Multidisciplinary Molecular Tumor Board Research Articles

Evidence blocks for effective presentation of genomic findings at molecular tumor boards: Single institution experience

Genomic profiling, or molecular profiling of the tumor, is becoming a key component of therapeutic decision making in clinical oncology, and is typically carried out via next generation sequencing. However, the interpretation of the results and evaluation of rationale for targeting the uncovered alterations is challenging and requires a deep understanding of cancer biology, genetics, genomics and oncology. Multidisciplinary molecular tumor boards represent a promising strategy in the facilitation of molecularly-informed therapeutic decisions, and usually consist of specialists with various fields of expertise. To effectively communicate the biological and clinical significance of genomic findings, as well as to make molecular tumor board discussions more productive, we developed and implemented evidence blocks into case discussions in our center. We found that this approach facilitated clinicians’ understanding of the results of genomic profiling, and resulted in shorter yet more efficient case discussions within the molecular tumor board. Here, we discuss our experience with evidence blocks and how their implementation influenced the molecular tumor board practice.

Abstract 2558: Molecularly matched targeted therapies benefit high risk pediatric cancer patients

Abstract Introduction: Genomic technologies have the potential to transform the paradigm for diagnosing and treating children with cancer. Although druggable alterations are identified in a large fraction of pediatric cancer patients, the extent to which point-of-care genomic testing directly impacts therapeutic outcomes of individual patients in real-world settings is less well-known. A review of patients sequenced through the Precision in Pediatric Sequencing (PIPseq) program at Columbia University Irving Medical Center (CUIMC) was conducted to describe outcomes of patients treated with a molecularly matched targeted therapy (MTT). Methods: Matched tumor-normal whole exome and tumor transcriptome sequencing was conducted in a CLIA-certified laboratory at CUIMC between January 2013 and March 2023 on samples from 373 high risk pediatric cancer patients including those with <50% survival, rare cancers lacking standard therapies, and relapsed/refractory disease. All cases were reviewed at a multi-disciplinary molecular tumor board and reports were transmitted to the electronic health record (EHR). EHR data were reviewed to identify patients who received a MTT. Tumor-specific response and progression-free survival (PFS) among the MTT cohort were investigated. Clinical benefit was further assessed using the Growth Modulation Index (GMI) whereby patients served as their own control. GMI is the ratio of PFS on the MTT therapy to the PFS on the most recent prior therapy. A ratio of >/=1.3 indicates meaningful clinical activity. Results: Thirty pediatric patients (solid tumors, n=5; CNS tumors, n=15; hematologic malignancies, n=10) received a MTT. Median age at sequencing was 11 years, range 10 months-23 years. Median time to MTT from sequencing was 4.5 months, range 7 days to 19.2 months. Best overall response included 7 complete responses (23%), 6 partial responses (20%), 5 with stable disease (17%), 10 with progressive disease (33%), and 2 indeterminate due to early death or lack of follow-up during therapy (7%). GMI was calculated for 19/30 patients (63%); median GMI=1.1. 11 patients were excluded due to lack of prior therapy, early death, insufficient follow-up, or lack of progression between prior and targeted therapies. GMI ratios indicated clinical benefit from MTT for 12/19 patients (63%), median GMI=1.5. Conclusions: Clinical comprehensive molecular profiling for pediatric patients with high risk cancers identified patients who are candidates for MTT. Overall, MTT led to stable disease, partial or complete response, for 60% of patients. Utilizing GMI ratios as an indicator of clinical benefit for select patients provided additional information beyond traditional endpoints. Twelve patients with GMI >/=1.3 experienced improved PFS compared to their most recent prior therapy. These results demonstrate real-world clinical benefit from MTT, supporting molecular profiling of pediatric high risk tumors. Citation Format: Alice Tao, Jovana Pavisic, Jennifer A. Oberg. Molecularly matched targeted therapies benefit high risk pediatric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2558.

Molecular Tumor Board Improves Outcomes for Hispanic Patients With Advanced Solid Tumors.

Multidisciplinary molecular tumor boards (MTBs) decode complex genomic data into clinical recommendations. Although MTBs are well-established in the oncology practice in developed countries, this strategy needs to be better explored in developing countries. Herein, we describe the possible benefits and limitations of the first MTB established in Colombia. Demographic, clinical, and genomic information was collected between August 2020 and November 2021. By mid-2020, an MTB strategy was created to discuss clinical cases with one or more genomic alterations identified by next-generation sequencing using an open-access virtual platform. We characterized the patient population as benefiting from the recommended treatment option. We assessed the benefits and access to available targeted therapies that have the potential to change clinical management by making recommendations to treating oncologists on the basis of genomic profiling. However, we did not assess the treatment oncologists' compliance with MTB recommendations because they were not intended to replace clinical judgment/standard of care. A total of 146 patients were included in the discussions of the MTB. The median age was 59 years, and 59.6% were women. Genomic results prompting a change in therapeutic decisions were obtained in 53.1% of patients (95% CI, 44.9 to 61.3). The most prevalent malignancy was non-small-cell lung cancer (51%). Other malignancies represented 60%, 50%, and 30% of patients with soft-tissue sarcomas, brain tumors, and breast cancer, respectively. Using an open-access virtual platform, MTBs were feasible in low- and middle-income countries on the basis of the capability to provide the benefits and access to available targeted therapies that are not standard of care. Furthermore, MTB recommendations were made available to the treating oncologist in different locations across Colombia, providing the option to modify clinical management in most of these patients.

1-Year Data Analysis from a Cancer Center Molecular Tumor Board Dedicated to Clonal Hematopoiesis

Background Nearly 25% of cancer patients harbor clonal hematopoiesis of indeterminate potential (CHIP). Detection of clonal hematopoiesis (CH) in routine clinical practice is increasing due to incidental findings during sequencing analysis of circulating cell-free DNA (cfDNA) or exploration of unexplained cytopenia. To improve clinical management of these patients in our institution, we set up a multidisciplinary molecular tumor board (MTB) dedicated to patient cases with CH, CHIP, and clonal cytopenia of undetermined significance (CCUS) in 2022. Methods Between June 2022 and June 2023, our MTB reviewed a total of 345 cases, of which 212 referred by the solid tumor MTB and 133 referred by hematologists. The former 212 cases with CH were identified through cfDNA sequencing (FoundationOne Liquid CDx) within the Gustave Roussy Cancer Profiling study (NCT04932525), which includes some genes recurrently mutated in hematologic malignancies ( ASXL1, DNMT3A, IDH1, IDH2, JAK2, MPL, MYD88, SF3B1, TET2, U2AF1). A variant allele frequency (VAF) of at least 10% for the CH mutation was required to refer cases to the MTB, except for JAK2, MPL, and MYD88 mutations. The latter 133 cases were screened for CH mutations on peripheral blood leukocytes using a next-generation sequencing (NGS) assay targeting 174 genes recurrently mutated in hematologic malignancies. In addition to molecular data, standard clinical and biological parameters were recorded for each individual case. Results Patients referred by the solid tumor MTB In this cohort of 212 patients, median age was 72 years old (range, 48-91), sex ratio (M/F) was 1.4, median prior anticancer treatment lines was 2 (0-9), and time between MTB and cancer diagnosis was 2.3 years (0.2-34). The most frequent tumor types were lung (23%), colorectal (20%), prostate (19%), gynecological (12%) and breast (9%) cancers. The most frequently mutated genes were DNMT3A (59%), TET2 (30%), ASXL1 (24.5%), JAK2 (23%), SF3B1 (7.5%), and MYD88 (6%), with a median VAF of 4.2%, 3.0%, 8.5%, 1.0%, 5.0%, and 0.20%, respectively. Fifty percent of patients harbored more than 1 mutation. Six patients had a known history of myeloproliferative neoplasm (MPN). The proportion of cases with CH, CHIP, and CCUS was 15%, 59%, and 17%, respectively. The CH risk score of myeloid malignancy (CHRS, Weeks et al.) could be calculated in 126 cases but may underestimate risk due to the limited gene list considered, and revealed 69 (55%) low-risk, 52 (41%) intermediate-risk, and 5 (4%) high-risk patients. Our MTB recommended hematologic consultation for additional investigations in 58 patients, of which 22 were actually referred (main reason for not referring patients was advanced cancer disease). Four patients were diagnosed with hematologic malignancy (1 MPN, 1 chronic myeloid leukemia, 2 myelodysplastic syndromes [MDS]). Patients referred by a hematologist In this cohort of 133 patients, median age was 69 years old (53-89), and sex ratio (M/F) was 0.6. Eighty-six percent of patients had a cancer history, median prior anticancer treatment lines was 2 (0-7), time between MTB and cancer diagnosis was 3.5 years (0.2-34). The most frequent tumor types were lymphoid disorders (39%), breast cancer (15%), and gynecological cancer (15%). The proportion of CH, CHIP, and CCUS was 11%, 33%, and 41%, respectively. The most frequently mutated genes were DNMT3A (48,5%), PPM1D (24%), TET2 (22%), TP53 (17%), ASXL1 (6%), JAK2 (4.5%) and CHEK2 (4.5%), with a VAF of 2.5%, 2,3%, 4.0%, 2.0%, 8.0%, 1.0%, and 2.5%, respectively. Sixty percent of patients harbored more than 1 mutation. The CHRS could be calculated in 98 cases and revealed 34% low-risk, 50% intermediate-risk, and 16% high-risk CH patients. No need for a specific follow-up was recommended by the MTB in 33 patients. Among the 85 patients with hematologic follow-up, 3 (for which the CHRS was intermediate in 2 cases and high in 1 at the time of MTB evaluation) rapidly progressed to a myeloid malignancy ( Figure 1) (2 MDS and 1 MDS/MPN). Conclusions Our study highlights the utility of a MTB dedicated to CH, CHIP and CCUS for the identification of high-risk patients, early detection of hematologic malignancies, and appropriate therapeutic management. Long-term follow-up is needed to validate the CHRS but the design of a specific score for patients with cancer may be helpful due to the specific features of this population (high prevalence of PPM1D mutations, post-treatment cytopenia).

Implementation of an academic-community partnership model for equitable access to precision oncology decision support in rural community cancer centers.

141 Background: Comprehensive genomic profiling (CGP) is an essential tool for selecting cancer therapies and matching patients to clinical trials, however patients in rural community cancer centers are less likely to receive CGP. We developed an academic-community partnership model to expand Duke’s Molecular Tumor Board (MTB) clinical decision-making and trial-matching services to Duke Cancer Network (DCN), a series of affiliated community cancer centers across rural North Carolina. Methods: The Duke Precision Cancer Medicine Initiative created a Molecular Registry of Tumors database to aggregate CGP results from multiple vendors and enable review by a multidisciplinary MTB. Patients treated at DCN sites had their CGP results and relevant clinical data reviewed by the Duke MTB. After review, clinical recommendations were communicated in a standardized note and returned to DCN providers within one week. One year into implementation, DCN providers were anonymously surveyed to identify persistent barriers to utilization of CGP. Results: Between Jan 2022 and June 2023, 96 patients were consented, enrolled, and reviewed by Duke MTB. 29.2% were Black, 19.8% were Native American, and 5 .2% were of Hispanic ethnicity. 57.3% patients were found to have an actionable genomic biomarker. Of these, 14 of 22 (63.6%) received matched FDA-approved therapies and 0 of 17 (0%) with molecular criteria for a clinical trial at Duke successfully enrolled at time of submission. 85% DCN providers reported comfort ordering CGP and 45% reported comfort interpreting the results. Most frequently reported major barriers to clinical trial participation included distance (70%), lack of transportation (55%), and lack of local trials (50%). Conclusions: Our implementation of a novel academic-community partnership serves as a sustainable and reproducible model to expand access to MTB services. Further research and interventions are necessary to mitigate persistent urban versus rural barriers to utilizing CGP, especially those in clinical trial enrollment. By providing MTB support to historically underserved communities and a framework to identify salient barriers in the process, our model can be adopted by academic cancer centers nationally, contributing to improved and equitable outcomes in oncology.[Table: see text]

Molecularly Stratified Treatment Options in Primary Refractory DLBCL/HGBL with MYC and BCL2 or BCL6 Rearrangements (HGBL, NOS with MYC/BCL6).

There is growing evidence supporting multidisciplinary molecular tumor boards (MTB) in solid tumors whereas hematologic malignancies remain underrepresented in this regard. The present study aimed to assess the clinical relevance of MTBs in primary refractory diffuse large B-cell lymphomas/high-grade B-cell lymphomas with MYC and BCL2 rearrangements (prDLBCL/HGBL-MYC/BCL2) (n = 13) and HGBL, not otherwise specified (NOS), with MYC and BCL6 rearrangements (prHGBL, NOS-MYC/BCL6) (n = 6) based on our previously published whole-exome sequencing (WES) cohort. For genomic analysis, the institutional MTB WES pipeline (University Cancer Center Schleswig-Holstein: UCCSH), certified for routine clinical diagnostics, was employed and supplemented by a comprehensive immunohistochemical work-up. Consecutive database research and annotation according to established evidence levels for molecularly stratified therapies was performed (NCT-DKTK/ESCAT). Molecularly tailored treatment options with NCT-DKTK evidence level of at least m2A were identified in each case. We classified mutations in accordance with biomarker/treatment baskets and detected a heterogeneous spectrum of targetable alterations affecting immune evasion (IE; n = 30), B-cell targets (BCT; n = 26), DNA damage repair (DDR; n = 20), tyrosine kinases (TK; n = 13), cell cycle (CC; n = 7), PI3K-MTOR-AKT pathway (PAM; n = 2), RAF-MEK-ERK cascade (RME; n = 1), and others (OTH; n = 11). Our virtual MTB approach identified potential molecularly targeted treatment options alongside targetable genomic signatures for both prDLBCL/HGBL-MYC/BCL2 and prHGBL, NOS-MYC/BCL6. These results underline the potential of MTB consultations in difficult-to-treat lymphomas early in the treatment sequence.

Overcoming barriers to adoption of precision medicine in community oncology centers in the rural southeastern United States using novel informatics tools and academic collaborations.

e13514 Background: Comprehensive genomic profiling (CGP) is an important tool to identify actionable biomarkers and guide cancer therapy. However, patient (pt) race, socioeconomic status, and clinical setting are associated with lower access to CGP, targeted therapies, and clinical trials. To address this, we expanded a novel framework for genomic data management and clinical decision support developed at a large academic medical center to a network of affiliated community cancer centers located in rural, traditionally underserved communities. Methods: The Duke Precision Cancer Medicine Initiative (PCMI) developed a centralized database to aggregate and normalize CGP results. This database enables CGP review by a multi-disciplinary Molecular Tumor Board (MTB). PCMI established a protocol that allows the MTB to review CGP results and relevant clinical data for consented patients. This protocol opened enrollment at four DCN-affiliated cancer centers in rural North Carolina. Clinical recommendations are captured in a standard note and returned to DCN providers following each review. Our protocol also includes an anonymous survey sent to oncology providers asking about barriers to access and utilization of CGP. Results: Between Jan 2022 and Jan 2023, 62 pts were enrolled and had CGP results reviewed by the MTB; 13 pts (21.0%) were Native American and 20 (32.3%) were Black. 61 actionable genomic alterations were identified from 38 pts, including 16 (25.6%) that molecularly matched clinical trial inclusion criteria. Most DCN providers reported being comfortable ordering (14/20) CGP though fewer expressed comfort with interpretation (9/20) CGP; provider-reported barriers included cost/insurance for targeted therapies (12/20) and distance to clinical trials (14/20). Conclusions: Successful academic-community partnerships to expand access to CGP, clinical trials, and targeted therapies are feasible when supported by fit-for-purpose informatics tools and scalable workflows. Additional work is required to develop comprehensive solutions that ensure equal access to CGP and precision medicine for all patients. [Table: see text]

Comprehensive genomic profiling and individual therapeutic planning in high-risk/refractory pediatric solid tumors: A single-center real-world study.

10035 Background: Despite major improvements in the survival of pediatric cancer patients that were achieved through the intensification of chemotherapy and the perfection of supportive care in the past decades, treatment outcomes for high-risk, relapsed, and refractory solid cancers remain unsatisfactory. Accelerating the progress of pediatric oncology requires both therapeutic advances and attention to reducing the long-term cytotoxic treatment-related side effects. This could be achieved by targeting specific molecular changes that drive pediatric malignancies. Methods: From September 2016 to August 2020, a total of 192 patients with pediatric high-risk solid tumors successfully underwent comprehensive genomic profiling. Since more than thirty patients had two or more biopsies from recurrent relapses, the total number of samples examined was 295. In the cohort, there were 78 cases of central nervous system tumors, 68 sarcomas, 14 neuroblastomas, 10 lymphomas, and 22 tumors of other histology. Whole-exome sequencing was performed in all patients, fusion gene analysis in 96% of patients, whole-transcriptome profiling in 84% of patients, and CNV analysis in 63% of patients. Results: The diagnostic yield of therapeutically actionable findings was 40%, with single-nucleotide variants and small insertions/deletions being the most common actionable alteration types. In 23% of patients, a clinically relevant gene fusion was identified. The majority of the identified fusions were of diagnostic significance, and 18% of those were therapeutically targetable gene fusions involving BRAF, RAF1, ALK, FGFR1, or NTRK2. Four patients were eligible for immunotherapy based on high tumor mutational burden ( > 10 mut/Mb). Lymphomas and CNS tumors showed the highest rate of patients with therapeutically actionable findings (60% and 56%, respectively), followed by neuroblastomas (36%), sarcomas (25%), and other solid tumors (23%). All results and individual treatment plans were discussed and approved at multidisciplinary molecular tumor boards. Conclusions: Precision medicine in pediatric oncology has rapidly developed over the last decade and resulted in new therapeutic options based on molecular biomarkers and increased our understanding of the complexity of pediatric malignancies. Supported by the Ministry of Health of the Czech Republic, grant nr. NU20-03-00240 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU.

Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.

Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored. We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes. During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%). Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.

Abstract 1057: Development/validation of a molecular and clinical evidence-based algorithm for selecting optimal precision therapeutic strategy for cancer patients

Abstract Background Tumor complexity and heterogeneity require matching of actionable genomic alterations with available therapy to increase response rates and prolong survival in patients. However, it has been a long-standing challenge for treating oncologists to select an effective patient-specific therapeutic strategy due to the molecular rationale, disease relevance, and patient-specific issues. To provide a decision-support tool to aid oncologists and educate patients, we have developed a set of molecular and clinical evidence-based criteria as an algorithm for ranking therapeutic strategies in order to deliver optimal care and improve outcomes in patients with malignancy. Methods History of present illness (HPI) and comprehensive genomic profiling (CGP) results of 203 patients with malignant tumors were reviewed by our multidisciplinary Molecular Tumor Board (MTB) from June 2021 to August 2022, and therapeutic recommendations were provided with Matching Score based on molecular matching only as well as with Ranking Score calculated by our molecular and clinical evidence-based algorithm with the criteria not only focusing on molecular matching, but also including disease relevance, patient-specific clinical considerations and treatment availability as weighting factors (Cohort 2). The other 50 patients with previously treated solid tumors reviewed by MTB (before 2018) and treatment recommendations provided with Matching Score only, were used as a control group (Cohort 1). The matching rates from recommendations and treatment outcomes of the patients were then assessed. Results In Cohort 1, of the 50 patients, 33 patients (66%) received matched therapeutic plans recommended by our MTB. The other 17 patients were not on a matched plan from the MTB. Twelve patients (36.4% of 33 patients) achieved progression-free survival (PFS) at 12-week time point, including 8 patients (24.2%) achieved PFS at 6-month time point. The other 21 patients (63.6% of 33 patients) could not be assessed due to treatment termination per drug toxicity or death before the follow-up time point. The median PFS/overall survival (OS) for patients with a Matching Score > 50% (N = 17) were 7.5/10.5 months, whereas with Matching Score ≤ 50% (N = 16) were 3/7.35 months. In Cohort2, of the 203 patients, 89 (43.8%) patients have initiated matched therapeutic plans and follow-up is ongoing. Updated results will be presented at the meeting. Conclusion Our novel molecular and clinical evidence-based algorithm may be used to support oncologists decision-making to utilize the most clinically appropriate and effective therapeutic options. Further validation studies and development of an user-friendly computational ranking platform based on the algorithm are planned in order. Citation Format: Yuliang Sun, Tobias Meissner, Rachel Elsey, Leah Theisen, Crystal Hattum, Bing Xu, John Lee, Casey Williams. Development/validation of a molecular and clinical evidence-based algorithm for selecting optimal precision therapeutic strategy for cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1057.

Abstract 4511: Impact of the comprehensive genomic profiling on the individual therapeutic planning in high-risk/refractory tumors: real-world precision medicine in pediatric oncology

Abstract Background: Despite major improvements in the survival of pediatric cancer patients that were achieved through the intensification of chemotherapy and the perfection of supportive care in the past decades, treatment outcomes for high-risk, relapsed, and refractory solid cancers remain unsatisfactory. Accelerating the progress of pediatric oncology requires both therapeutic advances and attention to reducing the long-term cytotoxic treatment-related side effects. This could be achieved by targeting specific molecular changes that drive pediatric malignancies. Material and Methods: From September 2016 to August 2020, a total of 192 patients with pediatric high-risk solid tumors successfully underwent comprehensive genomic profiling. Since more than thirty patients had two or more biopsies from recurrent relapses, the total number of samples examined was 295. In the cohort, there were 78 cases of central nervous system tumors, 68 sarcomas, 14 neuroblastomas, 10 lymphomas, and 22 tumors of other histology. Whole-exome sequencing was performed in all patients, fusion gene analysis in 96% of patients, whole-transcriptome profiling in 84% of patients, and CNV analysis in 63% of patients. Results: The diagnostic yield of therapeutically actionable findings was 40%, with single-nucleotide variants and small insertions/deletions being the most common actionable alteration types. In 23% of patients, a clinically relevant gene fusion was identified. The majority of the identified fusions were of diagnostic significance, and 18% of those were therapeutically targetable gene fusions involving BRAF, RAF1, ALK, FGFR1, or NTRK2. Four patients were eligible for immunotherapy based on high tumor mutational burden (>10 mut/Mb). Lymphomas and CNS tumors showed the highest rate of patients with therapeutically actionable findings (60% and 56%, respectively), followed by neuroblastomas (36%), sarcomas (25%), and other solid tumors (23%). All results and individual treatment plans were discussed at multidisciplinary molecular tumor boards. Conclusion: Precision medicine in pediatric oncology has rapidly developed over the last decade and resulted in new therapeutic options based on molecular biomarkers and increased our understanding of the complexity of pediatric malignancies. Supported by the Ministry of Health of the Czech Republic, grant nr. NU20-03-00240 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU. Citation Format: Petra Pokorna, Hana Palova, Sona Adamcova, Vojtech Bystry, Michal Kyr, Dagmar Al Tukmachi, Sona Mejstrikova, Peter Mudry, Jaroslav Sterba, Ondrej Slaby. Impact of the comprehensive genomic profiling on the individual therapeutic planning in high-risk/refractory tumors: real-world precision medicine in pediatric oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4511.

Clinical management of molecular alterations identified by high throughput sequencing in patients with advanced solid tumors in treatment failure: Real-world data from a French hospital.

In the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy. A FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients. Samples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0-86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0-117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48-2.26)]. This study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials.

Primary refractory plasmablastic lymphoma: A precision oncology approach.

Hematologic malignancies are currently underrepresented in multidisciplinary molecular-tumor-boards (MTB). This study assesses the potential of precision-oncology in primary-refractory plasmablastic-lymphoma (prPBL), a highly lethal blood cancer. We evaluated clinicopathological and molecular-genetic data of 14 clinically annotated prPBL-patients from initial diagnosis. For this proof-of-concept study, we employed our certified institutional MTB-pipeline (University-Cancer-Center-Schleswig-Holstein, UCCSH) to annotate a comprehensive dataset within the scope of a virtual MTB-setting, ultimately recommending molecularly stratified therapies. Evidence-levels for MTB-recommendations were defined in accordance with the NCT/DKTK and ESCAT criteria. Median age in the cohort was 76.5 years (range 56-91), 78.6% of patients were male, 50% were HIV-positive and clinical outcome was dismal. Comprehensive genomic/transcriptomic analysis revealed potential recommendations of a molecularly stratified treatment option with evidence-levels according to NCT/DKTK of at least m2B/ESCAT of at least IIIA were detected for all 14 prPBL-cases. In addition, immunohistochemical-assessment (CD19/CD30/CD38/CD79B) revealed targeted treatment-recommendations in all 14 cases. Genetic alterations were classified by treatment-baskets proposed by Horak etal. Hereby, we identified tyrosine-kinases (TK; n=4), PI3K-MTOR-AKT-pathway (PAM; n=3), cell-cycle-alterations (CC; n=2), RAF-MEK-ERK-cascade (RME; n=2), immune-evasion (IE; n=2), B-cell-targets (BCT; n=25) and others (OTH; n=4) for targeted treatment-recommendations. The minimum requirement for consideration of a drug within the scope of the study was FDA-fast-track development. The presented proof-of-concept study demonstrates the clinical potential of precision-oncology, even in prPBL-patients. Due to the aggressive course of the disease, there is an urgent medical-need for personalized treatment approaches, and this population should be considered for MTB inclusion at the earliest time.

Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan

Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine. To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases. This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study's central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021. Simulated cases of cancer. The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation. The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance. The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

Clinical Implication of Molecular Tumor Board

Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it is expected that extensive tumor DNA or RNA sequencing will be applied in standard of care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, as a multidisciplinary approach to keep pace with the growing knowledge of complex molecular alterations in patients with advanced solid cancer. MTBs are designated to interpret these data and provide clinical recommendations. Not all patients with cancer have access to advice of an MTB. We aimed to determine the current status, opportunities, and challenges of the organization of MTBs in the Korea.

Italian Precision Medicine in Pediatric Oncology: Moving beyond Actionable Alterations

Neuroblastoma (NB) is the most common extracranial solid tumor encountered in childhood. Although there has been significant improvement in the outcomes of patients with high-risk disease, the prognosis for patients with metastatic relapse or refractory disease is poor. Hence, the clinical integration of genome sequencing into standard clinical practice is necessary in order to develop personalized therapy for children with relapsed or refractory disease. The PeRsonalizEdMEdicine (PREME) project focuses on the design of innovative therapeutic strategies for patients suffering from relapsed NB. We performed whole exome sequencing (WES) of patient-matched tumor-normal samples to identify genetic variants amenable to precision medicine. Specifically, two patients were studied (First case: a three-year-old male with early relapsed NB; Second case: a 20-year-old male who relapsed 10 years after the first diagnosis of NB). Results were reviewed by a multi-disciplinary molecular tumor board (MTB) and clinical reports were issued to the ordering physician. WES revealed the mutation c.G320C in the CUL4A gene in case 1 and the mutation c.A484G in the PSMC2 gene in case 2. Both patients were treated according to these actionable alterations, with promising results. The effective treatment of NB is one of the main challenges in pediatric oncology. In the era of precision medicine, the need to design new therapeutic strategies for NB is fundamental. Our results demonstrate the feasibility of incorporating clinical WES into pediatric oncology practice.

Pan-cancer molecular tumor board experience with biomarker-driven precision immunotherapy

Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.

Molecular tumor board assisted care in an advanced cancer population: Results of a phase 2 clinical trial (139)

Molecular tumor board assisted care in an advanced cancer population: Results of a phase 2 clinical trial (139)

Development of a molecular and clinical evidence-based algorithm for selecting optimal precision therapeutic strategy for patients with ovarian carcinoma (157)

<b>Objectives:</b> Genomic sequencing of tumors is done frequently in oncology due to tumor complexity and heterogeneity, which necessitate matching actionable genomic alterations with available therapies for improved outcomes. Molecular rationale, the robustness of disease-specific data, patient-specific supportive care, and access to treatments must all be taken into account in order to select an effective regimen. However, as the molecular proteomics analysis of tumors is performed earlier in the disease course and the number of targeted therapies rises, it becomes increasingly difficult to effectively and efficiently choose the most appropriate treatment. We have developed a set of molecular and clinical evidence-based criteria to rank therapeutic strategies to deliver optimal care and improve outcomes. <b>Methods:</b> Patients included in the analysis received comprehensive genomic profiling (CGP), including blood/tissue DNA sequencing, transcriptome profiling, and immunohistochemistry for selected biomarkers. CGP results of 50 patients (from our clinical database) with previously treated, stage IV solid tumors were reviewed by our multidisciplinary Molecular Tumor Board (MTB), after which treatment recommendations were generated based on molecular matching only (Cohort 1). CGP results of an additional 50 patients with ovarian carcinoma will be reviewed by MTB, and therapeutic recommendations (including standard of care therapies, clinical trials, and offlabel drugs) will be provided with ranking scores calculated by our algorithm with the criteria not only focusing on molecular matching but also including disease relevance, patient-specific clinical considerations and treatment availability as weighting factors (Cohort 2). The matching rates from recommendations and treatment outcomes of the two cohorts will be assessed. <b>Results:</b> In Cohort 1, of the 50 patients, 34 patients (68%) were initiated with personalized, therapeutic plans predominantly based on molecular matching that was recommended by our MTB. The other 16 patients were not treated with molecular matching therapeutic plans recommended by MTB as a result of treating oncologists' choices, treatment availability, or patient preference. Patients were followed, and outcomes were then evaluated. Thirteen patients (38.2% of 34 patients) achieved progression-free survival (PFS) (including stable disease, <i>n</i>=6, and partial response, <i>n</i>=7) at 12 weeks, and six patients achieved PFS (including stable disease, <i>n</i>=4, and partial response, <i>n</i>=2) at six months. The other 21 patients (61.8% of 34 patients) could not be assessed due to disease progression, treatment termination per drug toxicity, or death before the follow-up time point. Cohort 2 is ongoing, the results of which will be presented at the meeting. <b>Conclusions:</b> Our novel molecular and clinical evidence-based algorithm may be used to support clinicians' decision-making to utilize the most evidence-based and effective therapeutic options. Additional studies with larger sample sizes in different types of solid tumors are planned in order to determine a clinically and statistically relevant range of scores for the treatment recommendations with optimal clinical outcomes.

Impact of Molecular Tumor Board on the Clinical Management of Patients With Cancer.

PURPOSEMultidisciplinary molecular tumor boards (MTBs) help in interpreting complex genomic data generated by molecular tumor profiling and improve patients' access to targeted therapies. The purpose of this study was to assess the impact of our institution's MTB on the clinical management of patients with cancer.METHODSThis study was conducted at a tertiary cancer center in India. Cases to be discussed in the MTB were identified by molecular pathologists, scientists, or oncologists. On the basis of the clinical data and molecular test reports, a course of clinical management was recommended and made available to the treating oncologist. We determined the proportion of patients who were recommended a change in the clinical management. We also assessed compliance of the treating oncologists with MTB recommendations.RESULTSThere were 339 discussions for 328 unique patients. The median age of the cohort was 54 years (range 17-87), and the majority of the patients were men (65.1%). Of 339 cases, 133 (39.2%) were recommended continuation of ongoing therapy while the remaining 206 (60.7%) were recommended a change in clinical management. Compliance with MTB recommendations for a change in clinical management was 58.5% (79 of 138 evaluable cases). Compliance and implementation for MTB's recommendation to start a new therapy in 104 evaluable cases were 60.5% and 44.2%, respectively. A total of 248 biopsies had at least one actionable mutation. A total of 646 mutations were identified in the cohort, with EGFR being the most frequently altered gene.CONCLUSIONMTBs help in interpreting results of molecular tests, understanding the significance of molecular abnormalities, and assessing the benefits of available targeted therapies and clinical trials in the management of patients with targetable genetic alterations.