional predictive biomarkers for targeted therapy selection. Variant allele frequency (VAF), measuring the proportion of variant alleles within a genomic locus, provides insights into tumor clonality in somatic genomic testing, yielding a strong rationale for targeting dominant cancer cell populations. The prognostic and predictive roles of VAF have been evaluated across different studies. Yet, the absence of validated VAF thresholds and a lack of standardization between sequencing assays currently hampers its clinical utility. Therefore, analytical and clinical validation must be further examined. This Review summarizes the evidence regarding the use of VAF as a predictive biomarker and discusses challenges and opportunities for its clinical implementation as a decision-making tool for targeted therapy selection.

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Declaration of interests MR received travel expenses reimbursement from Sanofi. CC reports personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, and Pfizer. VS served consulting or advisory role for MedImmune, Helsinn Therapeutics, Relay Therapeutics, Pfizer, and Loxo/Lilly. Research funding: Novartis, GlaxoSmithKline, NanoCarrier, Northwest Biotherapeutics, Genentech/Roche, Berg Pharma, Bayer, Insyte, Fujifilm, PharmaMar, D3 Oncology Solutions, Pfizer, Amgen, AbbVie, Multivir, Blueprint Medicines, LOXO, Vegenics, Takeda, Alfasigma, Agensys, Idera, Boston Biomedical, Inhibrx, Exelixis, Turning Point Therapeutics, and Relay Therapeutics. Travel, accommodation, expenses: PharmaMar, Bayer, Novartis, Helsinn Therapeutics, and Foundation Medicine. Other relationships: Medscape. GC received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, and MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, and NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, and Mylan; Honoraria for writing engagement: Novartis and BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dohme, Janssen-Cilag, Philogen, Bayer, Medivation, and Medimmune. The remaining authors have no conflict of interest to declare.