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The coming decade in precision oncology: six riddles

Abstract

High-throughput methods to investigate tumour omic landscapes have quickly catapulted cancer specialists into the precision oncology era. The singular lesson of precision oncology might be that, for it to be precise, treatment must be personalized, as each cancer’s complex molecular and immune landscape differs from patient to patient. Transformative therapies include those that are targeted at the sequelae of molecular abnormalities or at immune mechanisms, and, increasingly, pathways previously thought to be undruggable have become druggable. Critical to applying precision medicine is the concept that the right combination of drugs must be chosen for each patient and used at the right stage of the disease. Multiple puzzles remain that complicate therapy choice, including evidence that deleterious mutations are common in normal tissues and non-malignant conditions. The host’s role is also likely to be key in determining treatment response, especially for immunotherapy. Indeed, maximizing the impact of immunotherapy will require omic analyses to match the right immune-targeted drugs to the individualized patient and tumour setting. In this Perspective, we discuss six key riddles that must be solved to optimize the application of precision oncology to otherwise lethal malignancies.

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Fig. 1: Is it about time?
Fig. 2: When is a deleterious mutation pathogenic?
Fig. 3: Do cancer mutations possess tissue tropism?
Fig. 4: Which tumour clone should be targeted?
Fig. 5: How well should oncologists know their patients?

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Acknowledgements

The authors apologize to all their esteemed colleagues whose work could not be included owing to space constraints. This Perspective was inspired by D. R. Green’s work “The coming decade of cell death research: five riddles” (Cell 177, 1094–1107 (2019)). A.W. and L.B. are supported by the Claudia von Schilling foundation. A.W. was supported by the Torsten-Haferlach Leukaemia Diagnostics Foundation. P.L. and S.F. are supported by the Molecular Precision Oncology Program of the National Center for Tumour Diseases in Heidelberg. S.F. is supported by the German Cancer Consortium. The authors are grateful for critical discussions with D. R. Green, P. Vandenabeele, J. C. A. Melms, M. Bostock, M. Hlevnjak and J. P. Suppelna. The National Center for Tumor Diseases (NCT) Heidelberg is a partnership between the German Cancer Research Center (DKFZ) and Heidelberg University Hospital.

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A.W., L.B. and R.K. conceived and wrote the manuscript. S.F., P.J.J., A.S. and P.L. provided conceptual support and critically reviewed the manuscript draft.

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Correspondence to Adam Wahida, Lars Buschhorn or Razelle Kurzrock.

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A.W., L.B. and P.L. declare no competing interests. S.F. has received consulting or advisory honoraria from Bayer, Illumina and Roche, honoraria from Eli Lilly, PharmaMar and Roche, research funding from AstraZeneca, Pfizer, PharmaMar and Roche, and travel or accommodation expenses from Eli Lilly, Illumina, PharmaMar and Roche. P.J.J. has had a consulting or advisory role for and has received honoraria, research funding and/or travel/accommodation expenses from Ariad, Abbvie, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Servier, Roche, Celgene (Bristol Myers Squibb), Pierre Fabre, Janssen (Johnson & Johnson) and MSD. A.S. has received research grants from Celgene, Roche and AbbVie, honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Eli Lilly, GlaxoSmithKline, Seagen, Gilead Sciences, Bayer, Amgen, Pierre Fabre, streamedup!, promedicis, onkowissen.de, Metaplan and Connect Media, and travel support from Roche, Celgene and Pfizer. R.K. has received research funding from Biological Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant Health, Incyte, Konica Minolta, Medimmune (AstraZeneca), Merck Serono, Omniseq, Pfizer, Sequenom, Takeda and TopAlliance, has received consultant and/or speaker fees and/or has been an advisory board member for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Biological Dynamics, Daiichi Sankyo, Eisai, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, NEOMED, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics and X-Biotech, has an equity interest in CureMatch, CureMetrix and IDbyDNA, serves on the board of CureMatch and CureMetrix, and co-founded CureMatch.

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Wahida, A., Buschhorn, L., Fröhling, S. et al. The coming decade in precision oncology: six riddles. Nat Rev Cancer 23, 43–54 (2023). https://doi.org/10.1038/s41568-022-00529-3

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