Molecular Tumor Board Research Articles

A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.

Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician's discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.

Comprehensive genomic profiling for advanced hepatocellular carcinoma in clinical practice.

Although several therapeutic agents show efficacy in advanced hepatocellular carcinoma (HCC), biomarkers such as comprehensive genomic profiling (CGP) for the selection of second-line treatments after immunotherapy have not been established. We evaluated the value of CGP for the treatment decision in patients with HCC. We retrospectively studied 52 patients with advanced HCC who received CGP tests at three tertiary hospitals between February 2022 and November 2023. Genomic profiles were obtained using one of three CGP tests; 49 and 3 patients were evaluated using tissue-based and blood-based assay, respectively. The impact of CGP results on subsequent treatment selection in clinical practice and correlations between representative gene alterations and patient characteristics or responses to immunotherapy were evaluated. The most frequently observed variants were TERT mutations, followed by CTNNB1, TP53, ARID1A, and MYC mutations. Potentially druggable gene alterations were observed in 45 patients (87%), and 34 patients (65%) were recommended to receive treatments based on specific gene alterations by a molecular tumor board. Treatments were covered by health insurance in 13 patients (25%). Five patients (10%) received the recommended treatment by the date of data cut-off. There were no differences in the efficacy of immunotherapy with respect to mutation status in hTERT, CTNNB1, TP53, ARID1A, and MYC. The results of the present study suggested that druggable gene alterations may provide useful information not only in proposing alternative treatment after standard of care but also in selecting second-line targeted treatments after immunotherapy for patients with advanced HCC.

CTNI-49. PRECISION MEDICINE CLINICAL TRIAL FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract Salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median overall survival of 9 months (OS-9) and 6-month progression-free survival (PFS-6) of 10-25%. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. An initial 15-patient cohort evaluated the feasibility and safety of treating patients with rGBM with an individualized treatment regimen; we added a second 15-patient expansion cohort to improve the power of preliminary efficacy assessment. Patients underwent clinically indicated surgery with genomic profiling using the UCSF500 targeted DNA sequencing panel. Each personalized treatment regimen combined up to 4 FDA-approved drugs, including one cytotoxic agent, as determined by consensus discussion at an individualized molecular tumor board for each patient. Bevacizumab was not utilized in these combinations. The primary objective of the combined 30-patient cohort was efficacy of individualized treatment regimens by OS-9; secondary objectives included safety and additional efficacy measures including PFS-6. Median age was 53 years (range 32-71). Of 30 patients, 18 were male, 23 were enrolled at first recurrence, 29 had IDH-wildtype glioblastoma, 1 had IDH-mutant astrocytoma, and 10 had MGMT promoter methylation. A total of 12 FDA-approved drugs were used in 18 combinations; the most common regimen prescribed was lomustine, afatinib, and abemaciclib (7; 23%,); second-most common was temozolomide, olaparib, and afatinib (4; 13%). OS-9 of the combined cohort was 70% (95% CI 0.55 – 0.89) and PFS-6 was 27% (95% CI 0.15 – 0.48), with median OS of 11.6 months (95% CI 9.7 – 16.7) and median PFS of 3.7 months (95% CI 2.0 – 5.5).While overall efficacy was modest, implementation of individualized treatment regimens in a timely fashion was safe and feasible for patients with surgically resectable rGBM. Analysis is ongoing to assess whether specific genomic profiles or treatment regimens were particularly efficacious.

Retrospective Comparison of Targeted Anticancer Drugs Predicted by the CNS-TAP Tool Versus Those Selected by a Molecularly Driven Tumor Board in Children With DIPG.

The recent trial Pediatric Neuro-Oncology Consortium 003 (PNOC003) utilized a molecular tumor board to recommend personalized treatment regimens based on tumor sequencing results in children with DIPG. We separately developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which numerically scores targeted anticancer agents using preclinical, clinical, and patient-specific data. We hypothesized that highly scored agents from CNS-TAP would overlap with the PNOC003 tumor board's recommendations. For each of the 28 participants, actionable genetic alterations were derived from PNOC003 genomic reports and input to CNS-TAP to identify the highest scoring agents. These agents were then compared with PNOC003 recommendations, with a resultant concordance percentage calculated. Overall, 38% of the total agents recommended by the tumor board were also selected by CNS-TAP, with higher concordance (63%) in a subanalysis including only targeted anticancer agents. Furthermore, nearly all patients (93%) had at least 1 drug chosen by both methods. We demonstrate overlap between agents recommended by CNS-TAP and PNOC003 tumor board, though this does not appear to improve survival. We do observe some discordance, highlighting strengths and limitations of each method. We propose that a combination of expert opinion and data-driven tools may improve targeted treatment recommendations for children with DIPG.

Precision Oncology implementation in a regional-based health care system: a professional consensus to define the pathway

Precision Oncology requires deep changes in organizational settings but little evidence has been identified about the best strategy to guarantee the delivery of this innovation to patients. In the Italian health care system, high heterogeneity could jeopardize equal access opportunity for patients. Following a consensus method, we aim to define shared solutions to address these issues in clinical practice. A Delphi RAND method was chosen to record the consensus among involved health care professionals in the Italian region of Friuli Venezia Giulia. The item generation phase was conducted following a bottom-up approach. Ten statements were defined on the main topics that emerged from the direct observation of the current practice, focusing on Molecular Tumor Board organization, massive parallel sequencing technology application, laboratory report content and informed consensus submission. All the statements reached a strong consensus and have been shared with the health care government authorities of our region. The direct observation of the current practice in different health care authorities allowed to define ten statements as solution proposals to solve the identified complexities. This methodological approach could be applied in different organizational models but aiming to achieve a homogeneous clinical outcome for patients.

Molecular tumor board in patients with metastatic breast cancer.

Comprehensive genomic profiling is becoming increasingly important in the management of patients with metastatic breast cancer (mBC). Real-world clinical outcomes from applying molecular tumor boards (MTBs) recommendations in this context remain limited. Accordingly, we conducted a retrospective, single-institution analysis to evaluate the clinical impact of discussing patients affected by mBC at the MTB. Clinicogenomic data of patients affected by mBCs referred to the European Institute of Oncology MTB between August 2019 and December 2023 were reviewed. Genomic alterations were classified by ESCAT framework. Clinical outcomes of patients showing actionable alterations and receiving molecular-matched therapy (MMT) were compared to those receiving standard therapy (ST). Ninety-six patients were included. Following MTB discussion, genetic counseling was recommended in 27% (n = 26) of patients, while additional molecular analyses were requested in 25% (n = 24) cases. Fifty-six patients (58%) displayed at least one actionable alteration. For patients with available follow-up (n = 50), 32 (64%) received MMTs and 18 (36%) ST. No differences in real-world progression-free survival (rwPFS) (4.07 months [95% CI 2.14-8.28] vs. 3.12 months [95% CI 1.51-NE], P = 0.8) and 12-month overall survival (OS) (58% [95%CI 43-78] vs. 57% [95%CI 34-97), P = 0.9) were observed between the MMT- and ST-group. Level I ESCAT alterations yielded longer rwPFS (5.82 months [95% CI 3.12-8.41]) compared to ESCAT II (2.14 months [95%CI 1.61-NE]) and ESCAT III (2.10 months [95% CI 2.04-NE]; P = 0.03). Twenty-four percent of patients showed a PFS2/PFS1 ratio > 1.3 from MMT. Molecular tumor boards can provide additional treatment options for patients affected by mBC. Besides treatment recommendations, MTBs also have the utility to assess the validity of discussed genomic reports and to identify alterations worthy of genetic counseling.

Molecular Tumor Boards impact on patients’ health: towards a policy brief in the Can.Heal project

Abstract Background Molecular Tumor Boards (MTBs) are pivotal in the current management of oncological patients, integrating molecular diagnostics with clinical expertise to tailor precise treatments. Within the framework of EU-funded ‘Building EU Cancer and Public Health Genomics platform’ (Can.Heal) project that aims at streamlining genomics implementation in public health, we are developing a policy brief to promote MTBs’ adoption across the EU. Methods A two-step approach was employed to delineate strategies for MTB implementation. Firstly, we conducted a systematic review and meta-analyses (if feasible) up to November 2023, on studies assessing the MTBs’ clinical impact. Secondly, based on the results of the review, we conducted an expert consultation to identify key areas to improve MTBs implementation and impact. Results 48 studies were included, whose results were heterogeneous in terms of organizational aspects and number of experts involved (mean n: 6, range: 2-19). Average implementation rate of the recommendations issued by the MTB was 43.1% (3.2%-92%), with a turnaround time from testing to recommendation of 36 days (15-58). By pooling data from 12 studies (n = 1623), a favorable overall survival [HR = 0.63 (95% CI 0.53-0.76), I2 42.0%] was reported for patients managed in hospitals with MTBs versus not. Similar estimates were reported when the outcome was progression free survival [HR = 0.63 (95% CI 0.54-0.72), I2 = 0.0%], based on 8 studies (n = 1106). The subsequent expert consultation identified 5 key areas for MTB implementation: genetic data sharing, standards for results’ interpretation, equitable access to MTB, optimization of the testing process, and funding and reimbursement. Conclusions The policy brief underscores the significant clinical benefits of MTB-recommended therapy, improving patients’ outcomes. Nevertheless, addressing resource allocation and infrastructure development is essential to optimize MTB utilization and enhance patient outcomes. Key messages • Our results highlight that MTBs-recommended therapy translates into tangible clinical benefits. • More fundings and resources are needed to optimize and fully implement MTBs in clinical practice.

The Molecular Tumor Board Turns 10: The Age of Complexity.

Gene sequencing has brought a titanic of complex data into clinical precision oncology. Deciphering this complexity for practice requires new constructs. In 2014, the Molecular Tumor Board (MTB) was introduced into the literature by a publication in The Oncologist. Ten years later, MTBs have become globally established vehicles that integrate rapidly emerging "omic" information, helping to transform cancer management.

P1.06B.05 Utility of Molecular Tumor Board Driven by Precision Medicine Service and Cloud-Based Datamart for Therapy and Trial Matching

P1.06B.05 Utility of Molecular Tumor Board Driven by Precision Medicine Service and Cloud-Based Datamart for Therapy and Trial Matching

Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes.

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.

Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on Google's Gemini Pro LLM, MEREDITH uses retrieval-augmented generation and chain of thought. We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to PubMed-indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment). MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, P = .01). Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.

Poly (ADP-ribose) Polymerase Inhibitor Resistance Driven by Emergence of Polyclonal Mutations With Convergent Evolution: A Molecular Tumor Board Discussion.

Polyclonal convergent evolution to PARPi resistance in a patient with metastatic breast cancer with gPALB2.

Increasing access to biomarker-driven treatment for lung cancer in Alabama: The Alabama Access initiative.

159 Background: Lung cancer is the leading cause of cancer death in Alabama, with an estimated 2,550 deaths in 2024. Non-small cell lung cancer (NSCLC) represents 85% of these cases. Despite national guidelines recommending comprehensive biomarker testing (CBT) for metastatic NSCLC, significant disparities persist in the utilization of CBT and targeted therapies among Alabama residents. Methods: In March 2024, we launched the "Alabama Access" initiative – a partnership between the LUNGevity Foundation and the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham – to foster academic and community oncology partnerships to increase access to biomarker-driven treatments. We used a population health science and geospatial mapping approach to visualize oncology practices serving counties with Alabama's highest lung cancer burden. Practices in Walker, Dothan, Marengo, Morgan, Jackson, Marshall, and Montgomery counties were identified as the highest priority based on annual mortality rates. Key interventions will include virtual molecular tumor boards and oncology navigation to facilitate the integration of resources and expertise and ensure that patients in nonacademic practices benefit from the latest advances in precision oncology. After roll-out, we will collect feasibility and acceptability data around program integration. Results: Our analysis revealed that 62.0% of the state’s population resides in Primary Care Health Professional Shortage Areas (HPSAs), and 58 out of 67 counties are classified as Medically Underserved Areas. The poverty rate in 89.6% of counties surpasses the national average, contributing to higher lung cancer incidence and mortality rates, with 62.0% of cases diagnosed at advanced stages. The state also shows a higher smoking prevalence, affecting 97.0% of counties compared to national figures. We will present practice-level testing data, including barriers to CBT. Conclusions: This pilot aims to mitigate disparities in CBT through enhanced collaboration between academic and community oncology settings. Integrating molecular navigation into community practices will be pivotal in disseminating program information and collecting data on current testing practices to improve overall lung cancer care quality in Alabama.

Actionable alterations in glioblastoma: Insights from the implementation of genomic profiling as the standard of care from 2016 to 2023

Abstract Background In 2016, genomic profiling was implemented for patients with grade 4 primary brain tumors at Rigshospitalet, Denmark. The aim of this study was to discover actionable alterations and to match these with targeted therapies. Methods Between January 2016 and December 2023, 483 brain tumor patients were profiled. We retrieved clinical data and molecular data. Whole exome, whole genome, or panel sequencing, along with SNP array analyses, and RNA-seq were performed on resected primary tumor tissue. Alterations were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) following the European Association of Neuro-Oncology (EANO) guideline on rational molecular testing. Results A total of 200 (41.4%) patients’ tumors harbored an alteration of interest according to the EANO guideline. Twenty (4.1%) patients had an ESCAT high-tier alteration (tier I or II), while 155 patients (32.1%) had an alteration corresponding to ESCAT IIIA. Thirty-five patients (7.2%) had an actionable alteration, and 15 (3.1%) received targeted therapy. The treated targets were BRAFV600E mutations, FGFR alterations, NTRK fusions, PDGFRA fusions, PTPRZ1-MET fusions, and TMB-high. The overall response rate was 20%, with a median duration of response of 12 months, and 47% achieved stable disease as the best response. Conclusions Genomic profiling uncovers alterations of interest in a substantial number of patients, but only a minority are considered by the Danish National Molecular Tumor Board to have actionable alterations, and even fewer receive targeted therapy. Nevertheless, factors, such as promising targets and the increasing availability of trials, may contribute to a future increase in the number of patients benefiting from targeted therapies based on genomic profiling.

Abstract C008: Patient-derived organoids and precision medicine: Insights from the PASS-01 clinical trial in PDAC

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is challenging as most patients are diagnosed at an advanced stage with limited treatment options. Tailoring therapies for individual patients is paramount due to the aggressive nature of the disease. Our work explores patient- derived organoids (PDOs) as in vitro tumor models to dissect molecular signatures and conduct pharmacotyping, aiming to enhance precision medicine. Methods: In the PASS-01 stage IV PDAC clinical trial, biopsies were collected for molecular correlatives, including establishment of PDO models. Tissue samples were collected from patients at six institutes across the United States and Canada, highlighting our ability to integrate PDO models into a robust, multi- institutional clinical framework. Most biopsies were collected from liver metastases, followed by primary pancreas tumors, peritoneal, omental, lymph node, lung, and brain metastases. KRAS mutation status by ddPCR was used to validate neoplastic cells in the organoid cultures and identify pseudonormal outgrowth. Established PDO lines were subjected to high throughput drug screening for 120+ compounds, comprising both standard-of-care (as monotherapy and in combination therapies) and experimental agents. Subsequently, validated PDO lines were expanded, biobanked and harvested for RNA and DNA sequencing. Results: During the trial, 186 biopsies from 183 enrolled patients were shipped to CSHL for PDO establishment. The overall malignant PDO establishment rate was 50% across all biopsy sites and patients. Interestingly, PDOs could be generated more often from patients that rapidly progressed on therapy (p = 0.03). Furthermore, by comparing the characteristics of the primary biopsies to the established PDO, PDOs were more frequently generated from Moffitt subtype classical (64% establishment) compared to basal (35%), and from those with a KRASminor imbalance (67% establishment) compared with KRAS wild-type (36%), balanced (58%), and KRASmajor imbalance (52%). The average time from tissue receipt to first drug screen data was 65 days, with six PDOs screened in under 30 days. This turnaround time enabled PDO therapeutic data to be presented at monthly molecular tumor boards. Consequently, these data were considered alongside other clinical trial correlates to aid in selection of second-line therapies when patients progressed. Conclusions: The PASS-01 trial facilitated the real-time generation of PDO models and reporting of therapeutic results. We identified correlations between PDO establishment and patient characteristics, and improved the methods to detect pseudonormal outgrowth. PDO pharmacoptyping identified sensitivity that correlated with patient outcomes on GnP, while also highlighting challenges of using empiric drug testing for chemotherapy sensitivity. Moving forward we aim to continue incorporation of PDOs and tumor molecular profiling to aid in patient therapy selection. We anticipate this work to be crucial as targeted therapies, including KRAS inhibitors, become mainstream in PDAC care. Citation Format: Amber N. Habowski, Dennis Plenker, Hardik Patel, Caitlin Tsang, Luce St. Surin, Fatim Kouassi, Deepthi Budagavi, Grainne M O'Kane, Stephanie Ramotar, Kenneth H Yu, Faiyaz Notta, Andrew Aguirre, Brian Wolpin, Dan Laheru, Daniel A King, Elizabeth M Jaffee, Jennifer J Knox, David A Tuveson. Patient-derived organoids and precision medicine: Insights from the PASS-01 clinical trial in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C008.

Abstract PR-17: Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial

Abstract Overall survival for patients with advanced PDAC remains less than 1 year. Biomarkers are needed to select chemotherapy regimens, either alone or in combination with novel agents. PASS-01 compared mFOLFIRINOX and Gemcitabine/nab-Paclitaxel in a phase II randomised control trial while prospectively exploring tissue, liquid and organoid biospecimens to interrogate putative biomarkers of chemotherapy response and resistance. Methods PASS-01 was conducted across 6 sites in North America. Patients with de novo metastatic disease and a lesion amenable to core biopsy were included. Cases with germline pathogenic variants in BRCA1/2 or PALB2 were excluded. Up to 6 core biopsies were obtained with priorities for clinical diagnosis, patient derived organoids (PDOs), and whole genome and transcriptome sequencing (WGTS). WGTS were performed at a single site following laser capture microdissection. WGS reports were clinically (CAP) accredited and annotated mutations, copy number alterations, mutational signatures, TMB and structural variant patterns. KRAS allelic states were documented with major imbalances in mutant KRAS (KRASmaj) defined as mutant: WT copy number >3. Transcriptomic subtypes (classical vs. basal-like) were classified as previously described (Moffitt et al., 2015). WGTS results were discussed at a molecular tumor board with PDO pharmacotyping to determine best second line options. Results: 160 patients were included in the intention to treat population, of these WGS was available in 127 (79%) and additional NGS reports in 20 (13%). RNA-seq was successful in 119 (74%) and the basal-like subtype accounted for 29% and was associated with inferior outcomes. KRASm were evident in 91% and KRASG12D represented 45%. Tumor suppressors TP53, CDKN2A and SMAD4 were lost in 81%, 76% and 39% respectively. MTAP deletion was present in 40%, largely synonymous with CDKN2A deletions. Commonly co-altered genes in the dataset included epigenetic regulators (ARID1A, KMT2C, KDM6A) and TGFBR2. KRASmaj was present in 30% of cases and polyploid tumors in 50%. 50% of basal-like PDAC harboured KRASmaj compared to 22% of classical PDAC, p<0.01. Dominant signatures (SBS) included age related SBS1, 5 and 8. Additionally, we saw a prevalence of SBS17 and APOBEC SBS2/13, signatures which occurred more frequently compared to a similarly characterised resected cohort. Unstable genotypes were present in 24% with somatic-HRD evident in 3%. Of KRASWT PDAC, 58% harboured class I-II BRAF variants. KRAS WT PDAC had fewer co-mutations and in one case where an NGS report did not find a driver, a novel fusion in SLC4A4-RASGRF2 was identified. 28 molecular tumor boards took place throughout the trial influencing 50% obtaining a 2nd-line treatment. Conclusion: The PASS-01 cohort exhibits a heterogeneous group of genotypes and molecular subgroups. Certain mutational processes are more evident in advanced compared to resected PDAC. The impact of subgroups on survival and chemotherapy response is ongoing with a planned data lock on July 15th. Results will be presented at the meeting. Citation Format: Grainne M O'Kane, Gunho Jang, Trevor J Pugh, Julie Wilson, Stephanie Ramotar, Daniel A King, Dan Laheru, Ken H Yu, Kimberly J Perez, Amber Habowski, Erica S Tsang, Robert C Grant, Andrew J Aguirre, Raymond W-J Jang, Craig E Devoe, Eileen M O'Reilly, Anna Dodd, Brian M Wolpin, Xiang Y Ye, Elizabeth M Jaffee, David Tuveson, Steven Gallinger, Jennifer J Knox, Faiyaz Notta. Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-17.

KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening.

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Clinical Utility of Molecular Tumor Board Review for Identification of Possible Germline Pathogenic Variants on Tumor Next-Generation Sequencing Reports.

Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs. Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR). Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40). The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.

120P A prospective comparative evaluation of automatic trial match tools in a molecular tumor board

120P A prospective comparative evaluation of automatic trial match tools in a molecular tumor board

122P Practice patterns and treatment outcomes of molecular tumour board (MTB)-based personalized cancer therapies: A single-center experience

122P Practice patterns and treatment outcomes of molecular tumour board (MTB)-based personalized cancer therapies: A single-center experience