The FPG500 project (NCT06020625) is a prospective, single-institution comprehensive genome profiling (CGP) program developed at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. It is designed to systematically integrate broad molecular testing into the routine clinical management of patients with advanced solid tumors.
Preliminary results from the lung cancer cohort, representing one of the largest histology-selected genomic profiling experiences from a European academic center, were recently published, providing a concrete framework for understanding the clinical value and operational complexity of embedding CGP and molecular tumor boards (MTB) into daily oncology practice.1
Comprehensive Genomic Profiling in NSCLC
Non-small cell lung cancer (NSCLC) is a paradigmatic example of precision oncology. The landscape of oncogene-addicted diseases continues to expand, with targeted agents now approved for several validated biomarkers, yielding unprecedented survival benefits. International guidelines from both the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) strongly endorse early molecular profiling for all patients with advanced non-squamous histology, regardless of clinical characteristics such as age, race, or smoking status, as well as selected patients with squamous cell carcinoma, including those without smoking history or who are age 40 or older.2,3
In the FPG500 program, patients with advanced-stage NSCLC respecting the above-mentioned criteria underwent CGP using the TruSight Oncology 500 High Throughput (TSO500HT, Illumina Inc.) assay, capable of detecting single-nucleotide variants, insertions and deletions, copy number variations, fusions, splicing variants, tumor mutational burden, and microsatellite instability across 523 genes simultaneously. Genomic findings were recorded in a clinical report, which was reviewed by molecular biologists, bioinformaticians, pathologists, and geneticists to ensure quality control. The report was officially included in patients’ electronic health records.1
From Data to Decision: The Role of the MTB
A genomic report, however comprehensive, is not a treatment prescription. Accurate interpretation of genomic findings requires integration with clinical context, treatment history, sample characteristics, co-mutation landscape, and knowledge of available therapeutic options, including approved agents, expanded access programs, and ongoing clinical trials. This is precisely the function of the MTB.
In our experience, genomic data were integrated into a structured MTB workflow, with biweekly meetings convening medical oncologists, radiation oncologists, molecular biologists, pathologists, geneticists, and bioinformaticians. Among patients enrolled in the FPG500 lung cancer cohort, 59% harbored at least one actionable genomic alteration, and 41% received a molecularly matched targeted therapy: 25% through approved agents and 16% through experimental access facilitated directly by MTB discussion. Patients receiving matched therapies demonstrated substantially improved outcomes, with matched targeted therapy recipients achieving a median overall survival of nearly 24 months versus approximately 11 months for non-matched patients.1
The recently published IASLC consensus statement identifies key figures and essential principles for an efficient MTB, confirming our model. A pathologist or a clinically experienced molecular biologist and a tumor-specific medical oncologist are considered indispensable members, with additional expertise from clinical geneticists, bioinformaticians, and clinical trial specialists.
Beyond target identification, MTB responsibilities encompass evaluation of co-mutations within the clinical context, detection of resistance mechanisms, identification of germline variants warranting genetic counseling, and resolution of diagnostic uncertainty arising from molecular-pathological discrepancies. MTBs further serve a critical governance function by applying existing evidence to assess the appropriateness of experimental matching therapies and generating formal recommendations to facilitate off-label access and funding for drug prescription.4,5
Clinical Implementation
Translating CGP and MTB-guided care into routine practice is feasible and highly needed, but requires adequate expertise and facilities. The IASLC consensus, corroborated by our own programmatic experience, provides a practical roadmap.
The clinical value of CGP depends entirely on the quality of the infrastructure supporting it. Validated bioinformatics pipelines, structured reporting integrated into electronic health records, and clearly defined MTB workflows are prerequisites rather than enhancements. In the FPG500 program, genomic findings were classified according to established actionability frameworks, with MTB reports signed by all participants and incorporated into each patient’s medical record.
Treatment options should be ranked according to ESCAT and OncoKB scales, prioritizing drug-target pairs supported by the highest level of clinical evidence, and listed regardless of local reimbursement status, with appropriate notation of access constraints. Case selection should be adapted to institutional volume and expertise. Classical alterations with established treatment algorithms can be managed through standard pathways, while the MTB adds greatest value in cases involving atypical or compound drivers, resistance mechanisms, germline findings, and situations where experimental or off-label access can be evaluated. For institutions without in-house infrastructure, referral to regional or national expert hubs through virtual participation represents a scalable and equitable alternative, explicitly endorsed by the IASLC consensus.1,4
The Gap Between Data and Equitable Access
The clinical benefits of CGP- and MTB-guided care are increasingly well documented, yet equitable access remains a substantial challenge. Worldwide, access to testing remains a critical unresolved issue. A global IASLC survey in 2024 identified cost as the greatest barrier to biomarker testing, followed by sample quality, turnaround time, and provider awareness, drawing a hierarchy of obstacles strikingly consistent across different healthcare systems. Among the most concerning findings, 43% of responding physicians reported sometimes or often treating patients before biomarker results were available, a practice that is difficult to reconcile with current evidence-based standards of care.6
Tissue quality is a frequent problem. Samples are often sufficient for diagnosis but inadequate for biomarker testing, necessitating repeat biopsies that may be challenging from risk, cost, and patient-preference standpoints. Working with ancillary services such as pulmonology or interventional radiology to ensure sufficient tissue at diagnosis and optimizing tissue handling to maximize the material available for molecular studies are important practical steps.7
Even when access to testing is feasible, turnaround time remains a concern. Recent data from the United Kingdom indicate that approximately 30,000 patients with lung cancer undergo genomic testing annually, yet only 60% receive results within the recommended 14-day turnaround time, with delays translating directly into deferred treatment initiation, deterioration in patient fitness, and compromised survival outcomes. Reflex testing, rather than waiting for a physician order, can help avoid missed test prescriptions, reduce turnaround time, and improve time to treatment initiation.8
Access to testing, however, is only part of the challenge; ensuring that patients can actually receive a matched targeted therapy remains an equally pressing concern. Real-world matched therapy rates across high-volume European and North American centers range from approximately 10% to 15% of all patients undergoing CGP, highlighting that a substantial proportion of patients with actionable alterations do not ultimately receive matched targeted therapy. Reimbursement policies often constitute the main barrier.
In our cohort, 18% of patients harboring an ESCAT Tier IA actionable alteration did not receive any matched targeted therapy, not because of clinical unsuitability, but because the relevant agent was not yet reimbursed by the national health system. The interval between regulatory approval and reimbursement varies widely across healthcare systems and is one of the most underappreciated sources of inequity in precision oncology, requiring coordinated engagement among regulatory agencies, academic institutions, and the pharmaceutical industry to ensure patients have timely and equitable access to novel treatment options.1
Closing the Gap
Precision oncology in NSCLC has moved decisively from research to clinical practice. The FPG500 program demonstrated that integrating CGP and MTB in daily practice is not only feasible but translates into measurable survival benefits for patients with actionable molecular alterations. As precision oncology advances with liquid biopsy, proteomics, radiomics, and many more emerging biomarkers, MTB will become an essential tool for clinicians to ensure patients receive the best available therapy.
The main challenge is not scientific but organizational. Closing the gap between genomic evidence and equitable patient access will require sustained investment in testing infrastructure, streamlined reimbursement pathways, and institutional commitment to the clinical and scientific expertise that transforms a sequencing result into a treatment decision.
References
- 1. Vitale A, Mastrantoni L, Russo J, et al. Impact of Comprehensive Genome Profiling on the Management of Advanced Non–Small Cell Lung Cancer: Preliminary Results From the Lung Cancer Cohort of the FPG500 Program. JCO Precis Oncol. 2024;(8). doi:10.1200/PO.24.00297
- 2. Kalemkerian GP, Narula N, Kennedy EB. Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement Summary of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Oncol Pract. 2018;14(5):323-327. doi:10.1200/JOP.18.00035
- 3. Hendriks LE, Kerr KM, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023;34(4):339-357. doi:10.1016/j.annonc.2022.12.009
- 4. Aldea M, Rotow JK, Arcila M, et al. Molecular Tumor Boards: A Consensus Statement From the International Association for the Study of Lung Cancer. Journal of Thoracic Oncology. 2025;20(11):1594-1614. doi:10.1016/j.jtho.2025.07.009
- 5. Pastò B, Buzzatti G, Schettino C, et al. Unlocking the potential of Molecular Tumor Boards: from cutting-edge data interpretation to innovative clinical pathways. Crit Rev Oncol Hematol. 2024;199:104379. doi:10.1016/j.critrevonc.2024.104379
- 6. Smeltzer MP, King JC, Connolly C, et al. The 2024 International Association for the Study of Lung Cancer Global Survey on Biomarker Testing. Journal of Thoracic Oncology. 2025;20(12):1801-1813. doi:10.1016/j.jtho.2025.07.114
- 7. Kerr KM, Bubendorf L, Lopez‐Rios F, et al. Optimizing tissue stewardship in non‐small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists. Histopathology. 2024;84(3):429-439. doi:10.1111/his.15078
- 8. Gourd E. Lung cancer treatment compromised by delayed genomic test results. Lancet Oncol. 2025;26(4):420. doi:10.1016/S1470-2045(25)00149-4
