Raffaella Casolino, Joaquin Mateo, Elisabeth G E de Vries, Amber Johns, Melanie Courtot, Rita T Lawlor, Sandra Perdomo, Stacy W Gray, Raquel Perez-Lopez, Clare Turnbull, David Torrents, Kerstin Noelle Vokinger, Dilara Akhoundova, Jean-Marc Bourque, Andrés F Cardona, Yoon Jung Chang, Debyani Chakravarty, Ievgeniia Chicherova, Karen Ann Cranston, Melissa Davis, Amanda Drury, Oskar Frisell, Raquel Manzano Garcia, Robert L Grossman, Yosr Hamdi, Simon Hediger, Thomas Hofmarcher, Oliver Hofmann, Jakob Nikolas Kather, Hannah Kim, Kazuto Kato, Bartha Maria Knoppers, Kjong-Van Lehmann, Dilani Lokuhetty, Patricia M LoRusso, Deborah Mascalzoni, Nicola Mulder, Travis Osterman, Folakemi Odedina, Aparna R Parikh, Solomon Rotimi, Brian Rous, Shawn Sweeney, Bhawna Sirohi, Zbyslaw Sondka, Ciara Staunton, Kjetil Taskén, Alex Wagner, C Benedikt Westphalen, Jianmin Wu, Joly Yann, Ma'n H Zawati, Andrew V Biankin, Takayuki Yoshino, Lincoln Stein, Mark Lawler
Cancer genomics and precision oncology are increasingly central to cancer care, but many health systems struggle to implement them equitably, effectively, and sustainably. This Commission defines the current global precision oncology landscape and analyses the scientific, structural, and health-system challenges shaping its delivery and impact. Findings indicate that access to cancer genomics and precision oncology remains profoundly unequal across and within countries, leaving millions of patients without guideline-indicated interventions each year. These disparities extend to research, with genomic studies and clinical trials concentrated in high-income settings and among populations of predominantly European ancestry. At the same time, fragmented and poorly integrated data ecosystems restrict evidence generation, knowledge sharing, and clinical impact. Beyond questions of access and implementation, the clinical benefit of precision oncology is highly heterogeneous. The greatest and most consistent gains are confined to a few well validated biomarker-treatment pairings, typically supported by companion diagnostics; broader approaches such as comprehensive genomic profiling and tumour-agnostic strategies, might expand options for selected patients, but only a few patients receiving matched therapy derive meaningful benefit. The Commission also identifies a paradox of success: rapid expansion of precision oncology has increased cognitive, organisational, data, workforce, and financial burdens, while evidence of broad population-level benefit has lagged behind. In response, the Commission offers a comprehensive and context-responsive approach for integrating cancer genomics and precision oncology into health systems effectively, equitably, and sustainably. The Commission developed a value-based resource-stratified implementation framework, a system-readiness assessment tool, a precision oncology workforce competency-based framework, a precision oncology monitoring and evaluation framework, and principles for responsible data sharing and health-system learning. Cancer genomics and precision oncology can improve outcomes and strengthen health systems if scaled equitably, sustainably, and according to evidence, public value, national context, and patient needs. This Commission offers a basis for global consensus on a more equitable, evidence-informed, and sustainable path forward.