Genomic actionability and matched targeted therapy in a decade-long institutional precision medicine program for solid tumors

Abstract

Background

Precision oncology has evolved from concept to clinical reality, advancing cancer treatment and drug development in the last decade. However, disparities persist in patient access to comprehensive genomic profiling and matched therapies.

Materials and methods

This was a retrospective analysis of all patients enrolled in the Vall d’Hebron Institute of Oncology (VHIO) precision medicine program (PMP) between 2014 and 2024. Tumor profiling outcomes were reviewed, focusing on actionable alterations, classified by the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT). Interpretation and therapy prioritization were standardized through regular multidisciplinary molecular tumor boards. Key performance indicators (KPIs) included the proportions of patients with ESCAT tier I-IV alterations and those receiving matched therapies, either via clinical trials or approved regimens. The analysis also considered advances in molecular diagnostics, such as liquid biopsies, and the evolving clinical trial portfolio requiring biomarkers.

Results

From 2014 to 2024, 12 168 unique patients underwent 13 718 multi-gene molecular profiles at VHIO PMP. The detection rate of actionable alterations increased substantially over time, from 10.1% in 2014 to 53.1% in 2024, paralleling advances in drug biomarkers, sequencing technology, and broader use of assays. Overall, 10.1% of patients received molecularly matched therapies, rising from 1% in 2014 to 14.2% in 2024. Among patients with actionable alterations, 23.5% received targeted therapies, with annual rates ranging from 19.5% to 32.7%. Liquid biopsy integration notably enhanced actionable target detection and therapy access. The proportion of clinical trials with molecular inclusion criteria varied, starting at 40.2% in 2014 and dropping to 19.4% in 2020 before rising to 34.2% in 2024.

Conclusion

Over a decade, VHIO’s institutionally integrated PMP has enabled robust actionable alteration detection and access to matched therapies. Standardized KPI monitoring enables ongoing evaluation and sustainability of program performance. Continued innovation in diagnostics and molecularly guided trials is essential for further progress in precision oncology.

Highlights

• •Molecular testing and target selection in institutional PMPs remains highly complex.
• •We measured programs’ efficiency in detecting actionable genomic alterations and matching to approved drugs or trials.
• •Actionable alteration detection rose from 10.1% in 2014 to 53.1% in 2024, mostly in common cancers with broad profiling.
• •Patients receiving matched therapies rose from 1% in 2014 to 14.2% in 2024, mostly clinical trials.
• •Overall, 23.5% with actionable alterations got biomarker-guided therapies, ranging from 19.5% to 32.7% yearly.

Introduction

Over the past decade, the field of precision oncology has evolved from a conceptual framework to a clinically validated strategy, fundamentally transforming oncology practice and drug development.¹ In 2025, >100 approved targeted agents can be matched to 62 different gene biomarkers across cancers in the United States.^2,3 Since 2020, the European Society for Medical Oncology (ESMO) advocates for the use of multi-gene next-generation sequencing (NGS) in selected patients with different metastatic or advanced solid tumors.^4,5 These guidelines emphasize that, alongside traditional protein-based assays such as immunohistochemistry (IHC), comprehensive genomic profiling is essential to accurately delineate the actionable molecular landscape of cancer and to inform optimal therapeutic decision making.

Access to genomic testing and approved or investigational therapies remains highly heterogeneous across European and global health care systems, reflecting disparities in national infrastructure and patient care networks, reimbursement, and regulatory hurdles.⁶ Academic institutions have driven progress by investing in foundational elements for molecular profiling, including standardized testing platforms and molecular tumor boards (MTBs) for data interpretation. Precision medicine programs (PMPs) in oncology usually operate as centralized genomic testing platforms with nested clinical trials and real-world data collection.⁷ The primary objective of PMPs is to identify actionable genomic alterations—molecular findings for which a matched therapy may be available, whether approved (on-label) or accessible through a clinical trial. The ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) categorizes molecular targets into four evidence-based tiers, providing oncologists with a standardized approach to prioritize molecular targets based on the strength of clinical evidence.⁸

There is high variability in the literature on the prevalence of actionable alterations on tumor genomic profiling, with reported rates ranging from 15% to 60%, depending on how ‘actionable’ is defined—ESCAT tiers I through IV—and the breadth of NGS panels employed in different tumor types.^9,10 Despite the high ‘theoretical’ actionability, a significant gap persists for access to matched therapies, which is close to 10% in multiple cohorts.9, 10, 11, 12, 13, 14, 15, 16 These findings highlight both the promise and the limitations of precision oncology in routine practice, underscoring the need for standardized collection of key performance indicators (KPIs) in institutional PMPs for somatic actionability analyses. ESMO has established guidelines for molecular matching that recommend specific quality-of-care indicators.¹⁷ The most important KPI is the proportion of patients with ESCAT tier I-IV alterations discussed in MTBs who ultimately receive molecularly guided treatments, or ‘pragmatic actionability’. The minimum benchmark is set at 10% of patients, the recommended benchmark at 25%, and the optimal benchmark at 33% of patients receiving molecularly guided therapy.

More than a decade ago, the Vall d’Hebron Institute of Oncology (VHIO) initiated the internal ‘prescreening’ PMP, a pioneering initiative in tumor molecular profiling integrated with clinical trials.¹⁸ Recognized for its large portfolio of early phase trials and genomic testing excellence, VHIO utilizes certified NGS assays and continually updates its diagnostic platforms—expanding panel size, increasing coverage of biomarkers, and integrating new technologies. We leveraged this experience to describe decade-long statistics on an ever-evolving institutional PMP, with an historical evaluation of program efficiency that reflects shifting biomarker and drug development priorities. A comprehensive analysis of the VHIO PMP utility is of great value, both to guide innovative research and to promote the long-term sustainability of the program. The primary hypothesis of this project is that a continuously evolving molecular diagnostic program delivers sustained value to patients by increasing opportunities for molecularly guided targeted therapies. Our objective is to measure the KPIs that assess the efficiency of the VHIO PMP in accurately detecting actionable alterations and expanding patient access to matched targeted therapies, either within molecularly guided clinical trials or as part of approved standard-of-care regimens.

Materials and methods

This was a retrospective cohort study analyzing the results of the VHIO PMP from 2014 to 2024, with 2014 marking the introduction of multi-gene NGS panels. All patients with at least one valid NGS test result were eligible for the study. Any patient with advanced or metastatic cancer who is eligible for standard-of-care targeted therapies or molecularly guided clinical trials, irrespective of treatment line, may be enrolled in the program at the discretion of the treating physician. Decision making for molecular testing and matched therapies is adapted to tumor type and clinical context, ensuring patients receive the most relevant genomic analysis to guide clinical trial enrollment or approved targeted agent use, with the entire process supported by rigorous clinical workflows and weekly MTBs, both disease-specific boards and pan-tumor discussion panels linked to the phase I VHIO unit.

Molecular profiling

From a technical perspective, at VHIO all NGS assays are optimized for use with archived formalin-fixed paraffin-embedded tumor tissues or circulating tumor DNA (ctDNA) from liquid biopsies, without matched germline sequencing. As shown in Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.105888, the VHIO PMP initially employed an NGS mutation assay covering 59 oncogenes and tumor suppressor genes (Broad NGS tissue v1.0, Thermo Fisher, Waltham, MA), a targeted fusion panel (Fusion v1.0, NanoString, Seattle, WA), IHC tests, and FISH analysis of selected genes. In 2016, the program was expanded to include an additional NGS panel (Copy v1.0, NanoString), new protein targets for IHC, various non-NGS assays (FISH), and updated versions of existing NGS panels to cover more genes. A significant milestone was reached in 2016 with an International Organization for Standardization (ISO) 15189 certification of the Broad NGS tissue v1.1 panel, allowing it to be officially used as an in-house alternative to companion diagnostic tests of approved drugs and clinical trials and enabling participation in international clinicogenomic data-sharing projects. In 2019, an exon-based NGS assay (Broad NGS tissue v2.0, Agilent, Santa Clara, CA) covering 431 genes was clinically implemented, allowing the assessment of genomic signatures such as microsatellite instability (MSI) and tumor mutational burden (TMB). This assay received ISO certification in 2021. In 2022 a new liquid biopsy assay (Broad NGS liquid v1.0, also called ‘Guardant360 CDx’, Guardant Health, Palo Alto, CA), developed through technology transfer from Guardant Health, was introduced and subsequently ISO certified in 2024. In recent years, the original copy number and fusion panels have been replaced with new technologies, either integrated into Broad NGS tissue v2.0 or as standalone assays (Fusion v2.0, Agilent). In parallel, various IHC assays were implemented, allowing for local testing and eliminating the need for sample shipment to central laboratories in clinical trials with antibody–drug conjugates and other molecular drugs. Likewise, an in-house-developed immunofluorescence (IF) assay for RAD51 foci as a functional biomarker of homologous recombination repair was introduced in 2021. Of note, the turnaround time is close to 1 week for IHC, FISH, or IF tests and ∼2-3 weeks for NGS panels in liquid and tissue samples, acceptable for clinical decision making in cancer patients.

Data management

The molecular data reported back to ordering physicians and patients is routinely extracted from the repositories of the Molecular Oncology and Cancer Genomics laboratories and stored in a relational database (SQL prescreening database) following codification (assignment of unique identifiers to each patient) and harmonization (application of universal data models for tumor types, genes, and alterations). To annotate molecular data with patient demographics and sample characteristics, a minimal set of clinical and pathological data is manually curated from electronic medical records. Study data were collected and managed using REDCap electronic data capture tools hosted at VHIO.¹⁹ Tumor types are classified according to OncoTree.²⁰ Data on the use of targeted therapies with mandatory molecular matches are also integrated into the SQL prescreening database. For approved agents administered after molecular testing, targeted therapies requiring a mandatory molecular match are sourced from VHIO’s institutional pharmacy registries (QuimioProcess and CITOS databases for intravenous and oral therapies). In parallel, data on experimental therapies administered in clinical trials are extracted from the institutional clinical trial management system (Fundanet). Each trial’s molecular criteria are defined by the PMP support team using standardized taxonomy in another dedicated REDCap form based on information available in international clinical trial databases (e.g. clinicaltrials.gov) and study protocols in cases of insufficient biomarker details in trials’ eligibility criteria.

Endpoints and data analysis

The endpoints of interest and related variables were defined as follows:

• -Actionable alteration at the gene and/or variant levels: defined according to ESMO ESCAT criteria in the year of testing, with adjustments for tumor type. The OncoKb resource³ was utilized to identify the year in which each alteration first achieved ESCAT tier I or II actionability status. For alterations categorized solely as ESCAT tiers III and IV, the year of actionability was based on the initiation of molecular trials with mandatory molecular inclusion criteria at VHIO. Protein biomarkers were excluded from actionable alteration metrics. Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105888, summarizes the levels of actionability of genomic biomarkers over the study period.
• -Molecularly matched therapy: defined as expert-determined matches to clinical trials or approved therapies requiring mandatory genomic markers, administered after molecular testing with an assay that detected the specific alteration in each patient. Of note, off-label use of targeted agents is not permitted at VHIO. Accordingly, all patients with actionable alterations received either on-label targeted therapies (ESCAT tier I) or accessed targeted agents through clinical trials (ESCAT tiers I-IV). Patients with known molecular alterations identified before enrollment in the VHIO PMP were not excluded from the analysis. However, if such patients had received targeted agents before multi-gene testing within the VHIO PMP, those therapies were not considered as ‘matched’ treatments.

Every patient who participated in the VHIO PMP from 2014 to 2024 was retrospectively assessed for the following: (i) tumor type as per OncoTree; (ii) presence of actionable alterations tier I-II or tier III-IV in the tumor based on the analysis of all molecular tests carried out in a given year (if a patient’s tumor had more than one actionable alteration, the highest level was counted); and (iii) exposure to molecularly matched therapies within clinical trials with a mandatory biomarker inclusion criterion or approved standard-of-care regimens after genomic testing in a given year (if a patient was exposed to molecular therapies for different targets over time, all matches were counted). In addition, every clinical trial open for recruitment at VHIO from 2014 to 2024 was assessed for (i) presence of a mandatory molecular inclusion criterion; (ii) details on the gene and protein biomarker; and (iii) corresponding molecular test from the VHIO PMP that can detect the specific molecular alteration. Of note, ERBB2 amplification detected by NGS in breast cancer patients who were already known to be human epidermal growth factor receptor 2 (HER2)-positive by IHC or FISH was not considered an actionable genomic driver in either breast or gastric cancer. Similarly, HER2-positive breast or gastric cancer (IHC 3+ or IHC 2+ with FISH positivity) was not regarded as a molecular inclusion criterion in clinical trials. Patients who had molecular profiling carried out in 2 or more years were considered as distinct observations for each respective year in the annual analyses of actionability and access to matched therapies.

All patients participating in the VHIO PMP provide informed consent under research project PR(AG)147/2009, which details the potential impact of molecularly guided therapies and the future use of clinical-genomics data for research purposes. Outcomes of clinical trials involving molecularly guided targeted therapies are proprietary to pharmaceutical companies and have not been analyzed in this project. Similarly, outcomes related to approved standard-of-care targeted drugs matched to genomic alterations are outside the scope of this study. This retrospective study was approved by the Vall d’Hebron University Hospital Ethics Committee with waiver of patient reconsent under research project PR(AG)34-2024. No comparative analyses were conducted; therefore, sample size estimation was not carried out. Trends in proportions over time (such as actionability rates, clinical trial molecular criteria, and matching to targeted agents) were evaluated using a binomial logistic regression model, with year (2014-2024) treated as a continuous linear term. The Cochran–Armitage trend test, equivalent to the score test for the linear term in logistic regression, was used to formally test for trends as a complementary check. Statistical significance was defined as a two-sided P value < 0.05. All analyses and figures were generated using the R programming language, version 4.5.0.

Results

Population characteristics and molecular diagnostic technologies

In total, 12 168 unique patients underwent 13 718 multi-gene NGS panels within the VHIO PMP program between 2014 and 2024. The most prevalent tumor types tested across all years were colon/rectum, with 2704 cases; breast, with 1623 cases; and lung, with 1409 cases. Additional tumor types included pancreas (975 cases), ovary (670 cases), brain (455 cases), biliary tract (380 cases), stomach (320 cases), prostate (290 cases), bladder (230 cases), head and neck (162 cases), and others (3495 cases). Figure 1A illustrates the annual number of patients tested, stratified by tumor type. The data indicate a steady increase from 546 patients in 2014 to 1244 in 2016. From 2017 through 2022, the number of patients tested annually remained relatively stable, with totals ranging from 1026 to 1190. A marked increase occurred in 2023, with 1960 patients tested, and this elevated level persisted in 2024, reaching 2172 patients. This substantial rise concurred with the introduction of liquid biopsy testing. The increase in patient testing observed in recent years affected all tumor types, though the degree of change varied. The rise in testing numbers for colon/rectum and breast cancers was less pronounced, whereas lung cancer and other tumor types experienced a particularly notable increase, as shown in Figure 1A. Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105888, shows the distribution of molecular tests carried out in the VHIO PMP, stratified according to categories. In 2014, a total of 1142 molecular tests were carried out, with the majority comprising Broad NGS tissue assays (n = 467), while in 2024 the annual number of tests had risen significantly to 4070. Although the volume of broad NGS tissue tests remained relatively stable throughout the decade, there was a marked surge in liquid biopsy testing beginning in 2023. Interest in other molecular assays and IHC fluctuated over time. However, the overall use of IHC increased significantly, rising from 323 tests in 2014 to 858 in 2024.

Figure 1.

Evolution of molecular testing and actionability. (A) Annual number of patients tested in the Vall d’Hebron Institute of Oncology Precision Medicine Program (solid line), stratified by tumor type (colored stacked barplots). Annual number of patients with tier I/II actionable alterations as per ESMO ESCAT (dashed line), stratified by tumor type (shaded stacked barplots). (B) Annual number of patients tested in the Vall d’Hebron Institute of Oncology Precision Medicine Program (barplots), proportion of patients with actionable alterations tiers I/II (solid line), or I-IV (dashed line) as per ESMO ESCAT. ESCAT, ESMO Scale for Clinical Actionability of Molecular Targets; ESMO, European Society for Medical Oncology.

Proportion of patients with tumors harboring actionable alterations

Over the study period the number of biomarkers classified as tier I or II actionable increased from 12 in 2014 to 50 in 2024.² This progress translated into a substantial rise in the detection of actionable alterations. As depicted in Figure 1A, only eight tier I/II actionable alterations were identified among 546 patients tested in 2014 (1.5%). In contrast, by 2024, 338 actionable alterations were detected among 2172 patients (15.6%) (P value for trend < 0.001; OR 1.25). Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025.105888, further elucidates the distribution of actionable alterations over time. The most frequent tier I/II alterations included PIK3CA and ESR1 mutations in breast cancer, EGFR and KRAS mutations in lung cancer, and ERBB2 mutations/amplifications and BRAF mutations in various malignancies. Figure 1B provides an expanded overview of the detection rates for potentially actionable genomic alterations, encompassing all actionability tiers (I-IV) within the VHIO PMP from 2014 to 2024. Across all evaluated years, 5204 of 13 718 molecular profiles in the VHIO PMP (37.9%) were found to carry ESCAT tiers I-IV actionable alterations. The data reveal a marked and sustained increase in the proportion of tested patients harboring any actionable alteration over this period. In 2014, only 10.1% of patients had at least one actionable alteration identified. This proportion increased steadily, reaching 53.1% in 2024 (P value for trend < 0.001; OR 1.27). The analysis further indicates that, in 2024, approximately one-third of these actionable alterations were classified as tiers I/II, with 15.6% of tested patients harboring alterations in these categories.

Evolution of clinical trials with molecular inclusion criteria

There were significant changes in the landscape of interventional clinical trials over the past decade, as shown in Figure 2A. In 2014, there were 246 open interventional trials, a number that increased to 527 by 2024. Despite this overall growth, the number of unique clinical trials open for recruitment stabilized from 2021 onward, fluctuating between 511 and 542 trials per year. The proportion of trials incorporating molecular inclusion criteria exhibited notable variability. In 2014, 40.2% of trials included molecular criteria, but this proportion declined steadily, reaching a nadir of 19.4% in 2020. Subsequently, there was a gradual recovery, with molecularly selected trials comprising 34.2% of the total in 2024 (P value for trend = 0.002; OR 0.97). Out of 1390 clinical trials with biomarkers, 790 (57%) were phase II-III and 600 (44%) phase I. Figure 2B details the distribution of gene biomarkers and pathway alterations used as inclusion criteria in these trials. There has been a clear upward trend in trials targeting HER2 and RAS pathway alterations, as well as those involving programmed death-ligand 1 and MSI/TMB biomarkers. In contrast, other biomarkers such as BRAF, EGFR, ALK, KIT, and DNA damage repair (such as BRCA1 and BRCA2) have remained relatively stable over time. The frequency of trials focused on FGFR2-3, MET, and NTRK1-3 has decreased, while PIK3CA-targeted trials showed initial prominence in 2014-2016, a decline in 2019, and a subsequent resurgence by 2024. Importantly, there has been a discernible increase in interest for emerging biomarkers relevant to drug development, including RET, BRAF, RAF1, and NRG1 fusions, IDH1 and POLE mutations, as well as a variety of IHC markers for antibody–drug conjugates. These are collectively represented in the ‘other’ category, reflecting the expanding scope and complexity of molecular targets in contemporary clinical research.

Figure 2.

Evolution of molecular trials and targets. (A) Annual number of clinical trials open for recruitment in the Vall d’Hebron Institute of Oncology (barplots), and proportion of clinical trials with molecular inclusion criteria. (B) Annual distribution of molecular targets in clinical trials open for recruitment in the Vall d’Hebron Institute of Oncology. DDR, DNA damage repair pathway; EGFR, epidermal growth factor receptor; MSI, microsatellite instability; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden.

Proportion of patients treated with molecularly matched therapies

Figure 3A summarizes the evolving impact of the VHIO PMP on patient access to matched targeted therapies, either through molecularly guided clinical trials or the prescription of approved targeted drugs. Overall, 1226 out of 12 168 patients profiled (10.1%) were treated with molecularly matched drugs in following tumor profiling. From 2014 to 2018, there was a steady increase in the proportion of patients who, after molecular profiling, received matched targeted agents as part of molecular clinical trials. Specifically, this proportion rose from 0.4% in 2014 to 7.7% in 2018, reflecting the growing integration of precision oncology within the clinical trial landscape during this period. However, between 2019 and 2021, there was a marked reduction in both the availability of clinical trials with molecular biomarker inclusion criteria and the proportion of patients receiving targeted agents in such trials. This decline, reaching 4.1% in 2020 and 5.9% in 2021, coincided with broader trends in the clinical trial portfolio and was likely influenced by external factors, which prompted a shift in trial recruitment strategies and a temporary reduction of biomarker-driven studies. In the subsequent years, expansion of the clinical trial portfolio and access to more advanced molecular diagnostics led to a significant rebound. By 2024, the proportion of patients who received matched targeted agents in molecular trials had increased to 10% (P value for trend < 0.001; OR 1.14). With regard to the percentage of patients treated with approved targeted drugs outside of clinical trials, this proportion remained close to 1% from 2014 to 2019. There was a substantial increase in 2020 onwards, with ∼4% of patients receiving approved targeted therapies (P value for trend < 0.001; OR 1.23). Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105888, details temporal exposure to targeted therapies by mechanism of action, level of actionability, and drug access pathway (on-label versus clinical trial).

Figure 3.

Evolution of exposure to matched therapies. (A) Annual number of patients tested in the Vall d’Hebron Institute of Oncology Precision Medicine Program (barplots), proportion of patients with inclusions in clinical trials with molecular match (solid line), and proportion of patients treated with approved targeted drugs (dashed line). (B) Annual number of patients tested in the Vall d’Hebron Institute of Oncology Precision Medicine Program (light green barplots); annual number of patients with actionable alterations tier I-IV as per ESMO Scale for Clinical Actionability of Molecular Targets (green barplots); annual number of patients treated with molecular matched trials or approved drugs (dark green barplots); and annual proportion of patients with actionable alterations tier I-IV who were treated in molecular matched trials or with approved drugs. ESMO, European Society for Medical Oncology.

The efficiency of the VHIO PMP in translating molecular profiling into targeted therapeutic interventions can be evaluated by examining the proportion of patients who received molecularly matched therapies—either through clinical trials or approved drugs—relative to the total number of patients with actionable alterations classified as tiers I-IV. Over the study period, 23.5% of the actionable population ultimately received a molecularly matched therapy. Figure 3B provides a comprehensive view of the program’s clinical impact over time. In 2014, 5.5% of patients with actionable alterations received a matched targeted therapy. This proportion rose steadily, reaching a peak of 32.7% in 2018, which coincided with heightened activity in precision oncology drug development. Subsequently, there was a gradual decline in the proportion of eligible patients treated as per molecular profile results, with the lowest point observed in 2022 at 19.5%, followed by a gradual increase in subsequent years, totaling 26.3% in 2024 (P value for trend = 0.42; OR 0.99).

Next, we carried out a comparative analysis of the distribution of tumor types profiled within the VHIO PMP and those subsequently recruited into molecular clinical trials, offering insight into the relative efficiency of trial matching across different malignancies. As shown in Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2025.105888, the three most frequently tested tumor types—colon/rectum, breast, and lung cancer—were also the most represented among patients recruited into molecular trials. However, the data reveal a particularly high efficiency in trial matching for lung cancer, which accounted for 10.3% of the total patient cohort profiled between 2014 and 2024 and 24.4% of the population recruited into molecular trials. In contrast, rare malignancies, which are typically associated with a lower frequency of actionable genomic alterations, comprised 32.8% of patients tested but only 14.1% of those recruited into molecular trials. This discrepancy underscores the challenges in identifying trial opportunities for patients with less common tumor types and highlights the limitations imposed by the scarcity of validated molecular targets in these diseases.

Discussion

The systematic collection and rigorous analysis of clinicogenomic data are indispensable components of institutional PMPs, particularly those utilizing in-house developed assays and maintaining an expansive portfolio of clinical trials. The VHIO PMP has substantially expanded its diagnostic capabilities over the past decade, introducing new assays and biomarker-matching opportunities that have significantly enhanced patient profiling. In 2024, the number of patients profiled was more than fourfold higher, accompanied by an equivalent increase in molecular tests carried out when compared with 2014. This growth reflects a steadily increasing interest in biomarker testing driven by advancements in molecularly guided drug development and technological innovations.

Despite the complexities in defining actionability tiers by tumor type for such a long observation period, we have demonstrated a consistent evolution of cancer biomarkers that guide use of on-label and experimental therapies. Given the increased number of biomarkers classified as tier I/II, VHIO’s Molecular Oncology and Cancer Genomics laboratories have expanded the diagnostic toolkit. The growing clinical adoption of liquid biopsy technologies, particularly in lung cancer, has positively influenced the detection of tier I/II alterations from 2023 onward. Notably, even in 2022, when the uptake of the new ctDNA assay was still modest, an increase in the detection of actionable alterations was observed, suggesting that the expansion is predominantly driven by the integration of new genomic biomarkers that advanced through clinical development, such as KRAS^G12C. The observed decrease in actionable alterations in 2024 relative to 2023 likely reflects the rising inclusion of patients with rare tumor types in the VHIO PMP, which generally present with a lower frequency of therapeutically relevant molecular drivers. Indeed, the evolution of actionability rates could partly reflect case mix changes.

Between 2014 and 2024, the number of active clinical trials annually conducted at VHIO doubled, reflecting robust growth in clinical research activities. The proportion of clinical trials incorporating mandatory biomarker inclusion criteria exhibited remarkable fluctuations over this period. This temporal pattern is likely indicative of evolving industry priorities, including a focus on immunotherapy trials between 2018 and 2020, many of which did not necessitate molecular selection, as well as the disruptive effects of the coronavirus disease 2019 (COVID-19) pandemic on clinical trial design and patient recruitment, especially between 2020 and 2021. Despite these external challenges, the VHIO PMP maintained strong appeal for molecularly driven clinical trials, facilitating robust collaborations with industry partners and sustaining renewed momentum in precision medicine drug development.

From the overall population tested for genomic biomarkers, the annual proportion of patients treated with molecularly matched therapies within clinical trials also fluctuated significantly during the study period, ranging from 3% in 2015 to 10% in 2024. The decline observed during the COVID-19 pandemic coincided with a prioritization of immunotherapy trials, which negatively impacted this metric; however, this trend has since reversed in recent years. The VHIO PMP numbers are comparable with the literature, as detailed in Table 1, but variations are influenced by factors such as the year of study conduct, tumor type distribution, and portfolio of targeted agents in clinical trials.9, 10, 11, 12, 13, 14, 15, 16 Interestingly, during the COVID-19 pandemic there was a clear increase in the prioritization of approved molecular therapies relative to trial enrollment, but the proportion of patients receiving on-label standard-of-care targeted agents has always been lower than experimental drugs in clinical trials. This trend underscores the ongoing challenge in translating genomic insights into routine practice, such as limited access to approved agents and many logistical barriers for off-label drug use.

Table 1.

Summary of selected precision medicine programs reported in the literature

Cohort	Country	Panel	Therapies	Number	Actionable, n (%)	Treated, n (%)	Treated/actionable (%)	Year	Reference
Veteran Affairs	USA—multi-site	Broad NGS, multiple assays	On-label, off-label	3192	587 (18.4)	136 (4.3)	23.2	2016-2018	9
CoPPO	Denmark—Rigshospitalet	Broad NGS, whole-genome/transcriptome seq	Trials	1866	1062 (57)	256 (13.7)	24.1	2013-2021	10
COMPACT	Canada—PMCC	Broad NGS, multiple assays	Trials	1640	553 (33.7)	245 (14.5)	44.3	2012-2014	11
MSKCC	USA—MSKCC	Broad NGS, MSK Impact	On-label, off-label, trials	11 369	3792 (36.7)	527 (4.6)	13.9	2014-2016	12
Curie	France—Curie	Broad NGS, multiple assays	Trials	442	207 (46.8)	45 (10.2)	21.7	2014-2017	13
RATIONAL	Italy—multi-site	Broad NGS, FoundationOne	On-label, off-label, trials	738	290 (39.3)	67 (9.1)	23.1	2018-2021	14
ProfiLER	France—multi-site	Broad NGS, multiple assays	Trials	2579	699 (27.1)	163 (6.3)	23.3	2013-2017	15
SNUBH	South Korea—SNUH	Broad NGS, SNUBH Pan-cancer V2	Trials	990	257 (26.0)	35 (3.5)	13.6	2019-2020	16
VHIO PMP	Spain—VHIO	Broad NGS, multiple assays	On-label, trials	13 718	5204 (37.9)	1226 (8.9)	23.5	2014-2024	Present study

NGS, next-generation sequencing; VHIO, Vall d’Hebron Institute of Oncology.

In line with ESMO guidelines, we also measured as KPI the proportion of patients who received molecularly matched therapies relative to the total number of patients harboring actionable alterations classified within tiers I-IV, which varied throughout the study period. The highest percentage was observed in 2018 (32.7%), while the lowest occurred in 2022 (19.5%), but there was no significant trend upward or downward for this KPI. These variations reflect the dynamic and evolving nature of precision oncology, influenced by factors such as shifting industry priorities, regulatory developments, and global events. Despite this interannual variability, the proportion of eligible patients ultimately receiving a molecularly matched therapy from 2014 to 2024 was close to the ESMO MTB-recommended benchmark of 25%, underscoring the VHIO medical team’s enduring commitment to delivering precision cancer therapies. This KPI ranges from 13% to 44% in other PMPs, with an average number of treated patients over the actionable population of 23%, as detailed in Table 1. The VHIO institutional target for this KPI is set at 33%, anticipated to be attainable in the coming years through sustained investment and ecosystem shaping, particularly scalable MTBs and clinical trial matching tools. Our robust data management and information technology system will allow continuous monitoring of this KPI in the future.

Conclusion

In conclusion, our data suggest that the evolution toward a multimodal paradigm in precision oncology is characterized by several key developments: (i) the adoption of combined or sequential molecular profiling strategies that integrate tissue-based analyses with liquid biopsy modalities, thereby increasing the detection rate of rare actionable genomic alterations across diverse tumor types; (ii) an expanding portfolio of biomarkers that guide both targeted and immunotherapy drug development, which collectively necessitate ongoing adaptation of gene panels and diagnostic assays; and (iii) a critical imperative to co-invest in the establishment of a comprehensive clinical trial portfolio enriched with molecular inclusion criteria to ensure patient access to innovative targeted therapies because approved agents presently constitute a small fraction of available precision oncology treatments. Ultimately, these initiatives are crucial for maximizing the clinical impact and sustainability of precision medicine approaches in oncology.