Despite substantial progress in biomarker-driven therapeutic strategies, precision oncology continues to face significant evidence generation challenges, particularly within molecular tumor boards (MTBs) and off-label treatment contexts. Real-world evidence (RWE) provides a vital complementary source to traditional clinical trials by capturing clinical outcomes directly from routine healthcare settings. Major initiatives like PRIME-ROSE, the Drug Rediscovery Protocol (DRUP), and the AACR Project GENIE demonstrate the potential of RWE in clinical decision-making, regulatory processes, and policy development. Nevertheless, substantial hurdles in data standardization, interpretation, and regulatory recognition remain. Systematic policy frameworks, international collaboration, and rigorous validation are crucial to enhancing RWE’s integration, thus fostering sustainable advancements in precision oncology.

As highlight by recent recommendations by the American Society of Clinical Oncology (ASCO) and the European Society of Clinical Oncology (ESMO), comprehensive genomic profiling (CGP) via next-generation sequencing (NGS) for advanced cancers can now be considered standard of care across a broad spectrum of malignancies^1,2. However, beyond standard of care, particularly within molecular tumor board (MTB) settings and for off-label therapeutic applications, the individualized and exploratory nature of treatments presents significant limitations for traditional randomized controlled trials (RCTs). Patient populations in these scenarios are often heterogeneous and characterized by rare genomic alterations, complicating traditional clinical trial approaches³.
These intrinsic limitations underscore the necessity for alternative evidence generation methods. Real-world evidence (RWE), derived from routine clinical care, thus provides a critical means to bridge the evidence gap, reflecting practical patient management complexities and outcomes. Comprehensive RWE integration is essential for addressing unanswered clinical questions in precision oncology⁴.

Real-world data (RWD) includes various patient-related sources such as electronic health records (EHRs), cancer registries, administrative claims, patient-reported outcomes (PROs), and genomic information obtained from MTBs³,⁴. In the future, structured analyses of RWD might yield robust RWE, ideally informing clinical decisions, regulatory approvals, and reimbursement strategies, particularly when traditional clinical trial evidence is unavailable or insufficient.

European initiatives, such as PRIME-ROSE, aim to utilize synthetic control arms derived from RWE, informing regulatory processes and reimbursement discussions, particularly in rare or molecularly defined cancers⁵. The Drug Rediscovery Protocol (DRUP) in the Netherlands systematically assesses off-label drug use guided by genomic profiling, exemplifying the clinical utility and practicality of RWE in precision oncology^6,7.

Finally, the AACR Project GENIE, a global consortium pooling genomic and clinical data from over 110,000 tumor samples, significantly enhances genomic biomarker validation, clinical trial enrollment predictions, and the discovery of genomic drivers, particularly in rare cancers. This large-scale international collaboration illustrates RWE’s transformative role in global precision oncology efforts^8,9.

Effective utilization of RWE faces significant challenges due to the variability in genomic data generation, analytical methodologies, and clinical interpretations across institutions. Diverse genomic assays, inconsistent documentation practices, and varied molecular interpretations complicate reliable data aggregation and analysis. Thus, ensuring rigorous quality assurance through standardized and validated procedures is essential.

Addressing these challenges requires harmonized guidelines such as those by the ESMO Precision Oncology Working Group, which advocates standardized genomic assay protocols, consistent use of clinical actionability scales like the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)¹⁰, and structured documentation standards within MTBs¹¹. These measures significantly enhance data comparability, reliability, and utility, crucial for meaningful clinical interpretation and implementation. Operational challenges identified in MTBs include frequency of meetings, clinician participation, streamlined workflows, and clinician education to improve genomic data interpretation and integration into clinical practice. Addressing these operational and educational aspects is essential for fully realizing precision oncology’s potential^11,12,13.

Future developments in precision oncology will increasingly depend on integrating multimodal biomarker data, encompassing genomic, transcriptomic, proteomic, epigenomic, and immune profiling. Combined with robust RWE frameworks, this integrative approach promises significant advancements in patient stratification, clinical decision-making, and personalized treatment strategies, markedly refining therapeutic precision.
Global real-world evidence registries, exemplified by the AACR GENIE initiative, capturing diverse patient populations and clinical outcomes, are critical. These registries will address gaps left by traditional trials, improving generalizability and supporting regulatory acceptance of RWE as complementary evidence, especially for rare diseases and genomic subsets.

Regulatory frameworks must evolve systematically to integrate RWE, requiring clear, harmonized guidelines recognizing RWE’s clinical value. Policy-level adaptations and international collaborations are necessary to facilitate seamless integration into clinical practice, regulatory decisions, and health policy.

Real-world evidence is essential for sustainable advancements in precision oncology, particularly in scenarios inadequately addressed by traditional clinical trials. Rigorous standardization, comprehensive validation, and multimodal biomarker data integration, supported by global registries and collaborative initiatives, are fundamental. Multi-stakeholder collaboration among clinicians, regulators, academia, and industry is imperative to overcoming barriers, optimizing RWE utilization, and maximizing patient benefits, thereby fully realizing precision oncology’s potential.

Competing Interests: C. Benedikt Westphalen has received honoraria from AstraZeneca, Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, Lilly, MSD, Merck, Janssen, Ipsen, QuiP GmbH, Roche, Servier, SIRTeX, and Taiho; served on advisory boards for AstraZeneca, Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; received travel support from AstraZeneca, Bayer, Celgene, Janssen, MSD, RedHill, Roche, Servier, and Taiho; and research grants (institutional) from Roche. He serves as faculty for the European Society of Medical Oncology (ESMO), Deutsche Krebshilfe (DKH), and Arbeitsgemeinschaft Internistische Onkologie (AIO); is a member of the EU Commission expert group: Mission Board for Cancer; and a member of the BFTR steering committee: Strategiekreis Dekade gegen Krebs.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

This article is published under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0).

© C. Benedikt Westphalen, 2025. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.